1: Fertil Steril 2000 Apr;73(4):667-76
Evaluating strategies for improving ovarian response of the poor responder
undergoing assisted reproductive techniques.
Surrey ES, Schoolcraft WB
Colorado Center for Reproductive Medicine, Englewood, Colorado, USA.
OBJECTIVE: To assess the efficacy of various controlled ovarian hyperstimulation
(COH) regimens in the prior poor-responder patient preparing for assisted
reproductive techniques. DESIGN: English-language literature review. PATIENT(s):
Candidates for assisted reproductive techniques who had been defined as having a
prior suboptimal response to standard COH regimens. INTERVENTION(s): A variety
of regimes are reviewed, including increased gonadotropin doses, change of
gonadotropins, adjunctive growth hormone (GH), luteal phase (long) GnRH agonist
(GnRH-a) initiation, early follicular phase (flare) GnRH-a initiation, low-dose
luteal phase (ultrashort) GnRH-a initiation, progestin pretreatment, and
microdose flare GnRH-a initiation. MAIN OUTCOME MEASURE(s): Maximal serum E(2)
levels, follicular development, dose, and duration of gonadotropin therapy,
cycle cancellation rates, oocytes retrieved, embryos transferred, and clinical
and ongoing pregnancy rates. RESULT(s): A lack of uniformity in definition of
the poor responder and of prospective randomized trials make data interpretation
somewhat difficult. Of the varied strategies proposed, those that seem to be
more uniformly beneficial are microdose GnRH-a flare and late luteal phase
initiation of a short course of low-dose GnRH-a discontinued before COH.
CONCLUSION(s): No single regimen will benefit all poor responders. General
acceptance of uniform definitions and performance of large-scale prospective
randomized trials are critical. Development of a reliable precycle screen will
allow effective differentiation among normal responders, poor responders, and
those who will not conceive with their own oocytes.
Publication Types:
Review
Review, tutorial
PMID: 10731523, UI: 20198090
2: Fertil Steril 1999 Mar;71(3):420-4
Add-back therapy and gonadotropin-releasing hormone agonists in the treatment of
patients with endometriosis: can a consensus be reached? Add-Back Consensus
Working Group.
Surrey ES
Reproductive Medicine and Surgery Associates, Beverly Hills, California, USA.
OBJECTIVE: To reach a consensus on the role of add-back therapy for patients
with endometriosis administered GnRH agonists (GnRH-a). DESIGN: Results of
consensus conference reviewing MEDLINE search of English language abstracts of
both prospective and retrospective series. SETTING: Consensus conference of 31
specialists in gynecologic surgery and reproductive endocrinology. PATIENT(S):
Patients with symptomatic endometriosis who were candidates for GnRH-a therapy
in treatment courses ranging in duration from 6 to 12 months. INTERVENTION(S):
Oral steroidal and nonsteroidal add-back regimens. MAIN OUTCOME MEASURE(S):
Alteration in painful symptoms, extent of disease, vasomotor symptoms, bone
mineral density, and serum lipid profile. RESULT(S): When added to GnRH-a for 6
months, both 2.5 mg of norethindrone and 0.625 mg of conjugated equine estrogens
with 5 mg/d of medroxyprogesterone acetate provide effective relief of vasomotor
symptoms and decrease but do not eliminate bone mineral density loss. During 12
months of GnRH-a therapy, bone mineral density loss is eliminated effectively
with an add-back of 5 mg of norethindrone acetate alone or in conjunction with
low-dose conjugated equine estrogens. Organic bisphosphonates also may play a
role. CONCLUSION(S): In patients with symptomatic endometriosis, the efficacy of
GnRH agonists may be preserved and therapy prolonged while overcoming
hypoestrogenic side effects with the use of appropriate add-back regimens.
Publication Types:
Consensus development conference
Review
PMID: 10065775, UI: 99163658
3: Fertil Steril 1998 Aug;70(2):293-6
Historical prospective cohort study of the recurrence of pain after
discontinuation of treatment with danazol or a gonadotropin-releasing hormone
agonist.
Miller JD, Shaw RW, Casper RF, Rock JA, Thomas EJ, Dmowski WP, Surrey E, Malinak
LR, Moghissi K
University of Illinois College of Medicine, Rockford 61107, USA. jamesm@uic.edu
OBJECTIVE: To determine the duration of time to the recurrence of pain
attributable to endometriosis after the discontinuation of treatment with
danazol or a GnRH agonist (GnRH-a) in patients who have had a satisfactory
response to the treatment. DESIGN: Retrospective study. SETTING: Nine academic
medical centers in three countries. PATIENT(S): Three hundred twenty-seven women
with diagnosed and staged endometriosis who were treated with at least 6 months
of danazol or a GnRH-a and who experienced significant pain relief with therapy.
INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Duration of pain relief after
completion of treatment as determined by a patient-initiated report of pain
recurrence or increase in pain severity requiring intervention. RESULT(S): The
median time to the recurrence of pain was 6.1 months for patients treated with
danazol and 5.2 months for patients treated with a GnRH-a. CONCLUSION(S):
Although there was a lack of uniformity in treatment effects across sites, the
analyses have taken into account major covariant effects. The time to the
recurrence of endometriosis-associated pain after danazol treatment was slightly
longer than that after GnRH-a treatment.
PMID: 9696224, UI: 98359413
4: Gynecol Obstet Invest 1998;45 Suppl 1:31-4; discussion 35
Add-back therapy: extending safety and efficacy of GnRH analogues in the
gynecologic patient.
Surrey ES
Department of Obstetrics and Gynecology, University of California, Los Angeles
School of Medicine, USA.
GnRH analogues have been demonstrated to be effective medical therapy for
symptomatic endometriosis. The use of these agents has been limited to 6 months
due to hypoestrogenic side effects. A variety of steroidal and nonsteroidal
add-back regimens have been used in an effort to eliminate such side effects
while maintaining efficacy in order to enhance compliance, safety and duration
such side effects while maintaining efficacy in order to enhance compliance,
safety and duration of administration of these agents. Only 3 regimens have been
shown to be efficacious in prolonging analogue use beyond 6 months by reducing
vasomotor symptoms as well as preventing significant bone mineral density loss.
These include daily norethindrone acetate 5 mg alone or in conjunction with
conjugated equine estrogens 0.625 mg daily, as well as norethindrone 2.5 mg
daily in conjunction with an organic bisphosphonate. With further investigation,
such regimens may allow safe prolongation of GnRH analogue use without
sacrificing efficacy in those endometriosis patients with severe pelvic pain.
Publication Types:
Review
Review, tutorial
PMID: 9628522, UI: 98290486
5: Obstet Gynecol 1998 Jan;91(1):16-24
Leuprolide acetate depot and hormonal add-back in endometriosis: a 12-month
study. Lupron Add-Back Study Group.
Hornstein MD, Surrey ES, Weisberg GW, Casino LA
Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard
Medical School, Boston, Massachusetts 02115, USA.
mdhornstei@bics.bwh.harvard.edu
OBJECTIVE: To evaluate the efficacy and safety of a GnRH agonist, leuprolide
acetate depot, alone and in combination with three hormonal add-back regimens in
the management of endometriosis-associated pelvic pain. METHODS: Two hundred and
one patients were enrolled in this multicenter, randomized, double-blind, 1-year
trial. All patients were given an intramuscular injection of leuprolide acetate
depot 3.75 mg every 4 weeks. Patients were assigned to one of four treatment
groups: Group A received placebos for progestin and estrogen, group B received
norethindrone acetate 5 mg daily and placebo for estrogen, group C received
norethindrone acetate 5 mg and conjugated equine estrogens 0.625 mg daily, and
group D received norethindrone acetate 5 mg and conjugated equine estrogens 1.25
mg daily. Pelvic pain scores were assessed monthly, and bone density was
measured after 24 and 52 weeks. RESULTS: By week 8, all four groups showed
significant improvement in pelvic pain scores compared with baseline levels. A
higher proportion of group D patients terminated the study prematurely due to a
lack of improvement in symptoms. Group A experienced a 6.3 +/- 2.3% (P < or =
.001) loss in bone density after 52 weeks of treatment, whereas bone density was
preserved in all three add-back groups. CONCLUSION: The use of leuprolide
acetate depot in combination with norethindrone acetate 5 mg alone, or with
norethindrone acetate and conjugated equine estrogens 0.625 mg, provides
effective suppression of pelvic pain symptoms associated with endometriosis
while protecting against bone loss.
Publication Types:
Clinical trial
Multicenter study
Randomized controlled trial
Comments:
Comment in: Obstet Gynecol 1998 May;91(5 Pt 1):793-4
PMID: 9464714, UI: 98124361
6: Med Interface 1997 Mar;10(3):119-24
An economically rational method of managing early-stage endometriosis.
Surrey E
UCLA School of Medicine, USA.
Endometriosis is a common gynecologic disease among women of reproductive age.
The lesions of early endometriosis may be missed during laparoscopy, which has
been considered to be the definitive means of both diagnosis and treatment.
Moreover, laparoscopic treatment of minimal-to-mild (stage 1 to 2) endometriosis
does not always resolve associated chronic pelvic pain in many women. Instead,
medical therapy with gonadotropin-releasing hormone (GnRH) agonists may be more
effective in providing long-lasting pain relief in patients with similar disease
stages. The author outlines the cost effectiveness of a trial course of GnRH
agonists in women presenting with chronic pelvic pain.
PMID: 10172946, UI: 97253836
7: Fertil Steril 1995 Oct;64(4):673-85
Steroidal and nonsteroidal "add-back" therapy: extending safety and efficacy of
gonadotropin-releasing hormone agonists in the gynecologic patient.
Surrey ES
Department of Obstetrics-Gynecology, University of California, Los Angeles
School of Medicine, USA.
OBJECTIVE: To assess the efficacy of various steroidal and nonsteroidal add-back
regimes in ameliorating hypoestrogenic side effects of long-term GnRH agonist
(GnRH-a) therapy in gynecologic patients. DESIGN: English language literature
review. PATIENTS: Gynecologic patients administered GnRH-a as therapy for
ovarian hyperandrogenism, premenstrual syndrome, dysfunctional uterine bleeding,
uterine leiomyomata, and symptomatic endometriosis. INTERVENTIONS: Steroidal and
nonsteroidal add-back regimes including estrogens with progestins, progestins
alone, and progestins with organic bisphosphonates in combination with various
GnRH-a for > or = 6 months of therapy. MAIN OUTCOME MEASURES: Vasomotor
symptoms, bone density changes, lipid profiles, alterations in presenting
symptoms, and disease state. RESULTS: Estrogens in combination with progestins
were efficacious as add-back in the management of ovarian hyperandrogenic
states, dysfunctional uterine bleeding, premenstrual syndrome, and leiomyomata.
Medroxyprogesterone acetate alone is ineffective as add-back for treatment of
endometriosis or leiomyomata. Norethindrone is effective as add-back in the
management of endometriosis but not leiomyomata, although high doses alter lipid
profiles in an undesirable fashion. Organic bisphosphonates show great promise
in preserving bone density without other untoward effects. CONCLUSIONS: No
single add-back regime is appropriate for all gynecologic indications for
GnRH-a. Ideal protocols preserve the efficacy of agonists while suppressing
associated vasomotor symptoms and bone density loss.
Publication Types:
Review
Review, tutorial
PMID: 7672133, UI: 95402215
8: Fertil Steril 1995 Apr;63(4):747-55
Prolonged gonadotropin-releasing hormone agonist treatment of symptomatic
endometriosis: the role of cyclic sodium etidronate and low-dose norethindrone
"add-back" therapy.
Surrey ES, Voigt B, Fournet N, Judd HL
Department of Obstetrics-Gynecology, Cedars-Sinai Medical Center, University of
California, Los Angeles School of Medicine.
OBJECTIVE: To examine the safety and efficacy of combining cyclic sodium
etidronate and low-dose norethindrone with a long-acting GnRH agonist (GnRH-a)
for prolonged therapy of symptomatic endometriosis. DESIGN: Prospective
randomized open label study. SETTING: Tertiary care university-affiliated
reproductive medicine program. PATIENTS: Nineteen regularly cycling women with
laparoscopically diagnosed symptomatic endometriosis and 18 regularly cycling
untreated controls without endometriosis. INTERVENTIONS: All patients received a
depot preparation of the GnRH-a leuprolide acetate IM monthly for 48 weeks.
Group I patients (n = 10) received supplemental sodium etidronate cycled with
calcium carbonate as well as 2.5 mg norethindrone daily. Group II patients (n =
9) received only supplemental 10 mg norethindrone daily. Group III volunteers (n
= 18) were untreated and followed for bone density changes. MAIN OUTCOME
MEASURES: Disease extent at follow-up laparoscopy; pain, vasomotor, and vaginal
symptom scores; bone mineral density (serial dual-energy roentgenogram
absorptiometry scans); serum estrogens, lipids, and glucose and insulin response
to glucose challenge. RESULTS: Painful symptoms and extent of endometriosis were
reduced in both treatment groups. Despite maintenance of a chronically
hypoestrogenic state for 48 weeks, no changes in bone density over time or in
comparison to group III untreated controls were noted. Similarly, no evidence of
significant vasomotor symptoms were reported in either treatment group. However,
adverse changes over time in circulating low-density lipoprotein (LDL)
cholesterol and apolipoprotein A1 levels as well as the ratio of high-density
lipoprotein to LDL were noted only in group II. CONCLUSIONS: The combination of
cyclic sodium etidronate and low-dose norethindrone with a long-acting GnRH-a
served to safely prolong medical therapy of symptomatic endometriosis. Clinical
efficacy was preserved while prophylaxis against significant hypoestrogenic side
effects was achieved.
Publication Types:
Clinical trial
Randomized controlled trial
PMID: 7890057, UI: 95196884
9: Int J Gynaecol Obstet 1999 Feb;64 Suppl 1:S25-31
Extending the treatment boundaries: Zoladex and add-back.
Schlaff WD
Department of Obstetrics and Gynecology, University of Colorado, Denver, USA.
OBJECTIVE: To review the evidence that add-back hormone replacement therapy
(HRT) can ameliorate the metabolic consequences of gonadotropin-releasing
hormone (GnRH) agonist treatment in women with symptomatic endometriosis.
METHODS: A review of relevant literature. RESULTS: Early studies suggested that
add-back HRT maintained bone mineral density (BMD) without reducing the
symptomatic benefit of GnRH treatment. Both high-dose progestogen and low dose
progestogen plus cyclical etidronate are effective in maintaining BMD. Standard
and low dose HRT add-back may be more effective in relieving the hypo-estrogenic
side-effects of GnRH agonist therapy. Randomized controlled studies have shown
that both low-dose and standard-dose add-back HRT reduce the side-effects of
GnRH agonist therapy, and that this benefit extends to 12 months of treatment.
CONCLUSIONS: GnRH agonist treatment with add-back HRT seems to offer the hope of
improved treatment for women with endometriosis, but the optimum treatment
duration and time to start HRT have yet to be defined.
Publication Types:
Review
Review, tutorial
PMID: 10096462, UI: 99194126
10: Fertil Steril 1990 Apr;53(4):620-6
The effects of combining norethindrone with a gonadotropin-releasing hormone
agonist in the treatment of symptomatic endometriosis.
Surrey ES, Gambone JC, Lu JK, Judd HL
Department of Obstetrics and Gynecology, University of California Los Angeles,
School of Medicine.
Treatment of endometriosis with gonadotropin-releasing hormone agonists (GnRH-a)
is associated with side effects secondary to the induced hypoestrogenic state.
In an effort to ameliorate these symptoms, 10 patients with symptomatic
endometriosis self-administered the GnRH-a [D-His6(Imbzl)-Pro9-NET]-GnRH in
combination with norethindrone daily for 24 weeks. Painful symptoms were
significantly suppressed after therapy (P less than 0.005). Objective review of
photographs taken at laparoscopy before and after therapy demonstrated
significant reduction of visible implants (P less than 0.005). Vasomotor
symptoms were minimized when compared with a group of 16 patients previously
treated with GnRH-a alone. Bone mineral density of the distal radius assessed by
single photon absorptiometry was not reduced during therapy, although lumbar
spine bone density assessed by quantitative computerized tomography was
minimally but reversibly reduced. No metabolic derangements were detected. The
combination of norethindrone with GnRH-a is a well tolerated and effective means
of treating symptomatic endometriosis.
PMID: 2108056, UI: 90201399
11: Fertil Steril 2000 Sep;74(3):534-9
Gonadotropin-releasing hormone agonist plus "add-back" hormone replacement
therapy for treatment of endometriosis: a prospective, randomized,
placebo-controlled, double-blind trial.
Franke HR, van de Weijer PH, Pennings TM, van der Mooren MJ
Department of Obstetrics and Gynecology, Medisch Spectrum Twente Hospital Group,
Enschede, The Netherlands. hfranke@xs4all.nl
OBJECTIVE: To assess the effect of add-back therapy with continuous combined
estrogen-progestin on the GnRH agonist-induced hypoestrogenic state and its
effectiveness in healing of endometriotic lesions. DESIGN: A prospective,
randomized, placebo-controlled, double-blind trial. SETTING: Multiple centers in
The Netherlands. PATIENT(S): 41 premenopausal women with laparoscopically
diagnosed endometriosis (revised American Fertility Society scores >/=2).
INTERVENTION(S): Patients were randomly assigned to receive a subcutaneous depot
formulation of goserelin, 3. 6 mg, every 4 weeks, plus oral placebo or oral
continuous combined estradiol-norethisterone acetate add-back therapy daily for
24 weeks. MAIN OUTCOME MEASURE(S): Endometriosis response, bone mineral density,
transvaginal ultrasonographic changes, endocrinologic effects, and subjective
side effects. RESULT(S): The number of endometriotic implants was significantly
reduced in both groups. In the group that received GnRH agonist plus placebo,
bone mineral density of the lumbar spine decreased by 5.02%. CONCLUSION(S): The
effectiveness of GnRH agonist treatment for endometriosis was not decreased by
the addition of add-back continuous combined hormone replacement therapy. Bone
mineral density of the lumbar spine was maintained and subjective side effects
were diminished.
Publication Types:
Clinical trial
Multicenter study
Randomized controlled trial
PMID: 10973651, UI: 20428529
12: Semin Reprod Endocrinol 1997;15(3):273-84
The role of GnRH agonists plus add-back therapy in the treatment of
endometriosis.
Gargiulo AR, Hornstein MD
Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Agonistic analogs of GnRH have emerged as effective drugs in the treatment of
pelvic pain associated with endometriosis. Iatrogenic hypoestrogenism is the
fundamental mechanism through which GnRH agonists induce regression of the
exquisitely estrogen-dependent endometriotic lesions. The decrease in bone mass
consistently observed in women on long-term GnRH agonist treatment has prompted
regulatory agencies such as the FDA to approve the use of these drugs for a
maximum of six months in the treatment of endometriosis. The very high
recurrence rate of pelvic symptomatology after the interruption of medical
therapy underlines the importance of strategies aiming at improving the safety
of effective long-term treatments. Data has recently become available suggesting
the existence of an ideal range of circulating estradiol levels which would
maintain a normal bone metabolism and still cause atrophy of endometriotic
lesions. Add-back regimens including estrogen preparations have been therefore
studied with variable results. In strict analogy, as oral progestins have been
shown to improve bone mass in postmenopausal women, regimens employing progestin
add-back have been proposed. Our review describes most of the currently
published studies employing these and other substances in association with the
commonly used GnRH agonists in patients with symptomatic endometriosis.
Publication Types:
Review
Review, tutorial
PMID: 9383836, UI: 98045102
13: Fertil Steril 2000 Apr;73(4):799-804
Treatment of endometriosis with a decreasing dosage of a gonadotropin-releasing
hormone agonist (nafarelin): a pilot study with low-dose agonist therapy
("draw-back" therapy).
Tahara M, Matsuoka T, Yokoi T, Tasaka K, Kurachi H, Murata Y
Department of Obstetrics and Gynecology, Osaka University Faculty of Medicine,
Osaka, Japan.
OBJECTIVE: To evaluate the efficacy of half-dose GnRH agonist therapy for
endometriosis. DESIGN: Prospective, longitudinal pilot study. SETTING: Osaka
University Hospital. PATIENT(s): Patients with symptomatic endometriosis.
INTERVENTION(s): Fifteen patients were randomized to receive either full-dose
nafarelin treatment (200 microgram b.i.d.) for 24 weeks (n = 7) or full-dose
nafarelin treatment for 4 weeks followed by half-dose nafarelin treatment (200
microgram daily) for 20 weeks (n = 8). MAIN OUTCOME MEASURE(s): Clinical
symptoms and the results of physical examinations. Serum E(2) and carcinoma
antigen 125 (CA125) levels, lipid profiles, and urinary levels of the
N-telopeptide of type I collagen. Bone mineral density of the lumbar spine.
RESULT(s): Subjective and objective manifestations of endometriosis were
decreased to a similar extent in both study groups. Adverse effects were
markedly reduced with half-dose administration. In the half-dose group, the mean
serum E(2) level was significantly suppressed by 4 weeks of treatment with
full-dose nafarelin and remained at approximately 30 pg/mL with half-dose
nafarelin. Loss of bone mineral density was significantly less with half-dose
treatment. CONCLUSION(s): Half-dose administration of nafarelin after pituitary
down-regulation with full-dose nafarelin ("draw-back" therapy) is a new protocol
for the treatment of endometriosis that is effective and associated with fewer
adverse effects.
Publication Types:
Clinical trial
Randomized controlled trial
PMID: 10731543, UI: 20198110
14: J Clin Endocrinol Metab 1992 Aug;75(2):558-63
Reduction of vasomotor symptoms and bone mineral density loss with combined
norethindrone and long-acting gonadotropin-releasing hormone agonist therapy of
symptomatic endometriosis: a prospective randomized trial.
Surrey ES, Judd HL
Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, University
of California, Los Angeles School of Medicine 90048.
The hypoestrogenic state induced by gonadotropin-releasing hormone agonists
(GnRHa) has been shown to suppress symptomatic endometriosis effectively but to
elicit vasomotor symptoms and loss of bone mineral density. The role of
norethindrone as a supplement to GnRHa in eliminating such side effects was
assessed by enrolling 20 patients with symptomatic endometriosis diagnosed
laparoscopically in a randomized, prospective, double-blinded trial. All
patients received the long-acting GnRHa leuprolide acetate 3.75 mg im every 4
weeks for 24 weeks. Ten patients self-administered norethindrone 5 then 10 mg by
mouth daily, whereas the remainder self-administered placebo tablets. Results of
this study showed that combination therapy was as effective as GnRHa alone in
significantly reducing circulating gonadotropin and estrogen levels (P less than
0.01), extent of visible endometriotic implants (P less than 0.01), and painful
symptoms (P less than 0.01). Marked vasomotor and vaginal symptoms experienced
by patients given GnRHa alone were minimized in those receiving GnRHa with
norethindrone. Lumbar spine bone mineral density loss, measured by dual energy
x-ray absorptiometry, was significantly reduced and more completely reversed in
patients receiving combination therapy (P less than 0.05). A reversible decrease
in high density lipoprotein-cholesterol and increase in low density
lipoprotein:high density lipoprotein ratio was noted only in the patients
receiving combination therapy, but not in those receiving GnRHa only. The
addition of norethindrone to GnRHa is an effective means of treating symptomatic
endometriosis while ameliorating side effects induced by GnRHa alone.
Publication Types:
Clinical trial
Randomized controlled trial
PMID: 1386374, UI: 92348654
15: J Reprod Med 1998 Mar;43(3 Suppl):293-8
Comparative effects of GnRH agonist therapy. Review of clinical studies and
their implications.
Agarwal SK
Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los
Angeles, CA 90048, USA.
OBJECTIVE: To understand why differences in gonadotropin releasing hormone
(GnRH) agonist therapeutic protocols may affect their efficacy and safety
profiles, to understand the important study design facets regarding the
literature on GnRH agonist treatment of endometriosis and to compare the
efficacy and side effect profiles of FDA-approved GnRH agonist therapies used
for the management of endometriosis and consider the implications. STUDY DESIGN:
Review of the English-language literature regarding the use of GnRH agonists for
the management of endometriosis. RESULTS: A limited number of studies are
available that directly compare the effects of different GnRH agonists. However,
contrary to medical opinion, it appears that there are significant differences
between GnRH agonist therapies. CONCLUSION: The data suggest that it may be
possible to reduce doses or alter regimens of GnRH agonists so as to reduce side
effects while maintaining efficacy.
Publication Types:
Review
Review, tutorial
PMID: 9564664, UI: 98225852
16: Keio J Med 1995 Dec;44(4):124-32
Long-term gonadotropin-releasing hormone agonist therapy: the evolving issue of
steroidal "add-back" paradigms.
Adashi EY
Department of Obstetrics and Gynecology, University of Maryland School of
Medicine, Baltimore 21201, USA.
The introduction of steroid "add-back" regimen draws on the recognition that
several clinical entities targeted for treatment with GnRHa are not "six-month
diseases". Included under this heading are individuals suffering from
symptomatic endometriosis (not desirous of pregnancy), uterine fibroids
(ineligible or disinterested in definitive surgical therapy), ovarian
hyperandrogenism, premenstrual syndrome, menopausal transition, or dysfunctional
uterine bleeding. A six month course of therapy with a GnRHa does not adversely
affect lipoprotein economy and therefore presumably the corresponding
cardiovascular risk. A six month course of GnRHa therapy appears to be
associated with a substantial decrease (of up to 8.2%) in lumbar bone density, a
phenomenon which may not be entirely reversible six months after discontinuation
of therapy. In principle, steroid "add-back" therapy should diminish some or all
of the side effects associated with GnRHa therapy, may provide a medical
treatment option for patients representing a high surgical risk, and may delay
surgical intervention if desired. On the other hand, a steroid "add-back"
therapy may delay tissue diagnosis, be associated with a substantial cost as
well as with the need in parenteral route of administration. Norethindrone-only
(but not medroxyprogesterone acetate-only) "add-back" regimens have proved
promising in the context of endometriosis. Non-concurrent estrogen/progestin
"add-back" regimens proved promising in the context of uterine fibroids.
Substantial additional studies would have to be carried out to validate the
utility of steroid "add-back" regimens. Special emphasis will have to be placed
on the evaluation of long-term utility with an eye towards assessing clinical
efficacy, impact on lipoprotein economy, impact on bone density, impact on
urogenital tissues, and impact on the hot flash. The concurrent or
non-concurrent use of non-steroid "add-back" regimen will also most likely
constitute a major component of future studies.
Publication Types:
Review
Review, academic
PMID: 8587224, UI: 96156904
17: Br J Obstet Gynaecol 1996 Oct;103 Suppl 14:10-3
Add-back therapy in the treatment of endometriosis: the European experience.
Edmonds DK
Department of Obstetrics and Gynaecology, Queen Charlotte's & Chelsea Hospital,
London, UK.
Add-back hormone replacement therapy (HRT) can alleviate the undesirable
hypo-oestrogenic effects of the gonadotrophin-releasing hormone (GnRH) agonists,
including loss in bone mineral content. However, this approach presents a
dilemma in patients with endometriosis as the re-introduction of oestrogen could
re-stimulate the endometriotic process. There have been three recently published
European studies investigating the combination of GnRH agonist plus add-back HRT
in the treatment of endometriosis. The loss of bone mineral density was
significantly diminished in a study using 25 micrograms oestradiol patches
combined with continuous medroxyprogesterone acetate (5 mg). Neither this low
oestrogen dose nor a full bone-sparing dose of oral oestradiol (2 mg daily)
reduced the efficacy of Zoladex (goserelin acetate) in patients with
endometriosis. Furthermore, in a small open study the gonadomimetic tibolone
totally prevented the loss of bone structure during GnRH agonist therapy. If a
GnRH agonist is considered the treatment of choice, then HRT should be used in
combination.
Publication Types:
Clinical trial
Randomized controlled trial
PMID: 8916980, UI: 97074553
18: Hum Reprod 1994 Jul;9(7):1380-97
Long-term gonadotrophin-releasing hormone agonist therapy: the evolving issue of
steroidal 'add-back' paradigms.
Adashi EY
Department of Obstetrics and Gynecology, University of Maryland School of
Medicine, Baltimore 21201.
The introduction of steroid 'add-back' regimens draws on the recognition that
several clinical entities targeted for treatment with gonadotrophin-releasing
hormone agonist (GnRHa) are not '6-month diseases'. Included under this heading
are individuals suffering from symptomatic endometriosis (not desires of
pregnancy), uterine fibroids (ineligible or disinterested in definitive surgical
therapy), ovarian hyperandrogenism, premenstrual syndrome, menopausal
transition, or dysfunctional uterine bleeding. A 6-month course of therapy with
a GnRHa does not adversely affect lipoprotein economy and therefore presumably
the corresponding cardiovascular risk. A 6-month course of GnRHa therapy appears
to be associated with a substantial decrease (of up to 8.2%) in lumbar bone
density, a phenomenon which may not be entirely reversible 6 months after
discontinuation of therapy. In principle, steroid 'add-back' therapy should
diminish some or all of the side-effects associated with GnRHa therapy, may
provide a medical treatment option for patients representing a high surgical
risk, and may delay surgical intervention if desired. On the other hand, a
steroid 'add-back' therapy may delay tissue diagnosis, be associated with a
substantial cost as well as with the need for parenteral route of
administration. Norethindrone-only (but not medroxyprogesterone acetate-only)
'add-back' regimens have proved promising in the context of endometriosis.
Non-concurrent oestrogen/progestin 'add-back' regimens proved promising in the
context of uterine fibroids. Substantial additional studies would have to be
carried out to validate the utility of steroid 'add-back' regimens. Special
emphasis will have to be placed on the evaluation of long-term utility with an
eye towards assessing clinical efficacy, impact on lipoprotein economy, impact
on bone density, impact on urogenital tissues, and impact on the hot flush. The
concurrent or non-concurrent use of non-steroid 'add-back' regimens will also
most likely constitute a major component of future studies.
Publication Types:
Review
Review, academic
PMID: 7962453, UI: 95051437
19: Am J Obstet Gynecol 1992 Feb;166(2):752-6
Gonadotropin-releasing hormone agonists: strategies for managing the
hypoestrogenic effects of therapy.
Judd HL
Department of Obstetrics and Gynecology, UCLA School of Medicine.
Gonadotropin-releasing hormone agonists have been shown to be comparable with
danazol for the treatment of endometriosis. These results are important because
danazol is associated with a significant number of side effects, particularly
androgenic effects, such as weight gain and acne. Although
gonadotropin-releasing hormone agonists are associated with hypoestrogenic side
effects, such as hot flashes and reversible bone density loss, recent studies
suggest that the risk of these side effects may be modified when
gonadotropin-releasing hormone agonists are combined with a progestin. These
findings suggest that such regimens may further enhance the clinical usefulness
of gonadotropin-releasing hormone agonist therapy for endometriosis and other
estrogen-mediated diseases.
Publication Types:
Review
Review, tutorial
PMID: 1531578, UI: 92160933
20: Fertil Steril 1996 Feb;65(2):342-8
The effect of add-back treatment with tibolone (Livial) on patients treated with
the gonadotropin-releasing hormone agonist triptorelin (Decapeptyl).
Lindsay PC, Shaw RW, Bennink HJ, Kicovic P
Royal Free Hospital School of Medicine, London, United Kingdom.
OBJECTIVE: To assess whether tibolone can prevent the bone loss and symptomatic
side effects normally associated with GnRH agonist (GnRH-a) use and whether
tibolone modifies the effect of GnRH-a on endometriosis. DESIGN: Prospective,
double-blind, placebo-controlled, group comparative study. SETTING:
Gynecological research unit in a London teaching hospital. PATIENTS: Twenty-nine
patients with endometriosis and two with fibroids. INTERVENTIONS: Six months of
treatment with 3.75 mg/mo IM triptorelin combined with daily tablets of either
placebo or 2.5 mg tibolone. MAIN OUTCOME MEASURES: Daily symptom diary for hot
flushes and bleeding episodes, laparoscopic scoring of endometriosis, endocrine
and biochemical changes, and bone mineral density scans. RESULTS: Lumbar spine
bone mineral density decreased significantly from baseline in the placebo group
(-5.1%) but not in the tibolone group (-1.1%). The frequency of hot flushes and
sweating episodes was reduced significantly by tibolone. There was no difference
between the two treatment groups with regard to the endometriosis scores.
CONCLUSIONS: The addition of tibolone to GnRH-a treatment reduces the bone loss
and vasomotor symptoms that normally occur with GnRH-a, thus making long-term
treatment with GnRH-a safer and more acceptable. It does not negate the
therapeutic effect of GnRH-a on endometriosis.
Publication Types:
Clinical trial
Controlled clinical trial
PMID: 8566259, UI: 96154015
21: Obstet Gynecol Clin North Am 2000 Sep;27(3):641-51
Update on the medical treatment of endometriosis.
Minjarez DA, Schlaff WD
University of Texas Southwestern Medical Center, Dallas, USA.
[Medline record in process]
The treatment of women with endometriosis can be a challenge. Therapeutic
strategies must be tailored to the individual symptoms, age, and desire for
fertility. Medical therapy continues to be based on endocrine treatment, such as
oral contraceptives, progestins, danazol, and GnRH agonists. Unfortunately,
recurrence rates are high after discontinuation of therapy. Recent clinical
research on GnRH analogues plus add-back therapy has produced favorable results.
Long-term treatment of patients using this approach has successfully reduced
pain while minimizing symptoms of hypoestrogenism and adverse metabolic effects,
such as loss of bone mineral density. Currently, GnRH analogues given with
add-back therapy seems to be the most effective long-term approach to the
treatment of symptomatic endometriosis. In the future, other modalities, such as
medicated vaginal rings, inhibitors of steroidogenic enzymes, and GnRH
antagonists, will most likely be options.
PMID: 10958009, UI: 20413882
22: J Clin Endocrinol Metab 1993 Jun;76(6):1439-45
A prospective, randomized trial of gonadotropin-releasing hormone agonist plus
estrogen-progestin or progestin "add-back" regimens for women with leiomyomata
uteri.
Friedman AJ, Daly M, Juneau-Norcross M, Rein MS, Fine C, Gleason R, Leboff M
Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard
Medical School, Boston, Massachusetts 02115.
Treatment of women with myomas with GnRH agonists (GnRH-a) for 3-6 months will
result in profound hypoestrogenism, a significant but temporary reduction in
uterine volume, and menstrual suppression. Long-term (i.e. > 6 months) treatment
with a GnRH-a is not recommended because of accelerated bone resorption and the
presence of hypoestrogenic symptoms. In this 2-yr study, women with myomas were
treated with GnRH-a plus one of two steroid "add-back" regimens to minimize
adverse sequelae of chronic hypoestrogenism. Fifty-one premenopausal women with
large, symptomatic uterine myomas all received the GnRH-a, leuprolide acetate
depot (LAD), every 4 weeks for 12 weeks at which time the women were randomized
to receive LAD plus either an estrogen-progestin or progestin-only add-back
regimen for an additional 92 weeks. Efficacy parameters assessed included serial
uterine volumes, hemoglobin concentrations, and hematocrits; safety parameters
evaluated included serial bone mineral density measurements, lipid profiles, and
medication-related symptoms. This report analyzes the first 52 weeks of study
data. Mean uterine volume decreased to 64% of pretreatment size at 12 weeks of
LAD treatment in both groups. The estrogen-progestin add-back group had no
significant regrowth of uterine volume, which was 75% of pretreatment size at
treatment week 52; in contrast, the progestin add-back group had a mean uterine
volume of 92% of pretreatment size by treatment week 52. Both groups
demonstrated significant improvements in mean hemoglobin concentrations and
hematocrits. The progestin add-back group had a significant decline in mean high
density lipoprotein-cholesterol concentration, which was not seen in the
estrogen-progestin add-back group. Finally, after a significant 3% bone loss
during the first 12 weeks of treatment, bone mineral density stabilized in both
add-back regimen groups. GnRH-a/steroid add-back regimens provide a useful
long-term treatment strategy in women with large, symptomatic uterine myomas and
may obviate the need for surgical intervention in selected cases. The
estrogen-progestin add-back regimen was superior or equal to the progestin
add-back regimen in all efficacy and safety parameters assessed.
Publication Types:
Clinical trial
Randomized controlled trial
PMID: 8501148, UI: 93273831
23: J Obstet Gynaecol Res 1999 Oct;25(5):295-301
Low-dose GnRH agonist therapy for the management of endometriosis.
Uemura T, Shirasu K, Katagiri N, Asukai K, Suzuki T, Suzuki N, Osada H, Hiroshi
M
Department of Obstetrics and Gynecology, Yokohama City University School of
Medicine, Japan.
OBJECTIVE: In order to examine whether treatment with a GnRH agonist alone can
maintain estrogen levels within the "estrogen window" that inhibits
endometriosis without influencing bone-mineral density, we studied the effects
of GnRH agonist therapy and changes in bone-mineral density. METHODS: Buserelin
acetate nasal spray was administered 3 times a day for 8 weeks (daily dose, 900
micrograms) to 21 women with endometriosis. The drug was then given twice a day
for 16 weeks (daily dose, 600 micrograms). The total duration of treatment was
24 weeks. The bone-mineral density of the lumbar vertebrae was measured by
dual-energy X-ray absorptiometry before treatment (baseline), at the end of
treatment, and 24 weeks after the end of treatment. RESULTS: The bone-mineral
density of the lumbar vertebrae at the end of treatment was 2.44% +/- 0.46%
(mean +/- standard error) lower than the baseline value. The value at 24 weeks
after the end of treatment was 1.10% +/- 0.64% lower than the baseline value.
More than 80% of the patients had serum-estradiol levels of 45 pg/ml or less.
During treatment, more than 90% of the patients had serum-estradiol levels of 60
pg/ml or less. Genital bleeding was inhibited in 90% of the patients. After 8
weeks of treatment, the clinical symptoms improved in 75% of the patients; such
improvement persisted for the duration of the treatment. CONCLUSION: Decreasing
the dose of GnRH agonist during treatment can minimize the loss of bone-mineral
density without lessening the beneficial effects on endometriosis. This
technique might be useful in the management of endometriosis.
PMID: 10533322, UI: 20003515
24: Gynecol Obstet Invest 1999;47(1):37-41
Effects of add-back therapy on bone mineral density and pyridinium crosslinks in
patients with endometriosis treated with gonadotropin-releasing hormone
agonists.
Gnoth CH, Godtke K, Freundl G, Godehardt E, Kienle E
Department of Gynecology and Obstetrics, Academic Hospital of the University of
Dusseldorf, Dusseldorf-Benrath, Germany. gnoth@uni-duesseldorf.de
Treatment of endometriosis with gonadotropin-releasing hormone agonists (GnRHa)
is limited to 6 months because of possible adverse effects on bone metabolism.
We designed a randomized, double-blind, placebo-controlled, prospective study of
27 patients with endometriosis who were given GnRHa with or without hormone
add-back therapy (+ 20 microg of ethinyl estradiol with 0.15 mg desogestrel)
designed to suppress the adverse effects of hypoestrogenism while preserving the
efficacy of GnRHa. Both regimens showed significant improvements in
endometriosis, dysmenorrhea, and pelvic pain; effects were significantly better
in the GnRHa + placebo group. The GnRHa + placebo group had significantly higher
serum calcium levels and a significantly higher loss of lumbar spine bone
mineral density (BMD). Urinary levels of pyridinium crosslinks increased
significantly in the GnRHa + placebo group, and declined to normal in the GnRHa
+ add-back group. The add-back therapy protects women taking GnRHas from severe
loss of BMD and accelerated bone collagen resorption, but reduces the efficacy
of the GnRHa.
Publication Types:
Clinical trial
Randomized controlled trial
PMID: 9852390, UI: 99069240
25: Br J Obstet Gynaecol 1996 Oct;103 Suppl 14:1-4
The need for add-back with gonadotrophin-releasing hormone agonist therapy.
Studd J, Leather AT
Chelsea & Westminster Hospital, London, UK.
The usefulness of the gonadotrophin-releasing hormone (GnRH) agonists in
treating benign chronic gynaecological disorders, such as endometriosis and
uterine fibroids, or pre-menstrual syndrome (PMS), is limited by their
hypo-oestrogenic side effects, including bone demineralisation and vasomotor
symptoms. Studies in patients receiving GnRH agonists and hormone replacement
therapy (HRT) show that whilst the efficacy of GnRH agonist monotherapy in
treating endometriosis and fibroids is maintained, the concomitant add-back HRT
can prevent the bone loss and reduce the incidence and severity of vasomotor
symptoms. However, in a study of add-back HRT (an oestrogenic plus a
progestogenic agent) in severe PMS, although the efficacy of Zoladex (goserelin
acetate) against oestrogen-responsive symptoms, such as mood, was still evident,
progestogenic side effects still occurred. It is likely that add-back HRT may
need to be tailored to individual indications.
Publication Types:
Clinical trial
Randomized controlled trial
PMID: 8916978, UI: 97074551
26: Fertil Steril 1995 Sep;64(3):474-81
Gonadotropin-releasing hormone analogue (goserelin) plus hormone replacement
therapy for the treatment of endometriosis: a randomized controlled trial.
Howell R, Edmonds DK, Dowsett M, Crook D, Lees B, Stevenson JC
Queen Charlotte's and Chelsea Hospital, London, United Kingdom.
OBJECTIVE: To determine whether treatment of endometriosis with a GnRH analogue
(GnRH-a; goserelin) combined with continuous estrogen and progestogen hormone
replacement therapy (HRT) would prevent the hypoestrogenic effects, including
loss of bone density, while maintaining efficacy for treatment of endometriosis.
DESIGN: Randomized controlled trial. PATIENTS: Fifty premenopausal women with
laparoscopically diagnosed endometriosis (revised American Fertility Score for
endometriosis implants equal to four or greater) and significant symptoms of
dysmenorrhoea, dyspareunia, and other pelvic pain. INTERVENTION: Patients were
randomized to receive either goserelin alone, 3.6 mg SC depot every 4 weeks for
24 weeks, or goserelin, 3.6 mg SC depot every 4 weeks for 24 weeks, plus HRT (25
micrograms transdermal 17 beta E2 daily and 5 mg medroxyprogesterone acetate
orally daily) for 20 weeks commencing with the second goserelin injection.
RESULTS: There was a significant reduction in the extent of pelvic endometriosis
in both groups, with no difference between the groups. Both groups experienced
an improvement in symptoms and signs, again with no difference between groups.
Hypoestrogenic side effects of hot flushes and loss of libido were significantly
less in the group that received HRT. The amount of bone mineral density loss was
significantly less in the HRT group at the lumbar spine, although it was not
prevented completely. CONCLUSION: The addition of HRT to GnRH-a for the
treatment of endometriosis did not reduce the efficacy of treatment, and adverse
hypoestrogenic effects were decreased, although not abolished.
Publication Types:
Clinical trial
Randomized controlled trial
Comments:
Comment in: Fertil Steril 1996 Oct;66(4):666-8
PMID: 7641897, UI: 95369485
27: Depress Anxiety 1998;7(4):171-7
Depressive symptoms associated with gonadotropin-releasing hormone agonists.
Warnock JK, Bundren JC, Morris DW
Department of Psychiatry, University of Oklahoma Health Sciences Center-Tulsa,
Oklahoma 74129, USA.
The gonadotropin-releasing hormone (GnRH) agonists are a relatively new class of
drugs that are potentially effective in treating disorders that are aggravated
either by estrogen or testosterone. GnRH agonists are effective in the treatment
of endometriosis, as well as other disorders, such as advanced prostrate cancer,
precocious puberty and uterine leiomyomata. While the GnRH agonists reduce the
extent of the endometrial lesions and the occurrence of pelvic pain associated
with endometriosis, these agents are associated with physical and psychiatric
side effects. The adverse effects of these agents are consistent with the
physiological effects of ovarian suppression, such as vasomotor instability,
vaginal dryness, and headaches. Preliminary results of a prospective,
double-blind placebo-controlled study and an open label trial indicates that
depressive mood symptoms increase in women treated with GnRH agonist therapy for
endometriosis. Additional evidence suggest that sertraline effectively manages
depressive mood symptoms associated with GnRH agonist therapy. The reason for
the decline in mood on GnRH agonists is postulated to be associated with the
decline in estrogen levels. Effective treatment strategies for depressive mood
symptoms in women on GnRH agonists therapy may offer insight into the mechanisms
of action of estrogen on mood.
Publication Types:
Review
Review, tutorial
PMID: 9706454, UI: 98371743
28: J Reprod Med 1998 Mar;43(3 Suppl):287-92
Endometriosis and the estrogen threshold theory. Relation to surgical and
medical treatment.
Barbieri RL
Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard
Medical School, Boston, Massachusetts 02115, USA.
Estrogen-dependent diseases often regress when estrogen production is reduced.
Endometriosis is an estrogen-responsive disease, and the pelvic pain associated
with it improves when estrogen production is reduced with bilateral oophorectomy
or chronic gonadotropin releasing hormone (GnRH) agonist treatment.
Unfortunately, reduction of estrogen production is associated with adverse side
effects, such as vasomotor symptoms and bone loss. In women with endometriosis
and pelvic pain, the combination of bilateral oophorectomy plus postoperative
low-dose estrogen treatment produces sustained improvement in pain symptoms and
reduces the hypoestrogenic side effects associated with bilateral oophorectomy.
In a parallel manner, chronic GnRH agonist treatment plus low-dose steroid
therapy (estrogen plus progestin or progestin only) is effective in the
treatment of pelvic pain caused by endometriosis and reduces the hypoestrogenic
effects associated with hypoestrogenism caused by the GnRH agonist. Since
chronic GnRH agonist treatment is reversible and avoids surgery, it may become
an important alternative to bilateral oophorectomy for the treatment of
endometriosis.
Publication Types:
Review
Review, tutorial
PMID: 9564663, UI: 98225851
29: Fertil Steril 1996 Jan;65(1):211
Retraction of Friedman AJ, Hornstein MD. In: Fertil Steril 1993 Aug;60(2):236-41
Gonadotropin-releasing hormone agonist plus estrogen-progestin add-back therapy
for endometriosis-related pelvic pain.
Friedman AJ
Publication Types:
Retraction of publication
PMID: 8557149, UI: 96170929
30: Am J Obstet Gynecol 1990 Feb;162(2):593-5
Gonadotropin-releasing hormone agonists and estrogen-progestogen replacement
therapy.
Barbieri RL
Department of Obstetrics and Gynecology, Harvard Medical School, Brigham and
Women's Hospital, Boston, MA 02115.
Gonadotropin-releasing hormone agonists are effective in the treatment of
endometriosis and myomas, both of which are estrogen-dependent processes, but
there is a high clinical recurrence rate after therapy is discontinued.
Long-term continuous therapy (2 years or more) has a cumulative effect on bone
loss and causes other uncomfortable or harmful side effects. Noninvasive
assessments of disease response in patients with myomas have shown that bone
changes might be prevented and other side effects of long-term therapy can be
alleviated by adding back small amounts of estrogen or progestin. No comparable
data are available for patients with endometriosis because the need for repeated
laparoscopy has made long-term studies impractical. Nevertheless, a short-term
study of patients with endometriosis showed that adding small amounts of
progestin during treatment with a gonadotropin-releasing hormone agonist may
help prevent bone changes.
Comments:
Comment in: Am J Obstet Gynecol 1991 Oct;165(4 Pt 1):1156-7
PMID: 2137979, UI: 90178314
31: Br J Obstet Gynaecol 1996 Oct;103 Suppl 14:15-7
Should add-back therapy for endometriosis be deferred for optimal results?
Kiesel L, Schweppe KW, Sillem M, Siebzehnrubl E
Department of Obstetrics and Gynaecology, University of Tubingen, Germany.
Add-back hormone replacement therapy has been shown to alleviate some of the
hypo-oestrogenic side effects associated with gonadotrophin-releasing hormone
agonists, including demineralisation of bone. Studies on patients with uterine
fibroids have shown that concomitant add-back therapy reduced the efficacy of
these agents, but that deferred administration was less detrimental. This trial
set out to investigate if deferred add-back therapy could offer any advantages
to patients with endometriosis compared with immediate therapy. Zoladex
[goserelin acetate (3.6 mg every 4 weeks)] was given for 24 weeks either with
placebo, with medrogestone (10 mg/day) for 24 weeks (immediate add-back
therapy), or with placebo for 12 weeks followed by medrogestone (10 mg/day) for
12 weeks (deferred add-back therapy) to 123 patients. The number of responders
measured using the Revised American Fertility Society score (decrease in this
score of > or = 50%) was greatest in the immediate add-back therapy group,
although there were no significant differences between groups. All three
treatment groups showed significant decreases in bone mineral density compared
with baseline but smaller losses were generally observed in the add-back groups.
A significantly smaller number of patients in the immediate add-back group
reported hot flushes during the first 12 weeks of treatment compared with the
deferred add-back group. In conclusion, it appears that there is no extra
advantage to patients with endometriosis being treated with goserelin in
delaying the start of add-back therapy.
Publication Types:
Clinical trial
Multicenter study
Randomized controlled trial
PMID: 8916982, UI: 97074555
32: Drug Saf 1994 Aug;11(2):104-13
A risk benefit assessment of drugs used in the treatment of endometriosis.
Shaw RW
Department of Obstetrics and Gynaecology, University of Wales College of
Medicine, Cardiff.
Medical treatments of endometriosis rely upon the hormonal dependence of
endometriotic implants for further growth and extension. The cyclic nature of
the symptoms means they may be helped by agents that suppress menstruation both
from the endometrium and within the endometriotic lesions. In comparative
trials, progestogens have been shown to achieve a similar reduction in symptoms
and to induce regression of deposits, but to date there are few long term
follow-up data concerning gestrinone. The recent introduction of
gonadotrophin-releasing hormone (GnRH) agonists, highly effective at inducing a
state of sustained hypoestrogenaemia, is providing another group of compounds
suitable for use in the treatment of endometriosis. In comparative trials with
danazol, a number of these compounds administered in novel formulations (as
intranasal sprays or sustained release depots), have been shown to significantly
reduce symptoms both during treatment and for 6 to 12 months post-treatment when
compared with baseline. In addition, there are highly significant reductions in
revised American Fertility Society (R-AFS) total and implant alone scores
following 6 months' therapy. Whilst these changes are not significantly
different from danazol, there are fewer patients discontinuing treatment with
GnRH agonists than with danazol. The low circulating levels of 17 beta-estradiol
seen during GnRH analogue therapy result in alterations of bone mineral
metabolism similar to those observed at the menopause. Continued prolonged use
would thus result in reduced bone mass and this factor will limit the duration
of use of GnRH agonists long term until appropriate combination ('add-back')
regimens to protect bone are developed.
Publication Types:
Review
Review, tutorial
PMID: 7945998, UI: 95032811
33: Fertil Steril 1993 Aug;60(2):236-41
Retracted by Friedman AJ. In: Fertil Steril 1996 Jan;65(1):211
Gonadotropin-releasing hormone agonist plus estrogen-progestin "add-back"
therapy for endometriosis-related pelvic pain.
Friedman AJ, Hornstein MD
Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard
Medical School, Boston, Massachusetts 02115.
OBJECTIVE: To evaluate the safety and efficacy of leuprolide acetate depot (LA,
Lupron; TAP Pharmaceuticals, Deerfield, IL) plus daily conjugated equine
estrogens (Es, Premarin; Wyeth-Ayerst Laboratories, Philadelphia, PA), and
medroxyprogesterone acetate (MPA, Provera; The Upjohn Company, Kalamazoo, MI)
"add-back" treatment of endometriosis-associated pelvic pain. DESIGN:
Retrospective case series. SETTING: Tertiary care, academic medical center.
PATIENTS: Eight patients with moderate to severe pelvic pain and
laparoscopically documented endometriosis. INTERVENTION: Leuprolide acetate
depot 3.75 mg IM every 4 weeks for 24 months. Oral conjugated equine Es 0.625
mg/d plus MPA 2.5 mg/d were also taken from treatment months 3 through 24.
RESULTS: Six women completed the 2-year study. Mean revised endometriosis scores
for implants, adhesions, and total values were significantly reduced at the
conclusion of treatment from pretreatment scores. Self-reported pelvic pain
scores were significantly lower at treatment months 3, 6, 12, 18, 24, and 6
months after therapy than pretreatment scores. Dual X-ray absorptiometry bone
density measurements of the lumbar spine did not change significantly during the
24-month treatment period. The proportion of women experiencing hot flushes was
significantly reduced after E-progestin add-back treatment from the proportion
at treatment month 3. CONCLUSION: Treatment with LA depot plus conjugated equine
Es and MPA for 2 years was a safe and effective therapy for women with
endometriosis and pelvic pain in this small retrospective study.
Publication Types:
Retracted publication
Comments:
Comment in: Fertil Steril 1994 Feb;61(2):404-6
Comment in: NIH Guide Grants Contracts 1996 May 10;25(15):2
PMID: 8339817, UI: 93339451
34: Curr Opin Obstet Gynecol 1991 Jun;3(3):352-7
Gonadotropin-releasing hormone agonists: emerging modification of treatment
regimens.
Hodgen GD
Jones Institute for Reproductive Medicine, Norfolk, Virginia.
GnRH agonist (GnRHa) medications are now routinely used by gynecologists,
urologists, medical endocrinologists, and pediatric endocrinologists alike.
GnRHa are frequently highly effective in diminishing pain derived from
endometriotic lesions. Current US Food and Drug Administration approval limits
GnRHa regimens to a 6-month course largely because of concern that the
hypoestrogenic state invoked by the medication can lead to loss of bone mineral
density. Most studies on this issue show either a very small diminution of bone
density over this interval or no detectable changes. The role of GnRHa in
shrinking uterine fibroids and/or diminishing bleeding, both before and during
surgery is much more an adjunctive-to-definitive surgical intervention than a
free-standing medical therapy. Attempts to suppress with GnRHa and co-administer
estrogens with progestins or progestins alone, either concurrently or
sequentially (delayed), are now being studied vigorously. The place of GnRHa in
medical management of a variety of endocrine conditions is no the standard of
care.
Publication Types:
Review
Review literature
PMID: 1813003, UI: 92256755
35: Fortschr Med 1990 Sep 10;108(26):498-500
[GnRH analogs in gynecology. Possibilities for therapeutic use].
[Article in German]
Niesert S
Frauenklinik im Krankenhaus Oststadt, Medizinischen Hochschule Hannover.
Gonadotropin releasing hormone (GnRH) agonists are synthetic peptide analogues
of the natural gonadotropin releasing hormone with a stronger and more prolonged
effect than the natural GnRH. Repeated administration of GnRH agonists induces
pituitary desensitization followed by a decrease in gonadotropin secretion and
estradiol synthesis. Thus reversible hypogonadotropic hypogonadism is produced.
Consequently, estrogen-dependent diseases can be treated successfully with GnRH
analogues. The therapeutic results obtained in patients with endometriosis,
leiomyoma, pubertas praecox, and metastatic breast cancer are discussed.
Furthermore the contraceptive properties of GnRH analogues, and combination
treatment with HMG to induce ovulation is reviewed.
Publication Types:
Review
Review, tutorial
PMID: 2262188, UI: 91085904
36: Fertil Steril 1994 Jan;61(1):21-34
Extending the use of gonadotropin-releasing hormone agonists: the emerging role
of steroidal and nonsteroidal agents.
Lemay A, Surrey ES, Friedman AJ
Hopital Saint-Francois d'Assise, Quebec, Canada.
OBJECTIVE: To review and summarize the state of the art as it relates to the
long-term application of GnRH agonists (GnRH-a). DESIGN: A retrospective
analysis of the available literature and results and an up-to-date review of a
rapidly evolving field. CONCLUSION: Although the precise use of long-term GnRH-a
therapy (in conjunction with sex steroid add-back therapy) remains unknown, the
information provided strongly supports additional studies in this area to
achieve a body of promising preliminary data.
Publication Types:
Review
Review, tutorial
PMID: 8293841, UI: 94123798
37: Prog Clin Biol Res 1990;323:157-78
Endometriosis and infertility: the mechanisms involved.
Halme J, Surrey ES
Department of Ob-Gyn, University of California, Los Angeles, School of Medicine
90024.
Publication Types:
Review
Review, tutorial
PMID: 2406745, UI: 90160468
38: Fertil Steril 1989 Oct;52(4):547-52
Effects of gonadotropin-releasing hormone (GnRH) agonist on pituitary and
ovarian responses to pulsatile GnRH therapy in polycystic ovarian disease.
Surrey ES, de Ziegler D, Lu JK, Chang RJ, Judd HL
Cedars-Sinai Medical Center, Los Angeles, California 90048.
Nine clomiphene citrate-resistant polycystic ovarian disease (PCOD) patients
received intravenous gonadotropin-releasing hormone (GnRH) pulses before and
immediately after 1 month of GnRH agonist (GnRH-a) therapy. Circulating
gonadotropin and ovarian steroid levels, as well as follicular development, were
measured throughout therapy. Results were compared with those obtained from five
hypogonadotropic patients treated with GnRH pulses only who ovulated during six
of seven treatment cycles. Only two PCOD patients ovulated normally with GnRH
pulses before GnRH-a therapy. Aberrant gonadotropin and ovarian steroid
secretory patterns were noted in the others. After GnRH-a, gonadotropin and
ovarian steroid hormone levels were similar to those of the hypogonadotropic
patients. Subsequent secretory responses to GnRH pulses were partially
normalized. However, only two additional PCOD patients ovulated.
PMID: 2680614, UI: 90033401
39: Obstet Gynecol Clin North Am 1989 Mar;16(1):79-91
Endometriosis as a cause of infertility.
Surrey ES, Halme J
Department of Obstetrics and Gynecology, UCLA Medical Center.
Although association between moderate or severe endometriosis and infertility is
fairly well established, the link between lesser disease stages and infertility
is more tenuous. The proposed mechanisms underlying this association are
reviewed. These include mechanical factors, changes in the peritoneal fluid
environment, activation of local or systemic immune response, and abnormalities
of ovulation, fertilization, and early pregnancy.
Publication Types:
Review
Review, tutorial
PMID: 2664624, UI: 89314702
40: Fertil Steril 1999 Nov;72(5):889-95
Long-term administration of tibolone plus gonadotropin-releasing hormone agonist
for the treatment of uterine leiomyomas: effectiveness and effects on vasomotor
symptoms, bone mass, and lipid profiles.
Palomba S, Affinito P, Di Carlo C, Bifulco G, Nappi C
Department of Gynecology, Obstetrics and Pathophysiology of Human Reproduction,
University of Naples Federico II, Italy.
OBJECTIVE: To evaluate the effects of long-term administration of GnRH agonist
(GnRH-a) plus tibolone for uterine leiomyomatosis. DESIGN: Prospective open
clinical trial. SETTING: Department of Gynecology, Obstetrics and
Pathophysiology of Human Reproduction, University of Naples "Federico II",
Naples, Italy. PATIENT(S): Twenty-five subjects with symptomatic uterine
leiomyomas. INTERVENTION(S): Treatment for 2 years with leuprolide acetate (3.75
mg IM every 28 days) and tibolone (2.5 mg/d per os). MAIN OUTCOME MEASURE(S):
Uterine and uterine leiomyoma sizes, endometrial thickness, lumbar spine bone
mineral density (BMD), bone metabolism, lipid profile, myoma-related symptoms at
baseline and every 6 months. Hot flashes and vaginal bleeding episodes recorded
in a daily symptom diary. RESULT(S): After 6 months of treatment, a significant
reduction was observed in uterine and leiomyoma volumes and myoma-related
symptoms compared with baseline values. No significant change was observed in
bone turnover, lumbar BMD, or serum total cholesterol, low-density lipoprotein
cholesterol, or triglyceride levels. High-density lipoprotein cholesterol values
were significantly lower than baseline values after 6 months of treatment but
not after 18 months of therapy. A low mean number of hot flashes per day was
observed. CONCLUSION(S): Long-term administration of GnRH-a plus tibolone
reduces hot flashes and prevents bone loss without changing the lipid profile.
Publication Types:
Clinical trial
PMID: 10560995, UI: 20023651
41: Acta Obstet Gynecol Scand Suppl 1994;159:22-34
Hormonal therapies for endometriosis: implications for bone metabolism.
Dawood MY
Department of Obstetrics, Gynecology and Reproductive Sciences, University of
Texas Medical School at Houston.
The non-surgical treatment of endometriosis involves hormone therapy that either
affects the lesions directly, or indirectly inhibits endometrial proliferation
and induces atrophy through estrogen deprivation, or through a combination of
these effects. The medications used to treat endometriosis are progestins (e.g.
norethindrone, medroxyprogesterone acetate), oral contraceptives (e.g.
estrogen-progesterone acetate), androgens and their derivatives (e.g. danazol,
gestrinone), and gonadotropin-releasing hormone (GnRH) agonists (e.g. buserelin,
leuprolide acetate, nafarelin, goserelin, tryptorelin). Agents such as GnRH
agonists that produce sustained and prolonged hypoestrogenemia, similar to the
postmenopausal hypogonadal state, can have a significant negative impact on
trabecular bone mass. Evidence from the use of oral contraceptives and
medroxyprogesterone acetate indicated that they had no apparent adverse effect
on bone mass. Initial studies with dual-photon absorptiometry were unable to
detect any appreciable bone loss with GnRH agonists. Later studies, however,
have invariably found significant bone loss as early as 3 months after the start
of treatment. Quantitated computerized tomography always shows significant
trabecular bone loss of the vertebrae and hip with GnRH agonists. Depot
preparations appear to produce more marked loss than daily intranasal sprays.
Recovery of bone loss may take 6-12 months after the end of therapy, with
considerable individual variations. In contrast, treatment of endometriosis with
danazol produces bone gain. If endometriosis has to be treated with
bone-depleting agents, prevention or attenuation of bone loss using combined
therapy with progestins, etidronate or calcitonin together with GnRH agonists
should be considered; however, further studies are necessary to define the
efficacy of such combined therapy. Smoking and excessive caffeine intake should
be avoided. The risk of bone loss should be considered when choosing the
appropriate management of endometriosis, the selection of patients, repeat
therapies for recurrent endometriosis, and the formulation of such therapies, in
order to minimize or overcome it.
Publication Types:
Review
Review, tutorial
PMID: 8209669, UI: 94270134
42: Int J Gynaecol Obstet 1999 Feb;64 Suppl 1:S5-13
Today's treatments: medical, surgical and in partnership.
Donnez J
Department of Gynaecology, Catholic University of Louvain, Belgium.
OBJECTIVE: To provide an overview of the medical, surgical and combined therapy
options for endometriosis. RESULTS: Available medical options include danazol,
progestogens, gestrinone, oral contraceptive agents, analgesics and
gonadotropin-releasing hormone (GnRH) agonists. Used in the short-term, most of
these agents relieve pain in a large proportion of patients and produce disease
regression, however, they do not prevent recurrence, and are associated with
side-effects. However, few data confirm any benefit of short-term medical
therapy on fertility. One of the most promising medical approaches appears to be
GnRH agonists with add-back hormone replacement therapy. Surgery may relieve
pain, eradicate visible disease and improve fertility. A combined approach may
facilitate surgery and relieve pain, although any fertility benefit is as yet
unproven. CONCLUSION: Both short-term medical treatment and surgery relieve
endometriosis-associated pain and decrease endometriotic implants. However, all
approaches have side effects which must be balanced against the benefits when
defining suitable treatment for a particular patient.
Publication Types:
Review
Review, tutorial
PMID: 10096459, UI: 99194123
43: Gynecol Obstet Invest 1998;45 Suppl 1:22-30; discussion 35
Steroidal 'add-back' therapy in patients treated with GnRH agonists.
Freundl G, Godtke K, Gnoth C, Godehardt E, Kienle E
Department of Gynaecology and Obstetrics, Academic Hospital, University of
Dusseldorf, Dusseldorf-Benrath, Germany.
GnRH analogues (GnRH-a) are well established in the treatment of endometriosis.
However, due to hypooestrogenic effects, treatment is limited to 6 months. The
aim of this randomized, double-blind, comparative study was to evaluate whether
symptoms and signs of hypooestrogenism, e.g. hot flushes, sweating and
sleeplessness, could be avoided by a steroidal add-back regimen, while the
beneficial effect of a GnRH-a on endometriosis could be maintained. In group A,
14 patients were treated with 3.75 mg leuprorelin acetate depot per month i.m.
in combination with 20 mg ethinyloestradiol plus 0.15 mg desogestrel orally for
3 weeks. In group P, 13 patients received leuprorelin acetate, following the
same schedule as in group A, and placebo. Treatment duration was 6 months. At
first-look laparoscopy (postoperatively) group A had an r-AFS score of 23.57 and
group P of 24.23. After 6 months of treatment with leuprorelin acetate depot
r-AFS scores had dropped to 16.14 in group A and to 6.25 in group P at
second-look laparoscopy, achieving statistical significance in both groups (p <
0.001). Hypooestrogenic adverse drug reactions (e.g. hot flushes, sweating and
sleeplessness) were more frequently reported in group P, whereas the occurrence
of headache was comparable in both groups. Dysmenorrhoea was significantly
reduced in both groups, whereas dyspareunia was only decreased in group P.
Variations in laboratory values were within normal ranges and did not give any
concern about drug safety. Loss of bone mineral density caused by the GnRH-a was
reduced by the combined oestrogen/progestin add-back therapy. In conclusion,
this therapy can lead to a reduction in hypooestrogenic adverse drug reactions
and mostly preserves agonist efficacy with the chance of treatment prolongation.
Publication Types:
Clinical trial
Randomized controlled trial
PMID: 9628521, UI: 98290485
44: J Reprod Med 1998 Mar;43(3 Suppl):299-308
Human issues and medical economics of endometriosis. Three- vs. six-month
GnRH-agonist therapy.
Heinrichs WL, Henzl MR
Department of Gynecology and Obstetrics, Stanford University School of Medicine,
CA 94305, USA.
OBJECTIVE: To project the efficacy and economic consequence of short-term
intranasal gonadotropin-releasing hormone agonist (GnRH-a) for diagnosis of and
therapy for endometriosis. STUDY DESIGN: Multicenter, placebo-controlled
clinical trials of GnRH-a comparing three vs. six months of treatment, three
months of retreatment and three months of postoperative treatment for the
symptoms and signs of laparoscopically diagnosed endometriosis. RESULTS: The
reduction in symptoms and signs of endometriosis was similar at the end of three
months to the relief at six months. Retreatment was as effective as initial
treatment, and the return of symptoms after laparoscopic surgery plus
postoperative treatment for three months was delayed by approximately 18 months
as compared to surgery alone. The projected charges for the surgical approaches
(laparoscopy or minilaparoscopy) to diagnosis and therapy were 50-60% greater
than those for the medical approach. CONCLUSION: GnRH-a administration for three
months could be a cost-effective approach to the presumptive diagnosis and
treatment of endometriosis among women with chronic pelvic pain.
Publication Types:
Clinical trial
Multicenter study
PMID: 9564665, UI: 98225853
45: Fertil Steril 1997 Jun;67(6):1013-8
Retreatment with nafarelin for recurrent endometriosis symptoms: efficacy,
safety, and bone mineral density.
Hornstein MD, Yuzpe AA, Burry K, Buttram VC Jr, Heinrichs LR, Soderstrom RM,
Steinberger E, Lin JS
Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston,
Massachusetts 02115, USA.
OBJECTIVE: To assess the efficacy, safety, and effect on bone mineral density of
a 3-month course of retreatment with intranasal nafarelin acetate for recurrent
symptoms of endometriosis. DESIGN: Multicenter, open-label, nonrandomized
clinical trial. SETTING: Eleven hospital-based and private practices.
PATIENT(S): Thirty-six women with endometriosis symptoms recurring after 3 or 6
months of treatment with nafarelin. INTERVENTION(S): Nasal nafarelin 200
micrograms twice daily for 3 months. MAIN OUTCOME MEASURE(S): Assessments for
dysmenorrhea, dyspareunia, pelvic pain, tenderness, and induration. Measurement
of bone mineral density of the lumbar spine. RESULT(S): Improvements from
admission to the end of retreatment were significant for dysmenorrhea, pelvic
pain, tenderness, induration, and dyspareunia. Three months after retreatment
ended, mean symptom scores for dysmenorrhea and pelvic tenderness, although
worse than at the end of retreatment, were still significantly better than
scores at admission. Mean bone mineral density 3 months after retreatment was
0.56% lower than before retreatment and 1.94% lower than before initial
treatment. CONCLUSION(S): Three-month nafarelin retreatment for recurrent
endometriosis symptoms was effective and safe.
Publication Types:
Clinical trial
Multicenter study
PMID: 9176437, UI: 97319534
46: Ann N Y Acad Sci 2000;900:435-43
Current and potential application of GnRH agonists in gynecologic practice.
Tzafettas JM
3rd University Department of Obstetrics and Gynecology, Hippokrateio Hospital,
Thessaloniki, Greece. IVFthes@compulink.gr
The development of GnRH-a (analogues or agonists) is a major leap forward in the
treatment of various hormone-dependent diseases in medicine. Their introduction
in reproductive endocrinology, in in vitro fertilization/embryo transfer
(IVF/ET) and other assisted reproduction techniques had a revolutionary impact.
They have been effective in other gynecologic conditions including fibroids,
endometriosis, anovulatory disorders, precocious puberty, dysfunctional uterine
bleeding, and operative hysteroscopy. Medical castration induced by GnRH-a has
become first-line therapy in metastatic breast cancer. Their long-term use,
though, has been associated with a variety of adverse effects such as bone loss
and decreased cardioprotection. "Steroid add-back" therapy in these cases
apparently is an effective alternative. It may allow their safe long-term
application beyond 6 months, averting unpleasant side-effects and maintaining
bone mass and cardioprotection.
PMID: 10818434, UI: 20278375
47: Gynecol Endocrinol 1999 Dec;13(6):382-9
Estriol add-back therapy in the long-acting gonadotropin-releasing hormone
agonist treatment of uterine leiomyomata.
Nakayama H, Yano T, Sagara Y, Kikuchi A, Ando K, Wang Y, Watanabe M, Matsumi H,
Osuga Y, Momoeda M, Taketani Y
Department of Obstetrics and Gynecology, Faculty of Medicine, University of
Tokyo, Japan.
The hypoestrogenic state induced by gonadotropin-releasing hormone agonists
(GnRHa) has been shown to be effective in the treatment of uterine leiomyomas
but to induce bone loss. Estriol has been described to be a weak and
short-acting estrogen without an increased risk of endometrial proliferation and
hyperplasia. The purpose of this study was to evaluate whether treatment of
uterine leiomyomata with GnRHa plus oral estriol add-back therapy could prevent
bone loss, without deteriorating the therapeutic effect of GnRHa. Twelve
premenopausal women with symptomatic uterine leiomyomas were randomized to
receive either leuprolide acetate depot alone at a dose of 3.75 mg s.c. every
month for 6 months (non add-back group; n = 6), or GnRHa for 6 months plus oral
estriol 4 mg/day for 4 months commencing with the third GnRHa injection
(add-back group; n = 6). In the add-back group, leiomyoma volume, as measured by
transvaginal ultrasound, decreased to 59.1% of baseline at 2 months of GnRHa
therapy with no significant change in size during the remaining treatment
period. In contrast, it decreased to 31.3% of pretreatment size at the end of
treatment in the non add-back group. The levels of bone metabolic markers such
as CrossLaps, deoxypyridinoline, osteocalcin and bone-specific alkaline
phosphatase, increased significantly throughout the treatment in the non
add-back group, whereas they were suppressed by the add-back therapy. The bone
mineral density of lumbar spine (L2-L4) as measured by dual-energy X-ray
absorptiometry decreased significantly by 7.5% at the end of treatment in the
non add-back group, but did not change significantly in the add-back group. In
conclusion, GnRHa plus estriol add-back therapy might be considered for
long-term treatment of uterine leiomyomata.
Publication Types:
Clinical trial
Randomized controlled trial
PMID: 10685331, UI: 20149592
48: Fertil Steril 1997 Feb;67(2):390-3
Effective treatment of severe menstrual migraine headaches with
gonadotropin-releasing hormone agonist and "add-back" therapy.
Murray SC, Muse KN
Department of Obstetrics and Gynecology, University of Kentucky, Lexington
40536-0084, USA. murrays@pop.uky.edu
OBJECTIVE: To determine the efficacy of treating women with severe menstrual
migraine headaches with GnRH agonist (GnRH-a) therapy, alone and combined with
continuous estrogen-progestin "add-back." DESIGN: Nonrandomized, prospective
treatment study. SETTING: Outpatient clinic in a university medical center.
PATIENT(S): Five women who had repetitive, severe, migraine headaches limited to
the perimenstrual period were selected carefully. INTERVENTION(S): After 2
months of basal evaluation, all subjects received GnRH-a (leuprolide acetate
depot formulation, 3.75 mg IM, monthly) for 10 months. Beginning with the 5th
month, "add-back" therapy (the addition of transdermal E2, 0.1 mg daily, and
oral medroxyprogesterone acetate, 2.5 mg daily) was initiated. MAIN OUTCOME
MEASURE(S): Patients rated headache severity from 0 (absent) to 3 (severe) each
day; these were combined each month to obtain a cumulative score for that month.
In addition, patients were asked their overall assessment of the treatments.
RESULT(S): The mean headache scores for the GnRH-a treatment months (4.0 +/-
1.5, mean +/- SEM) and for the GnRH-a and "add-back" treatment months (3.1 +/-
0.7) were each significantly lower than those of the control months (15.3 +/-
2.4). The patients uniformly found both treatments to be well tolerated and
near-curative for their condition. CONCLUSION(S): Gonadotropin-releasing hormone
agonist administration, alone or with "add-back" therapy, is a very effective
treatment for carefully selected patients with severe, perimenstrual migraine
headaches.
Publication Types:
Clinical trial
PMID: 9022620, UI: 97174960
49: Acta Obstet Gynecol Scand 1996 Feb;75(2):162-5
Reduction of bone mineral density by gonadotropin-releasing hormone agonist,
nafarelin, is not completely reversible at 6 months after the cessation of
administration.
Taga M, Minaguchi H
Department of Obstetrics and Gynecology, Yokohama City University School of
Medicine, Japan.
STUDY OBJECTIVE: To determine the reversibility of bone mineral density after
the cessation of GnRH agonist treatment for endometriosis. DESIGN: Longitudinal
trial with 6-month treatment period and 6-month follow-up. PATIENTS: 28 Japanese
premenopausal women with endometriosis. INTERVENTIONS: Daily dose of 400
micrograms nafarelin was administered for 6 months. MEASUREMENT AND MAIN
RESULTS: The spine bone mineral density was measured by dual energy X-ray
absorptiometry, and blood and urinary bone metabolic parameters were analyzed.
The decrease of lumbar bone mineral density, which took place during treatment,
continued during the first 3 months after the cessation of treatment and did not
return to the initial baseline level even at 6 months after the withdrawal of
treatment. The biochemical parameters, which showed a state of enhanced bone
turnover during nafarelin treatment, almost returned to the pretreatment level 6
months after the termination of treatment. CONCLUSION: These results indicate
that relatively long period of bone metabolic change might be required to alter
the actual bone mineral density after GnRH analog administration.
Publication Types:
Clinical trial
PMID: 8604604, UI: 96189374
50: Br J Obstet Gynaecol 1992 Feb;99 Suppl 7:9-12
The role of GnRH analogues in the treatment of endometriosis.
Shaw RW
Academic Department of Obstetrics and Gynaecology, Royal Free Hospital, School
of Medicine, London, UK.
Publication Types:
Review
Review, tutorial
PMID: 1554688, UI: 92207891
51: Biol Psychiatry 1998 Mar 15;43(6):464-5
Sertraline in the treatment of depression associated with gonadotropin-releasing
hormone agonist therapy.
Warnock JK, Bundren JC, Morris DW
University of Oklahoma, Tulsa, USA.
BACKGROUND: Endometriosis is thought to affect 5-10% of reproductive age women
in the general population and is commonly treated with gonadotropin-releasing
hormone (GnRH) agonists. Recent studies suggest depressive symptoms are
associated with women treated with GnRH agonist for endometriosis. METHODS: A
retrospective pilot study of 42 female patients, 22 in the treatment group
(sertraline) and 20 in the control group (no sertraline), was conducted. All
subjects had laproscopically diagnosed endometriosis and were treated with 24
weeks of GnRH agonist therapy. Assessment instruments included the Hamilton
Depression Rating Scale and the Menopausal Symptom Index. RESULTS: The results
indicate that patients receiving concomitant sertraline reported significantly
less depressive symptoms, but did not differ significantly in physical symptoms
than the group receiving a GnRH agonist alone. CONCLUSIONS: Antidepressants,
such as sertraline, appear to be significantly helpful in the treatment of mood
symptoms during the course of GnRH agonist therapy.
Publication Types:
Clinical trial
PMID: 9532352, UI: 98193520
52: Obstet Gynecol Clin North Am 1997 Jun;24(2):361-73
Modern medical management of endometriosis.
Kettel LM, Hummel WP
Department of Reproductive Medicine, University of California, San Diego, USA.
The modern medical management of endometriosis has changed considerably since
the first attempts were made to control this disease hormonally over four
decades ago. Currently, there are multiple choices for the clinician and
patient, including oral contraceptives, danazol, GnRH agonist analogues, and
gestrinone. Several advances have been made in the use of GnRH agonists in
preventing some of the untoward effects of prolonged hypoestrogenism. These
add-back regimens provide the best therapy available today for prolonged medical
control of endometriotic symptoms. The antiprogesterones (RU-486) hold promise
for the future, but are still in the investigational stage of development.
Publication Types:
Review
Review, tutorial
PMID: 9163772, UI: 97306471
53: Obstet Gynecol 1998 May;91(5 Pt 1):793-4
Leuprolide acetate depot and hormonal add-back in endometriosis: a 12-month
study.
Marik JJ
Publication Types:
Comment
Letter
Comments:
Comment on: Obstet Gynecol 1998 Jan;91(1):16-24
PMID: 9572232, UI: 98231943
54: Minerva Ginecol 1997 Sep;49(9):417-9
[Use of a GnRH analogue (leuprorelin) in the therapy of endometriosis].
[Article in Italian]
Grio R, Geranio R, Porpiglia M, Leidi L, Piacentino R
Dipartimento di Discipline, Ginecologiche e Ostetriche, Universita degli Studi,
Torino.
BACKGROUND: Endometriosis is undoubtedly an extremely complex disease from both
a diagnostic and therapeutic point of view. The finding that the continuous
administration of GnRH analogs suppresses gonadotropin release by the
hupophysis, thus blocking ovary function, has promoted researchers to use these
drugs in the treatment of endometriosis. AIM: Having reviewed the data reported
in the literature, the authors selected from the numerous drugs used to resolve
implants (oestroprogestogens, danazol, progestogens, clomiphene citrata, GnRH
analogs), a GnRH analog with a depot action known as leuprorelin
(D-Leu6-Pro9-NH-Ethylamide). MATERIALS AND METHOD: This drug was administered to
98 patients suffering from endometriosis at a dose of one intramuscular phial
every 30 days for six months. RESULTS AND CONCLUSIONS: The results obtained
(complete resolution of disease in 610.2% of cases, partial remission in 30.6%
of cases, transient improvement in 9.2% of cases owing to reduced patient
compliance, percentage of pregnancies after treatment 12%), allow the authors to
conclude that the use of a GnRH antagonist, like leuprorelin, owing to its
efficacy and good tolerability, represents a valid alternative to
oestroprogestogens and Danazol in the treatment of implants and the symptoms of
endometriosis.
PMID: 9446077, UI: 98024770
55: Acta Eur Fertil 1989 Jan-Feb;20(1):5-10
The GnRH agonists in the treatment of uterine leiomyomas.
Bianchi S, Fedele L
Clinica Ostetrica-Ginecologica, Universita di Milano.
The observation that fibroids regress after the menopause has led many authors
to use GnRH agonists to obtain a reversible state of hypoestrogenism in patients
with this tumor. In all the studies performed GnRH agonists have been found
effective in inducing a marked regression of fibroids and resolution of the
related symptoms. The only serious side effect reported has been a decrease of
bone mineral density, which necessarily limits the duration of treatment.
Fibroids have been observed to grow back in almost all patients a few months
after suspension of treatment, and this limits the indications for the use of
GnRH agonist in the treatment of this condition. GnRH agonists are the treatment
of choice, however, in inoperable patients and in those with severe anemia,
whereas further studies are needed to better define their use in preoperative
treatment and in women in perimenopausal age.
Publication Types:
Review
Review, tutorial
PMID: 2675524, UI: 89389739
56: Acta Obstet Gynecol Scand Suppl 1997;164:94-7
Treatment of uterine fibroids with GnRH-analogues prior to hysterectomy.
Stjernquist M
Department of Obstetrics & Gynaecology, University Hospital, Malmo, Sweden.
GnRH-analogues have a longer half-life and stronger receptor affinity than
native GnRH. They block the secretion of gonadotropins from the anterior
pituitary, producing a hypoestrogenic state. Preoperative treatment with
GnRH-agonists for 3 months prior to hysterectomy reduces the size of uterine
fibroids by about 50%. The hematologic profile is improved and subjective
symptoms reduced. Other results are: a smaller peroperative blood loss, a
shorter hospitalization time, and a tendency to easier operations. Side effects
are predominantly hypoestrogenic. Treatment with GnRH-agonists before
hysterectomy is recommended in cases of large fibroids, when technical problems
may be anticipated, when preoperative anemia is present, or when it is desirable
to postpone surgery.
PMID: 9225649, UI: 97369161
57: Obstet Gynecol 1987 Mar;69(3 Pt 1):403-11
Treatment of endometriosis with a long-acting gonadotropin-releasing hormone
agonist.
Steingold KA, Cedars M, Lu JK, Randle D, Judd HL, Meldrum DR
Sixteen women with endometriosis were treated with daily subcutaneous injections
of a potent agonist of gonadotropin-releasing hormone (GnRH) for six months.
Ovarian estrogen secretion was reduced to castrate levels during most of the
course of treatment. Blinded evaluation of laparoscopic photographs confirmed
marked suppression of visually apparent disease, but biopsy specimens showed
occult, inactive endometriosis in most cases. Marked pain relief was noted by
all patients. As a result of this "medical oophorectomy," the women experienced
severe hot flashes, and many had insomnia and emotional disturbances. Vaginal
cytology showed menopausal changes but related symptoms were generally mild.
Calcium excretion rose to menopausal levels. High-density lipoprotein and total
cholesterol remained unchanged. These results indicate that GnRH agonist
administration has impressive effects on endometriotic implants, and these
actions may be enhanced with longer therapy. Further development of this new
form of therapy should involve either use of lesser degrees of ovarian
suppression or adjunctive therapy to counter the side effects of "medical
oophorectomy."
PMID: 2950349, UI: 87145433
58: J Reprod Med 1998 Mar;43(3 Suppl):316-20
Combined treatment of endometriosis. GnRH agonists and laparoscopic surgery.
Hemmings R
Department of Obstetrics and Gynecology, Royal Victoria Hospital, McGill
University, Montreal, Quebec, Canada.
Use of preoperative gonadotropin-releasing hormone (GnRH) agonists may be
beneficial in the case of laparoscopic surgery for large endometriomas. Further
studies are necessary to confirm the claim that preoperative GnRH agonists
facilitate laparoscopic surgery for endometriosis. Use of GnRH agonists after
laparoscopic treatment of endometriosis has beneficial effects in preventing the
recurrence of pelvic pain associated with endometriosis.
Publication Types:
Review
Review, tutorial
PMID: 9564667, UI: 98225855
59: Int J Gynaecol Obstet 1999 Feb;64 Suppl 1:S15-21
Today's treatments: how do you choose?
Barlow D
Nuffield Department of Obstetrics and Gynaecology, University of Oxford, UK.
OBJECTIVE: To provide a view on how the clinician can select appropriate
treatment when managing individual patients with endometriosis. METHODS: Review
of randomized controlled trials and personal experience. RESULTS: The main
determinants of therapy choice are personal experience and patient
acceptability. Placebo-controlled trial results support the use of naproxen,
dydrogesterone, danazol and leuprolide for pain relief. Laser laparoscopy is
more effective than expectant management for pain relief. In direct comparisons,
oral contraceptives, Zoladex, danazol, gestrinone, nafarelin and leuprolide have
similar efficacies in relieving pain, but have different side-effect profiles.
In controlled trials, only laser laparoscopy was shown to improve fertility in
minimal/mild disease. The physiological response of bone metabolism to GnRH
agonist therapy should be seen in context and the place of add-back regimens
understood. The general medical history of the patient must be considered when
choosing therapy. CONCLUSIONS: The clinician must provide the patient with
appropriate information on the treatment options to allow her to make an
informed choice.
Publication Types:
Review
Review, tutorial
PMID: 10096460, UI: 99194124
60: J Am Assoc Gynecol Laparosc 1996 Aug;3(4):495-501
The efficacy of drugs in the management of endometriosis.
Bulletti C, Flamigni C, Polli V, Giacomucci E, Albonetti A, Negrini V, Galassi
A, Morselli-Labate AM
Unit of Special Pelvic Surgery, Operative Laparoscopy and Hysteroscopy, First
Institute of Obstetrics and Gynecology, University of Bologna, Via Massarenti
13, 40138 Bologna, Italy.
STUDY OBJECTIVE: To establish the crude effects of danazol and
gonadotropin-releasing hormone (GnRH) analogs in the management of
endometriosis. DESIGN: Prospective case-control study. SETTING: Unit of the
Pathophysiology of Reproduction outpatient department. PATIENTS: Two groups of
110 women each with endometriosis (American Fertility Society score 1-3) who
received danazol and GnRH analogs, and a control group who did not receive any
drugs. INTERVENTIONS: Women in the treatment groups received danazol 200 mg
every 8 hours for 6 months, or a different GnRH agonist at standard dosages for
6 months. Laparoscopy was performed twice, at the time of diagnosis and just
before the end of treatment (or no therapy for controls). Surgical treatment of
the implants was performed at the second laparoscopy. MEASUREMENTS AND MAIN
RESULTS: Samples of both eutopic and ectopic endometrium were collected during
both laparoscopies. Both danazol and GnRH agonists were useful in reducing the
AFS scores to inactive endometriotic implants, and there were no significant
differences between the effects (p <0.001). Fibrosis was found after 6 months of
observation in the implants in one control woman (0.9%), in 20 patients (18.2%)
treated with danazol (p <0.001 vs controls), and in 4 patients (3.6%) treated
with GnRH agonists (NS vs controls). A correlation between a clinical diagnosis
of AFS score zero and histologic features of fibrosis in the ectopic specimens
after therapies was observed in 28% of women, with poor agreement (k = 0.07).
CONCLUSIONS: Fibrosis, which represent the absence of endometrial cells within
the specimens of endometriotic lesions or eutopic endometrium, did not appear in
eutopic endometria but it was found in some endometriotic implants. Danazol and
GnRH agonists reduced the clinical AFS scores of endometriosis, but their
histologic effects in completely and permanently eliminating endometriotic
implants were unacceptable.
PMID: 9050678, UI: 97238330
61: Fertil Steril 1994 Nov;62(5):932-7
Depot leuprolide acetate with estrogen and progestin add-back for long-term
treatment of premenstrual syndrome.
Mezrow G, Shoupe D, Spicer D, Lobo R, Leung B, Pike M
Department of Obstetrics and Gynecology, University of Southern California
School of Medicine, Los Angeles, California.
OBJECTIVE: To test the effectiveness and safety of long-term depot leuprolide
acetate (GnRH-a) plus estrogen and progestin add-back therapy in the treatment
of moderate and severe premenstrual syndrome (PMS). DESIGN: A prospective trial
with each patient serving as her own control. SETTING: University teaching
hospital. PARTICIPANTS: Ten women with regular menstrual cycles complaining of
moderate to severe PMS. Premenstrual syndrome was diagnosed when symptoms
increased > or = 25% during the luteal phase. TREATMENT: Four-week cycles of IM
injections of placebo or GnRH-a with all patients receiving saline (placebo),
the first cycle followed by 12 cycles of GnRH-a, 7.5 mg. Conjugated equine
estrogen (0.625 mg/d) was started Monday through Saturday within the first cycle
and increased as needed. Medroxyprogesterone acetate (MPA), 10 mg/d, was taken
orally for 10 days after 4, 8, and 12 cycles of GnRH-a therapy. MAIN OUTCOME
MEASURES: Changes in three symptom categories (water retention, pain, and
psychological function), serum levels of total cholesterol and HDL, HDL-2, and
LDL cholesterol, E2, and estrone. Endometrial biopsy was obtained 1 day after
the end of the 12th GnRH-a cycle, and bone density was assessed using
quantitative computer tomography at the end of the 12th GnRH-a cycle. RESULTS:
During treatment, there was a significant decrease compared with baseline and
placebo in all three symptom categories. There were no significant changes in
lipids. Endometrial biopsies revealed progestational changes with no evidence of
hyperplasia. Quantitative computer tomography bone density dropped 3.7 on
average compared with baseline after 12 months of treatment, but this was not
statistically significant. CONCLUSION: Gonadotropin-releasing hormone agonist
therapy with hormonal add-back therapy is effective in treating PMS symptoms
with progressive improvement over a 12-month period. This therapy prevents
changes in lipids and adequately protects the endometrium with the addition of
MPA every 4th cycle. Quantitative computer tomography bone density dropped at 12
months; further examination of bone changes is necessary.
Publication Types:
Clinical trial
Controlled clinical trial
PMID: 7926137, UI: 95010890
62: Fertil Steril 1998 Jul;70(1):111-8
A clinical trial of the effects of tibolone administered with
gonadotropin-releasing hormone analogues for the treatment of uterine
leiomyomata.
Palomba S, Affinito P, Tommaselli GA, Nappi C
Department of Gynecology and Obstetrics, University of Naples Federico II,
Italy.
OBJECTIVE: To evaluate the effects of tibolone therapy in association with
GnRH-a on uterine leiomyomata, on climacteric-like symptoms, on bone metabolism,
and on the lipid profile. DESIGN: A prospective, randomized, double-blind,
placebo-controlled, clinical trial. SETTING: Department of Gynecology and
Obstetrics, University of Naples "Federico II," Naples, Italy. PATIENT(S): Fifty
women with symptomatic uterine leiomyomata. INTERVENTION(S): Six months of
treatment with leuprolide acetate (3.75 mg every 28 days IM) combined with daily
placebo tablets (group A) or with 2.5-mg of tibolone per os (group B). MAIN
OUTCOME MEASURE(S): Uterine and uterine leiomyomata sizes, lumbar spine bone
mineral density, biochemical markers of bone metabolism, lipid profile, and
myoma-related symptoms were measured at baseline and after 6 months of
treatment. Daily symptom diary in which hot flushes and vaginal bleeding
episodes were recorded. RESULT(S): No differences between the 2 groups in
uterine and uterine leiomyomata size and myoma-related symptoms were detected.
After 6 months of treatment, there were statistically significant changes from
baseline in bone mineral density and in biochemical markers of bone metabolism
in group A but not in group B. Vasomotor symptoms were significantly lower in
group B than in group A. There was a statistically significant increase (P<.01)
in serum total cholesterol, high-density lipoprotein cholesterol, and
triglycerides in group A after 6 months of treatment in comparison with baseline
values. The difference in serum total cholesterol and triglyceride levels after
6 months of treatment in group B was not statistically significant in comparison
with baseline values, but was statistically significant in comparison with group
A values (P<.01). In group B, levels of high-density lipoprotein cholesterol
were significantly lower after 6 months of therapy in comparison with baseline
values and in comparison with group A values (P<.01). There were no
statistically significant changes at baseline and after 6 months of treatment in
the level of low-density lipoprotein cholesterol in either group. CONCLUSION(S):
Administration of tibolone in association with GnRH-a reduces vasomotor symptoms
and prevents bone loss, without compromising the therapeutic efficacy of GnRH-a
alone.
Publication Types:
Clinical trial
Randomized controlled trial
PMID: 9660431, UI: 98321868
63: Fertil Steril 1998 May;69(5):821-5
Women of reproductive age with endometriosis are not osteopenic.
Ulrich U, Murano R, Skinner MA, Yin H, Chesnut CH 3rd
University of Washington, Seattle, USA.
OBJECTIVE: To determine whether women of reproductive age with endometriosis are
osteopenic and whether bone density decreases with higher stages of
endometriosis. DESIGN: A multicenter cross-sectional study was performed.
SETTING: Thirty-nine gynecological clinics in the United States, Canada, and
Puerto Rico. PATIENT(S): Two hundred forty-one women of reproductive age with
laparoscopically proved endometriosis. INTERVENTION(S): Diagnostic laparoscopy,
bone densitometry. MAIN OUTCOME MEASURE(S): Endometriosis stages according to
the criteria of the American Society for Reproductive Medicine, lumbar spine
bone mineral density (L2-L4) as measured by dual-energy x-ray absorptiometry.
RESULT(S): The mean lumbar spine bone mineral density, as well as the
distribution of bone mineral density, of the women with endometriosis was
similar to that of a normal population. There were no significant differences
between endometriosis stage groups I-IV regarding bone mineral density as well
as body weight, body mass index, and height. CONCLUSION(S): Women of
reproductive age with endometriosis are not osteopenic. More advanced stages of
endometriosis are not associated with a decrease in lumbar spine bone mineral
density.
Publication Types:
Multicenter study
PMID: 9591486, UI: 98252160
64: Fertil Steril 1991 Feb;55(2):411-5
Time-related effects of gonadotropin-releasing hormone analog treatment in
experimentally induced endometriosis in the rat.
Zanagnolo VL, Beck R, Schlaff WD, Damewood MD, Bobbie D, Rock JA
Department of Gynecology and Obstetrics, Johns Hopkins Medical Institutions,
Baltimore, Maryland.
The purpose of our study was to characterize the time-dependent effect of
gonadotropin-releasing hormone analog (GnRH-a) therapy on endometriosis explant
using the rat model. Endometriosis was induced in 60 mature female rats. One
group of treated animals as well as controls were killed at 2, 4, 6 and 8 weeks
of treatment at which time the explant was evaluated. Explant volume was
significantly reduced in all treatment groups, an effect that was more
significant in animals treated for greater than or equal to 4 weeks compared
with those treated for only 2 weeks. We conclude that GnRH-a treatment caused
gradual regression of endometrial explant that was effectively complete by 4
weeks of treatment. We further conclude that this experimental model may be
useful in the evaluation of other modes of endometriosis therapy.
PMID: 1991539, UI: 91122356
65: Am J Obstet Gynecol 1992 Feb;166(2):740-5
Hormone treatment of endometriosis: the estrogen threshold hypothesis.
Barbieri RL
Department of Obstetrics and Gynecology, State University of New York, Stony
Brook 11794-8091.
In women with recurrent pelvic pain caused by endometriosis, hormonal therapy
with a gonadotropin-releasing hormone agonist is an effective alternative to
surgical therapy. The basis for medical treatment of endometriosis is that
endometriosis lesions are dependent on estradiol for continued growth. Further,
end organ tissue varies in its sensitivity to estradiol. This forms the basis of
the estrogen threshold hypothesis, that is, that a concentration of estradiol
that will partially prevent bone loss may not stimulate endometrial growth. Thus
there is a hierarchy of organ response to estradiol such that calcium metabolism
is most sensitive followed by gonadotropin secretion, vaginal epithelial growth,
lipid metabolism, and liver protein production. Similarly, breast cancer is most
sensitive and endometriosis is least sensitive to estrogen. These differences
may allow the design of regimens with a gonadotropin-releasing hormone agonist
that maintain a therapeutic response and ameliorate potential adverse effects.
Publication Types:
Review
Review, tutorial
PMID: 1536260, UI: 92160931
66: Fertil Steril 1992 Dec;58(6):1104-7
Pituitary function before, during, and after chronic gonadotropin-releasing
hormone agonist therapy.
Cedars MI, Steingold KA, Lu JH, Judd HJ, Meldrum DR
Department of Obstetrics and Gynecology, University of California-Los Angeles.
OBJECTIVE: To examine possible adverse effects on pituitary function of
long-term administration of gonadotropin-releasing hormone agonist (GnRH-a).
DESIGN: Prospective analysis of blood sampling before, during, and after GnRH-a
therapy. SETTING: Tertiary institutional outpatient care. PATIENTS: Twelve
normally ovulatory women with a diagnosis of endometriosis. INTERVENTIONS:
Six-month suppression with GnRH-a. MAIN OUTCOME MEASURES: Serum levels of
follicle-stimulating hormone, luteinizing hormone, free thyroxin index, cortisol
(F), growth hormone (GH), prolactin (PRL), and thyroid-stimulating hormone
(TSH). RESULTS: Basal and stimulated values of gonadotropins, PRL, F, TSH, and
GH were normal and unchanged by 6 months of GnRH-a after resumption of menses.
CONCLUSIONS: Utilizing dynamic pituitary function tests, we were unable to
demonstrate an adverse effect of long-term GnRH-a therapy on pituitary function.
PMID: 1459255, UI: 93093177
67: Fertil Steril 1997 Nov;68(5):860-4
Use of nafarelin versus placebo after reductive laparoscopic surgery for
endometriosis.
Hornstein MD, Hemmings R, Yuzpe AA, Heinrichs WL
Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston,
Massachusetts 02115, USA.
OBJECTIVE: To evaluate the efficacy of the GnRH agonist (GnRH-a) nafarelin
compared with placebo administered for 6 months after reductive laparoscopic
surgery for symptomatic endometriosis. DESIGN: Randomized, prospective,
placebo-controlled, multicenter clinical trial. SETTING: Thirteen clinics
including private practice and university centers. PATIENT(S): One hundred nine
women aged 18-47 with laparoscopically proven endometriosis and pelvic pain who
had undergone reductive laparoscopic surgery for endometriosis. INTERVENTION(S):
Patients were randomized to receive either the GnRH-a nafarelin (200 micrograms
twice daily) or placebo for 6 months. MAIN OUTCOME MEASURE(S): Time to
initiation of alternative treatment (the length of time from beginning study
medication to receiving alternative therapy or to deeming that the study drug
was ineffective) and patient-reported and physician-assessed pelvic pain scores.
RESULT(S): The median time to initiation of alternative treatment was > 24
months in the nafarelin group versus 11.7 months in the placebo group. Fifteen
(31%) of 49 nafarelin-treated patients required alternative therapy, compared
with 25 (57%) of 44 placebo-treated patients. The patients' pelvic pain scores
dropped significantly in the nafarelin and placebo groups after 6 months of
treatment. Physician summary ratings showed significant improvement in the
nafarelin group and no significant changes in the placebo group after 6 months
of treatment. CONCLUSION(S): Compared with placebo, nafarelin administered after
reductive laparoscopic surgery for endometriosis significantly delays the return
of endometriosis symptoms requiring further treatment.
Publication Types:
Clinical trial
Multicenter study
Randomized controlled trial
PMID: 9389816, UI: 98051255
68: J Endocrinol 2000 May;165(2):467-73
Comparison of the effects of add-back therapy with various natural oestrogens on
bone metabolism in rats administered a long-acting gonadotrophin-releasing
hormone agonist.
Wang Y, Yano T, Kikuchi A, Yano N, Matsumi H, Ando K, Kasai Y, Watanabe M,
Okagaki R, Osuga Y, Taketani Y
Department of Obstetrics and Gynecology, Faculty of Medicine, University of
Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
The hypoestrogenic state induced by gonadotrophin-releasing hormone agonist
(GnRHa) has been shown to be effective in the treatment of oestrogen-dependent
disorders but to induce bone loss. Adding back low doses of oestrogen in GnRHa
therapy has been proposed to prevent bone loss. The purpose of this study is to
assess the efficacy of add-back therapy with different natural oestrogens such
as oestrone (OE(1)), oestradiol (OE(2)) and oestriol (OE(3)). Three-month-old
female rats (250 g) were subcutaneously administered microcapsules of
leuprorelin acetate in doses of 1 mg/kg of body weight every 4 weeks. GnRHa
therapy lasted 16 weeks, and pellets of OE(1), OE(2) or OE(3) (0.5 mg/pellet, 60
day release), as an add-back agent, were implanted at 8 weeks of treatment. At
the end of treatment, GnRHa alone decreased bone mineral density of the femur
and lumbar vertebrae, and increased serum levels of bone metabolic markers such
as alkaline phosphatase and osteocalcin levels. As for cancellous bone
histomorphometry, GnRHa decreased bone volume while it increased osteoid volume,
osteoid surface, eroded surface, mineral apposition rate and bone formation
rate. All the oestrogens tested prevented these changes caused by GnRHa therapy.
GnRHa induced a significant increase in body weight and a marked reduction in
uterine weight, which was not observed in OE(1) or OE(2) add-back group. Body
weight and uterine weight of the OE(3) add-back group were the same as those of
the GnRHa group. These findings indicate that GnRHa induces high turnover bone
loss which can be prevented by concomitant administration of natural oestrogens
such as OE(1), OE(2) and OE(3) to the same extent. In addition, OE(3) is unique
in that it is much less effective than OE(1) and OE(2) in blocking body weight
gain and in promoting growth of uterine tissues. Because of its tissue-selective
actions, OE(3) could be considered as one of the most appropriate oestrogens
used for GnRHa add-back therapy.
PMID: 10810310, UI: 20271919
69: Int J Gynaecol Obstet 1995 Sep;50 Suppl 1:S11-5
The impact of bone loss in women with endometriosis.
Stevenson JC
Wynn Department of Metabolic Medicine, National Heart and Lung Institute,
London, UK.
Low peak adult bone mass in a premenopausal woman puts her at increased risk for
osteoporosis postmenopausally. Episodes of hypo-estrogenism premenopausally are
associated with loss of bone density. This is seen with gonadotropin-releasing
hormone agonist therapy for endometriosis, and thus prolonged or repeated
courses of such treatment may increase the future risk of osteoporosis. Danazol
and related compounds do not result in any bone loss but may have certain
metabolic disadvantages.
Publication Types:
Review
Review, tutorial
PMID: 8529769, UI: 96100160
70: Postgrad Med 1994 May 1;95(6):111-8
Gonadotropin-releasing hormone agonists. Current uses for these increasingly
important drugs.
Winkel CA
Jefferson Medical College, Department of Obstetrics/Gynecology, Philadelphia, PA
19107.
Use of gonadotropin-releasing hormone (GnRH) agonists produces a transient
increase and subsequent long-term reduction in concentrations of pituitary
hormones, resulting in gonadal hormone suppression. This reversible suppression
is useful in treating diseases dependent on these hormones. GnRH agonists have
been approved for use in patients with endometriosis, advanced prostate cancer,
and precocious puberty. As research continues, GnRH agonists are expected to
change the clinical approach to the treatment of many other reproductive and
nonreproductive diseases.
Publication Types:
Review
Review, tutorial
PMID: 8170869, UI: 94224695
71: Fertil Steril 2000 Sep;74(3):540-6
Intermittent leuprolide acetate for the nonsurgical management of women with
leiomyomata uteri.
Scialli AR, Levi AJ
Georgetown University Medical Center, Washington, D.C. 20007-2197, USA.
sciallia@gunet.georgetown.edu
OBJECTIVE: To evaluate the feasibility of intermittent 6-month courses of
leuprolide acetate for the long-term control of symptoms attributed to
leiomyomata uteri. DESIGN: Prospective open-label feasibility study. SETTING:
University department of obstetrics and gynecology. PATIENT(S): Thirty women
with abnormal bleeding or discomfort (pain or pressure) due to leiomyomata
uteri. INTERVENTION(S): Patients received an initial 6-month course of the GnRH
agonist leuprolide acetate, after which they were observed for symptom
recurrence. Symptom recurrence was managed by repeated 6-month courses of
leuprolide acetate. MAIN OUTCOME MEASURE(S): Relief of symptoms, responses on a
quality-of-life questionnaire, serum lipid levels, blood count, and ferritin
level. The number of doses of leuprolide acetate required to maintain symptom
control was recorded. Serial bone mineral density measurements were made in
selected patients. RESULT(S): Twenty of the 30 women who began therapy with
leuprolide acetate continued in the protocol. Each individual 6-month course of
leuprolide acetate therapy was followed by a median of 9 additional months of
symptom control (range, 2 to >25 months). Women remaining in the protocol
experienced a mean decrease of 2.4% in bone mineral density of the lumbar spine;
bone mineral density of the hip did not change. CONCLUSION(S): Intermittent
courses of leuprolide acetate can be used in the nonsurgical management of women
with symptomatic leiomyomata uteri. Use of antiresorptive add-back therapy and
monitoring of bone mineral density can be considered when repeated courses of
leuprolide acetate are given.
Publication Types:
Clinical trial
PMID: 10973652, UI: 20428530
72: Cochrane Database Syst Rev 2000;(2):CD000346
Gonadotrophin-releasing hormone analogues for pain associated with
endometriosis.
Prentice A, Deary AJ, Goldbeck-Wood S, Farquhar C, Smith SK
Department of Obstetrics and Gynaecology, University of Cambridge, The Rosie
Hospital, Robinson Way, Cambridge, UK, CB2 2SW. ap128@mole.bio.cam.ac.uk
BACKGROUND: Endometriosis is a common gynaecological condition that frequently
presents with the symptom of pain. The precise pathogenesis (mode of
development) of endometriosis is unclear but it is evident that endometriosis
arises by the dissemination of endometrium to ectopic sites and the subsequent
establishment of deposits of ectopic endometrium. The observation that
endometriosis is rarely seen in the hypo-oestrogenic (low levels of oestrogen)
post-menopausal woman led to the concept of medical treatment by induction of a
pseudo-menopause using Gonadotrophin Releasing Hormone Analogues (GnRHas). When
administered in a non-pulsatile manner (the pituitary is normally stimulated by
pulses of natural GnRH and all analogues act on the pituitary at a constant
level) their use results in down regulation (switching off) of the pituitary and
a hypogonadotrophic hypogonadal state (low levels of female hormones due to non
stimulation of the ovary). OBJECTIVES: To determine the effectiveness of
Gonadotrophin Releasing Hormone analogues (GnRHas) in the treatment of the
painful symptoms of endometriosis by comparing them with no treatment, placebo,
other recognised medical treatments, and surgical interventions. SEARCH
STRATEGY: The search strategy of the Menstrual Disorders and Subfertility review
group (please see Review Group details) was used to identify all randomised
trials of the use of GnRHas for the treatment of the painful symptoms of
endometriosis. SELECTION CRITERIA: Trials were included if they were randomised,
and considered the effectiveness of GnRHas in the treatment of the painful
symptoms of endometriosis. DATA COLLECTION AND ANALYSIS: Twenty-six studies had
data appropriate for inclusion in the review. The largest group (15 studies)
compared GnRHas with danazol. There are 5 studies comparing GnRHas with GnRHas
plus add-back therapy, 3 comparing GnRHa with GnRHa in a different form or dose,
one compares them with gestrinone, one with the combined oral contraceptive
pill, and one with placebo. Data was extracted independently by two reviewers.
The authors of 11 studies have been contacted to clarify missing or unclear
data. Only 4 have replied to date. Data on relief of pain, change in revised
American Fertility Society (rAFS) scores, and side effects was collected. MAIN
RESULTS: No difference was found between GnRHas and any of the other active
comparators with respect to pain relief or reduction in endometriotic deposits.
The side effect profiles of the different treatments were different, with
danazol and gestrinone having more androgenic side effects, while GnRHas tend to
produce more hypo-oestrogenic symptoms. REVIEWER'S CONCLUSIONS: There is little
or no difference in the effectiveness of GnRHas in comparison with other medical
treatments for endometriosis. GnRHas do appear to be an effective treatment.
Differences that do exist relate to side effect profiles. Side effects of GnRHas
can be ameliorated by the addition of addback therapy.
Publication Types:
Review
Review, academic
PMID: 10796530, UI: 20257620
73: Minerva Ginecol 1997 Dec;49(12):567-70
[Treatment of endometriosis with GnRH analogues].
[Article in Italian]
Zarcone R, Vullo G, Monarca M, Longo M, Tommasillo G, Lizza R, Tartaglia E
Istituto di Ginecologia ed Ostetricia, Facolta di Medicina e Chirurgia, II
Universita degli Studi, Napoli.
BACKGROUND: Since a continuous administration of adequate doses of luteinizing
hormone-releasing hormones (LHRH) or of an agonist leads to a hypogonadism-like
condition, it is possible to use this effect for the treatment of endometriosis.
The present study reports the results obtained in the Gynaecology and Obstetrics
Institute of the Second University of Naples, with a long-acting formulation of
a GnRH analogues (D-Trp6-LHRH) in biodegradable microcapsules, at monthly
intervals. MATERIALS AND METHODS: The study was carried out on 40 women with
endometriosis diagnosed by laparoscopy or laparotomy. The duration of treatment
in patients in stage I-II was of 6 months, in patients in stage III or IV was of
9 months. RESULTS: After 12 months from the end of therapy, 27 patients did not
show any sign of endometriosis with ultrasound and clinical examination; 13
patients still showing endometriosis were from III or IV stage. CONCLUSIONS:
This long-acting formulation should offer a better approach for chronic
treatment.
PMID: 9557486, UI: 98218245
74: Hum Reprod 1999 Oct;14(10):2661-4
Non-functioning pituitary tumour after long-term treatment with
gonadotrophin-releasing hormone agonists in a patient with vaginal agenesis who
underwent neovaginoplasty and cauterization of endometriosis under laparoscopy.
Takai Y, Tsutsumi O, Momoeda M, Osuga Y, Sadatsuki M, Kaibara M, Taketani Y
Department of Obstetrics and Gynecology, Faculty of Medicine, University of
Tokyo, Tokyo, Japan.
Vaginal agenesis combined with a functional uterus is a rare condition in which
treatment modalities that preserve reproductive function are controversial. A 21
year old female presented with congenital vaginal agenesis combined with
cervical atresia. She was treated with gonadotrophin-releasing hormone (GnRH)
agonists for a total period of over 5 years when a non-functioning pituitary
tumour was detected by brain magnetic resonance imaging (MRI). A
laparoscopically assisted reconstruction of a neovagina and neoendocervical
canal was performed utilizing lyophilized porcine dermal skin to line the
neovagina. Endometriosis of the pelvis was revealed and adhesiolysis and
cauterization were also carried out under laparoscopy. The GnRH agonist was
discontinued and the patient resumed cyclic menses with no abdominal pain. The
pituitary tumour decreased in size 6 months after the cessation of GnRH
agonists. We raise the question as to whether pituitary MRI should be performed
for patients who need long-term administration of GnRH agonists.
PMID: 10528004, UI: 99459367
75: J Clin Endocrinol Metab 2000 Mar;85(3):1215-9
Close correlation between estrogen treatment and renal phosphate reabsorption
capacity.
Uemura H, Irahara M, Yoneda N, Yasui T, Genjida K, Miyamoto KI, Aono T, Takeda E
Department of Obstetrics and Gynecology, The University of Tokushima, School of
Medicine, Japan. uemura@clin.med.tokushima-u.ac.jp
To determine the influence of estrogen on the activity of renal proximal tubular
reabsorption of inorganic phosphate (Pi) in women, we examined the changes of
the renal threshold phosphate concentration (also denoted as TmP/GFR), as well
as the changes in the concentrations of mineral components in the circulation in
two groups of women--one receiving hormone replacement therapy (HRT) and one
receiving gonadotropin-releasing hormone agonists (GnRH-a) therapy. We also
examined the changes in the concentrations of serum PTH in the GnRH-a group. The
patients in the HRT group were continuously treated with 0.625 mg conjugated
equine estrogens plus 2.5 mg medroxyprogesterone acetate per day. The patients
in the GnRH-a group were treated with a monthly injection of 3.75 mg leuprolide
acetate depot for 6 months. The values of TmP/GFR decreased in all of the
patients who received HRT. The mean percentage change in TmP/GFR was -14.5%
(range, -24.3% to -9.6%). In contrast, in all of the patients treated with
GnRH-a, the values of TmP/GFR increased after 6 months of treatment (the mean
percentage change was 28.5%; range, 18.2-78.3%) and returned to the
preadministration level at 12 weeks after stopping therapy. In these patients,
both the values of TmP/GFR and the concentrations of serum Pi correlated
significantly with circulating estradiol levels (r = -0.767, P < 0.01 and r =
-0.797, P < 0.01, respectively), but the concentrations of serum corrected
calcium did not correlate. Moreover, in the same patients, the levels of serum
intact PTH decreased significantly (P < 0.05) after 6 months of treatment, but
at 12 weeks after stopping therapy the trends of these levels varied among
individual patients. These results suggest that estrogen could act directly to
suppress sodium-dependent Pi reabsorption in the renal proximal tubules.
Publication Types:
Clinical trial
PMID: 10720065, UI: 20182984
76: Akush Ginekol (Sofiia) 1998;37(4):25-6
[The use of Ovestin to overcome the side effects of treatment with GnRH
agonists].
[Article in Bulgarian]
Ivanov S, Ivanov S
The LHRH analogues are used very much in gynecological practice, mostly for a
long treatment periods. The menopausal side effects occur often and causes the
patients to withdraw from treatment. The GnRh analogues are used for the
treatment of endometriosis, uterine fibroids, for breast cancer, and pre and
post operatively as hormonal therapy for endometrial cancer. 12 patients were
given combined vaginal Ovestin and GnRh analogues (Zoladex). Another 12 patients
were taking GnRh analogues alone without Ovestin creme, and this group searched
as a control group. The group with the Ovestin had less side effects than the
control group. This difference was statistically significant about the
cervicovaginal symptoms (p less than 0.01). The treatment with vaginal
estrogenes can better and improve the tolerance to therapy with GnRh analogues.
Publication Types:
Clinical trial
PMID: 10360048, UI: 99288265
77: JAMA 1998 Sep 23-30;280(12):1067-73
Prevention of estrogen deficiency-related bone loss with human parathyroid
hormone-(1-34): a randomized controlled trial.
Finkelstein JS, Klibanski A, Arnold AL, Toth TL, Hornstein MD, Neer RM
Endocrine Unit, Massachusetts General Hospital, Boston, Mass 02114, USA.
finkelstein@helix.mgh.harvard.edu
CONTEXT: Short-term intermittent administration of parathyroid hormone (PTH)
prevents bone loss from the spine in women treated with a gonadotropin-releasing
hormone (GnRH) analog. However, the effects of a longer period of PTH
administration on bone mass in estrogen-deficient women, particularly on the hip
and on cortical bone of the total body, are unknown. OBJECTIVE: To determine
whether more prolonged PTH administration can prevent estrogen deficiency bone
loss from the hip, spine, and total body in young women with endometriosis
receiving GnRH analog (nafarelin acetate) therapy. DESIGN: Randomized controlled
trial. SETTING: General Clinical Research Center of a tertiary care,
university-affiliated hospital. PATIENTS: Forty-three women between the ages of
21 and 45 years with symptomatic endometriosis. INTERVENTION: Nafarelin alone
(200 microg intranasally twice daily) or nafarelin plus human parathyroid
hormone-(1-34) (hPTH-[1-34]) (40 microg subcutaneously daily). MAIN OUTCOME
MEASURES: The primary end points were bone mineral density (BMD) of the
anterior-posterior and lateral spine, femoral neck, trochanter, radial shaft,
and total body at 12 months of treatment. RESULTS: In the women who received
nafarelin alone, the mean (SEM) BMDs of the anterior-posterior spine, lateral
spine, femoral neck, trochanter, and total body were 4.9% (0.6%) (P<.001), 4.9%
(0.8%) (P<.001), 4.7% (1.1%) (P<.001), 4.3% (0.9%) (P<.001), and 2.0% (0.6%) (P=
.003) lower than at baseline after 12 months of therapy. In contrast,
coadministration of hPTH-(1-34) increased BMD of the anterior-posterior spine by
2.1% (1.1%) (P=.09) and lateral spine by 7.5% (1.9%) (P=.002) and prevented bone
loss from the femoral neck, trochanter, and total body, despite severe estrogen
deficiency. Radial shaft BMD did not change significantly in either group. Serum
bone-specific alkaline phosphatase and osteocalcin concentrations and urinary
excretion of hydroxyproline and deoxypyridinoline increased 2-fold to 3-fold
during the first 6 to 9 months of therapy in the women who received nafarelin
plus hPTH-(1-34) and then declined. Changes in urinary deoxypyridinolone
excretion were strongly predictive (r= 0.85) of changes in spinal BMD in the
women who received nafarelin plus hPTH-(1-34). CONCLUSIONS: Parathyroid hormone
prevents bone loss from the proximal femur and total body and increases lumbar
spinal BMD in young women with GnRH analog-induced estrogen deficiency.
Publication Types:
Clinical trial
Randomized controlled trial
PMID: 9757854, UI: 98428821
78: Fertil Steril 1998 Aug;70(2):371-3
Basal hormone levels in women who use acetaminophen for menstrual pain.
Cramer DW, Liberman RF, Hornstein MD, McShane P, Powers D, Li EY, Barbieri R
Obstetrics-Gynecology Epidemiology Center, Brigham and Women's Hospital, Boston,
Massachusetts 02115, USA.
OBJECTIVE: To compare basal gonadotropin and estradiol levels between women
using acetaminophen versus those using no or other types of analgesics. DESIGN:
Observational study. SETTING: Three IVF clinics in greater Boston. PATIENT(S):
Three hundred eighty-six women accepted for their first IVF treatment who
completed questionnaires recording medical history, including analgesic use for
menstrual pain, and who had blood drawn during the menstrual phase of a cycle
before treatment. MAIN OUTCOME MEASURE(S): Basal FSH, LH, and estradiol.
RESULT(S): Basal hormone levels, especially LH, were lower for women who
regularly used acetaminophen compared with women who used no medication or other
types of analgesics. Lower hormone levels in acetaminophen users were
consistently observed when women were subdivided by age, body mass index,
smoking history, and degree of menstrual pain-features that might have
influenced analgesic use or hormone levels. CONCLUSION(S): This study provides
preliminary evidence that acetaminophen may lower gonadotropin and estradiol
levels and offers a biologic basis for the epidemiologic observation that
acetaminophen use may reduce the risk of ovarian cancer.
Publication Types:
Clinical trial
Controlled clinical trial
PMID: 9696240, UI: 98359429
79: J Assist Reprod Genet 1998 Apr;15(4):193-7
Effects of endometriomas on ooccyte quality, embryo quality, and pregnancy rates
in in vitro fertilization cycles: a prospective, case-controlled study.
Yanushpolsky EH, Best CL, Jackson KV, Clarke RN, Barbieri RL, Hornstein MD
Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard
Medical School, Boston, Massachusetts 02115, USA.
PURPOSE: The effect of endometriomas on oocyte quality, embryo quality, and
pregnancy rates in in vitro fertilization (IVF) cycles was evaluated. METHODS:
Forty-five women had "chocolate" cysts aspirated at the time of oocyte
retrieval, and cyst fluid CA 125 levels were measured to ascertain presence of
"true" endometriomas. Fifty-seven women without any complex cysts at the time of
oocyte retrieval served as controls. IVF cycle outcome parameters were compared
between the two groups. RESULTS: Women with endometriomas experienced a
significantly higher rate of early pregnancy loss compared to controls (47 vs
14%). There was also a trend toward fewer oocytes retrieved and fewer embryos
reaching at least the four-cell stage 48 hr after retrieval in patients with
true endometriomas vs controls. CONCLUSIONS: The presence of endometriomas at
the time of oocyte retrieval is associated with increased rates of early
pregnancy losses. The number of oocytes retrieved and the embryo quality may
also be affected adversely in the presence of endometriomas.
PMID: 9565848, UI: 98226970
80: Obstet Gynecol 1999 Jan;93(1):51-8
Randomized controlled trial of depot leuprolide in patients with chronic pelvic
pain and clinically suspected endometriosis. Pelvic Pain Study Group.
Ling FW
Department of Obstetrics and Gynecology, University of Tennessee-Memphis, 38103,
USA. fling@utmem1.utmem.edu
OBJECTIVE: To evaluate and compare the safety and efficacy of leuprolide versus
placebo in managing chronic pelvic pain in women with clinically suspected
endometriosis. METHODS: Women 18-45 years of age with moderate to severe pelvic
pain of at least 6 months' duration underwent extensive, noninvasive diagnostic
testing and laboratory evaluation, including pelvic ultrasound, complete blood
count, determination of erythrocyte sedimentation rate, and endocervical
cultures. Those with clinically suspected endometriosis were randomized to
double-blind treatment for 3 months with depot leuprolide (3.75 mg/mo) or
placebo. The accuracy of the clinical diagnosis of endometriosis was evaluated
by posttreatment laparoscopy. RESULTS: Of 100 women randomized, 95 completed the
study: 49 in the leuprolide group and 46 in the placebo group. Women in the
leuprolide group had clinically and statistically significant (P < or = .001)
mean improvements from baseline after 12 weeks of therapy in all pain measures.
These mean improvements were significantly greater (P < or = .001) than those in
the placebo group. At 12 weeks, mean decreases in physician-rated scores for
dysmenorrhea, pelvic pain, and pelvic tenderness were 1.7, 1.0, and 0.8 points
greater, respectively, in the leuprolide group than in the placebo group (on a
four-point scale). Thirty-eight (78%) of 49 and 40 (87%) of 46 patients in the
leuprolide and placebo groups, respectively, had laparoscopically confirmed
endometriosis after 12 weeks of treatment. No women withdrew from the study
because of adverse events. CONCLUSION: Depot leuprolide was effective and safe
for treating patients with chronic pelvic pain and clinically suspected
endometriosis, confirming the potential of its empiric use in these patients.
Publication Types:
Clinical trial
Randomized controlled trial
PMID: 9916956, UI: 99113994
81: Int J Fertil Womens Med 1997 Nov-Dec;42(6):406-11
Gonadotropin-releasing hormone analogue plus hormone replacement therapy for the
treatment of endometriosis: a randomized controlled trial.
Gregoriou O, Konidaris S, Vitoratos N, Papadias C, Papoulias I, Chryssicopoulos
A
2nd Department of Obstetrics and Gynecology, University of Athens, Areteion
Hospital, Greece.
OBJECTIVE: The aim of this study was to determine whether or not continuous
combined HRT used with GnRH-a for the treatment of endometriosis can prevent
hypoestrogenic side effects associated with GnRH-a. METHODS: Forty premenopausal
women with laparoscopically proven endometriosis entered the study. The patients
were randomized into two groups. Group I (n = 19) received 3.75 mg i.m.
leuprolide acetate (LA) every 4 weeks for 24 weeks. Group II (n = 21) received
3.7 mg LA combined with 1.25 mg oral conjugated equine estrogen (CEE) and 5 mg
oral medroxyprogesterone acetate (MA). RESULTS: Total revised AFS score as well
as total pelvic pain scores decreased significantly (P < .001) in both groups.
However, a statistically significant difference of hot flushes and sweating was
reported by women receiving LA + HRT as compared to those treated with LA alone
(P < .001). Furthermore, the bone loss at the lumbar spine was 4.2% in group I
compared to 0.9% in group II at the end of the study. CONCLUSIONS: This study
suggests that 1.25 mg CEE + 5 mg MA is effective in preventing hypoestrogenic
side effects caused by GnRH-a, while the treatment of endometriosis is not
impaired.
Publication Types:
Clinical trial
Randomized controlled trial
PMID: 9459084, UI: 98120705
82: Hum Reprod 1994 Sep;9(9):1618-25
Long-term medical therapy for leiomyomata uteri: a prospective, randomized study
of leuprolide acetate depot plus either oestrogen-progestin or progestin
'add-back' for 2 years.
Friedman AJ, Daly M, Juneau-Norcross M, Gleason R, Rein MS, LeBoff M
Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard
Medical School, Boston, MA 02115.
Treatment of women with leiomyomata with gonadotrophin-releasing hormone
agonists (GnRHa) for > 6 months is not recommended because of concerns regarding
adverse sequelae of prolonged hypoestrogenism. It has been postulated that
addition of low-dose sex steroids to GnRHa treatment, i.e. 'add-back' therapy,
may avert some of these adverse effects (accelerated bone resorption, vasomotor
flushes) without altering the efficacy of GnRHa therapy. To evaluate the effects
of long-term GnRHa therapy on uterine size, bleeding patterns, bone mass and
lipids, 51 pre-menopausal women with leiomyomata were treated with the GnRHa
leuprolide acetate depot, 3.75 mg every 4 weeks for 2 years. After 3 months of
leuprolide therapy, the women were randomized to receive either low-dose
continuous oestropipate, 0.75 mg daily, plus cyclic norethindrone, 0.7 mg on
days 1-14 each month (the oestrogen-progestin add-back group) or higher-dose
norethindrone, 10 mg daily (the progestin add-back group), for the remaining 21
months. Mean uterine volume decreased by 40% in both treatment groups during the
first 3 months on leuprolide treatment. There was no significant change in
uterine size following oestrogen-progestin add-back. However, mean uterine
volume in the progestin add-back group increased to 87% of pre-treatment size by
treatment month 12 and 95% of pre-treatment size by treatment month 24. Mean
bone density of the lumbar spine as measured by dual X-ray absorptiometry
decreased significantly by 2.6% during the first 3 months in all patients, but
did not change significantly following steroid add-back in both treatment groups
during the final 21 treatment months.
Publication Types:
Clinical trial
Randomized controlled trial
PMID: 7836510, UI: 95138250
83: Dig Dis Sci 1998 Jun;43(6):1347-55
Effect of leuprolide acetate in treatment of abdominal pain and nausea in
premenopausal women with functional bowel disease: a double-blind,
placebo-controlled, randomized study.
Mathias JR, Clench MH, Abell TL, Koch KL, Lehman G, Robinson M, Rothstein R,
Snape WJ
University of Texas Medical Branch, Galveston, USA.
We have previously reported impressive results in using a gonadotropin-releasing
hormone analog, leuprolide acetate (Lupron), in the treatment of moderate to
severe symptoms (especially abdominal pain and nausea) in patients with
functional bowel disease (FBD). Pain is the hallmark of patients with FBD, and
there is no consistent therapy for the treatment of these patients. The purpose
of the present study was to expand the investigation to study similar patients
(menstruating females) in a multicenter, double-blind, placebo-controlled,
randomized study using Lupron Depot (which delivers a continuous dose of drug
for one month), 3.75 mg (N = 32) or 7.5 mg (N = 33), or placebo (N = 35) given
intramuscularly every four weeks for 16 weeks. Symptoms were assessed using
daily diary cards to record abdominal pain, nausea, vomiting, early satiety,
anorexia, bloating, and altered bowel habits. Additional assessment tools were
quality of life questionnaires, psychological profile, oral-to-cecal transit
using the hydrogen breath test, antroduodenal manometry, reproductive hormone
levels, and global evaluations by both patient and investigator. Patients in
both Lupron Depot-treated groups showed consistent improvement in symptoms;
however, only the Lupron Depot 7.5 mg group showed a significant improvement for
abdominal pain and nausea compared to placebo (P < 0.001). Patient quality of
life assessments and global evaluations completed by both patient and
investigators were highly significant compared to placebo (P < 0.001). All
reproductive hormone levels significantly decreased for both Lupron
Depot-treated groups by week 4 and were significantly different compared to
placebo at week 16 (P < 0.001). This study shows that leuprolide acetate is
effective in controlling the debilitating symptoms of abdominal pain and nausea
in patients with FBD.
Publication Types:
Clinical trial
Multicenter study
Randomized controlled trial
PMID: 9635630, UI: 98297553
84: Int J Fertil Womens Med 1998 Jan-Feb;43(1):24-7
Published erratum appears in Int J Fertil Womens Med 1999 Jun-Aug;44(4):215
Effect of norethindrone acetate in the treatment of symptomatic endometriosis.
Muneyyirci-Delale O, Karacan M
Department of Obstetrics and Gynecology, SUNY/Health Science Center at Brooklyn,
USA.
OBJECTIVE: The purpose of the study was to evaluate the efficacy of
norethindrone acetate (NA) treatment in 52 women with dysmenorrhea, dyspareunia,
noncyclic pelvic pain who had a diagnosis of endometriosis by laparoscopy.
RESULTS: Dysmenorrhea and noncyclic pelvic pain were relieved in 48/52 (92.3%)
and 25/28 (89.2%) of patients, respectively. Overall pain relief was obtained in
49/52 (94.2%) of patients. Breakthrough bleeding, of variable severity, was the
most common side effect experienced by 30 patients (57.6%); however, only 4
patients (7.7%) dropped out for this side effect. One other patient dropped out
for severe breast tenderness, and three for noncyclic pelvic pain. In general,
treatment was successful in 44/52 (84.5%) of patients with the above symptoms.
CONCLUSION: NA seems to be a cost-effective alternative with relatively mild
side effects in the treatment of symptomatic endometriosis.
PMID: 9532466, UI: 98193643
85: Obstet Gynecol 1993 Jan;81(1):104-7
The prevention of bone loss in young women treated with GnRH analogues with
"add-back" estrogen therapy.
Leather AT, Studd JW, Watson NR, Holland EF
Premenstrual Syndrome Clinic, Dulwich Hospital, London, United Kingdom.
OBJECTIVE: To determine whether the addition of a low dose of oral estrogen
replacement therapy (ERT) taken daily can prevent the bone loss associated with
continuous GnRH analogue use. METHODS: In a double-blind, placebo-controlled
study, 60 women aged 21-45 years were randomized to one of three treatment
groups: placebo implant every 4 weeks plus placebo ERT tablets daily, Zoladex
(goserelin 3.6 mg) implant every 4 weeks plus placebo ERT tablets daily, or
Zoladex (3.6 mg) implant every 4 weeks plus estradiol valerate, 2 mg/day, with
norethisterone 5 mg from days 22-28. A dual x-ray bone density scan was
performed before treatment and again after six treatment cycles. The percentage
bone change with respect to the initial bone density was calculated. RESULTS:
There was a significant loss of bone density at both the lumbar spine and
proximal femur in the group receiving Zoladex plus placebo after 6 months
compared with both pre-treatment values and with the group receiving placebo
plus placebo. The addition of estrogen "add-back" therapy to GnRH analogue
treatment (Zoladex plus ERT) resulted in no significant change in bone density
compared with either pre-treatment values or the group receiving placebo plus
placebo. The study had a dropout rate of 32%. CONCLUSION: The addition of
"add-back" estrogen therapy to continuous GnRH analogue use can prevent bone
loss.
Publication Types:
Clinical trial
Randomized controlled trial
PMID: 8416441, UI: 93101379
86: J Clin Endocrinol Metab 1996 Jul;81(7):2545-9
"Add-back" estrogen reverses cognitive deficits induced by a
gonadotropin-releasing hormone agonist in women with leiomyomata uteri.
Sherwin BB, Tulandi T
Department of Psychology, McGill University, Montreal, Quebec, Canada.
Treatment of women with uterine myomas with GnRH agonists results in symptoms of
hypoestrogenism which can be prevented by concurrent "add-back" estrogen
administration. We took advantage of these induced endocrine changes to
investigate their effects on cognitive functioning in young women with myomas.
Nineteen women with uterine myomas were tested before treatment. They all
received the GnRH agonist, leuprolide acetate depot (LAD), every 4 weeks for 12
weeks and were then randomized to receive LAD plus estrogen or LAD plus placebo
every 4 weeks for 8 additional weeks. Levels of all sex hormones decreased after
12 weeks of LAD treatment (P < 0.01), and only estradiol (E2) levels increased
(P < 0.01) following 8 weeks of subsequent treatment in the group that received
LAD plus E2. Scores on neuropsychological tests of verbal memory decreased from
pretreatment to 12 weeks posttreatment with LAD (P < 0.05). These memory
deficits were reversed in the group that received LAD plus E2 for 8 weeks
coincident with an increase in plasma E2, whereas memory scores remained
depressed in the group that received LAD plus placebo. These findings are
consistent with those from studies on surgically menopausal women and strongly
suggest that estrogen serves to maintain verbal memory in women. These results
provide support for the efficacy of add-back estrogen regimens in women treated
with GnRH agonists and also imply that estrogen may be important for maintaining
memory in the postmenopause.
Publication Types:
Clinical trial
Randomized controlled trial
Comments:
Comment in: J Clin Endocrinol Metab 1997 Feb;82(2):702-3
PMID: 8675575, UI: 96272875
87: Am Fam Physician 2000 Jun 15;61(12):3559-60
Is hysterectomy obsolete?
Scialli AR
Publication Types:
Comment
Editorial
Comments:
Comment on: Am Fam Physician 2000 Jun 15;61(12):3601-7, 3611-2
PMID: 10892629, UI: 20348718
88: Am J Cardiol 2000 Apr 15;85(8):969-72
Effectiveness of a low-fat vegetarian diet in altering serum lipids in healthy
premenopausal women.
Barnard ND, Scialli AR, Bertron P, Hurlock D, Edmonds K, Talev L
Physicians Committee for Responsible Medicine, Washington DC, USA.
nbarnard@pcrm.org
Few controlled trials have studied cholesterol-lowering diets in premenopausal
women. None has examined the cholesterol-lowering effect of a low-fat vegetarian
diet, which, in other population groups, leads to marked reductions in serum
cholesterol concentrations and, in combination with other life-style changes, a
regression of atherosclerosis. We tested the hypothesis that a low-fat,
vegetarian diet significantly reduces serum total and low-density lipoprotein
(LDL) cholesterol concentrations in premenopausal women. In a crossover design,
35 women, aged 22 to 48, followed a low-fat vegetarian diet deriving
approximately 10% of energy from fat for 2 menstrual cycles. For 2 additional
cycles, they followed their customary diet while also taking a "supplement"
(placebo) pill. Serum lipid concentrations were assessed at baseline and during
each intervention phase. Mean serum LDL, high-density lipoprotein (HDL), and
total cholesterol concentrations decreased 16. 9%, 16.5%, and 13.2%,
respectively, from baseline to the intervention diet phase (p<0.001), whereas
mean serum triacylglycerol concentration increased 18.7% (p<0.01). LDL/HDL ratio
remained unchanged. Thus, in healthy premenopausal women, a low-fat vegetarian
diet led to rapid and sizable reductions in serum total, LDL, and HDL
cholesterol concentrations.
Publication Types:
Clinical trial
Randomized controlled trial
PMID: 10760336, UI: 20273664
89: Obstet Gynecol 2000 Feb;95(2):245-50
Diet and sex-hormone binding globulin, dysmenorrhea, and premenstrual symptoms.
Barnard ND, Scialli AR, Hurlock D, Bertron P
Department of Obstetrics and Gynecology, Georgetown University School of
Medicine, Washington, DC, USA. nbarnard@pcrm.org
OBJECTIVE: To test the hypothesis that a low-fat, vegetarian diet reduces
dysmenorrhea and premenstrual symptoms by its effect on serum sex-hormone
binding globulin concentration and estrogen activity. METHODS: In a crossover
design, 33 women followed a low-fat, vegetarian diet for two menstrual cycles.
For two additional cycles, they followed their customary diet while taking a
supplement placebo pill. Dietary intake, serum sex-hormone binding globulin
concentration, body weight, pain duration and intensity, and premenstrual
symptoms were assessed during each study phase. RESULTS: Mean (+/- standard
deviation [SD]) serum sex-hormone binding globulin concentration was higher
during the diet phase (46.7 +/- 23.6 nmol/L) than during the supplement phase
(39.3 +/- 19.8 nmol/L, P < .001). Mean (+/- SD) body weight was lower during the
diet (66.1 +/- 11.3 kg) compared with the supplement phase (67.9 +/- 12.1 kg, P
< .001). Mean dysmenorrhea duration fell significantly from baseline (3.9 +/-
1.7 days) to diet phase (2.7 +/- 1.9 days) compared with change from baseline to
supplement phase (3.6 +/- 1.7 days, P < .01). Pain intensity fell significantly
during the diet phase, compared with baseline, for the worst, second-worst, and
third-worst days, and mean durations of premenstrual concentration, behavioral
change, and water retention symptoms were reduced significantly, compared with
the supplement phase. CONCLUSION: A low-fat vegetarian diet was associated with
increased serum sex-hormone binding globulin concentration and reductions in
body weight, dysmenorrhea duration and intensity, and premenstrual symptom
duration. The symptom effects might be mediated by dietary influences on
estrogen activity.
Publication Types:
Clinical trial
Randomized controlled trial
PMID: 10674588, UI: 20137053
90: J Reprod Med 1999 Nov;44(11):945-52
Evaluating chronic pelvic pain. A consensus recommendation. Pelvic Pain Expert
Working Group.
Scialli AR
Department of Obstetrics and Gynecology, Georgetown University Medical Center,
Washington, D.C. 20007-2197, USA. sciallia@gunet.georgetown.edu
OBJECTIVE: To identify a comprehensive approach to evaluating women with chronic
pelvic pain based on findings in the literature. STUDY DESIGN: A working group
of gynecologist pelvic pain specialists was convened to consider principles on
which consensus could be reached and to identify areas in which consensus is not
yet possible. RESULTS: Chronic pelvic pain affects 15% of American women. The
diagnostic and therapeutic approach to the complaint may be influenced
inordinately by the specialty of the practitioner to whom the woman presents. A
comprehensive approach to the complaint requires recognition of the multiple
organ systems that may be involved. Evaluation of the woman with chronic pelvic
pain begins with a comprehensive history and physical examination, followed by
selected laboratory and imaging studies. For those women in whom the evaluation
does not yield a likely cause of the complaint, the empiric use of nonsteroidal
antiinflammatory agents, oral contraceptives, and perhaps antibiotics or
antispasmodics is indicated. Women who fail to respond to empiric therapy should
be considered highly likely to have endometriosis or adenomyosis. Further
diagnostic (laparoscopy) or therapeutic (gonadotropin-releasing hormone agonist)
interventions should be directed toward the high likelihood of endometriosis or
adenomyosis. CONCLUSION: A comprehensive approach to chronic pelvic pain
includes consideration of multiple organ systems, with empiric therapy
appropriate after a thorough history and physical examination, to further
delineate the pain problem.
Publication Types:
Consensus development conference
Review
PMID: 10589405, UI: 20056845
91: Int J Fertil Womens Med 1998 Jul-Aug;43(4):186-91
Alternatives to hysterectomy for benign conditions.
Scialli AR
Department of Obstetrics and Gynecology, Georgetown University Medical Center,
Washington, DC 20007-2197, USA.
Hysterectomy is the second most commonly performed major operation in the United
States. Approximately one in three women will have this operation, resulting in
590,000 procedures per year. The most common indications for hysterectomy are
leiomyomata uteri, abnormal uterine bleeding, endometriosis, pelvic pain, and
pelvic organ prolapse. Although hysterectomy is an appropriate therapeutic
option for some women with these conditions, in many instances less radical
alternatives may be offered. Leiomyomata may be managed expectantly if symptoms
are not bothersome; for women with troubling leiomyomata symptoms, alternatives
to hysterectomy include: endoscopic removal or destruction of myomas, arterial
embolization, or hormonal therapy to inhibit or modify bleeding. Endometriosis
and abnormal uterine bleeding of leiomyomata are both amenable to hormonal
therapy. Pelvic pain is most effectively approached with a thorough evaluation
(particularly for nongynecologic illness), with specific therapy directed at the
cause of the pain. Pelvic organ prolapse may respond symptomatically to pelvic
floor exercises, or to the use of a pessary. After alternatives to removal of
the uterus are discussed, the informed woman may decide that hysterectomy is the
option best suited to her. It is unusual for hysterectomy to be her only option.
Publication Types:
Review
Review, tutorial
PMID: 9726846, UI: 98393447
92: Fertil Steril 1995 Aug;64(2):313-20
Sustained benefits of leuprolide acetate with or without subsequent
medroxyprogesterone acetate in the nonsurgical management of leiomyomata uteri.
Scialli AR, Jestila KJ
Department of Obstetrics and Gynecology, Georgetown University Medical Center,
Washington D.C. 20007-2197, USA.
OBJECTIVE: To determine the effectiveness of leuprolide acetate (LA) followed by
medroxyprogesterone acetate (MPA) in the treatment of abnormal uterine bleeding
attributed to leiomyomata uteri. DESIGN: Randomized, double-blinded, controlled
clinical trial. SETTING: Human volunteers in an academic research environment.
PATIENTS: Premenopausal women with abnormal uterine bleeding attributed to
leiomyomata uteri. INTERVENTIONS: Subjects received 6 months of LA after which
they were randomized to receive MPA or placebo. MAIN OUTCOME MEASURES: Control
of bleeding as assessed by menstrual calendar and self-report; hematologic
parameters (hemoglobin and ferritin); uterine size by ultrasonography. RESULTS:
More than three quarters of subjects became amenorrheic on LA. The proportion of
subjects with improvement in the bleeding abnormality after therapy was not
different in the group receiving MPA compared with placebo; however, women who
received MPA were less likely to be anemic after therapy than women receiving
placebo. Among the women assigned to placebo, 55% experienced an improvement in
bleeding compared with pre-GnRH agonist therapy that persisted after
discontinuation of LA. There was a high dropout rate (51%), largely associated
with failure of the regimens to control bleeding symptoms. CONCLUSIONS:
Approximately one half of women with abnormal bleeding attributed to leiomyomata
uteri have sustained symptomatic improvement after 6 months of therapy with LA
even when only placebo therapy is given, although MPA decreases the incidence of
anemia. Leuprolide acetate with or without subsequent progestin may be useful as
a component of nonsurgical management of these tumors, with monitoring of
hematologic status. The interpretability of these data is limited by the high
rate of therapy discontinuation in women with abnormal bleeding of the severity
studied here.
Publication Types:
Clinical trial
Randomized controlled trial
PMID: 7615109, UI: 95340005
93: Reprod Toxicol 1993 Jul-Aug;7(4):295-6
Risk assessment uncertainties.
Scialli AR
Publication Types:
Comment
Editorial
Comments:
Comment on: Reprod Toxicol 1993 Jul-aug;7(4):305-19
Comment on: Reprod Toxicol 1993 Jul-Aug;7(4):321-31
PMID: 8400619, UI: 94003730
94: Fertil Steril 1993 Mar;59(3):674-6
Leuprolide acetate and bone mineral density measured by quantitative digitized
radiography.
Scialli AR, Jestila KJ, Simon JA
Department of Obstetrics and Gynecology, Georgetown University Medical Center,
Washington, D.C. 20007-2197.
Quantitative digitized radiography uses low-energy photons to measure bone
density with precision not available in older techniques. Using this method,
lumbar spine density was evaluated in 12 women before and after 6 months of
therapy with LA. A 2.9% decrement in mean bone density was documented. The
reproducibility of quantitative digitized radiography suggests that this small
degree of bone mineral loss is a real phenomenon and not an artifact of
measurement. The clinical significance of this degree of bone mineral loss has
yet to be established.
PMID: 8458476, UI: 93209427
95: Reprod Toxicol 1988;2(1):1
How safe is safe for hormones?
Scialli AR
Publication Types:
Editorial
PMID: 2980396, UI: 92216527
96: Fertil Steril 1986 Mar;45(3):315-23
The reproductive toxicity of ovulation induction.
Scialli AR
Publication Types:
Review
PMID: 3081379, UI: 86136655
97: Teratog Carcinog Mutagen 1984;4(1):59-66
Fertility as a measurement in reproductive toxicology.
Scialli AR, Fabro SE
PMID: 6143421, UI: 84172907
98: Fertil Steril 1999 Jun;71(6):1115-8
Autoantibodies to markers of oxidative stress are elevated in women with
endometriosis.
Shanti A, Santanam N, Morales AJ, Parthasarathy S, Murphy AA
Department of Gynecology and Obstetrics, Emory University School of Medicine,
Atlanta, Georgia 30322, USA.
OBJECTIVE: To measure autoantibodies that recognize oxidatively modified
proteins in the sera of women with surgically proven endometriosis. DESIGN:
Prospective study. SETTING: Tertiary care academic medical center. PATIENT(S):
Women undergoing surgery for endometriosis or tubal ligation. INTERVENTION(S):
None. MAIN OUTCOME MEASURE(S): Serum and peritoneal fluid autoantibody titers to
malondialdehyde-modified low-density lipoprotein, oxidized low-density
lipoprotein, and lipid peroxide-modified rabbit serum albumin determined by
ELISA. Correlation of autoantibody titers with revised American Fertility
Society staging classification, symptoms, and morphologic type of endometriosis.
RESULT(S): Mean (+/-SEM) serum autoantibody titers (in optical density units) to
the three antigens were as follows: [1] lipid peroxide-modified rabbit serum
albumin, 0.49 +/- 0.12 units in the patients with endometriosis and 0.2 +/- 0.02
units in the controls; [2] oxidized low-density lipoprotein, 0.22 +/- 0.005
units in the patients with endometriosis and 0.18 +/- 0.006 units in the
controls; and [3] malondialdehyde-modified low-density lipoprotein, 0.21 +/-
0.005 units in the patients with endometriosis and 0.16 +/- 0.003 units in the
controls. There was no correlation between autoantibody titers and revised
American Fertility Society stage, symptoms, or morphologic type of
endometriosis. Peritoneal fluid did not contain autoantibodies to any of the
three antigens. CONCLUSION(S): Autoantibodies to markers of oxidative stress
were significantly increased in women with endometriosis. These findings
strongly support our data demonstrating that women with endometriosis have
enhanced oxidative stress.
PMID: 10360920, UI: 99287665
99: Semin Reprod Endocrinol 1998;16(4):263-73
Endometriosis: a disease of oxidative stress?
Murphy AA, Santanam N, Parthasarathy S
Department of Gynecology and Obstetrics, Emory University School of Medicine,
Atlanta, Georgia 30322, USA.
Our central hypothesis proposes that oxidatively damaged red blood cells (RBCs),
apoptotic endometrial cells or undigested endometrial tissue may signal the
recruitment and activation of mononuclear phagocytes. Women with endometriosis
are prone to respond to this stimulus with an inadequate macrophage scavenger
receptor response although the secretory response is not impaired. Activated
macrophages in the peritoneal cavity generate an oxidative stress, which
consists of lipid peroxides, their degradation products, and products formed
from their interaction with low-density lipoprotein (LDL) apoprotein and other
proteins. The lipoproteins of the peritoneal fluid (interstitial fluid) have
been shown to have lower vitamin E levels and to be more readily oxidized than
plasma, so peritoneal fluid may actually contribute to the disease process
actively rather than as a passive carrier of mediators of inflammation and
growth. As a result of such a stress, a sterile, inflammatory reaction with
secretion of growth factors, cytokines, and chemokines is generated, which is
deleterious especially to successful reproduction. We propose that such a
pro-oxidant environment (peritoneal fluid as well as activated macrophages)
promotes growth of ectopic endometrium. The data presented in this review are
just the beginning of exploring the role of oxidative stress in mediating the
pathophysiology of endometriosis. Only by understanding the mechanisms involved
in the pathogenesis of endometriosis can we develop the basis for new diagnostic
and therapeutic approaches.
Publication Types:
Review
Review, tutorial
PMID: 10101808, UI: 99202036
100: Obstet Gynecol Clin North Am 1999 Mar;26(1):121-33
Endoscopic treatment for endometriosis.
Morales AJ, Murphy AA
Department of Obstetrics and Gynecology, Emory University School of Medicine,
Atlanta, Georgia, USA.
Endometriosis is best regarded as a chronic disease that can vary in
symptomatology over time. Endoscopic therapy for relief of pelvic pain as well
as infertility is a therapeutic option. The formation of a rational treatment
plan before surgery will ensure a minimum number of reproductive surgeries over
the patient's lifetime.
PMID: 10083934, UI: 99183680
101: J Lipid Res 1998 Nov;39(11):2111-8
Estradiol as an antioxidant: incompatible with its physiological concentrations
and function.
Santanam N, Shern-Brewer R, McClatchey R, Castellano PZ, Murphy AA, Voelkel S,
Parthasarathy S
Department of Gynecology and Obstetrics, Emory University School of Medicine,
Atlanta, GA 30322, USA.
Estradiol has been documented to inhibit the oxidation of low density
lipoprotein (LDL). We show that physiological concentrations of estradiol do not
inhibit the oxidation of LDL by copper. LDL samples isolated from a)
premenopausal and postmenopausal women and from b) women at different time
periods during their menstrual cycle, who differ vastly in plasma estradiol
levels, were also oxidized at the same rates by copper. In contrast, LDL samples
isolated from c) women who were hyperstimulated during in vitro fertilization
(IVF), with estradiol concentrations above 2000 pg/ml, were resistant to
oxidation by copper. However, these LDL samples were also oxidized at a higher
rate by peroxidases. More importantly, subjects with high estradiol levels also
showed an increase in myeloperoxidase (MPO) protein in the plasma. Based on
these results, we conclude that at physiologic concentrations, it is unlikely
that estradiol could act as an antioxidant. In fact, the ability of estradiol to
induce MPO and become a prooxidant might instead suggest that MPO-mediated
oxidative clearance of LDL from plasma by liver might favorably influence the
outcome of atherosclerosis.
PMID: 9799796, UI: 99018023
102: Am J Obstet Gynecol 1998 Jun;178(6):1151-6
Preliminary report on the treatment of endometriosis with low-dose mifepristone
(RU 486).
Kettel LM, Murphy AA, Morales AJ, Yen SS
Department of Reproductive Medicine, University of California-San Diego, La
Jolla, USA.
OBJECTIVE: We have previously shown that treatment with mifepristone, 50 to 100
mg daily, results in amenorrhea, anovulation, and symptomatic improvement in
women with endometriosis. In this study we lowered the dose to 5 mg daily to
determine whether clinical efficacy is altered without other adverse actions.
STUDY DESIGN: After a baseline cycle, seven women with endometriosis were given
mifepristone, 5 mg daily, for 6 months. Daily symptom inventories were recorded.
Laparoscopy was performed during the sixth month of therapy. RESULTS: Pelvic
pain improved in six of seven patients. Cyclic bleeding ceased in all patients,
but four of the seven patients complained of irregular bleeding. Surgical
staging at the conclusion of the study (five of seven patients) did not detect a
change in endometriosis. CONCLUSIONS: Mifepristone, 5 mg daily, resulted in
symptomatic improvement, but did not stabilize the endometrium. From our
experience with three doses of mifepristone, we would recommend a dose of 50 mg
be used for continued investigations.
Publication Types:
Clinical trial
PMID: 9662295, UI: 98324672
103: Fertil Steril 1998 Jun;69(6):1092-4
Evidence for oxidatively modified lipid-protein complexes in endometrium and
endometriosis.
Murphy AA, Palinski W, Rankin S, Morales AJ, Parthasarathy S
Department of Gynecology and Obstetrics, Emory University, Atlanta, Georgia
30322, USA.
OBJECTIVE: To evaluate for the presence of oxidatively modified lipid-protein
complexes in endometriosis and endometrium of women with endometriosis and
controls. DESIGN: Controlled clinical study. SETTING: Academic tertiary care
center. PATIENT(S): Women undergoing surgery for pelvic pain, infertility,
endometriosis, or tubal ligation controls. INTERVENTION(S): Biopsy of
endometrium and endometriosis. MAIN OUTCOME MEASURE(S): Staining with antibodies
to oxidatively modified lipid proteins (HNE-7, MDA2), macrophages (HAM-56), and
muscle cell actin (HHF-35). RESULT(S): Both endometrium and endometriosis
tissues contain stromal cells that immunostain with HAM-56 and show
immunostaining (both intracellular and extracellular) with HNE-7 and MDA2. Some
endometriotic implants show patchy staining with HHF-35. Endometrium was devoid
of staining with HHF-35. Control staining with nonimmune sera in both tissues
was also devoid of staining. CONCLUSION(S): These data strongly implicate the
occurrence of oxidative stress in endometriosis tissue. These data also suggest
that oxidative modification is a normal physiological process in endometrium.
Publication Types:
Clinical trial
PMID: 9627298, UI: 98288987
104: Fertil Steril 1998 Jun;69(6):1085-91
Macrophage scavenger receptor(s) and oxidatively modified proteins in
endometriosis.
Murphy AA, Palinski W, Rankin S, Morales AJ, Parthasarathy S
Department of Gynecology and Obstetrics, Emory University, Atlanta, Georgia
30322, USA.
OBJECTIVE: To determine whether cultured human peritoneal macrophages have
functional scavenger receptor(s) and whether activation of macrophages in
endometriosis may involve an increase in scavenger receptor activity. DESIGN: A
controlled clinical study comparing peritoneal fluid (PF) macrophages of women
with endometriosis and controls without endometriosis. SETTING: Women undergoing
laparoscopic evaluation and treatment in a tertiary medical center. PATIENT(S):
Twenty-one women undergoing evaluation for pelvic pain or infertility and 10
women undergoing elective laparoscopic tubal ligation. INTERVENTION(S): None.
MAIN OUTCOME MEASURE(S): Evidence for functional macrophage scavenger receptor
and evidence of ligands for the scavenger receptor in PF. RESULT(S): Peritoneal
macrophages of women with endometriosis degrade significantly more endothelial
cell-low density lipoprotein (EC-LDL) and copper-oxidized LDL (Cu-LDL) than
native LDL. Macrophages of women with endometriosis also incorporate more
labeled oleic acid into cholesteryl ester in the presence of oxidized LDL
(Ox-LDL) than in the presence of native LDL. Western blot analysis demonstrates
the presence of adducts between lipid peroxidation products and proteins in PF
of patients with and without endometriosis. The PF of women with endometriosis
competes with labeled Ox-LDL for uptake by mouse peritoneal macrophages in a
dose-dependent manner. CONCLUSION(S): We demonstrate for the first time that
human macrophages have functional scavenger receptor(s) and that activation of
macrophages in endometriosis involves an increase in scavenger receptor
activity. Two lines of evidence indicate the presence of ligands for the
scavenger receptor in PF.
Publication Types:
Clinical trial
Controlled clinical trial
PMID: 9627297, UI: 98288986
105: Am J Obstet Gynecol 1997 Dec;177(6):1315-20; discussion 1320-1
Interaction of Interceed oxidized regenerated cellulose with macrophages: a
potential mechanism by which Interceed may prevent adhesions.
Reddy S, Santanam N, Reddy PP, Rock JA, Murphy AA, Parthasarathy S
Department of Obstetrics and Gynecology, Emory University, Atlanta, Georgia
30322, USA.
OBJECTIVE: The objective of the study was to determine whether Interceed
oxidized regenerated cellulose (Johnson & Johnson Medical, Arlington, Tex.),
because of its polyanionic nature, may compete for the macrophage scavenger
receptor. STUDY DESIGN: RAW macrophages were incubated with Interceed oxidized
regenerated cellulose and known scavenger receptor ligands. The production of
interleukin-1beta by mouse peritoneal macrophages was measured in the presence
of Interceed cellulose. RESULTS: When macrophages were incubated with Interceed
cellulose, increasing concentrations inhibited the uptake of fluorescent acetyl
low-density lipoprotein. In the presence of Interceed cellulose there was a
decrease in the production of interleukin-1beta by mouse macrophages.
CONCLUSION: These results suggest that the interaction of Interceed oxidized
regenerated cellulose with macrophages with scavenger receptors may result in a
decreased secretion of matrix components, inflammatory mediators, and cellular
growth factors. Thus Interceed cellulose may function as a biologic barrier in
preventing adhesions.
PMID: 9423730, UI: 98084346
106: Am J Obstet Gynecol 1996 Aug;175(2):248-57; discussion 257-9
The effect of RU 486 and related compounds on cultured macrophage
differentiation and function.
Roberts CP, Murphy AA, Santanam N, Parthasarathy S
Department of Gynecology and Obstetrics, Emory University School of Medicine,
Atlanta, GA 30322, USA.
OBJECTIVE: Our purpose was to examine RU 486 and related compounds on macrophage
scavenger receptors and cellular adhesion. STUDY DESIGN: THP-1 cells were
activated with phorbol myristate acetate and treated with dexamethasone,
levonorgestrel, and RU 486 alone or in combination. Scavenger receptor activity
was determined by counting adhered cells. In addition, fluorescently labeled
acetyl low density lipoprotein uptake was determined. RESULTS: Both
dexamethasone and RU 486 significantly decreased activated macrophages (81% and
26% of control). Levonorgestrel stimulated adherent cells in activated monocytes
(130% of control). RU 486 and dexamethasone were antagonistic when combined (p <
0.001). In contrast, dexamethasone could not overcome the stimulatory effect of
levonorgestrel (p < 0.001). Fluorescent studies yielded similar results.
CONCLUSIONS: RU 486 is a known antiglucocorticoid with novel antioxidant
properties. Levonorgestrel has antiglucocorticoid but no antioxidant activity.
Glucocorticoids decrease scavenger receptors and antioxidants regulate
inflammatory cytokines. RU 486 antagonized the inhibitory effect of
dexamethasone on scavenger receptors, whereas levonorgestrel was stimulatory. It
is therapeutically important to up-regulate scavenger receptor activity by
antiglucocorticoids in the peritoneal cavity of women with endometriosis.
However, because these mechanisms also induce inflammatory cytokines, a balance
of antioxidants and antiglucocorticoids may prove beneficial.
PMID: 8765239, UI: 96347719
107: Fertil Steril 1996 Jul;66(1):90-4
Inhibition of oxidative modification of proteins by RU486.
Carpenter SE, Santanam N, Murphy AA, Rock JA, Parthasarathy S
Department of Gynecology and Obstetrics, Emory University School of Medicine,
Atlanta, Georgia 30322, USA.
OBJECTIVES: To elucidate further the antioxidant properties of RU486. We
determined whether it can protect biologic molecules such as proteins (albumin,
low-density lipoprotein [LDL] and oxidized LDL) from damage by pre-existing
lipid peroxides. DESIGN: In vitro study. INTERVENTIONS: We tested the effects of
RU486 on the formation of fluorescent oxidatively modified proteins by
pre-existing lipid peroxides. We used two model systems, the incubation of
oxidized linoleic acid with serum albumin and the incubation of human LDL with
copper. MAIN OUTCOME MEASURES: The formation of modified protein was established
by determining fluorescence at excitation wavelength of 330 nm and emission
wavelength between 390 and 500 nm. Modified protein has a characteristic
emission between 425 and 430 nm. RESULTS: The addition of increasing amounts of
RU486 inhibited the formation of fluorescent oxidatively modified protein
products in both model systems. CONCLUSION: These results provide evidence that
RU486 not only can prevent the formation of lipid peroxide, but also can block
the formation of fluorescent protein adducts in the presence of pre-existing
lipid peroxides.
PMID: 8752616, UI: 96281824
108: Clin Obstet Gynecol 1996 Jun;39(2):451-60
Mifepristone: clinical application in general gynecology.
Morales AJ, Kettel LM, Murphy AA
University of California, San Diego 92093-0633, USA.
Publication Types:
Review
Review, tutorial
PMID: 8734009, UI: 96319236
109: Fertil Steril 1996 Jan;65(1):23-8
Treatment of endometriosis with the antiprogesterone mifepristone.
Kettel LM, Murphy AA, Morales AJ, Ulmann A, Baulieu EE, Yen SS
University of California-San Diego, La Jolla, USA.
OBJECTIVE: To evaluate the safety and efficacy of an antiprogesterone
(mifepristone, RU486; Roussel-Uclaf, Romaineville, France) on endometriosis.
DESIGN: An open, prospective clinical trial. SETTING: The clinical practice of
an academic faculty. PATIENTS: Nine women with endometriosis were studied.
INTERVENTIONS: RU486 (50 mg/d) was administered for 6 months. MAIN OUTCOME
MEASURES: Daily symptom inventories and urinary steroid metabolites were
assessed before, during, and after treatment. Blood for hormone analysis was
obtained weekly for 4 weeks and monthly thereafter. The extent of endometriosis,
bone mineral density, circadian rhythm of cortisol, and LH pulsatility were
determined before and after treatment. Safety laboratory measurements were made
before and at 1, 2, and 6 months of treatment. RESULTS: Pelvic pain and uterine
cramping improved in all patients. Endometriosis regressed by 55%. All patients
exhibited endocrine features of anovulatory amenorrhea without hypoestrogenism.
A rise in serum LH and T levels was observed during the first month of treatment
and one patient developed an elevation of liver transaminases during the last
month of treatment. All other measurements were unchanged. CONCLUSION: RU486
appears to be effective in improving the symptoms and causing regression of
endometriosis in the absence of significant side effects.
Publication Types:
Clinical trial
Comments:
Comment in: Fertil Steril 1996 Oct;66(4):669-70
PMID: 8557150, UI: 96109028
110: Fertil Steril 1995 Jul;64(1):187-90
Regression of uterine leiomyomata to the antiprogesterone RU486: dose-response
effect.
Murphy AA, Morales AJ, Kettel LM, Yen SS
School of Medicine, Department of Reproductive Medicine, University of
California, San Diego, La Jolla, USA.
OBJECTIVE: To study the response of uterine leiomyomata to three daily doses of
RU486 (5, 25, and 50 mg). DESIGN: Prospective nonrandomized trial of women with
symptomatic leiomyomata. SETTING: Patients from the clinical practice of the
authors at the University of California, San Diego Medical Center. PATIENTS: Ten
patients with symptomatic leiomyomata previously reported after treatment with
50 mg of RU486 daily for 3 months. Eleven patients treated with 25 mg of RU486
daily and nine patients placed on 5 mg of RU486 daily for 12 weeks. MAIN OUTCOME
MEASURES: Changes in leiomyomata volume as measured with vaginal ultrasounds at
baseline and monthly thereafter. Frequent blood samples for hematology,
chemistry, and hormone levels were obtained. Twenty-four-hour urine collections
for free cortisol and creatinine were obtained at baseline and at 12 weeks.
RESULTS: All three doses induce ovarian acyclicity. Administration of 50 mg of
RU486 decreases leiomyomata volume to 78.1% +/- 4.8% of baseline at 4 weeks,
60.5% +/- 6.6% at 8 weeks, and 51.0% +/- 9.2% after 12 weeks of treatment.
Regressive response in patients treated with 25 mg of RU486 daily was 76.3% +/-
5.0% of baseline at 4 weeks, 54.0% +/- 5.1% at 8 weeks, and 44.0% +/- 5.0% after
12 weeks. At 5 mg of RU486 leiomyomata volume was 80.6% +/- 8.3% of baseline
after 4 weeks, 63.7% +/- 14.6% after 8 weeks, and 74.4% +/- 19.8% after 12 weeks
of therapy. CONCLUSIONS: Although acyclicity is seen at all three doses, an
effective dose to cause a clinically significant (50%) decrease in leiomyomata
volume appears to be 25 mg daily.
Publication Types:
Clinical trial
PMID: 7789557, UI: 95309447
111: Fertil Steril 1995 May;63(5):1021-6
Published erratum appears in Fertil Steril 1995 Sep;64(3):668
Expanded polytetrafluoroethylene (Gore-Tex Surgical Membrane) is superior to
oxidized regenerated cellulose (Interceed TC7+) in preventing adhesions.
Haney AF, Hesla J, Hurst BS, Kettel LM, Murphy AA, Rock JA, Rowe G, Schlaff WD
Duke University Medical Center, Durham, North Carolina 27710, USA.
OBJECTIVE: To compare the impact of expanded polytetrafluoroethylene (PTFE;
Gore-Tex Surgical Membrane; W. L. Gore & Associates, Inc., Flagstaff, AZ) and
oxidized regenerated cellulose (Interceed TC7, Johnson & Johnson Medical, Inc.,
Arlington, TX) on the development of postsurgical adhesions. DESIGN: A
multicenter, nonblinded, randomized clinical trial. SETTING: University medical
centers. INTERVENTIONS: Each barrier was allocated randomly to the left or right
sidewall of every patient. PATIENTS: Thirty-two women with bilateral pelvic
sidewall adhesions undergoing reconstructive surgery and second-look
laparoscopy. MAIN OUTCOME MEASURES: Adhesion score (on a 0- to 11-point scale),
the area of adhesion (cm2), and the likelihood of no adhesions. RESULTS: The use
of both barriers was associated with a lower adhesion score and area of adhesion
postoperatively. However, those sidewalls covered with PTFE had a significantly
lower adhesion score (0.97 +/- 0.30 versus 4.76 +/- 0.61 points, mean +/- SEM)
and area of adhesion (0.95 +/- 0.35 versus 3.25 +/- 0.62 cm2). Overall, more
sidewalls covered with PTFE had no adhesions (21 versus 7) and, when adhesions
were present on the contralateral sidewall, the number of sidewalls covered with
PTFE without adhesions was greater than those covered with oxidized regenerated
cellulose (16 versus 2). CONCLUSION: Expanded polytetrafluoroethylene was
associated with fewer postsurgical adhesions to the pelvic sidewall than
oxidized regenerated cellulose.
Publication Types:
Clinical trial
Multicenter study
Randomized controlled trial
PMID: 7720911, UI: 95237421
112: Fertil Steril 1995 Apr;63(4):761-6
Endometrial effects of long-term low-dose administration of RU486.
Murphy AA, Kettel LM, Morales AJ, Roberts V, Parmley T, Yen SS
Department of Reproductive Medicine, University of California, San Diego, La
Jolla.
OBJECTIVE: To examine endometrial response to long-term low-does RU486
administration. DESIGN: Retrospective controlled study of women with
endometriosis treated for 6 months with 50 mg RU486 daily for 6 months. Controls
consisted of women in the follicular phase of a spontaneous cycle undergoing
endometrial biopsy. SETTING: Patients from the clinical practice of the authors
at the University of California, San Diego Medical Center. PATIENTS AND
INTERVENTIONS: Nine patients treated with long-term low-dose RU486 and nine
normal cycling controls undergoing hysterectomy or endometrial biopsy for benign
disease. MAIN OUTCOME MEASURES: Changes in endometrial morphology and
immunohistochemical analysis for estrogen receptor (ER) and progesterone
receptor (PR) protein. RESULTS: All patients treated with RU486 exhibited
abnormal endometrial morphology. The endometrial glands were irregular in size
and shape. The stroma was varied but consisted predominantly of dense cellular
stroma with frequent mitotic figures. The glands were lined by a combination of
epithelial types some of which were secretory. No cytologic atypia was seen.
Levels of ER immunoreactivity, as determined by image analysis, were greater in
the stroma with no difference in PR immunoreactivity compared with controls. No
difference in ER and PR immunoreactivity were seen in the glands compared with
normal controls. CONCLUSION: The generalized cystic changes demonstrated are
consistent with a chronic unopposed estrogen effect and are concordant with
hormonal data showing early to midfollicular phase levels of estrogens. They
also are consistent with our findings of increased ER immunoreactivity in the
stroma. Evidence of minimal P agonist effect was noted.
Publication Types:
Clinical trial
Controlled clinical trial
PMID: 7890059, UI: 95196886
113: J Clin Invest 1994 Nov;94(5):1990-5
Antioxidant: a new role for RU-486 and related compounds.
Parthasarathy S, Morales AJ, Murphy AA
Department of Gynecology and Obstetrics, Emory University School of Medicine,
Atlanta, Georgia 30322.
RU-486 (17 beta-hydroxy-4-dimethylaminophenyl-17-alpha-propenyl estrone 4,9
diene-3-one; mifepristone) is suggested to act by binding to progesterone and
glucocorticoid receptors. Based on its chemical nature, we anticipated that
RU-486 may have potent antioxidant properties. We used the oxidation of LDL as
our model system. RU-486 and a similar compound, onapristone, at 1-5-microM
concentrations, decreased the formation of oxidized LDL. LDL isolated from
plasma of subjects who were orally supplemented with RU-486 was resistant to
oxidation, as compared to LDL isolated from control plasma. The antioxidant
effect of RU-486 appears to reside in the dimethylaminophenyl side chain moiety.
Reduction of the A-ring of the steroid molecule had no effect on its antioxidant
property. Analogs of RU-486 which lack the dimethylaminophenyl group, were
without antioxidant activity. Levonorgestrel, which lacks the
dimethylaminophenyl group failed to inhibit the oxidation of LDL even at
100-microM levels. In contrast, ethinylestradiol and estradiol which do not
possess the dimethylamino group, were able to inhibit the oxidation of LDL by
virtue of their phenolic steroid "A" ring. Thus RU-486, with its long half life,
high plasma concentrations, association with lipoproteins, and ability to
readily enter the cell may have additional intra- and extra-cellular antioxidant
effects.
PMID: 7962545, UI: 95051544
114: Am J Obstet Gynecol 1994 Jun;170(6):1623-7; discussion 1627-8
The effects of RU 486 and leuprolide acetate on uterine artery blood flow in the
fibroid uterus: a prospective, randomized study.
Reinsch RC, Murphy AA, Morales AJ, Yen SS
Department of Obstetrics and Gynecology, Kaiser Permanente, University of
California, San Diego 92103.
OBJECTIVE: Our purpose was to examine the effects of RU 486 and leuprolide
acetate on uterine artery blood flow and uterine volume. STUDY DESIGN: Patients
were randomly assigned to group A (eight patients) receiving 25 mg of RU 486
daily for 3 months or group B (six patients) receiving 3.75 mg of leuprolide
acetate monthly for 3 months. Uterine artery blood flow change was determined by
resistive index by means of vaginal color Doppler ultrasonography. Uterine
volume was measured before and during the study with abdominal ultrasonography.
RESULTS: Both groups showed an increase in resistive index. Patients receiving
RU 486 had uterine artery blood flow decreased by 40%, and those receiving
leuprolide acetate had a 21% decrease. We noted a significant decrease in
uterine volume compared with pretreatment in both groups at 3 months. There was
no significant decrease between groups. CONCLUSION: Both RU 486 (25 mg daily)
and leuprolide acetate (3.75 mg monthly) are effective in decreasing blood flow
to the uterus (increasing resistive index) and decreasing uterine volume at 3
months. A significant decrease in uterine artery blood flow may provide a
mechanism for the decrease in uterine size and the decrease in uterine blood
loss at the time of surgery.
Publication Types:
Clinical trial
Randomized controlled trial
PMID: 8203418, UI: 94262654
115: Curr Opin Obstet Gynecol 1994 Jun;6(3):269-78
RU486: pharmacology and potential use in the treatment of endometriosis and
leiomyomata uteri.
Murphy AA, Castellano PZ
Department of Gynecology and Obstetrics, Emory University School of Medicine,
Atlanta, Georgia.
More than a decade after the serendipidous discovery of RU486, numerous
antiprogestins have been synthesized and studied. Interest in how antiprogestins
exert their antagonist effect has led to novel information about the molecular
mechanisms of progesterone action. The pivotal role that progesterone plays in
reproductive biology has led to research in many areas where a potential role
for these compounds may be found in health and disease. RU486 has been shown to
relieve pelvic pain associated with endometriosis and to decrease American
Fertility Society endometriosis scores. Uterine leiomyomata show a significant
reduction in size after administration of RU486 for 3 months. Although much
research remains to be carried out, RU486 appears promising as alternative
therapies for these diseases.
Publication Types:
Review
Review, tutorial
PMID: 8038415, UI: 94312667
116: Hum Reprod 1994 Jun;9 Suppl 1:116-20
Clinical efficacy of the antiprogesterone RU486 in the treatment of
endometriosis and uterine fibroids.
Kettel LM, Murphy AA, Morales AJ, Yen SS
Department of Reproductive Medicine, University of California, San Diego, La
Jolla 92093.
To evaluate the long-term effects of treatment with RU486 and to test its
efficacy in endometriosis, a 3-month trial was conducted to evaluate the effects
of daily administration (100 mg/day or approximately 2 mg/kg/day) on the
functional activity of the reproductive axis, as well as implants, in patients
with symptomatic pelvic endometriosis. All women became amenorrhoeic and
acyclic. However, ovarian suppression was incomplete. In 24 h sampling studies,
mean luteinizing hormone (LH) and LH pulse amplitude were increased without a
change in LH pulse frequency. Additionally, an antiglucocorticoid effect was
demonstrated. Treatment resulted in improvement in pelvic pain in all subjects
without significant changes in the extent of disease as evaluated by
laparoscopy. We also attempted to reduce the growth of uterine fibroids by using
50 mg/day of RU486 for 3 months in 10 patients. Myoma size decreased
approximately 22% at 4 weeks, 39% at 8 weeks and 49% at 12 weeks. Serum
concentrations of LH, androstenedione and testosterone increased in the first 3
weeks of treatment and then returned to baseline. In conclusion, daily
administration of RU486 resulted in ovarian inhibition and menstrual acyclicity
and in an improvement in the pain associated with pelvic endometriosis and
decreased the size of uterine fibroids. This ovarian inhibition was achieved
without oestrogen deprivation and may provide a novel long-term approach to the
treatment of ovarian steroid-dependent disease processes.
Publication Types:
Clinical trial
PMID: 7962456, UI: 95051440
117: Fertil Steril 1993 Oct;60(4):642-6
Rapid regression of uterine leiomyomas in response to daily administration of
gonadotropin-releasing hormone antagonist.
Kettel LM, Murphy AA, Morales AJ, Rivier J, Vale W, Yen SS
Department of Reproductive Medicine, University of California.
OBJECTIVE: The efficacy of acute and sustained pituitary gonadotropin
down-regulation by the Nal-Glu GnRH antagonist (Nal-Glu) was evaluated in the
treatment of uterine leiomyomas. DESIGN: Prospective, open clinical trial.
PATIENTS: Seven normally cycling women with symptomatic leiomyomas.
INTERVENTIONS: Nal-Glu (50 micrograms/kg per day) was administered
subcutaneously for 3 months. MAIN OUTCOME MEASURES: Baseline ultrasound
examinations were obtained and repeated monthly throughout treatment. Each
leiomyoma was mapped and measured in three dimensions. Blood samples were drawn
daily for 7 days, weekly for 4 weeks, and monthly for the remaining 2 months.
RESULTS: Mean leiomyoma size decreased 52.8 +/- 7.3% (means +/- SD) after 1
month of therapy and remained unchanged for the remainder of the study. Serum
levels of E2 (35.9 +/- 11.8 to 9.3 +/- 0.8 pg/mL, 131.7 +/- 43.3 to 34.0 +/- 1.4
pmol/L), estrone (37.3 +/- 7.5 to 13.0 +/- 2.5 pg/mL, 138.1 +/- 27.7 to 48.1 +/-
9.1 pmol/L), and P (1.6 +/- 1.1 to 0.3 +/- 0.01 ng/mL, 5.0 +/- 3.6 to 0.9 +/-
0.04 nmol/L) declined rapidly (within 48 hours) and remained suppressed
throughout treatment. Serum LH, FSH, androstenedione, T, and DHEA levels did not
change significantly. In two subjects who did not have surgical removal,
leiomyomas grew to original size within the 1st month off drug. Six patients
remained amenorrheic and the other subject spotted during the last 2 months of
therapy. CONCLUSIONS: Continuous treatment with Nal-Glu induces immediate and
sustained pituitary-gonadal down-regulation that results in regression in
leiomyoma size. By circumventing GnRH agonist-induced pituitary-ovarian
up-regulation, GnRH antagonists may prove to be superior tools in the medical
management of leiomyomas.
Publication Types:
Clinical trial
Comments:
Comment in: Fertil Steril 1994 May;61(5):994-5
PMID: 8405517, UI: 94009765
118: J Clin Endocrinol Metab 1993 Feb;76(2):513-7
Regression of uterine leiomyomata in response to the antiprogesterone RU 486.
Murphy AA, Kettel LM, Morales AJ, Roberts VJ, Yen SS
Department of Reproductive Medicine, University of California, San Diego School
of Medicine, La Jolla 92093-0802.
Uterine leiomyomata are steroid hormone dependent tumors which possess receptors
for estrogen (ER) and progesterone (PR). We reasoned that an antiprogesterone
(RU 486) may induce regression of leiomyomata by withdrawal of progesterone
action and/or by its interference of estrogen action. Accordingly, we examined
the effects of daily administration of RU 486 (50 mg) for a period of 3 months
in 10 patients with uterine leiomyomata and regular menstrual cycles. Baseline
ultrasound examinations were obtained and repeated monthly during treatment as a
measure of leiomyomata volume. Hormonal parameters were monitored by blood
samples obtained prior to treatment and daily for 7 days, weekly for 4 weeks and
monthly for the duration of therapy. Myomectomy or hysterectomy was performed in
6 of 10 patients at the end of treatment. Leiomyomata and myometrial tissue was
obtained for immunocytochemical analysis of ER and PR protein. Amenorrhea was
induced in all patients during treatment. Leiomyomata volume (mean +/- SE)
decreased 21.9 +/- 4.8% after 4 weeks, 39.5 +/- 6.6% (P < 0.001) after 8 weeks,
and 49.0 +/- 9.2% (P < 0.001) after 12 weeks of treatment compared to
pretreatment measurements. Serum LH levels (P < 0.005), but not FSH levels, more
than doubled during the first 3 weeks of treatment with a concomitant increase
in serum androstenedione (P < 0.006) and testosterone (P < 0.0001) levels. These
elevated hormonal levels returned to baseline at 4 weeks without further changes
during the remainder of treatment. A significant rise in serum
dehydroepiandrosterone sulfate (P < 0.0001) and cortisol (P < 0.01) was seen at
12 weeks, suggesting an antiglucocorticoid effect of RU 486 has occurred. Serum
estradiol, estrone, progesterone, sex hormone binding protein,
thyroid-stimulating hormone, and PRL were unchanged from early follicular phase
values. PR but not ER immunoreactivity was significantly reduced in both
leiomyomata and myometrium after RU 486 treatment compared with tissues from
untreated patients, suggesting that regression of tumors may be attained through
a direct antiprogesterone effect. However, an alteration in ER functionality
cannot be excluded. We conclude that RU 486 is well tolerated, safe, and
effective; thus, it may prove to be a novel mode of management for uterine
leiomyomata.
PMID: 8432797, UI: 93163234
119: Fertil Steril 1991 Sep;56(3):402-7
Endocrine responses to long-term administration of the antiprogesterone RU486 in
patients with pelvic endometriosis.
Kettel LM, Murphy AA, Mortola JF, Liu JH, Ulmann A, Yen SS
Department of Reproductive Medicine, University of California-San Diego Medical
Center 92103.
OBJECTIVE: To examine endocrine and clinical responses to long-term
administration of RU486 in patients with endometriosis. DESIGN: Prospective open
trial. SETTING: Faculty practice of the authors. PATIENTS, PARTICIPANTS: Six
normally cycling women with endometriosis were recruited. INTERVENTIONS:
Subjects received RU486 100 mg/d for 3 months. MAIN OUTCOME MEASURE(S): Hormonal
changes during RU486 were compared with control data obtained in the preceding
cycle during the early follicular phase. Clinical responses were determined by
patient assessment and second-look laparoscopy. RESULTS: All women became
amenorrheic, and daily urinary levels of ovarian steroid metabolites remained
acyclic. Mean luteinizing hormone (LH) (P less than 0.02) and LH pulse amplitude
(P less than 0.05) were increased without changes in LH pulse frequency. An
antiglucocorticoid effect was demonstrated by an increase in serum cortisol (P
less than 0.01) and adrenocorticotropic hormone (P less than 0.05) levels.
Treatment resulted in an improvement in pelvic pain in all subjects without
significant change in the extent of disease as evaluated by follow-up
laparoscopy. CONCLUSIONS: Daily administration of RU486 results in acyclic
ovarian function and improvement in the subjective painful symptoms of
endometriosis.
PMID: 1716596, UI: 91372421
120: Clin Obstet Gynecol 1990 Mar;33(1):137-44
Laparoscopy in the diagnosis and therapy of chronic pelvic pain.
Roseff SJ, Murphy AA
Reproductive Endocrinology and Infertility, Saint Barnabas Medical Center,
Livingston, NJ 07039.
Publication Types:
Review
Review, tutorial
PMID: 2138070, UI: 90183127
121: Fertil Steril 1989 Jun;51(6):1072-4
Microscopic peritoneal endometriosis.
Murphy AA, Guzick DS, Rock JA
Publication Types:
Comment
Letter
Comments:
Comment on: Fertil Steril 1988 Oct;50(4):665-6
PMID: 2721728, UI: 89252134
122: Obstet Gynecol Clin North Am 1989 Mar;16(1):167-77
Combination medical and surgical therapy for infertile patients with
endometriosis.
Kettel LM, Murphy AA
Department of Reproductive Medicine, University of California, San Diego, La
Jolla.
Endometriosis is a difficult problem for practicing gynecologists and is
commonly associated with infertility. The diagnosis of endometriosis should only
be made at the time of laparoscopy or laparotomy and should be confirmed with
biopsy if possible. Once the diagnosis is made, it should be classified
according to the revised AFS system. The treatment of infertility associated
with endometriosis is controversial and usually consists of either medical
therapy with hormonal manipulation designed to suppress the disease, surgical
therapy designed to debulk the disease and repair anatomic distortion, or a
combination of both. Despite an abundance of research on the treatment of
endometriosis, the pregnancy rate for patients with endometriosis remains lower
than that of the normal population. The reasons for this are obscure.
Endometriosis does not respond to hormonal changes the same way that normal
endometrium does and has been shown to persist despite extensive medical
therapy. The recurrence rate of the disease is impressively high after either
medical or surgical therapy. Interestingly, expectant management of minimal or
mild disease is associated with pregnancy rates equal to those of any other type
of therapy. Only when the disease is more extensive does aggressive treatment
appear to show improvement in pregnancy rates. Whether combination therapy of
endometriosis is better than single agent therapy remains open to debate. Some
of the best-designed studies using combination therapy have shown no difference
in pregnancy rates. Yet, when taken as a whole, it would appear that if
combination medical and surgical therapy is chosen, the medical therapy should
be given preoperatively. The literature abounds with a wide variety of
classification systems, methods of calculating pregnancy rates, and inclusion of
control groups. Because of this disparity between studies, reliable conclusions
cannot be drawn.
Publication Types:
Review
Review, tutorial
PMID: 2664616, UI: 89314694