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Adjuncts for ovarian stimulation: when do we adopt ••orphan indications•• for approved drugs?
Adjuncts for ovarian stimulation: when do we adopt‘‘orphan indications’’ for approved drugs?
David R. Meldrum, R. Jeffrey Chang, M.D.,Dominique de Ziegler, M.D.,William B. Schoolcraft, M.DRichard T. Scott, Jr., and Antonio Pellicer, M.D.
a Reproductive Partners Medical Group, Redondo Beach, California; b Department of Reproductive Endocrinology andInfertility, University of California, San Diego, San Diego, California; c Universite Paris Descartes, Service de GynecologieObstetrique II et Medecine de la Reproduction, CHU Cochin Saint Vincent de Paul, Paris, France; d Colorado Center forReproductive Medicine, Englewood, Colorado; e Reproductive Medicine Associates of New Jersey, Morristown, New Jersey;and f Instituto Valenciano de Infertilidad, University of Valencia, Valencia, Spain
Several drugs, shown to be safe for other uses, have proven to be highly effective adjuncts for ovarian stimulation.
The authors evaluate these ‘‘orphan’’ indications and make recommendations so that more patients will benefitfrom their use. (Fertil SterilÒ 2009;92:13–8. Ó2009 by American Society for Reproductive Medicine.)
Key Words: Ovarian stimulation, metformin, dexamethazone, hCG, aspirin, cabergoline, androgens
As with orphan drugs that help too few patients to make de-
B. Basic scientific studies elucidating a logical mecha-
velopment worthwhile without financial incentives from the
government, frequently manufacturers do not invest the con-
C. Negative trials or meta-analysis indicating that the effect
siderable financial resources necessary to establish new indi-
may be less than originally indicated, because only very
cations for established drugs, particularly when they apply to
large trials or collections of studies can establish an accu
a small group of patients or when the indications fall outside
rate estimate of the treatment effect.
of the usual patient groups to which they apply, or when the
drugs are already generic. A prominent example in the area of
IVF is the use of leuprolide acetate (LA) to prevent prematureLH release and ovulation. This contribution will make thecase that there are a number of such medications that are im-
portant adjuncts to controlled ovarian hyperstimulation
A More than 20 years ago, LA was found to effectively block
(COH). The decision as to when to adopt these ‘‘orphan indi-
premature ovulation, which otherwise resulted in the cancel-
cations’’ is complex. The authors will illustrate the decision-
ation of about 20% of IVF cycles. This benefit was so clear
making process by using a dozen examples grouped into nine
and dramatic that one of the authors (D.M.) suggested that
strategies ranging from widely accepted to still somewhat
uncertain. Recommendations regarding use and informedconsent will be made for each.
B The mechanism has been clearly delineated.
The decision-making process is influenced by the follow-
D A subsequent meta-analysis found that the likelihood of
A. Evidence based on well-designed, randomized, placebo-
a successful pregnancy using LA was increased almost two-
controlled trials (including meta-analysis of such trials),
fold , although that was likely an overestimate due to the
and corroborating evidence from other studies.
inclusion of studies where the control group not given LAalso received clomiphene citrate (CC). Also, more embryos
Received September 8, 2008; revised March 12, 2009; accepted March
are available for cryopreservation, resulting in more pregnan-
20, 2009; published online May 6, 2009.
D.R.M. has nothing to disclose. R.J.C. has performed consulting for
Beckman-Coulter. D. de Z. holds stock in Ultrast, serves on the advisory
board for Ferring, and has performed consulting for IBSA Pharmaceuti-cals. W.B.S. has nothing to disclose. R.T.S. has received research
Conclusion After more than 20 years of use and clear evi-
grants from EMD Serono, Organon, and Ferring. A.P. has nothing to
dence of benefit with minimal risk, use of LA continues to
be ‘‘off label’’ as an adjunct for IVF. Use is so widespread
Reprint requests: David Meldrum, M.D., Reproductive Partners Medical
that informed consent is not required, except as part of a com-
Group, 510 North Prospect Avenue, Suite 202, Redondo Beach, CA90277 (FAX: 310-798-7304; E-mail:
Fertility and Sterilityâ Vol. 92, No. 1, July 2009
Copyright ª2009 American Society for Reproductive Medicine, Published by Elsevier Inc.
Oral Contraceptives (OCs) and Estrogen (E)
. Addition of metformin to FSH treatment for CC-resis-
A Although GnRH agonists can be used to schedule cycles,
tant patients with PCOS has been reported to reduce the num-
pronounced side effects can occur during extended ovarian
ber of preovulatory follicles and the peak level of E2
suppression. Biljan et al. reported that OC pretreatment
Ovulation induced with metformin has been associated
reduced the amount of gonadotropin required for COH and
with decreased T levels and marked increases of glycodelin
therefore appeared to improve synchronization of the follic-
levels during the luteal phase in women with PCOS
ular cohort instead of agonist alone, suggesting it as a useful
Uterine blood flow is reduced in PCOS and both metformin
adjunct for scheduling cycles and improving IVF outcome.
and blockade of the effect of T by flutamide increase uterine
One of the authors (D. de Z.) was first to suggest use of luteal
blood flow in those women . HOXA-10, required for
E for scheduling of COH , and that adjunct has subse-
implantation, is suppressed in PCOS by T, and that effect is
quently been reported to synchronize the follicles and im-
blocked by the T antagonist, flutamide Use of metfor-
prove the response to COH . Another of the authors
min in PCOS improves altered blood lipids and may reduce
(R.S.) has reported improved COH in poor responders with
E Lactic acidosis has rarely been reported. Liver and kidney
B The FSH and follicular growth are suppressed by either
disease should be excluded before use and metformin should
be stopped during acute illnesses and when radiologic dye isto be used.
Conclusion Metformin appears to have benefits in women
D Cyst formation resulting from GnRH agonists is also re-
with PCOS throughout ovulation induction treatments and
particularly during IVF cycles by reducing OHSS. The
OHSS is the most serious complication of IVF in womenwith PCOS and may lead to catastrophic complications andeven death. It should be noted that most clinical studies on
the use of metformin in PCOS have not been based on dem-
A A meta-analysis of five trials has reported a very highly
onstrated insulin resistance, although the criteria for the diag-
significant (P<.00001) decrease of ovarian hyperstimulation
nosis of PCOS has varied. Use is now sufficiently widespread
syndrome (OHSS) with metformin (odds ratio [OR] 0.21,
that a separate informed consent is not required.
95% confidence interval [CI] 0.11–0.41) in women withpolycystic ovary syndrome (PCOS) having IVF .
B One of the authors (J.C.) was first to make the observation
A In a meta-analysis of randomized trials in poor responders,
of elevated levels of insulin in PCOS, aside from the increase
growth hormone was reported to increase the PRs and birth
expected with the commonly associated obesity in this syn-
rates by approximately three- and fourfold, respectively,
drome Insulin, which is reduced by metformin, is one
compared with placebo Growth hormone was not effec-
of the principal factors that stimulates the production of vas-
tive in increasing ovarian response, which was the original
cular endothelial growth factor by luteinized granulosa cells
purpose of those trials. The authors suggested that further in-
(GC) . In an editorial discussing that study, one of the au-
formation was needed to confirm this finding. Subsequently,
thors (D.M.) suggested that various strategies, including rou-
a randomized trial was undertaken in poor responding
tine use of metformin, could be used to reduce insulin levels
women older than 40 years having IVF . Their poor re-
and the incidence of OHSS in women with PCOS having IVF
sponder status was clearly indicated by a peak level of E
. Also, because androgens stimulate GC FSH receptors,
of 912 pg/mL (SD 129), in spite of stimulation with 600 IU
metformin may reduce OHSS by decreasing the ovarian
of gonadotropins. Approximately four- and fivefold increases
of the PRs and delivery rates were noted, respectively, with
a trend toward better embryo quality with growth hormone,and intrafollicular E
D A prospective, randomized trial in women with PCOS has
2 levels were significantly increased.
One of the authors (W.S.), in a study of minidose LA together
reported significantly higher rates of ongoing pregnancy per
with growth hormone, reported a 25% rate of heartbeat per
cycle and per transfer with metformin versus placebo
transferred embryo in poor responders with a mean of almost
This finding is supported by a case-controlled study that
three failed cycles, consistent with the degree of benefit
also reported an increase in the pregnancy rate (PR) and
a highly significant increase of embryo quality with metfor-min , but in a meta-analysis of the five small randomized
B Increased apoptosis has been reported in the GCs of older
trials published to date (about 200 subjects total in each
women having IVF Growth hormone and its intermedi-
group), the 29% increase of the PR observed was not statisti-
ary, insulin-like growth factor I (IGF-I) are two of the most
cally significant . Very recently, a large meta-analysis of
well-characterized factors known to reduce apoptosis and
trials adding metformin or placebo to CC has reported signif-
improve the health and proliferation of GCs , which are
icant increases of ovulation and pregnancy with metformin
crucial to the nourishment of the maturing oocyte.
A Human chorionic gonadotropin has been routinely usedand is approved as an LH surrogate to induce ovulation.
E Minimal. Use in a diabetic could adversely influence blood
With the increasing use of recombinant FSH for ovarian stim-
ulation, one of the authors (D.M.) proposed that small doses
Conclusion Growth hormone has been reported to increase
of hCG would be effective adjuncts for ovarian stimulation,
successful IVF outcome in low responding women. However,
therfore the use of hMG would be unnecessary Most
as its use is not widespread, a specific informed consent is ad-
of the LH activity in hMG is from the approximately 10 units
of hCG in each 75 IU vial, but the amount of hCG and LHbioactivity varies from batch to batch and among suppliers.
Dilute hCG has the advantage of providing a consistent
LH-like effect, as long as a sufficient volume is used. Various
A Daly et al. were first to report that dexamethasone in-
compounding pharmacies are making up these small doses.
creased the response to CC in women with PCOS comparedwith placebo. Subsequent studies in women resistant to CC
B One of the authors (D. M.) showed that a single dose of 50
reported a high response rate, even when the levels of adrenal
IU of hCG increased the level of bioactive LH/hCG to normal
androgens were normal Dexamethasone was given
in the mid-to-late follicular phase in women suppressed with
in those trials as a daily dose of 0.5 mg. Subsequently, there
a potent GnRH antagonist . Because of its long half-life,
have been two additional randomized trials in women failing
we suggested that a daily dose of 20–30 IU would provide
to ovulate with up to 150–250 mg of CC The rate of
similar LH-like activity. A dose of 50 IU of hCG was subse-
ovulation increased four- to fivefold and the rate of preg-
quently used successfully in a patient with hypogonadotropic
nancy per cycle increased 8- to 10-fold. In these trials the
hypogonadism treated with pure FSH .
dose of dexamethasone was 2 mg, but given only during
the 5 days of CC and for the following 5 days (days 5–14for women receiving CC days 5 through 9). In those trials
Conclusion Use of 10–30 IU daily of hCG may be logically
hCG was routinely given to induce ovulation. Also, in a large
used as an alternative to substituting 75–225 IU of hMG for
randomized trial of dexamethasone during stimulation for
the same dose of pure FSH when addition of LH activity is
IVF, a dramatic decrease of cancelled cycles from 12.4%–
desired. A separate consent is not suggested.
2.8 % was noted, and the implantation rates and PRs werehigher, despite inclusion of those poor prognosis women go-
A Rubinstein et al., in 1999 in this journal , published
B The role of glucocorticoids in the follicle is not well de-
a large, well-designed trial that found increases of ovarian re-
fined, although it is certainly of interest that the ratio of cor-
sponse, pregnancy outcome, and ovarian and uterine blood
tisol (F) to cortisone in follicular fluid (FF) has been
flow with 100 mg of aspirin compared with placebo in a pop-
reported to strongly correlate with IVF success Al-
ulation residing in a large metropolis. The aspirin was begun
though the major increase of androgens during ovarian
with the onset of midluteal agonist and was continued
stimulation results from FSH stimulation, supression of ad-
renal production of androgens by dexamethasone may con-
B Low dose aspirin is thought to increase blood flow by
tribute to maximizing uterine receptivity by lowering total
changing the balance of vasoconstricting thromboxane rela-
androgen levels and resulting in the benefits discussed pre-
tive to vasodilating prostacyclin. Ovarian blood flow has
been reported to correlate with ovarian response and uterine
blood flow has been implicated in implantation, which isa highly vascular phenomenon. It is not known how long
ovarian blood flow must be increased to potentially influence
E Minimal. Glucocorticoids should not be used with peptic
ovarian response. The most important time for maximal
ulcer disease, infection, diabetes, or latent tuberculosis.
blood flow may be between hCG and egg retrieval, during
With its use before IVF, the authors did not use any steroid
boost for oocyte retrieval, nor did they describe any tapering
C Subsequently a meta-analysis has been published, also in
this journal, combining seven remarkably heterogeneous tri-
Conclusion Dexamethasone has been reported to be a highly
als with the conclusion that the ovarian response and PR are
effective adjunct to CC. However, it is not yet known whether
not increased In two of these trials the aspirin was
its benefits will accrue in women failing CC and metformin
started on the same day as ovarian stimulation was begun
therapy. Dexamethasone has been widely used in PCOS,
and in one trial the aspirin was stopped at the time of hCG ad-
but a center may wish to have separate informed consent be-
ministration. The patient populations varied widely from
cause the higher dose, short duration regimen has not yet
a small city in Scandinavia to environments closer to that
of the original trial. Two studies were in frozen embryo
cycles and egg donation recipients, where an effect on em-
Conclusion The pathophysiology of OHSS and the benefit of
bryo quality would not be seen, and the hormone levels are
cabergoline have been extensively worked out, and a well-de-
entirely different from the original trial. One trial was in
signed study reported that it successfully reduced vascular
poor responders and one trial was in women with an endome-
permeability, hemoconcentration, and ascites in donors at
trium refractory to usual doses of E. In a very large trial not
high risk. With careful informed consent, the benefits warrant
included in the meta-analysis, presumably due to the random-
use in certain high risk situations. Further experience is ad-
ization method, the aspirin was started only with embryo
vised before suggesting routine use in all egg donors at risk
transfer, yet a significant increase in the PR was observed
for OHSS or in women having IVF with embryo transfer.
. However, a reanalysis of published trials by the Divisionof Epidemiology of the National Institutes of Health concluded that the clinical PR was increased and ‘‘there is
no reason to change clinical management and discontinue
A Balasch et al. reported the use of transdermal T for 5
days preceding ovarian stimulation in poor responders, witha marked increase in the number of follicles and peak E
D Ovarian stimulation is accompanied by increases of clot-
and an increase of circulating IGF-I. Although the patients’
ting factors. The platelet-inhibiting effect of aspirin may
prior cycles were used as the control, therefore potentially bi-
reduce the chance of a thrombotic event with COH and
asing the study by regression to the mean, their inclusion of
a second control cycle with an identical poor response would
E The anticoagulant effect could increase the chance of
argue for a true treatment effect. One of the authors (A.P.) re-
ported in a pilot study that letrozole, which increases intrao-varian androgen by blocking conversion to E, was associated
Conclusion A meta-analysis would negate the findings of
with an increased ovarian response to gonadotropins, in-
a previous large, well-designed trial only if the subjects are
creased FF T, and a marked increase of implantation com-
similar and the study medication is applied as in the original
pared with women not given letrozole Barad et al.
trial. For the full effect to be seen, it may be necessary to start
have reported that giving DHEA (a precursor for T in
treatment well before the onset of stimulation, and to con-
the ovary) before and during IVF in poor responders was as-
tinue therapy uninterrupted until well after embryo transfer.
sociated with an increase in the number of oocytes, embryos,
Furthermore, the data have been reanalyzed with the conclu-
and the rate of clinical pregnancy compared with retrospec-
sion that there is indeed an increase of the PR. The presumed
benefit of aspirin must stand until refuted by a valid meta-analysis of similar trials. Because of the extremely low risk
B Androgens increase FSH receptor activity, and well-con-
of low dose aspirin and because it is widely used, a separate
trolled studies in the primate have reported increased ovarian
response using a comparable amount of T to that used in thestudy by Balash et al. Granulosa cell androgen receptor
messenger RNA (mRNA) in the primate has been reportedto correlate positively with proliferation and negatively
A One of the authors (A.P.) has published a study reporting
with apoptosis of GCs . Androgens increase IGF-I and
that 0.5 mg of cabergoline given daily for 8 days to egg do-
therefore may act on GCs in a way similar to growth
nors at high risk of OHSS starting at the time of hCG admin-
istration decreased hemoconcentration, ascites, and vascularpermeability compared with placebo . These authors also
C Testosterone gel did not increase ovarian response, but the
have done a pilot study in women having embryo transfer
circulating levels of T were lower than with the T patch
with no adverse effects on fertilization, implantation, and
E Although letrozole causes fetal abnormalities in animals,
B Cabergoline and other dopamine agonists decrease expres-
such an effect has not been demonstrated in humans when
sion of the receptor for vascular endothelial growth factor and
the drug is stopped 10–12 days before embryo transfer
therefore the actions of vascular endothelial growth factor incausing OHSS
Conclusion Androgens and drugs that increase ovarian an-drogens, such as letrozole, may become important adjuncts
for patients with low prognosis IVF. Well-designed prospec-
E Cabergoline is used in women with hyperprolactinemia at
tive, placebo-controlled studies will be necessary to defini-
up to 1.0 mg twice weekly. The most common side effects are
tively characterize them in enhancing ovarian response and
headache, nausea, and dizziness. With long-term treatment
valvular heart disease has rarely been observed (3/1,000),generally with doses much higher than 0.5 mg. No caseswere observed with less than 6 months of use. It is difficult
to ascribe any significant risk to administration for 8 days
It is the authors’ opinion that there are many important ad-
juncts to ovarian stimulation that likely will never receive
official indications for optimizing the outcomes of COH. In
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Ill.mo signor Dott. Giovanni Kessler Presidente del Consiglio provinciale SEDE Per le persone che si recano nei Paesi a rischio malaria a quanto è stato riferito da persone che recentemente si sono recate in questi Paesi, l’Azienda sanitaria suggerisce l’assunzione di Lariam (meflochina) usato come trattamento preventivo e curativo della malaria. Gli effetti collaterali di questo farmaco po