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Alternatives for Ovulation
Induction and Superovulation: Serms and Aromatase Inhibitors
David E. Tourgeman M.D., F.A.C.O.G.
Ovulatory
dysfunction is one of the most common causes for
infertility in otherwise fertile couples.
Once successful ovulation is achieved, fertility is
often restored. For many years, the first line of pharmacologic
ovulation induction has involved the use of selective
estrogen receptor modulators (SERMs), of which clomiphene
citrate (CC) has been most extensively studied.
The first trial of CC resulted in successful ovulation
induction in approximately 80% of women, and ultimately
half were able to achieve pregnancy. The use of CC for
superovulation in patients with unexplained infertility,
has also been the mainstay when coupled with
intrauterine insemination. Yet despite advances
in ultrasonographic technology, hormone assays, and
urinary leutinizing hormone kits, success with CC has
not changed dramatically. Therefore, it is important
that we evaluate our options for ovulation induction
and superovulation.
SERMs
SERMs
are structurally diverse non-steroidal compounds (triphenylethlene
derivatives) that bind to estrogen receptors and have
tissue-dependent agonistic and antagonistic effects.
CC is characterized by agonistic properties when endogenous
estrogen levels are low, and as a competitive antagonist
when levels are high. In anovulatory women, depletion
of estrogen receptors in the hypothalamus results in
normalization of gonadotropin releasing hormone (GnRH)
secretion and hence, secretion of pituitary follicle
stimulating hormone (FSH) levels are optimized. This
in turn will drive ovarian follicular development, resulting
in ovulation and possible resolution of infertility.
The
goal in anovulatory women is mono-ovulation, whereas
with superovulation multiple follicle development is
desired. However, even in anovulatory women, the use
of CC can result in the development of multiple follicles
as the result of prolonged clearance of its isomers.
Thus, the risk of multiple gestation is increased to
8%. Other side effects also limit the usefulness of
CC. Namely; CC exerts undesirable anti-estrogenic effects
in the periphery (endocervix, endometrium, and ovary)
that helps explain the discrepancy between ovulation
and conception rates. Additionally, vasomotor flushes
may occur as frequently as in 10% of cycles. Other side
effects include mood swings, visual disturbances, breast
tenderness, pelvic discomfort, and nausea.
The
use of tamoxifen (BMX), another SERM, for ovulation
induction has been the subject of clinical investigation
since the early 1970s. A recent prospective randomized
controlled trial compared the efficacy of TMX with CC
in anovulatory women. The overall rates of ovulation
and pregnancy were similar in both groups. Other studies
have suggested that TMX may be superior to CC in that
there does not appear to have an adverse impact on the
endometrium. TMX has been shown to be effective in the
treatment of ovulation induction even when CC has failed,
but has yet to be tested for superovulation.
Raloxifene,
a structurally related compound, also appears to increase
follicular phase FSH, with resultant elevation in estradiol
levels. However, it has not been evaluated as a potential
ovulation induction agent. In addition, raloxifene may
act primarily as an antagonist at the level of the endometrium.
Other
novel uses of the SERMs have included the combination
of CC and TMX. Their combined effects in the treatment
of anovulation appears to result in increased ovulation
rates and pregnancy. Although the combination of CC
and human menopausal gonadotropins induces ovulation
in anovulatory, patients undergoing in-vitro fertilization,
and those who have had a poor response to gonadotropins
alone, the combination of the newer SERMs and human
menopausal gonadotropins remains largely uninvestigated.
Aromatase Inhibitors
Aromatase
inhibitors are unique pharmacologic agents whose main
mode of action is to decrease peripheral estradiol production
by the ovary. This is in contrast to the SERMs that
act centrally, nonetheless the end result is similar;
namely, a decrease in central estrogen feedback that
stimulates a compensatory increase in pituitary gonadotropin
release. By reducing circulating estradiol levels, aromatase
inhibitors have been used to treat endometriosis, estrogen
responsive cancers, leiomyomata uteri, as well as to
induce ovulation. Primate studies have demonstrated
that administration of aromatase inhibitors during the
follicular phase results in the development of mature
follicles which, when coupled with hCG could be shown
to ovulate.
Summary- Alternative Ovulation
Induction Drugs
In
women with anovulatory infertility, the treatment of
first choice for induction of ovulation is most commonly
CC. However, not all women will ovulate with Clomid alone
or may have impaired endometrial development. Yet others
may have severe side effects limiting the use of CC.
In these patients, the use of other SERMs such as tamoxifen
may allow the achievement of our goals. Yet, the impact
of multiple gestation continues to reduce the appeal
of these medications. With our growing experience, aromatase
inhibitors may help accomplish mono-ovulation in this
group of patients. In couples with unexplained infertility
that are undergoing superovulation and intrauterine
insemination, it appears that the SERMs are most effective
in provoking the development of multiple follicles,
and thus remain our primary treatment modality.
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