There are a variety of effective treatment options to induce ovulation in women with polycystic ovary syndrome (PCOS). The most effective treatments are primarily reproductive and target the hypothalamic–pituitary–ovarian (HPO) axis. Letrozole, an aromatase inhibitor, is headed toward replacing clomiphene, a selective estrogen receptor modulator, as the first-choice option. Metabolic treatments likely work indirectly through the HPO axis. Many metabolic treatments have shown initial promise and later failed (troglitozone or d-chiro-inositol) or disappointed (metformin); further studies are needed of newer agents to treat type 2 diabetes. Weight loss interventions, lifestyle related, through obesity drugs or through bariatric surgery have shown mixed results on pregnancy outcomes. With both reproductive and metabolic treatments, combination therapies (such as metformin and clomiphene together) may offer greater benefit to distinct subgroups of patients.
Introduction
This chapter will review current strategies for ovulation induction in women with polycystic ovary syndrome (PCOS), focusing primarily on clinical aspects, identifying risk–benefit ratios, and areas of uncertainty. While it will acknowledge summary meta-analyses of treatment options where relevant, there will also be some detailed discussion of individual clinical trials and pearls obtained from the study. Treatments can primarily be divided into those that directly affect the reproductive axis, i.e., the hypothalamic-pituitary-ovarian axis, and those that act on metabolic factors and thus likely indirectly perturb the hypothalamic-pituitary-ovarian axis. Combination therapies with existing data will also be discussed.
Reproductive approaches to ovulation induction
Aromatase Inhibitors
Aromatase inhibitors are thought to induce ovulation in women with PCOS through reduction in inappropriate feedback of weak circulating estrogens, such as estrone, which correspondingly results in increased FSH secretion and follicular development. Many of these weak estrogens may result from peripheral conversion of androgens into estrogens by other tissues. Given the preponderance of adipose tissue in women with obesity, these drugs may offer a unique benefit in this subpopulation, though the data are mixed about whether obesity interacts with letrozole, the most studied aromatase inhibitor in ovulation induction to date. Other purported benefits are a lower rate of multifollicular recruitment and ovulation, a lesser anti-estrogenic effect on the endometrium than selective estrogen receptor modulators, and its own unique safety profile . The most common side effects with letrozole are headache and cramps. Compared to clomiphene, women on letrozole have fewer hot flashes, but more fatigue and dizziness. One of the initial concerns about letrozole, based on unpublished epidemiologic data, was an increased risk of congenital anomalies. Observational studies have supported that rates are similar to those after clomiphene ; further, two large prospective randomized trials that studied letrozole in women with PCOS and women with unexplained infertility support that cumulative rates of teratogenicity with letrozole are less than 5%, comparable to rates with clomiphene, and less than or equal to expected rates based on population reports of birth defects after ovulation induction or in vitro fertilization in an infertile population . The half-life of letrozole is around 2 days, which is substantially shorter than clomiphene. Despite these reassuring data, letrozole is proscribed in many parts of the world with “black box” warnings on the product label. This author, before making the recommendation for more studies showing safety, would first request the data showing harm in terms of increased congenital anomalies.
Success rates of letrozole compared to clomiphene, the usual first-line ovulation induction therapy in women with PCOS, based on current meta-analyses, suggest that women with PCOS are about 50% more likely to have a live birth with letrozole compared to clomiphene . The mechanisms behind this improved performance may be related to the lowering of estradiol levels (in comparison to other ovulation induction methods such as clomiphene and gonadotropins) and a relative increase in luteal progesterone levels, mimicking a more natural implantation environment ( Figure 1 ). The number of ovarian follicles that develop appears comparable to clomiphene. While there is a slight decrease in the multiple pregnancy rate compared to clomiphene, this is not statistically significant in trials or meta-analyses to date. From a public health perspective, further study of multiple pregnancy rates is necessary.
Anastrozole has also been studied, but it performed markedly inferiorly to clomiphene, and the development of the drug by the sponsoring pharmaceutical company was stopped . Single-dose therapy of anastrozole was also relatively ineffective .
Selective Estrogen Receptor Modulators
Clomiphene citrate is the most commonly used selective estrogen receptor modulator (SERM) in ovulation induction in women with PCOS, although tamoxifen has also been studied for this indication. Currently, the choice between letrozole and clomiphene as a first-line treatment agent for ovulation induction in women with PCOS is a debatable topic, though some voices in the wilderness argue for low-dose gonadotropin therapy . Interestingly, as with aromatase inhibitors, SERMS were originally developed for the treatment of hormone-dependent breast cancer. SERMs are thought to have a related, but unique mechanism of action as letrozole. Specifically, they are thought to function as estrogen receptor antagonists in the hypothalamus and stimulate GnRH and subsequent FSH secretion. They may also have similar effects elsewhere in the body; for instance, they may antagonize estrogen-stimulated endometrial development, thus inhibiting implantation while favoring ovulation. Overall, however, clomiphene has an estrogenic effect as indicated by the significant increases in circulating sex hormone binding globulin (SHBG) levels after even short exposures (i.e. 5 days). The increase in SHBG is much less with aromatase inhibitors. The metabolism of clomiphene is complex as it is a racemic mixture of two isomers (zu- and en-clomiphene that may have varying effects) and has a long half-life (5–7 days) such that metabolites may accumulate over time with carry-over effects in consecutive cycles .
Hot flashes are noted as a particularly annoying side effect by patients. Further, there is a theoretical concern about a sudden development of visual symptoms due to potential pituitary enlargement, and this can be a reason for treatment discontinuation, though clinically, it is often necessary to determine the source of such symptoms without intensive and expensive brain imaging. Multiple pregnancy rates are in the range of 5–8% and most are twins, though case reports have also documented high-order multiple pregnancies after clomiphene use.
Clinical Use of Anti-Estrogens and SERMS
Letrozole has been given in clinical studies in a similar fashion to the better established clomiphene. Both are given in the early follicular phase, or more correctly stated, the constant follicular phase of anovulatory women with PCOS. The starting dose for letrozole is 2.5 mg a day for 5 days, whereas for clomiphene, it is 50 mg a day for 5 days. Many groups will perform a baseline ultrasound with serum progesterone screening to rule out periodic and unexpected ovulation. At a minimum, it is prudent to perform a urine pregnancy test to rule out potential exposure of an early pregnancy to the medication before any dose is given. This advice is practical for all ovulation induction methods in women with PCOS.
It is debatable whether an induced withdrawal bleed is necessary prior to ovulation induction or between anovulatory cycles if a patient is nonresponsive to medication (i.e., letrozole or clomiphene resistant) . The present author’s current practice is to avoid it, unless there is ultrasound evidence of a potential abnormality. There are limited data to suggest that follicular phase monitoring and triggering of ovulation with hCG are superior to no monitoring and timed intercourse. It is expedient to monitor for ovulation in the follicular phase to allow for rapid advancement of starting doses if there is no ovulation or follicular development using the so-called stair-step protocol with dose increases every 2–3 weeks without follicular development . The dose of letrozole is increased by 2.5 mg a day up to a maximum daily dose of 7.5 mg for 5 days, and for clomiphene, the dose is increased by 50 mg a day up to a maximum daily dose of 150 mg a day. Higher daily doses of clomiphene have been given with reported success or longer duration of dosing beyond 5 days . Similar studies with letrozole have not been as widely reported.
Many issues with these two drugs still need to be addressed. The ideal number of cycles has not been established, but longer studies have shown that time does not diminish the per cycle pregnancy rates with clomiphene over 6 cycles or letrozole over 5 cycles . This, if a patient is ovulating, a longer course may be indicated if other factors do not lead to more advanced therapies. It is also unknown whether the sequential use is beneficial (and which sequence!)., i.e., if a patient ovulates but fails to conceive after letrozole, should she continue with clomiphene or shift to gonadotropins.
Gonadotropins
Recombinant or menopausal gonadotropins have been used traditionally as second-line therapy for ovulation induction, though head-to-head studies suggest a higher pregnancy rate than clomiphene . FSH preparations are thought to offer the best physiologic approach, given the relative elevation of circulating LH to FSH in many women with PCOS. Because women with PCOS are at an increased risk for the adverse events of gonadotropin use, such as ovarian hyperstimulation syndrome and multiple pregnancy, because of their relative youth compared to other infertility patients and their high number of antral follicles (and corresponding AMH levels), low-dose regimens should be used. Such low-dose regimens often begin at low daily doses of 37.5–75 units a day with a modest increase as needed only every 10–14 days, and dose reductions with over-response. Such regimens in experienced hands produce excellent pregnancy outcomes with a low multiple pregnancy rate . Often the first cycle of therapy is more prolonged as the optimal dose is discovered.
Pulsatile GnRH
Pulsatile GnRH has been given to women with PCOS and successfully results in ovulation and pregnancy. Limiting factors have been the unwieldiness of the pump compared to a daily shot or pill, the varying availability of GnRH for infusion, and the need, with increasing concern about infection, to avoid sharing the pump among patients as was commonly done when this form of therapy was first developed. There is current interest in this technology for other ovulatory disorders; thus, there may be renewed use of this therapy in the future.
Reproductive approaches to ovulation induction
Aromatase Inhibitors
Aromatase inhibitors are thought to induce ovulation in women with PCOS through reduction in inappropriate feedback of weak circulating estrogens, such as estrone, which correspondingly results in increased FSH secretion and follicular development. Many of these weak estrogens may result from peripheral conversion of androgens into estrogens by other tissues. Given the preponderance of adipose tissue in women with obesity, these drugs may offer a unique benefit in this subpopulation, though the data are mixed about whether obesity interacts with letrozole, the most studied aromatase inhibitor in ovulation induction to date. Other purported benefits are a lower rate of multifollicular recruitment and ovulation, a lesser anti-estrogenic effect on the endometrium than selective estrogen receptor modulators, and its own unique safety profile . The most common side effects with letrozole are headache and cramps. Compared to clomiphene, women on letrozole have fewer hot flashes, but more fatigue and dizziness. One of the initial concerns about letrozole, based on unpublished epidemiologic data, was an increased risk of congenital anomalies. Observational studies have supported that rates are similar to those after clomiphene ; further, two large prospective randomized trials that studied letrozole in women with PCOS and women with unexplained infertility support that cumulative rates of teratogenicity with letrozole are less than 5%, comparable to rates with clomiphene, and less than or equal to expected rates based on population reports of birth defects after ovulation induction or in vitro fertilization in an infertile population . The half-life of letrozole is around 2 days, which is substantially shorter than clomiphene. Despite these reassuring data, letrozole is proscribed in many parts of the world with “black box” warnings on the product label. This author, before making the recommendation for more studies showing safety, would first request the data showing harm in terms of increased congenital anomalies.
Success rates of letrozole compared to clomiphene, the usual first-line ovulation induction therapy in women with PCOS, based on current meta-analyses, suggest that women with PCOS are about 50% more likely to have a live birth with letrozole compared to clomiphene . The mechanisms behind this improved performance may be related to the lowering of estradiol levels (in comparison to other ovulation induction methods such as clomiphene and gonadotropins) and a relative increase in luteal progesterone levels, mimicking a more natural implantation environment ( Figure 1 ). The number of ovarian follicles that develop appears comparable to clomiphene. While there is a slight decrease in the multiple pregnancy rate compared to clomiphene, this is not statistically significant in trials or meta-analyses to date. From a public health perspective, further study of multiple pregnancy rates is necessary.
