Medical Approaches to Ovarian Stimulation for Infertility

Ovulation Induction

In the strict sense of the term, ovulation induction refers to the triggering of ovulation, that is, the rupture of the preovulatory Graafian follicle and release of the oocyte. In the clinical context, however, this term refers to the type of ovarian stimulation for anovulatory women aimed at restoring normal fertility by generating normoovulatory cycles (i.e., to mimic physiology and induce single dominant follicle selection and ovulation). Ovulation induction represents one of the most common interventions for the treatment of infertility. The indications for ovulation induction and the treatments depend on the etiology of the anovulation.

Ovarian Stimulation

This treatment modality has become an integral part of assisted reproductive technologies (ART). The aim of ART is to bring more male and female gametes closer together and thereby increase the chances of pregnancy. The goal of ovarian stimulation is to induce ongoing development of multiple dominant follicles and to mature many oocytes to improve chances for conception either in vivo (empirical ovarian stimulation with timed intercourse or intrauterine insemination [IUI]) or in vitro with IVF, a concept often referred to in the past as controlled ovarian hyperstimulation (COH) or superovulation. This approach of interfering with physiologic mechanisms underlying single dominant follicle selection is usually applied in normoovulatory women. Because the goal in this population is usually the recruitment and ovulation of multiple follicles, we will also at times use the terms superovulation or COH when this is the goal, and ovulation induction when the goal is the establishment of monofollicular ovulation. Although ovarian superovulation can also be performed in anovulatory women, this approach should be clearly differentiated from ovulation induction. The physiologic concepts that underlie current approaches to ovulation induction and ovarian superovulation are described later in this chapter.

Clomiphene Citrate

In the late 1950s, the first nonsteroidal estrogen antagonist (MER-25) was tested in women to assess its efficacy for treatment of cystic mastitis, breast cancer, endometrial hyperplasia, and endometriosis. Some of the women with endometrial hyperplasia were of reproductive age and suffering from long-standing amenorrhea due to the Stein-Leventhal syndrome (PCOS). To the great surprise of the investigators, the initiation of the medication in these women was followed by the recommencement of menstrual cycles. Shortly thereafter, the ovulation-inducing capacity of the next generation of closely related antiestrogens (MRL/41; clomiphene citrate [CC]) ( Fig. 34.1 ) was recognized. More than half a century later, CC is still one of the most utilized infertility therapies worldwide and consistently earns a spot on the WHO’s List of Essential Medicines. The principal indication for CC is the treatment of anovulatory infertility in women with an intact hypophyseal-pituitary-ovarian axis (WHO Group II Anovulation). However, it is also used empirically for ovarian stimulation in normoovulatory women. Given orally in the early to midfollicular phase, it causes a 50% rise in serum FSH levels, thus stimulating follicle growth. This rise in FSH is accompanied by a similar rise in serum LH levels. Limitation of the duration of administration to 5 days is aimed at allowing FSH levels to fall in the late follicular phase and the mechanisms for monofollicular development and ovulation to operate.

CC is classified as a selective estrogen receptor modulator (SERM). It is a racemic mixture of two stereoisomers: enclomiphene, which has a relatively short half-life and is an estrogen receptor antagonist; and zuclomiphene, which has estrogen agonist activity, and an extended half-life with drug levels still detectable up to 1 month after administration. The long half-life of zuclomiphene results in accumulation across consecutive cycles of treatment. However, the resulting concentrations are unlikely to be of clinical significance.

CC stimulates follicular development by elevating pituitary FSH secretion through the blockade of E ₂ steroid feedback. This is likely mediated at the level of the hypothalamus. Both LH and FSH levels increase significantly in normoovulatory and anovulatory women after CC administration in the early follicular phase, and this is likely due to an increase in the GnRH-mediated pulse frequency ( Fig. 34.2 ) . ^, Overall, a 50% to 60% increase in serum FSH levels above baseline has been described. The exact nature of the mechanism of action of CC is still uncertain. ^, CC-induced changes in other systems, such as insulin-like growth factor (IGF), may partly explain the capacity of CC to stimulate the ovary. However, antiestrogenic effects at the uterine level (cervical mucus production and endometrial receptivity) are believed to underlie the observed discrepancy between achieved ovulation and pregnancy rates. This antiestrogenic effect on the endometrium is often assessed by endometrial thickness in the sagittal plane by transvaginal ultrasound and clomiphene results in a thinner endometrium than other methods of ovulation induction in WHO Group II anovulation. The impact of a concomitant rise in LH on ovarian response to CC is also uncertain. CC for ovulation induction is considered to be relatively safe because steroid negative feedback remains intact. The oral route of administration and low costs represent additional advantages of this treatment. CC was originally developed for clinical use by the Wm. S. Merrell company in 1956, and it is still considered to represent, depending on the country, either a first or second-line treatment strategy in most anovulatory infertility. In addition, this compound was a central component in the early days of IVF. ^,

Insulin Sensitizing Agents

The role of insulin resistance in the pathogenesis of ovarian dysfunction in many PCOS patients led to the introduction of insulin-sensitizing agents as adjuvant or sole treatments for the induction of ovulation.

Metformin The most extensively studied insulin-sensitizing drug in the treatment of WHO Group II Anovulation is metformin. Metformin (dimethylbiguanide) is an orally administered drug used to lower blood glucose concentrations in patients with type 2 diabetes. It is antihyperglycemic in action and increases sensitivity to insulin by inhibiting hepatic glucose production and by increasing glucose uptake and utilization in muscle. These actions result in reduced insulin resistance, lower insulin secretion, and reduced serum insulin levels. Metformin is not metabolized and is excreted by the kidneys intact. The first studies reporting the use of metformin as an ovulation induction agent suggested that metformin improved insulin sensitivity, lowered LH and total and free testosterone concentrations, and increased FSH and sex hormone-binding globulin levels. ^, This and subsequent uncontrolled studies indicated that correction of hyperinsulinemia has a beneficial effect in anovulatory women, by increasing menstrual cyclicity, improving spontaneous ovulation, and thus promoting fertility. ^, While menstrual frequency is improved by roughly a third to a half from baseline, metformin does not always restore a regular menstrual cycle in women with PCOS. However, the majority of observational studies addressing weight loss with metformin have revealed a reduction in body mass index (BMI) of 1% to 4.3%. Metformin is often used in conjunction with lifestyle modification to treat PCOS. However, studies suggest that there is limited benefit to the addition of metformin beyond lifestyle modification alone in PCOS. The use of metformin as a first-line solo infertility therapy for WHO Group II Anovulation has not been supported by randomized trials, although it is superior to placebo, and there is emerging data about its utility as an adjuvant agent.

Thiazolidinediones Smaller trials have shown some benefit for this class of drugs for the treatment of infertility, usually in conjunction with CC. ^, However, concerns about hepatotoxicity, cardiovascular risk, weight gain, and reproductive toxicity in animal studies have limited the use of these drugs in women with PCOS. One of the thiazolidinediones, troglitazone, was removed from the U.S. market due to hepatotoxicity. Similarly, rosiglitazone has been restricted in many national markets because of increased cardiovascular events, and pioglitazone because of concerns about bladder cancer. Nonetheless, improving insulin sensitivity with these drugs is associated with a decrease in circulating androgen levels, improved ovulation rate, and improved glucose tolerance. However, given the restrictions on their use in patients with type 2 diabetes, the risk-to-benefit ratio appears very unfavorable for women with PCOS seeking fertility, and their use is not recommended.

GLP-1 agonists GLP-1 (Glucagon-like peptide) is an incretin secreted by the L cells of the intestine and it increases pancreatic beta cell insulin production and insulin sensitivity. It also has CNS effects which lead to decreased appetite through a variety of mechanisms. GLP-1 agonists have been approved both for the treatment of type 2 diabetes and in higher doses for the treatment of obesity in the U.S. These drugs offer a favorable treatment strategy for women with PCOS. However, studies have been limited, likely because of two factors: the requirement for parenteral injection of initial preparations although oral forms are now available (semaglutide, for example) and the relative expense of these drugs in both their parenteral and oral versions compared to other drugs. Small observational studies with GLP-1 agonists indicate that women with PCOS tend to lose weight, have improved menstrual frequency, and experience improvements in metabolic parameters related to insulin resistance. ^, One small randomized controlled study found the combination of low-dose liraglutide and metformin superior to metformin alone on the pregnancy rate in women with PCOS undergoing IVF. The use of these drugs is still experimental as an infertility therapy. Side effects of concern with this class of drugs include pancreatitis and an increased risk of thyroid cancer (medullary C), and concerns about CNS interactions in patients with psychiatric disorders.

Inositols Many supplements have been touted to improve ovulatory frequency in women with PCOS, most commonly inositols. Inositol is incorporated into cell membranes as phosphatidyl-myo-inositol, the precursor of the second messenger, inositol triphosphate, which functions in insulin (and other protein hormones, including gonadotropin) signaling. D-chiro-inositol, one of the stereoisomers of myo-inositol was thought to be deficient in PCOS, contributing to insulin resistance. An initial small randomized controlled study showed a remarkable improvement in ovulatory frequency compared to placebo, with significant decreases in serum androgen and triglyceride concentrations as well as blood pressure. Subsequently, the pharmaceutical company that developed the drug (INSMED), conducted two Phase II multicenter studies in women with PCOS. These studies showed no benefit (as did simultaneously conducted studies in type 2 diabetes) and the company discontinued the development of the drug for PCOS and for Type 2 diabetes. The full results of the Phase II studies were never published. Despite the lack of published data about the efficacy of d-chiro-inositol, experts proposed that there was an excess of d-chiro-inositol leading to an improper balance between myo-inositol and d-chiro-inositol in women with PCOS. Myo-inositol is the predominant inositol in humans, comprising more than 90% of inositols, although there are thought to be tissue-specific patterns in the relative abundance of the isomers, which is controlled by an insulin-sensitive epimerase. This led to several studies with replacement of myo-inositol alone or combinations of both inositols. ^{, ,} These studies noted an excess of circulating myo-inositol compared to d-chiro-inositol, which has been used as the rationale for many current proprietary formulations of myo-inositol and d-chiro-inositol. The evidence supporting improved pregnancy rates with the use of inositols is of poor quality, but this has not discouraged its use or promotion of it as an infertility therapy.

Gonadotropin Preparations

Clinical experiments in the late 1950s demonstrated that extracts derived from the human pituitary could be used to stimulate gonadal function. Subsequently, the extraction of both gonadotropic hormones, LH and FSH, from the urine of postmenopausal women led to the development of human menopausal gonadotropin (hMG) preparations. From the early 1960s, these preparations were used for the stimulation of gonadal function in the human. It soon became clear that hMG was a very potent agent. Its ability to directly stimulate the ovaries was accompanied by the inherent risks of superovulation. Initial use in the treatment of anovulation was associated with high rates of multiple pregnancy and OHSS. The potential for dangerous complications led to the need for careful monitoring of the ovarian response and dose adjustment. The introduction of low-dose protocols applied in conjunction with focused ovarian response monitoring has substantially contributed to improved treatment outcomes and reduced complication rates.

Initial attempts by Edwards and Steptoe to enable conception through IVF also involved hMG stimulation protocols. Because of a lack of pregnancies (presumed to be due to abnormal luteal function), treatment was switched to natural cycle IVF. It was an unstimulated cycle that led to the conception of the first IVF baby, Louise Brown, who was born on July 25, 1978. Subsequent IVF pregnancies were reported from Australia after ovarian stimulation with CC. The more widespread use of hMG for successful IVF was developed thereafter in the United States.

For over 2 decades, gonadotropin preparations have also been extensively applied for ovarian stimulation using superovulation in ovulatory women for empirical treatment of unexplained subfertility. The aim here is to increase monthly fecundity rates by increasing the number of oocytes available for fertilization in vivo (with or without the additional use of IUI). These trends and the rapid expansion in the use of IVF treatments underlie the enormous increase in worldwide demand and sales for gonadotropin preparations.

The early hMG extraction techniques were very crude, requiring around 30 L of urine to manufacture enough hMG needed for a single stimulation cycle. The FSH to LH bioactivity ratio of these early preparations was 1:1. These initial preparations were impure, with many contaminating proteins; less than 5% of the proteins present were bioactive gonadotropins. As purity improved, it was necessary to add human chorionic gonadotropin (hCG) to maintain the ratio of FSH:LH bioactivity. Bioactivity of gonadotropin preparations continues to be assessed by the crude in vivo rat ovarian weight gain Steehlman and Pohley assay. This rather anachronistic technique has the disadvantage of allowing considerable batch-to-batch inconsistency in bioactivity.

Improved protein purification technology allowed for the production of hMG with reduced amounts of contaminating proteins and eventually the development of purified urinary FSH (uFSH) preparations using monoclonal antibodies in the late 1980s. The currently available pure products allow for fewer hypersensitivity reactions and less painful subcutaneous administration. Because of the worldwide increased need for gonadotropin preparations, demands for postmenopausal urine increased tremendously, and adequate supplies could no longer be guaranteed. In addition, concerns regarding batch-to-batch consistency along with possibilities of pathogenic contaminants emerged.

Through recombinant DNA technology and the transfection of human genes encoding for the common α subunit and hormone-specific β subunit of the glycoprotein hormone ( Fig. 34.4 ) into Chinese hamster ovary cell lines, the large-scale in vitro production of human recombinant FSH (rFSH) has been realized (see Chapter 2 ). The first pregnancies using this novel preparation in ovulation induction and in IVF were reported in 1992. Since then, numerous large-scale, multicenter studies have been undertaken, demonstrating their efficacy and safety. The recombinant products offer improved purity, consistency, and large-scale availability. Because of its purity, rFSH can now be administered by protein weight rather than bioactivity, and so-called filled-by-mass preparations are now available for clinical use. Subsequently, recombinant LH (rLH) and recombinant hCG (rhCG) have also been introduced into clinical practice. Finally, a long-acting rFSH agonist (a synthetic chimeric hormone generated by the fusion of the carboxy-terminal peptide [CTP] of hCG to the FSH-β chain) has been introduced into the clinic after efficacy and safety was established in large sample size trials in which IVF clinics from all over the world participated. The first rFSH produced in a human cell line has been tested, and rFSH biosimilars have been introduced on the market.

Gonadotropin-Releasing Hormone Analogues

In 1971, the decapeptide GnRH was isolated and its structure was elucidated by Schally and Guillemin ( Fig. 34.5 ). Years later, both investigators jointly received the Nobel Prize for this discovery. Amino acid substitutions have revealed the significance of specific amino acid residues for their stability, receptor binding, and activation of gonadotrope cells. This decapeptide is secreted by the hypothalamus into the portal circulation in an intermittent fashion, stimulating the pituitary gonadotropes to synthesize and secrete LH and FSH. Early studies demonstrated that pituitary downregulation could be induced by the continued administration of GnRH.

Clinically safe, GnRH agonists were developed by replacing one or two amino acids. An increased potency could be achieved by replacing glycine for D-amino acids at position 6 and by replacing Gly-NH ₂ at position 10 with ethylamide. Such simple structural changes render these compounds more hydrophobic and more resistant to enzymatic degradation. The administration of GnRH agonists induces an initial stimulation of gonadotropin release for 2 to 3 weeks (the so-called flare effect ) followed by a downregulation (or desensitization) due to the clustering and internalization of pituitary GnRH receptors.

GnRH agonists have been used clinically since 1981 to induce a “chemical castration” for steroid-dependent disease states such as fibroids and endometriosis in females and prostate cancer in males. The first paper concerning its use in IVF for the prevention of a premature LH rise also appeared in the early 1980s. Shortly thereafter, the use of GnRH agonists such as buserelin, triptorelin, or leuprorelin to downregulate the pituitary prior to administration of gonadotropins (a strategy that became known as the “long protocol”) became the standard of care. The more recent clinical introduction of GnRH antagonists has slowly changed practice in IVF, and most IVF cycles currently apply GnRH antagonist cotreatment.

It has taken almost 3 decades to develop GnRH antagonists with acceptable safety and pharmacokinetic characteristics. The first-generation antagonists were developed by replacing amino acids histidine at position 2 and tryptophan at position 3, but these compounds suffered from low potency. In second-generation compounds, the activity was increased by incorporating a D-amino acid at position 6. However, the widespread clinical application of these compounds was hampered by frequent anaphylactic responses due to histamine release. By introducing further replacements at position 10, third-generation compounds were developed. ^, Subsequently, both ganirelix and cetrotide were shown to be safe and efficacious in IVF. These third-generation GnRH antagonists were registered in 2001 for use in IVF. The immediate suppression and recovery of pituitary function render these compounds appropriate for short-term use in IVF. Meta-analyses have confirmed that GnRH antagonist cotreatment is effective and safer than GnRH agonists.

Ovulation Induction

Amenorrheic women with anovulation have virtually no chance of spontaneous conception, and those with WHO Group II Anovulation with oligomenorrhea have reduced chances compared to normoovulatory women. Ovulation induction may restore normal fertility in both groups. However, the aim of mimicking normoovulatory cycles (with rare multifollicular ovulation) cannot always be achieved, so the risk of complications such as multiple pregnancy or OHSS should be taken seriously, especially in patients diagnosed with PCOS. Oligomenorrheic women may or may not have incidental spontaneous ovulations; therefore, spontaneous pregnancies may occur. The balance between success and complications resulting from ovulation induction is dependent on many factors, including patient characteristics, type of drugs used, gonadotropin preparations and dose regimens used, the intensity of monitoring ovarian response to stimulation, and willingness to cancel the cycle in case of hyperresponse. An alternative option under these circumstances would be convert to IVF with elective single embryo transfer. Cumulative live birth rates of ovulation induction in some populations have been reported to be as high as 75% to 80%, ^, with a coinciding incidence of multiple pregnancies of around 10% and of OHSS of less than 2%. However, if other factors that impair fertility are present, such as obesity or advanced maternal age, much lower cumulative pregnancy rates have been reported.

OHSS is a potentially life-threatening complication characterized by ovarian enlargement, high serum sex steroids, and extravascular fluid accumulation, primarily in the peritoneal cavity. In severe cases, depleted intravascular volumes and hemoconcentration can lead to hypotension, reduced renal perfusion, and potentially oliguria, as well as hypercoagulability. Deranged liver function tests, venous and arterial thrombosis, renal failure, and adult respiratory distress syndrome can ensue, and fatalities have been reported. Moderate to critical OHSS is very rare with CC or letrozole but constitutes an important complication of gonadotropin use. The incidence of mild, moderate, and severe OHSS following gonadotropin ovulation induction has been reported to be 20%, 6% to 7%, and 1% to 2%, respectively. In addition to PCOS, risk factors for the development of OHSS include young age and low body weight. The risk is further increased when adjuvant GnRH agonist treatment is employed.

The contribution of ovulation induction treatment to the number of triplet and higher-order pregnancies is considerable. It has been calculated that 40% of higher-order multiple births in the United States could be attributed to the use of ovulation-inducing drugs without assisted reproduction. It is likely that the use of gonadotropins has disproportionately contributed to the high-order multiple pregnancies compared to oral agents where twinning is the usual multiple pregnancy outcome. ^,

Ovarian Stimulation

As previously outlined, the aim of ovarian stimulation alone or in combination with assisted reproduction techniques is to bring an increased number of gametes (oocytes and sperm) in close proximity to augment pregnancy chances. The associated risk of OHSS and the occurrence of twin and higher-order multiple births are dependent on the magnitude of ovarian stimulation, the intensity of ovarian response monitoring, and the criteria applied for cycle cancellation should too many follicles develop. The overall incidence of severe ovarian OHSS associated with ovarian hyperstimulation is less than 5%.

Initial studies suggested that a threefold increase in the monthly probability of pregnancy can be achieved with empirical ovarian stimulation in the treatment of the unexplained infertility. Subsequently, a large multicenter study showed that ovarian hyperstimulation with gonadotropins and IUI both exhibit an independent additive effect on the chances of pregnancy. Moreover, overall cumulative pregnancy rates with this combined therapy were reported to be 33% within three cycles, but at the price of an unacceptably high multiple pregnancy rate of 20% for twins and 10% for higher-order multiple pregnancy. It has been proposed that a similar cumulative pregnancy rate could be achieved by expectant management over a 6-month period, obviously with much lower chances of multiple pregnancy. Another more recent, well-designed randomized controlled trial (RCT) of ovarian stimulation in unexplained infertility comparing gonadotropins, the aromatase inhibitor, letrozole, and CC concluded that gonadotropins are superior in terms of cumulative clinical pregnancy rates, but again at the expense of a high multiple pregnancy rate of 32% ( Fig. 34.6 ). These studies as noted are comparative effectiveness studies. It has been more difficult to design and complete trials with a “placebo” arm of expectant management. A well-designed trial of ovarian stimulation (with either CC or gonadotropins) with intrauterine insemination for up to 3 treatment cycles had a comparison group of no treatment (i.e., only expectant management for the equivalent of 3 menstrual cycles or 120 days). This study documented a nearly threefold higher pregnancy rate with treatment (31%) versus expectant management (9%) (risk ratio [RR] 3·41, 95% confidence interval [CI] 1·71–6·79; p = 0·0003) with exceptionally low multiple pregnancy rates ( Fig. 34.7 ).

Less intense ovarian stimulation may reduce the incidence of higher-order multiple pregnancies, but probably at the expense of a reduction in the overall conception rate. Based on a 2-year experience in a large US infertility clinic involving 3347 consecutive ovarian stimulation cycles (ovulation induction and ovarian hyperstimulation combined) in approximately 1500 women, a 30% pregnancy rate was reported. Twenty percent of these pregnancies were twins, along with 5% triplets and 5% quadruplets or higher order. The most worrying conclusion of this analysis was that the number of large antral follicles or serum E ₂ levels during the late follicular phase had only limited value in predicting higher-order multiple gestations. The true rate of multiple pregnancies arising from ovarian stimulation with or without IUI remains uncertain, however, as few national registries record the outcome of ovarian stimulation with superovulation.

It has been estimated that ovarian stimulation with or without IUI is responsible for around 30% of multiple births ( Fig. 34.8 ). It is easier to influence chances for multiple gestations after IVF because the occurrence is primarily dependent on the number of embryos transferred. Therefore, ovarian stimulation for IVF is merely the factor allowing for the generation of multiples, but it is not the sole determining factor as in IUI. Unsurprisingly, the incidence of twin pregnancies following IVF without stimulation or with ovarian stimulation combined with single embryo transfer (SET) is close to normal. ^, Over the years, the number of embryos transferred in IVF has decreased globally, and with the increasing utilization of elective single embryo transfer after culture of embryos to the blastocyst stage, multiple pregnancy rates from IVF have plummeted. (see Chapter 35 ).

Given the risks associated with ovarian stimulation, couples should be counseled regarding their chances for spontaneous pregnancy prior to commencing empirical therapy for unexplained infertility ( Table 34.1 ). These chances are often underestimated. Although demographic trends support a declining birth rate in most developed countries, external events can clearly affect the utilization of infertility services. The COVID-19 pandemic, after an initial shutdown of infertility care in the U.S. in 2020 was followed by a significant increase in patients seeking infertility diagnosis and treatment among all ages of women, substantially increasing utilization. This suggests that there was also diminished uptake of expectant management among the U.S. population.

Higher-order multiple pregnancies have a major adverse impact on perinatal morbidity and mortality rates. The mortality rate is increased 4- to 7-fold in twins and up to 20-fold in triplets. Children born from multiple pregnancies have more chances for perinatal complications and subsequent health problems, chiefly associated with prematurity and low birth weight. Risk for cerebral palsy is increased almost 50-fold in children from triplet pregnancies. Even the second child from a twin pregnancy delivered at term presents with a significantly increased risk for death due to complications of vaginal delivery. Besides the medical and emotional burden, the financial costs associated with multiple pregnancies should be considered by policymakers. Obstetric and neonatal costs are increased fivefold to sevenfold in higher-order multiples, and by the age of eight, costs for low-birth-weight children are increased eightfold. Finally, possibilities of more subtle health risks that may be revealed only later in life should also be considered.

One strategy that may drive improved outcomes would be to define success in infertility therapy in a new way, shifting from pregnancy rate per treatment cycle to a healthy live birth per course of treatment (which may involve multiple treatment cycles) in the context of cost, burden of treatment, and maternal and infant complication rates. ^,

Time to pregnancy is a significant factor determining the choice of infertility therapies in couples with unexplained infertility, and it tends to favor IVF in comparative epidemiologic studies or studies of sequential treatment of ovarian stimulation/IUI and IVF. The FASTT trial randomized women aged 21 to 39 years to either conventional treatment with three cycles of CC/IUI, three cycles of FSH/IUI, and up to six cycles of IVF or an accelerated treatment (n = 256) that omitted the three cycles of FSH/IUI (i.e., the fast track). An increased rate of pregnancy was observed in the fast track arm (hazard ratio [HR], 1.25; 95% CI, 1.00–1.56) compared with the conventional arm. ( Fig. 34.9 ) The fast track also had a lower median time to pregnancy and was more cost-effective than the conventional track.

Head-to-head trials of superovulation/IUI compared to IVF are limited and would inform the relative ranking of these treatments. The best example of such a trial (and hopefully a harbinger of future trials) compared the effectiveness of IVF with single embryo transfer or IVF. in a modified natural cycle with that of intrauterine insemination with controlled ovarian hyperstimulation in terms of the birth of a healthy child. The population consisted of women aged 18 to 39 with unexplained infertility or a mild male factor. Designed as a noninferiority trial, none of the treatments met the cut point for inferiority (i.e., all had comparable outcomes). The birth of a healthy child occurred in 52% of couples in the IVF with single embryo transfer group, 43% in the IVF with a modified natural cycle group, and 47% in the IUI with controlled ovarian hyperstimulation group. This came with the caveat that conventional IVF tended to have higher earlier healthy live births, and the COH/IUI group tended to move on to other therapies as the trial progressed ( Fig. 34.10 ) .

Principles of Ovulation Induction

The aim of induction of ovulation in anovulatory women is to stimulate a single follicle to develop up to the preovulatory stage and subsequently ovulate. As stated before, this therapeutic goal should be clearly distinguished from two other forms of ovarian stimulation. First, ovulatory women with unexplained infertility may undergo ovarian stimulation aimed at producing two or three follicles and an increased chance of fertilization in each cycle. This treatment, which is frequently combined with IUI, is discussed later in the chapter. Second, ovarian stimulation may be applied in ovulatory women undergoing IVF treatment where multifollicular development is required to produce multiple oocytes.

In contrast, ovulation induction aims to mimic the normal physiologic monofollicular ovulatory cycle. Ovulation induction is characterized, therefore, by tighter therapeutic margins and a need for careful monitoring and skilled management if success without complications is to be achieved. Ovarian surgical techniques such as laparoscopic drilling offer an alternative to medical therapies in this context. Again, the aim of this treatment paradigm is to institute monofollicular ovulatory cycles.

Anovulatory disorders account for around 25% of all causes of infertility. This proportion may increase with the rising prevalence of obesity. Anovulation is usually manifested as the absence (amenorrhea) or infrequent occurrence (oligomenorrhoea) of menstrual periods. Although oligomenorrhoea may be associated with occasional ovulation, the chance of a woman conceiving within a year of unprotected intercourse is clearly diminished unless there are therapeutic interventions. Many medical approaches have been developed to achieve the goal of inducing the monthly development of a single dominant follicle and subsequent ovulation. In recent years, an increased understanding of the pathophysiology of ovarian dysfunction has enabled the development of clinical strategies that aim to mimic the endocrine control of normoovulatory cycles. Achieving this within the narrow therapeutic margins of stimulating single rather than multiple follicular developments remains a challenge to clinicians.

The second European Society of Human Reproduction and Embryology (ESHRE) and Association of Reproductive Managers (ASRM) sponsored PCOS consensus workshop as well as the subsequent International Evidence-Based Guidelines have acknowledged that much attention should be paid to the condition of the woman (in terms of food intake, lifestyle, and smoking habits) before embarking on any form of ovulation induction. ^, Such a periconception strategy emphasizes the general observation that chances for pregnancy complications and compromised child outcomes are directly related to the health status of the woman prior to achieving a pregnancy.

Clomiphene Citrate

Preparations and Regimens

The conventional starting dose of CC is 50 mg/day, starting from day two until day 5 of the menstrual cycle, for 5 consecutive days. In normogonadotropic amenorrheic women, conventional treatment was often initiated after a progesterone-induced withdrawal bleed, Whether CC is commenced on cycle day 1 or 5 does not appear to affect outcomes. However, there are data suggesting this may adversely affect both subsequent ovulation and pregnancy rates. ( Fig. 34.11 ) Thus, upon confirmation of a follicular phase environment, CC can be immediately started and an iatrogenic progestin withdrawal bleed avoided. Should 50 mg/day fail to elicit follicle growth, the dose should be increased to 100 mg/day in the subsequent cycle, followed by 150 mg/day, which is usually considered to be the maximum dose beyond which alternative treatments are indicated. By skipping the progestin-induced withdrawal bleed and immediately increasing the dose, faster dose escalation can be achieved, potentially saving weeks ( Fig. 34.12 ) . This method has been popularized as the “stair-step” protocol. The LH surge occurs between 5 and 12 days following the last day of CC administration. Intercourse is, therefore, advised for 10 to 14 days from the fifth day after the last day of CC administration. Some advocate hCG administration to trigger ovulation and to better time intercourse. However, studies have shown no improvement in outcomes, despite the increased monitoring required to time hCG administration. ^,

Clinical Outcome

In anovulatory women with normal weight, between 60% and 85% will become ovulatory with CC, and 30% to 40% will become pregnant over multiple cycles. In a meta-analysis based on four placebo-controlled studies in oligomenorrheic patients, the odds ratio with CC was 6.8 for ovulation and 4.2 for pregnancy. Why some women with WHO Group II Anovulation do not ovulate after CC is not fully understood. Altered individual requirements for FSH at the ovarian level, the local intraovarian effect of autocrine or paracrine factors, and variations in FSH receptor expression or FSH receptor polymorphisms may contribute (see Chapter 2 ). A number of studies have pointed to being overweight or obese as a negative factor. In a multivariate analysis of factors found to predict the outcome of CC ovulation indication, the free androgen index (FAI), BMI, presence of amenorrhea (as opposed to oligomenorrhea), and ovarian volume were found to be independent predictors of ovulation.

The occurrence of ovulation can be established using temperature charts and midluteal urinary or salivary pregnanediol or serum progesterone measurements. Although results of large trials indicate that monitoring by ultrasound is not mandatory to ensure good outcomes, the practice in many centers is to monitor the first cycle to allow adjustment of dose where necessary. The cumulative pregnancy rate in good prognosis ovulatory women with CC in 6 to 12 months of treatment is around 70%, with conception rates per cycle of around 22% and even lower in other populations. Interestingly, pregnancy rates remain steady over the first 5 to 6 cycles of ovulation induction, suggesting that sometimes persistence rather than treatment escalation is the best choice. Why do some women who become ovulatory with CC not conceive? Reasons include patient selection, the regimen used, and the presence of other causes of subfertility. The antiestrogenic effects of CC on the reproductive tract have been implicated. Negative effects on tubal transport, quantity and quality of cervical mucus, and the endometrium have all been reported. Studies have indicated that both the frequency and quality of ovulation (as determined by the subsequent ovulation rate) vary significantly between oral ovulation induction agents. All induced ovulations are not alike. When normalized to whether a patient ovulated in the Pregnancy in Polycystic Ovary Syndrome (PPCOS) studies, a patient who ovulated on metformin was significantly less likely to have a live birth compared to a woman receiving CC (with or without metformin). Similarly, a woman who has ovulated on letrozole is more likely to achieve a live birth than on CC ( Fig. 34.13 ) . Further examination of midluteal hormone levels shows that women with PCOS on letrozole have higher serum progesterone to estradiol levels than on CC. This may create a more optimal endometrial environment than a superovulated endometrium exposed to higher estradiol levels.

Miscarriage rates of 13% to 25% are reported. Although these numbers appear high, they are similar to the spontaneous miscarriage rate and those observed in infertile women undergoing IVF. In general, it does not appear that the miscarriage rate is significantly increased in anovulatory women treated with CC.

Side Effects and Complications.

Apart from hot flushes, which may occur in up to 10% of women taking CC, side effects are rare. Nausea, vomiting, mild skin reactions, breast tenderness, dizziness, and reversible hair loss have been reported, but less than 2% of women are affected. The mydriatic action of CC may cause reversible blurred vision in a similar number of women. The appearance of this symptom is considered a contraindication for further use. The multiple pregnancy rate in an anovulatory population clusters around 5% and OHSS is rare. The putative increased risk of ovarian cancer reported to be associated with the use of CC for more than 12 months, not validated in subsequent studies, ^, has nevertheless led CC to be licensed for just 6 months of use in some countries.

Insulin-Sensitizing Agents (Metformin)

Many reports have been published advocating the use of metformin for ovulation induction. The absence of well-designed and properly powered studies did not dampen enthusiasm for metformin in this context, and it has been widely introduced into clinical practice. However, two large, placebo-controlled randomized studies comparing metformin to CC and metformin as adjunctive therapy to CC have shown no benefit of metformin. ^, In the largest trial to date, CC was roughly three times more effective at achieving a live birth compared to metformin alone ( Fig. 34.14 ).

Similarly, the use of metformin throughout pregnancy in women with PCOS has not been associated with clear benefits beyond blunting gestational weight gain. Surprisingly, in this large multicenter trial, there was no prevention of gestational diabetes. In other populations, metformin has been found to have similar effects as insulin for the treatment of gestational diabetes, yet is better tolerated by patients, and does not result in a change in birth weights when given to obese women who are pregnant.