Anovulation represents one of the main causes of female infertility, and establishing the underlying cause is critical to ensure effective treatment. This chapter details the various disorders of ovulation, including polycystic ovary syndrome, which is the most common cause. It discusses the systematic approaches to treating disorders of ovulation and reproductive endocrine disorders associated with infertility.
Infertility is defined as the inability to achieve a clinical pregnancy after 12 months of regular unprotected sexual intercourse. Infertility can result from male and female contributing factors, assessed as part of baseline infertility investigations, and disorders of ovulation account for nearly a quarter of all infertility cases. The World Health Organization (WHO) classifies ovulation disorders into three groups, based on the most common reasons for anovulatory infertility:
Group I: Hypothalamic–pituitary disorders (hypothalamic amenorrhoea or hypogonadotropic hypogonadism)
Group II: Hypothalamic–pituitary–ovarian dysfunction (predominately polycystic ovary syndrome)
Group III: Ovarian failure
Cyclic mono-follicular recruitment and ovulation occur as a result of a complex interaction of hormones secreted by the hypothalamus, pituitary and ovary. The hypothalamus secretes gonadotropin-releasing hormone (GnRH), a decapeptide released in a pulsatile manner which stimulates the anterior pituitary secretion of gonadotrophins: follicle-stimulating hormone (FSH) and luteinising hormone (LH). Through their action on the ovary, FSH and LH in turn facilitate follicular recruitment, maturation, ovulation and the various stages of the menstrual cycle. This chapter details the various ovulatory disorders and their fertility management, the most common cause being polycystic ovary syndrome. As good practice would dictate, it is important to ensure that other factors contributing to infertility are excluded or dealt with appropriately before ovulation induction treatment for ovulatory disorders.
2.2 WHO Group II: Polycystic Ovary Syndrome
Polycystic ovary syndrome (PCOS) is the most common female endocrine disorder and is responsible for approximately 75% of ovulatory disorders. It is a complex reproductive and metabolic disorder and was first described in 1935 as Stein–Leventhal syndrome. The aetiology of PCOS remains unclear and the variations in phenotype lead to challenges for clinical management. PCOS is associated with clinical manifestations and health implications during adolescence and the reproductive and post-reproductive stages of a woman’s life. Quite a few definitions and criteria have been proposed for the diagnosis of PCOS, of which the most commonly endorsed is the 2003 Rotterdam consensus on diagnostic criteria for PCOS . According to the Rotterdam criteria, the diagnosis of PCOS is based on the fulfilment of any two of the following three criteria: (1) oligo- or anovulation, (2) clinical and/or biochemical signs of hyperandrogenism and (3) polycystic ovaries (Figure 2.1) and exclusion of other aetiologies (congenital adrenal hyperplasia, androgen-secreting tumours, Cushing’s syndrome).
Traditionally, the first-line management of women with PCOS has been weight management to optimise both reproductive and metabolic outcomes. Observational studies have reported pregnancies after loss of as little as 5% of initial body weight [2, 3]. Weight optimisation is also suggested to enhance outcomes of pharmacological and surgical ovulation induction treatments. However, recent studies have not been able to confirm the beneficial effects of weight loss and successful pregnancies in women with anovulatory PCOS . Nonetheless, given the beneficial effects of weight loss in mitigating the adverse metabolic associations with PCOS and obesity, preconceptual weight optimisation is a useful intervention. The following is an overview of the treatment options and treatment hierarchy for women with PCOS and anovulation.
2.2.1 Clomiphene Citrate for Ovulation Induction in PCOS
Clomiphene citrate (CC) is an anti-oestrogen which competes for receptor-binding sites with endogenous oestrogens. By blocking oestrogen receptors in the hypothalamus and pituitary, CC interferes with the feedback mechanism of endogenous oestrogen on the pituitary and hypothalamus. This results in an increase in FSH and LH secretion by the anterior pituitary, which stimulates ovarian follicular recruitment and ovulation (Figure 2.2). Clomiphene citrate has been used for ovulation induction in anovulatory women since the first published results on its application in 1961 .
There is evidence of a higher pregnancy and ovulation rate with CC compared to placebo or no treatment [6, 7]. Clomiphene citrate induces ovulation in 75%–80% of women [8, 9], with cumulative live birth rates of 50%–60% after six cycles . The National Institute for Clinical Excellence (NICE) guidelines state that first-line pharmacological treatment for women with PCOS should be CC for up to six cycles . They recommended a starting daily dose of CC of 50 mg for 5 days in the early phase of the menstrual cycle. If ovulation is not achieved with the lowest dose of 50 mg daily, the dose of CC can be increased in 50-mg increments to 100 mg, and ultimately a maximum of 150 mg daily. If ovulation is confirmed, treatment with CC can be continued for six cycles. Failure to ovulate after the maximum dose of 150 mg daily is termed CC resistance. Second-line ogvulation induction options should be considered in cases of CC resistance.
Clomiphene citrate can induce multiple follicular recruitment and is associated with a multiple pregnancy rate of around 10%. Clomiphene citrate has anti-oestrogenic effects on the endometrium which can result in a thin endometrium, although the implications are unclear . Ultrasound monitoring, at least in the first cycle of treatment, is indicated to assess follicular recruitment and the endometrial thickness. Strict criteria (usually two or three follicles ≥14 mm based on female age) for cycle cancellation in case of multiple follicles should be established to reduce multiple pregnancies with CC therapy.
Tamoxifen is another anti-oestrogen that can be used for ovulation induction in WHO group II women. A Cochrane review on anti-oestrogen for ovulation induction for women with PCOS showed no significant differences between CC and tamoxifen for outcomes of live birth, clinical pregnancy and miscarriage. There were insufficient data to draw any conclusion regarding multiple pregnancies . The dosage of tamoxifen varied from 10 mg to 60 mg daily among the studies included in the Cochrane review and pooled in the meta-analysis. There was no consistency in the duration of treatment.
Polycystic ovary syndrome is an insulin-resistant disorder characterised by hyperinsulinaemia (Figure 2.3). Increased insulin resistance, hyperandrogenism and obesity have a significant impact on menstrual cyclicity and reproductive health.
Figure 2.3 Insulin resistance contributing to PCOS symptoms.
Metformin is an anti-hyperglycaemic biguanide and a commonly used insulin-sensitising drug. It is considered to be beneficial for women with PCOS for fertility and control of metabolic symptoms. The UK NICE guidelines (2013) recommend metformin alone or in combination with CC as first-line treatment for women with PCOS and anovulation on the basis of its insulin-sensitising property. However, the evidence for beneficial reproductive outcomes is not conclusive. The most recent Cochrane review on metformin versus placebo for ovulation induction in women with PCOS showed metformin to be associated with higher clinical pregnancy rates (odds ratio [OR] 1.93; 95% CI 1.42 to 2.64) and may improve live birth rates (OR 1.59; 95% CI 1.00 to 2.51) but the quality of evidence for the latter was low (13). When metformin plus CC was compared to CC alone, higher clinical pregnancy rates were found with the combined therapy compared to CC alone (OR 3.97; 95% CI 2.59 to 6.08). There was, however, no conclusive difference in live birth rates between metformin plus CC versus CC alone (OR 1.21; 95% CI 0.92 to 1.59) but the quality of evidence was low.
The recent WHO guidance on the management of anovulatory infertility in women with PCOS recommends metformin used alone if facilities are not available for monitoring of CC or letrozole, which are more effective. It also recommends metformin in combination with CC to improve fertility outcomes in women with PCOS who are CC resistant . Metformin is frequently associated with gastrointestinal side effects, which should be considered when prescribing.
Aromatase inhibitors were introduced for ovulation induction in 2001 . They prevent aromatisation of androgens to oestrogens and this decrease in oestrogens releases the pituitary from the negative feedback effect, with a resulting increase in FSH that effects ovarian stimulation and follicular recruitment (Figure 2.4). A network meta-analysis of studies comparing the effectiveness of first-line ovulation induction treatment options for women with PCOS showed the aromatase inhibitor letrozole was the most effective treatment in terms of live birth . Compared to CC alone, treatment with letrozole led to significantly higher ovulation (OR 1.99; 95% CI 1.38 to 2.87), pregnancy (OR 1.58; 95% CI 1.25 to 2.00) and live birth rates (OR 1.67; 95% CI 1.11 to 2.49) and significantly lower multiple pregnancy rates (OR 0.46; 95% CI 0.23 to 0.92). A recent updated Cochrane review on the use of letrozole as an ovulation induction agent showed a higher live birth rate with letrozole compared to CC (OR 1.68; 95% CI 1.42 to 1.99). The UK NICE guidance on fertility which was updated before this evidence does not recommend letrozole for ovulation induction. However, other recent guidelines such as the WHO  and International PCOS guideline  recommend letrozole use for ovulation induction in women with PCOS.
Surgical ovarian wedge resection, first performed by Stein and Leventhal in 1935 and carried out via laparotomy, was a treatment for women with anovulatory PCOS but was largely abandoned both due to the risk of post-surgical adhesions and the introduction of medical ovulation induction. However, not all ovulation induction medications are successful in inducing ovulation and ovarian surgery continues to be a second-line treatment option. The advent of laparoscopy has facilitated laparoscopic ovarian drilling (LOD) which can be performed with fewer post-operative side effects over open surgery. In the current set-ups LOD can be performed as day case procedures, making it more cost effective. The UK NICE guideline recommends LOD as a treatment option for CC-resistant PCOS. The endocrine changes following surgery are also thought to convert the adverse androgen-dominant intrafollicular environment to an oestrogenic one and to restore the hormonal environment to normal by correcting disturbances of the ovarian–pituitary feedback mechanism .
Both local and systemic effects are thought to promote follicular recruitment, maturation and subsequent ovulation following LOD in women with PCOS and anovulation. The rationale is to destroy ovarian androgen-producing tissue and reduce the peripheral conversion of androgens to oestrogens. The fall in serum oestrogens causes a resultant rise in FSH which stimulates the ovaries and promotes follicular recruitment. The Cochrane review comparing gonadotropins with LOD in women with CC-resistant PCOS found that there was no difference between the two options in terms of live birth rate, long-term cost and quality of life. Laparoscopic ovarian drilling was associated with significantly lower multiple pregnancy rate compared to gonadotropins (OR 0.13; 95% CI 0.03 to 0.52) and short-term treatment costs (P < 0.00001) . In addition to CC-resistant PCOS, LOD may be useful for women who are unable to comply with the intensive ultrasound monitoring needed with gonadotropin treatment. The minimum effective (intervention/dose) should be used for ovarian drilling to achieve ovulation and minimise the risk of ovarian damage and potential effect on ovarian reserve. There is inconsistent evidence on the minimum effective (intervention/dose) to achieve ovulation and minimise the risk of ovarian damage when using LOD, and the potential effect on ovarian reserve requires further investigation .
2.2.5 Gonadotrophins for Ovulation Induction in PCOS
Use of gonadotrophins for ovulation induction is indicated in women who have failed to conceive despite evidence of ovulation following alternative treatments or in women with CC-resistant PCOS. This strategy is potentially associated with a high risk of multiple pregnancy, which necessitates intensive ultrasound monitoring and strict cycle cancellation criteria. The aim is to achieve successful unifollicular ovulation and avoid multiple pregnancy as well as ovarian hyperstimulation syndrome (OHSS).
Treatment strategies such as the step-up regime, step-down regime and low-dose step-up regimes have been advocated to enhance the effectiveness of gonadotropin ovulation induction with minimal side effects (Figure 2.5).