Hypogonadotropic Hypogonadal Anovulation

Group I is the smallest and often the most challenging of the WHO groups to treat. Hypothalamic amenorrhoea results from a change in the normal pattern of episodic secretion by the GnRH pulse generator with failure of ovulation and amenorrhoea. The causes are functional hypothalamic amenorrhoea (triggered by excessive exercise, nutritional deficits, or psychological distress), physiological hypothalamic amenorrhoea (postpartum and breast feeding), pharmacological anovulation (opiates) and amenorrhoea associated with psychiatric disorders, such as anorexia–bulimia. Hypothalamic amenorrhoea may also result from organic defects of the hypothalamic–pituitary axis, including congenital GnRH deficiency (idiopathic hypogonadotropic hypogonadism).

Functional hypothalamic amenorrhoea is the absence of menstrual cycles for more than 6 months without evidence of anatomical or organic abnormalities, and thus is a diagnosis of exclusion. Three main types of functional hypothalamic amenorrhoea have been recognized, associated with stress, weight loss, or exercise. Being underweight is not a prerequisite for this diagnosis. Reduced calorific intake appears to be the critical factor in both weight loss and exercise‐induced forms of hypothalamic amenorrhoea. Careful history taking will elucidate these factors. Leptin appears to play a critical role in the regulation of hypothalamic dysfunction, and leptin administration has been shown to induce GnRH pulsatility and menstruation. Rare variants in genes associated with idiopathic hypogonadotropic hypogonadism have been identified in women with hypothalamic amenorrhoea. Weight gain, exercise reduction, and appropriate psychological counselling are usually effective in relieving the symptoms of amenorrhoea in young patients (Caronia et al. 2011).

Hypothalamic lesions, although rare, such as infiltrative diseases or tumors, can result in decreased GnRH secretion and amenorrhoea. Idiopathic hypogonadotropic hypogonadism usually can be distinguished from functional amenorrhoea since it presents with primary amenorrhoea and associated symptoms, including anosmia (Figure 10.1).

Normogonadotropic Anovulation

The largest WHO group of women with anovulation, Group II, includes women with normal gonadotropins and oestrogen levels. PCOS is the most frequent endocrine disorder in women of reproductive age. Being a heterogeneous condition, diagnostic criteria may vary but currently the ‘Rotterdam criteria’ are the most popular for defining this disorder (Rotterdam ESHRE/ASRM 2004). PCOS is diagnosed when at least two of the following three clinical findings are present: oligo‐ or anovulation, clinical or biochemical signs of hyperandrogenism, and polycystic ovaries on ultrasound or direct inspection (Figure 10.2). The ultrasound criteria to define polycystic ovaries are the presence of 12 or more subcapsular ovarian cysts with a diameter of less than 10 mm or an increase in ovarian volume of more than 10 mL (Balen et al. 2003). Using the newer ‘Rotterdam criteria’, the prevalence of PCOS may be as high as 18% in a community‐based population (March et al. 2010). In women with oligomenorrhoea or hirsutism, the reported prevalence was respectively 85–90% and 70% (Sirmans and Pate 2014).

The aetiology of PCOS has been attributed to three major mechanisms:

1. PCOS has a strong familial occurrence, therefore hereditary factors are very likely.
   
2. There are indications that an ovarian dysfunction at the level of steroidogenesis may be present because of deficiencies in the cytochrome P450 pathway.
   
3. Hyperinsulinaemia may interfere with follicular maturation preventing selection of a dominant follicle (Carmina 2013). A decrease in insulin‐mediated glucose utilization or ‘insulin resistance’ is indeed a common finding in women with PCOS and they have a two‐ to fourfold higher risk for developing diabetes even after adjusting for BMI.

Although women with hirsutism and/or hyperandrogenaemia, and polycystic ovaries on ultrasound, i.e. PCOS according to the ‘Rotterdam criteria’, can have regular menstrual cycles (Carmina and Lobo 2001) and 60% of PCOS women are reported to be fertile (Brassard et al. 2008), the condition is associated with a higher risk of reproductive failure. This is not only because of oligo‐ or anovulation but also because they have an increased risk for preterm labour, pre‐eclampsia, and gestational diabetes (Legro 2007). The first‐line treatment for infertility because of PCOS should focus on weight reduction since 90% of infertile women with PCOS are overweight and obesity independently contributes to infertility. Exercise and diet programmes conceived for PCOS women are highly cost‐efficient in overcoming infertility because a weight loss of 5–10% may restore a regular menstrual pattern (Clark et al. 1998).