The patient is currently unemployed but previously worked as a healthcare assistant. She is fit and well and has unremarkable medical and surgical history and currently not taking any regular medication. She has not had any prior exposure to any chemotherapy or radiotherapy. She started having periods at the age of 12 years and always had regular periods with a cycle length of 28 days, which continued to be the case whilst on the COCP. She has never been pregnant. Since discontinuing the COCP 3 years ago, her periods have been very infrequent with cycle length varying between 38 and 90 days. Her period lasts from 3 and 5 days, and she describes her menstrual flow as normal, with no associated dysmenorrhoea. She had a cervical smear 2 years ago that was reported as normal.

Ovulatory dysfunction is one of the commonest causes of female infertility accounting for 20–40 % of all causes of infertility. Ovulatory dysfunction is generally manifested by irregularity of menstrual periods characterised by absence of menstruation (amenorrhoea), infrequent menstruation (oligomenorrhoea) or excessive bleeding (dysfunctional uterine bleeding). Ovulatory dysfunction can be caused by many factors; however, the majority of cases are related to female hormonal imbalances. The World Health Organisation (WHO) has provided a classification system that divides ovulatory disorders into three distinct groups based on aetiological factors [1] (Table 15.2).

WHO group 1 anovulatory infertility is caused by disorders that result in hypothalamic-pituitary-gonadal axis failure. These include hypothalamic or pituitary tumours or infection, hypothalamic or pituitary irradiation, chemotherapy, head trauma, genetic defects such as Kallmann syndrome and functional hypothalamic amenorrhoea induced by excessive exercise, lean body mass, weight loss, severe dietary restriction, anorexia or bulimia nervosa and chronic illness. Individuals with WHO group 1 ovulatory disorder have low serum concentrations of follicle stimulation hormone (FSH), luteinising hormone (LH) and oestradiol (hypogonadotrophic hypogonadism) and present with amenorrhoea, which could be primary or secondary depending on the cause [2]. Those who are underweight or over-exercise may have low-normal concentrations of FSH with an LH that is suppressed to a greater degree.

Cushing’s syndrome may present with chronic anovulation due to the inhibitory effect of high levels of cortisol releasing hormone (CRH) and adrenocorticotrophic hormone (ACTH) on hypothalamic-pituitary secretion. Congenital adrenal hyperplasia is also associated with anovulation and infertility due to secondary PCOS and hyperandrogenism, which inhibit the normal hormonal cycle. Elevation in serum 17 hydroxyprogesterone (17-OHP) and androstenedione are characteristic of CAH and disturb menstrual cyclicity, cervical mucus penetration by sperm and impair endometrial maturation and implantation.

Anovulatory infertility associated with conditions classified as WHO group 2 ovulatory disorders account for 85 % of cases of ovulatory infertility and results from hypothalamic-pituitary-ovarian dysfunction. The serum hormonal profile of these individuals will usually show normal FSH, normal or elevated LH and normal or high oestradiol levels (normogonadotrophic normogonadism) [3]. Polycystic ovary syndrome (PCOS) is the commonest cause of ovulatory disorders in this group of patients, accounting for 60–85 % of cases [4]. PCOS is a complex, heterogeneous endocrine disorder. It includes a spectrum of conditions rather than a single discrete disease. Symptoms vary widely in different individuals and include irregular or absent menses and associated anovulatory infertility, hyperandrogenism (hirsutism, alopecia and acne) and associated obesity. The criteria for the diagnosis of PCOS are based on a combination of clinical, ultrasound and biochemical criteria [5].

On further questioning she admitted to acne and severe and bothersome hirsutism involving her abdomen, face, chest, buttocks, legs and back. She initially tried shaving and waxing to remove her facial hair but this regrew quickly and her doctor has suggested referring her for laser treatment of her facial hair. In the last 4 years, she has noticed a rapid increase in her weight and she is thinking of joining the gym. She smokes one pack of cigarette a day and drinks 20 units of alcohol a week on average. Her mother and two of her older sisters have type 2 diabetes, but there is no history of infertility in the family. Her partner is fit and well and has an unremarkable medical and surgical history. He is a non-smoker and drinks alcohol socially. He has 1 child aged 12 years from a previous relationship. Examination revealed an obese woman with a body mass index of 35 kg/m² and a normal blood pressure of 125/75 mmHg. Significant hirsutism was noted on her face, chest, legs, and back. Also noticed were brown to black, poorly defined, velvety hyperpigmented areas in the lateral folds of the neck, the armpits and groin.

The likely diagnosis is PCOS. In 2003 the European Society for Human Reproduction and Embryology (ESHRE) and the American Society of Reproductive Medicine (ASRM) held a consensus meeting in Rotterdam and proposed that the diagnosis should be made if two out of three criteria are met: namely the presence of clinical or biochemical features of hyperandrogenism, oligo-ovulation or anovulation (in other words a menstrual cycle disturbance) and/or polycystic ovaries on ultrasound, once appropriate investigations have been performed to exclude other causes of menstrual disturbance and androgen excess [6]. The aetiology of PCOS has not been fully elucidated, but it is believed to be of multifactorial origin with insulin resistance, androgen excess, abnormal gonadotrophin secretion and genetic predisposition playing important roles. Obesity occurs in 40–50 % and has been implicated in the pathogenesis of PCOS [7] secondary to the development of insulin resistance and hyperinsulinaemia, which acts directly on the ovary to amplify the hyperandrogenism, interfering with folliculogenesis and resulting in anovulation and poor-quality oocytes [5].

The differential diagnosis of PCOS includes Cushing’s syndrome, virilising adrenal tumour and late onset “non-classical” congenital adrenal hyperplasia (Table 15.3). Cushing’s syndrome exhibits many clinical features similar those observed in PCOS, such as obesity, low sex hormone binding protein (SHBG), increased androgens, and hirsutism and anovulation. Cushing’s syndrome is rare compared with PCOS and associated with other symptoms such as easy bruising, moon facies, buffalo hump, abdominal striae, hypertension, and proximal myopathy.

Premature ovarian insufficiency (formerly known as “premature ovarian failure”) (WHO group 3) constitutes 5 % of ovulatory disorders and results from premature exhaustion of the ovarian primordial follicular pool and is characterised by amenorrhoea in women aged <40 years. The serum hormonal profile will show evidence of high gonadotropins and low oestradiol levels (hypergonadotrophic hypogonadism). Causes of premature ovarian failure include a number of genetic conditions such as Turner’s syndrome and Fragile X syndrome, previous exposure to chemotherapy and radiotherapy, and autoimmune diseases such as type 1 diabetes mellitus, systemic lupus erythematosis and Addison’s disease [3].