Endocrinology: Disorders of the reproductive system

Endocrinology: Disorders of the reproductive system

Physiology of the reproductive system

Physiology of female reproduction

The menstrual cycle

The average menstrual cycle lasts 28 days and is usually only interrupted by pregnancy or terminated by the menopause. It consists of two alternating phases: the follicular and luteal phases. The follicular phase takes up the first half of the cycle and is characterised by developing follicles which produce oestrogen. The luteal phase follows ovulation and is characterised by the presence of the corpus luteum which synthesises progesterone and oestrogen (Figure 23.1).

Follicular phase

The ruptured follicle forms the corpus luteum, which produces large amounts of progesterone and oestrogen. Progesterone and oestrogen inhibit LH and FSH release from the anterior pituitary. In the absence of fertilisation, the corpus luteum degenerates, leading to a significant fall in progesterone and oestrogen levels. FSH and LH levels then rise as they are no longer inhibited, and a new cycle commences.

Oestrogen and progesterone action

Oestrogen released from the developing follicle leads to proliferation of the endometrium, comprising uterine glands and epithelium. Progesterone released by the corpus luteum stimulates the uterine glands to secrete ‘uterine milk’ which is high in protein and glycogen and provides a suitable environment in the event of fertilisation. In pregnancy, oestrogen is also important for uterine muscle development whereas progesterone dampens uterine contractility and stimulates breast growth. Oestrogen is also important for the development and maintenance of female
secondary sexual characteristics after puberty, and in preserving bone mineral density.

Physiology of male reproduction

Hypothalamic and pituitary hormones

GnRH is secreted in a pulsatile manner by the hypothalamus, which stimulates the secretion of LH and FSH by the anterior pituitary. LH binds to its receptor in testicular Leydig cells to stimulate testosterone synthesis and secretion. FSH binds to its receptor in testicular Sertoli cells to regulate spermatogenesis, a process that takes >70 days. LH and FSH secretion is regulated positively by GnRH pulses and by negative feedback from testosterone, which inhibits both LH and FSH, and inhibin, which inhibits FSH only (Figure 23.4).

Testosterone

Testosterone is the principal androgen produced by the Leydig cells. It has a circadian rhythm, with peak levels reached at around 08.00. A small amount of oestradiol is also made by the testes, but most is generated by conversion (aromatisation) of androgens to oestradiol in adipose tissue. Only 2–4% of circulating testosterone is free and ‘biologically active’. The remainder is bound to proteins, especially SHBG and albumin. Testosterone is metabolised in target tissues to the more potent androgen dihydrotestosterone (DHT) by the enzyme 5α-reductase. Both
testosterone and DHT exert their effects by binding to androgen receptors.

Androgen action

Androgens have an important role in prenatal male sexual differentiation, in the development and maintenance of male secondary sexual characteristics after puberty, in spermatogenesis and in normal male behaviour.

Growth, puberty and sexual differentiation

Normal growth

Postnatal linear growth may be divided into three phases: infancy, childhood and puberty (Figure 24.1). In infancy and childhood, linear growth is rapid although height velocity decreases. Hormonal influences on growth predominate, particularly the GH–IGF-1 axis. The pubertal growth spurt, which starts roughly 2 years earlier in girls than boys, arises as a result of increased sex steroid in addition to GH production. In girls, this coincides with the start of breast development (thelarche), reaches a peak height velocity at around age 12, and is followed by the onset of menarche
(the first menstrual cycle) before declining. In contrast, the pubertal growth spurt in boys does not occur until puberty is well advanced (when testicular volumes are 10–12 mL). Males are thus on average 13–14 cm taller than females as a result of 2 additional years of pre-pubertal growth and a greater pubertal height velocity.

Normal puberty

Puberty normally occurs between the ages of 8 and 13 years in girls, and 9 and 14 years in boys. In girls, puberty begins with breast enlargement at an average age of 11. This is followed by pubic and axillary hair development (adrenarche), and the start of periods (menarche), which occurs at a mean age of 13.5 years. In boys, puberty begins with testicular enlargement (attainment of 4 mL testicular volume) at a mean age of 12 years, and is followed by pubic and axillary hair growth (Figure 24.2).

Short stature

This is arbitrarily defined as a height which is 2 standard deviations below the mean for the child’s age and gender. Assessment of the genetic contribution to stature is made by calculation of the target height centile range using parental height. Most children with short stature do not have an underlying condition and will not require further investigation. A thorough history, examination and clinical evaluation, including accurate serial plotting of height on growth charts (auxology) for assessment of height velocity, will determine which children need investigation
(Figure 24.3). Causes of short stature include:

  • Familial. The most common cause. The height standard deviation
    score will lie within target height.
  • Constitutional delay of growth and puberty (CDGP). A variant
    of normal and more common in boys than girls. There is
    often a family history of delayed puberty.
  • Chronic disease (e.g. renal failure).
  • Dysmorphic syndromes (e.g. Turner’s syndrome; Chapter 25)
    and Prader–Willi syndrome.
  • Endocrine disorders (e.g. growth hormone deficiency – mostly
    idiopathic – hypothyroidism or Cushing’s syndrome).

Precocious puberty

This is defined as the onset of puberty before age 8 in girls or age 9 in boys. Gonadotrophin-dependent precocious puberty (GDPP) refers to the development of secondary sexual characteristics in the normal sequence as a result of hypothalamic activation occurring early. Gonadotrophin-independent precocious
puberty (GIPP) occurs as a result of abnormal sex steroid production, is independent of hypothalamic–pituitary activation, and can result in non-consonant puberty (puberty occurring in an abnormal sequence). GDPP is more common in girls and is usually idiopathic. Treatment with a GnRH analogue can be considered. GIPP is rare and pathological causes (such as congenital adrenal hyperplasia, adrenal tumours or sex steroid-producing tumours) are more common.

Delayed puberty

This is defined as the absence of secondary sexual characteristics by age 13 in girls or age 14 in boys. Causes can
be divided into:

  • Hypogonadotrophic hypogonadism (inappropriately low gonadotrophins) for example resulting from CDGP. Treatment for CDGP, in the form of testosterone for boys or oestrogen for girls, is considered if there is an effect on psychological well-being.
  • Hypergonadotrophic hypogonadism (inappropriately high gonadotrophins) for example resulting from chromosomal abnormalities (Turner’s syndrome, Klinefelter’s syndrome; Chapter 28) or acquired gonadal failure (prior radiotherapy or chemotherapy).

Sexual differentiation

The term disorders of sex development (DSD) is used to describe congenital conditions in which the development
of chromosomal, gonadal or anatomical sex is atypical. The causes are described clinically as masculinised females, under-masculinised males, or true hermaphrotidism. The most common cause of ambiguous genitalia is congenital adrenal hyperplasia from 21-hydroxylase deficiency (see Chapter 26), leading to a masculinised female. The management of DSD, including gender assignment, is complex and should involve an experienced multidisciplinary team comprising a paediatric endocrinologist, paediatric urologist and psychologist.

Transition of young people into the adult service

This is a planned process that addresses the medical, educational and psychosocial needs of young people with chronic conditions as they move into adulthood. Transition clinics, involving joint input by paediatric and adult endocrine teams, improve continuity of care, enable better disease control, minimise the drop-out rate from follow-up and help patients’ acceptance of adult services. Increasing emphasis is placed on education and self-management of their condition.

Menstrual disturbance

Definition

Menstrual disturbance is classified as:

  • Amenorrhoea – absent menses for >6 months. This can be further subdivided into primary amenorrhoea (failure of menarche – the first appearance of periods– by age 16 years) or secondary amenorrhoea (cessation of menstrual periods for >6 months in women who have previously menstruated)
  • Oligomenorrhoea – reduced menstrual frequency to <9 periods/ year
  • Polymenorrhoea – frequent menstrual periods
  • Menorrhagia – heavy menstrual periods.
    Polymenorrhoea and menorrhagia can relate to hypothyroidism but usually reflect abnormal (dysfunctional)
    uterine bleeding (irregular bleeding, which is more common in adolescents and women approaching the menopause, and not caused by structural pathology). This is not considered further here as it is not usually managed by endocrinologists in clinical practice.

Causes

The causes of primary amenorrhoea, secondary amenorrhoea and oligomenorrhoea can be broadly divided into four groups:
1 Premature ovarian failure.
2 Disordered gonadotrophin secretion (hypogonadotrophic hypogonadism). This can be caused by hypothalamic–pituitary disease (Chapter 5), including hyperprolactinaemia, or hypothalamic amenorrhoea whereby low body weight (e.g. anorexia nervosa), intensive exercise, prolonged psychological stress or systemic illness lead to suppressed gonadotrophin pulsatility.
3 Hyperandrogenic disorders, including polycystic ovary syndrome (PCOS; Chapter 26).
4 Structural disease (e.g. uterine adhesions, congenital absence of the uterus).

Assessment

History

Symptoms of oestrogen deficiency (flushes, vaginal dryness and dyspareunia), androgen excess (hirsutism, acne), galactorrhoea, heavy exercise, weight change, emotional stress and systemic illness should be looked for. It is important to document the onset and duration of the menstrual disturbance.

Examination

This should include an evaluation of body habitus (e.g. anorexia nervosa, Turner’s syndrome), hyperandrogenism,
secondary sexual characteristics (pubic and axillary hair, breast development), visual fields and anosmia.

Investigations

These should initially be based on measurement of oestradiol, FSH and LH which will establish whether ovarian dysfunction is primary (raised gonadotrophins) or secondary (low–normal gonadotrophins) (Figure 25.1). FSH and LH should be measured in the follicular phase (days 0–5 of a period) to avoid the FSH/LH surge which can give the false impression of raised gonadotrophins. A pregnancy test may be indicated if the history is short, while a pelvic ultrasound helps exclude structural abnormalities and can show altered ovarian morphology (e.g. polycystic ovaries, ‘streak ovaries’ in Turner’s syndrome). Other tests may subsequently be needed depending on clinical suspicion and the pattern of the gonadotrophin results.

Treatment

Treatment is directed at the underlying cause (e.g. weight gain in low body weight, dopamine agonists for prolactinomas). Oestrogen replacement will improve symptoms of oestrogen deficiency and protect against decline in bone mineral density. In women seeking pregnancy, fertility can be improved with cause-specific treatment (Chapter 30).

Premature ovarian failure

This group of disorders are characterised by amenorrhoea, oestrogen deficiency and raised gonadotrophins in women <40years, due to loss of ovarian follicular function. Causes include:

  • Chromosomal abnormalities (60%), especially Turner’s syndrome
  • Autoimmune disease (20%)
  • Iatrogenic – following surgery, chemotherapy or radiotherapy
  • Genetic.

Turner’s syndrome

This affects 1 in 2500 female births and results from complete or partial absence of one X chromosome; the most common karyotype is 45 XO. Affected patients are characterised by short stature and gonadal dysgenesis (>90% have premature ovarian failure). Clinical features include webbing of the neck, widened nipples, cubitus valgus and a short 4th metacarpal (Figure 25.2).

Management

Optimisation of growth and puberty

This is achieved through use of high dose GH and oestrogen replacement. Oestrogen replacement is usually continued until an age at which menopause would normally be expected to occur.

Screening for and seeking to prevent complications

Patients with Turner’s syndrome have an increased risk of audiological (otitis media, sensorineural deafness), cardiac
(hypertension, coarctation of the aorta, bicuspid aortic valve, aortic dissection), renal (congenital abnormalities), hepatic (raised liver enzymes, fatty liver disease), metabolic (hypothyroidism, type 2 diabetes), skeletal (osteoporosis) and neuropsychological (motor coordination, visuospatial) complications. These should be screened for with annual measurement of body mass index (BMI), blood pressure, HbA1c, thyroid function, liver and renal blood tests, echocardiography every 3–5 years, and bone density and hearing tests every 5 years.

Hyperandrogenism

Hirsutism

Hirsutism is defined as the presence of excess hair growth in women occurring in an androgen-dependent pattern (top lip, chin, chest, periumbilical, inner thigh; Figure 26.1). It should be distinguished from hypertrichosis which is an excess of long fine vellus hairs and is not androgen-dependent. Hirsutism occurs as a result of increased androgen production and/or increased skin sensitivity to androgens. Androgens are produced from the ovaries and adrenal glands in
equal amounts in pre-menopausal women. Common causes of androgen excess are PCOS and idiopathic hyperandrogenism (more common in Mediterranean, South Asian and Middle Eastern populations). Rarer causes are Cushing’s syndrome (Chapter 4), congenital adrenal hyperplasia (CAH), ovarian or adrenal tumours, and medication (e.g. danazol) (Table 26.1).

Investigation and management

hyperandrogenism (acne, frontal balding, oligo-/amenorrhoea), with a particular focus on signs of virilisation (deepening of the voice, clitoromegaly, marked frontal balding, increased muscle bulk) as this can point to an underlying tumour. The history should also focus on duration of hirsutism (rapid onset suggests a virilising tumour) and the time spent on hair removal each day as a guide to severity and impact upon the patient. Investigation is mainly to exclude virilising tumours and other rare causes of hyperandrogenism, such as Cushing’s syndrome which requires a different approach to management from PCOS or idiopathic hyperandrogenism. A biochemical screen must include measurement of testosterone, because levels 5 nmol/L should lead to ovarian and adrenal imaging (MRI or CT) to exclude virilising tumours. Only 50% of patients with PCOS have elevated testosterone values, hence a normal reading
does not exclude the diagnosis. Other helpful biochemical tests are LH, FSH (the LH : FSH ratio is often raised in PCOS),
ovarian/adrenal androgens (androstenedione/DHEAS) and 09.00 17-hydroxyprogesterone (17-OHP; to screen for CAH).
In patients with features of Cushing’s syndrome, one or more of an overnight DST, late night salivary cortisol and 24-hour UFC should be undertaken as a screen. Treatment is directed at the underlying cause. General treatments for hirsutism include mechanical approaches (waxing, plucking, shaving, depilatory creams), laser removal and electrolysis, eflornithine cream (which slows down hair follicle growth), oestrogens (e.g. the combined oral contraceptive pill) and anti-androgens (e.g. cyproterone acetate, spironolactone). Because hair grows slowly, any treatment will need to be used for at least 6 months to judge efficacy.

Polycystic ovary syndrome

PCOS is a common endocrine condition that affects 5–10% of young women. It is characterised by hyperandrogenism,
oligo-/amenorrhoea and polycystic appearances to the ovaries on ultrasound (Figure 26.2). Two out of three of the
above features are needed to support a diagnosis, provided other mimicking conditions (e.g. Cushing’s syndrome, CAH,
hyperprolactinaemia) are excluded. Insulin resistance is a key underlying defect in both obese and lean women with PCOS, and leads to an increased lifetime risk of type 2 diabetes in addition to the well-recognised reproductive consequences (subfertility, oligo-/amenorrhoea) of the disorder.

Management

Transvaginal ultrasound can show a polycystic ovarian appearance of multiple small subcapsular follicles and an
increased central stroma, but a normal scan does not exclude the diagnosis. Equally, ultrasonic appearance of polycystic ovaries is common in the general population (up to 20% of young women) but on its own is insufficient to establish a diagnosis of PCOS. Biochemical tests, undertaken as for hirsutism, can support the diagnosis but are not specific.
Treatment is predominantly directed at the principal complaint. Because >70% of patients are overweight or
obese, weight loss is important, not only to improve clinical symptoms, but also to reduce the long-term metabolic health risks. Hirsutism is treated as for any other cause whereas menstrual irregularity can be treated with the combined oral contraceptive pill, cyclical progestogens or metformin (to improve insulin sensitivity) if fertility is not desired. Clomiphene is first line treatment to induce ovulation in women who desire pregnancy.

Congenital adrenal hyperplasia

CAH is a family of inherited disorders of adrenal steroidogenesis, the most common of which is 21-hydroxylase deficiency (90% of cases). This enzyme defect leads to a block in cortisol (± aldosterone) synthesis, consequent hypersecretion of ACTH, a build-up of precursors upstream of the defect (e.g. 17-OHP) and excess hormone synthesis (especially androgens) in pathways unimpaired by the enzyme defect (Figure 26.3). In ‘classic’ CAH, patients usually present in the neonatal period or as children with virilisation (e.g. causing ambiguous genitalia in girls) ± salt wasting (due to aldosterone deficiency). ‘Non-classic’ CAH, characterised by partial enzyme inactivity, presents later in life with features akin to PCOS (hirsutism, oligomenorrhoea). Demonstration of a raised 17-OHP value, either at baseline or in response to synthetic ACTH (Synacthen), confirms the diagnosis. Treatment comprises replacement therapy with
glucocorticoids (e.g. hydrocortisone or prednisolone); patients with salt-wasting also require mineralocorticoid replacement with fludrocortisone.

Menopause and HRT

Definition

The menopause is defined as the permanent cessation of menstruation as a result of ovarian failure. The average age of the menopause is about 50 years although there is significant interindividual variation.

Clinical presentation

Menstrual cycles vary in length from about 3–4 years before the menopause and become increasingly anovulatory. Oligomenorrhoea is commonly present before full amenorrhoea.

  • Vasomotor symptoms, including hot flushes and night sweats, affect some women more than others. Most will resolve spontaneously within 5 years of the menopause.
  • Mood changes include irritability, anxiety and difficulty in concentration.
  • Sexual dysfunction can occur as a result of vaginal dryness, leading to dyspareunia, in addition to reduced libido from a fall in androgen levels.
  • Urinary symptoms, including incontinence and increased frequency of urinary tract infections, can occur as a result of atrophy of the bladder and urethral mucosa (Figure 27.1).

Assessment

The history should assess symptom severity, and review risk factors for vascular disease, osteoporosis, thrombo-embolic disease and breast cancer if HRT is being considered. Blood pressure should be checked and the breasts also examined under such circumstances. Diagnosis is usually based on clinical assessment with no requirement for blood tests. Indeed, FSH levels tend to vary significantly in the peri-menopausal period and do not correlate well with symptoms. However, if measured, a low oestradiol and significantly raised FSH are consistent with the diagnosis.

Treatment

Many women do not require treatment but HRT can be considered for alleviation of menopausal symptoms when these
are troublesome. The choice of HRT formulation, including oral, transdermal, intranasal or subcutaneous preparation, should be considered on a case-by-case basis according to symptoms and health risks. Patients on systemic HRT with an intact uterus should be prescribed oestrogen in combination with a progestogen to reduce the risk of endometrial cancer. Locally administered intravaginal oestrogens, delivered as creams, gels, rings or tablets, can improve genitourinary symptoms, and offer an alternative to systemic HRT when this is contraindicated. Nonhormonal
therapies such as clonidine for flushing or cognitive behavioural therapy for low mood are useful alternatives in
patients for whom HRT is contraindicated or not tolerated. Side effects of HRT include breast tenderness, mood changes and irregular vaginal bleeding, and may necessitate a change in dose or preparation, or discontinuation.

Long-term risks and benefits

safety of HRT. The current evidence suggests that HRT increases the risks of the following (Figure 27.1a).Venous thromboembolic disease, although the absolute risk is still low. This risk is greater for oral than transdermal HRT
preparations. Breast cancer, in women taking combined oestrogen and progestogen. The risk relates to treatment duration and reverts to background risk when HRT is stopped. There is a small increased risk of stroke in women taking oral(but not transdermal) oestrogen, but it should be recognised that the population risk of stroke in women under age 60 is low. HRT does not increase the risk of cardiovascular disease when started under the age of 60 years, nor is there an effect on diabetes risk. The risks in relation to dementia are not known. The long-term benefits of HRT include reduced risk of osteoporotic fragility fracture, although the population risk of fragility facture in women around the menopause is low. A decision to prescribe HRT in an individual patient should thus take into account the woman’s personal and family risk of these conditions in addition to symptoms. Active breast or endometrial cancer, and active deep venous thrombosis are absolute contraindications to HRT.

Pre-menopausal oestrogen replacement

In patients with premature ovarian failure or other causes of low oestrogen in young women, sex steroid replacement
with either HRT or a combined oral contraceptive pill may be considered. Treatment should be continued until the age of the natural menopause, not only to alleviate symptoms, but also to maintain bone mineral density. The risk of breast cancer and cardiovascular disease in this age group is very low.

Male hypogonadism

Definition

Hypogonadism relates to a failure of the testes to produce sufficient testosterone. It can be divided into primary or secondary hypogonadism according to whether the gonadotrophins are elevated or not in the presence of a low 09.00 testosterone level, respectively (Figure 28.1). Patients present with failure to progress through puberty, infertility, erectile dysfunction and/or reduced libido. The clinical presentation depends on the severity, age of onset and duration of disease (Figure 28.2).

Primary hypogonadism

This occurs as a result of testicular failure. Causes include the following.

  • Klinefelter’s syndrome, affecting 1 in 500–1000 men. Most commonly caused by a 47XXY karyotype.
  • Other chromosomal disorders (e.g. XX males, mixed gonadal dysgenesis, XYY syndrome). Cryptorchidism. Although undescended testes are common in male neonates, most will descend into the scrotum. Postpubertal cryptocrchidism occurs in <0.5%. There is an increased risk of testicular malignancy in addition to infertility.
  • Testicular torsion, trauma or castration.
  • Infection (e.g. mumps orchitis, HIV).
  • Chemotherapy and radiotherapy (e.g. for lymphoma). Alkylating agents in particular are gonadotoxic.
  • Other causes including systemic illness such as renal failure, haemochromatosis (which can cause combined primary and secondary hypogonadism), liver cirrhosis, and drug or surgical treatment for prostate cancer.

Secondary hypogonadism

This occurs as a result of hypothalamic or pituitary disease. In addition to the causes of hypopituitarism listed in Chapter 5, specific causes of secondary hypogonadism include the following.

  • Kallmann’s syndrome. A genetic disorder arising from disrupted migration of GnRH producing neurons into the hypothalamus. Leads to isolated gonadotrophin deficiency, often but not invariably with ansomia (from failure of olfactory lobe development).
  • Drugs. Anabolic steroids and opiates. Potentially reversible with drug cessation but recovery can take a long time.
  • Systemic illness of any kind.
  • Type 2 diabetes and metabolic syndrome. Total testosterone levels are lower in men with these conditions related to central obesity and insulin resistance. Routine treatment with testosterone is not currently indicated in the absence of symptoms.

Late onset hypogonadism

Testosterone levels decline with age, at an average of 1–2% per year, because of both testicular and hypothalamic–pituitary dysfunction. As a result, a significant number of older men have testosterone levels below the lower end of the reference range for healthy young men. There is currently much uncertainty about the risks and benefits of testosterone replacement in this group, hence a decision to treat should be undertaken on an individual basis. This should be considered only in men with confirmed hypogonadism on more than one occasion and with definite
symptoms of androgen deficiency.

Assessment

Because testosterone levels show a circadian variation, blood samples for testosterone should be taken in the morning when concentrations are at their highest. If the initial result is in the mildly hypogonadal range, a repeat sample is recommended because up to 30% of men have a normal result on repeat testing. LH and FSH should be measured to distinguish primary from secondary hypogonadism. In men with secondary hypogonadism, further evaluation for hypothalamic and/or pituitary disease is needed with measurement of prolactin, ferritin (to screen for haemochromatosis) and pituitary function in addition to MRI (Chapter 2). In men with primary hypogonadism where the aetiology is unclear, a karyotype should be requested to test for Klinefelter’s syndrome.

Treatment

Androgen replacement can improve libido, erectile function, mood, muscle mass and strength, reduce fat mass and improve bone mineral density. Treatment is given as a testosterone gel or injection (monthly or 3-monthly depot preparations) and should be considered in symptomatic patients with biochemically confirmed hypogonadism provided the patient does not have prostate or breast cancer. Caution is needed in patients with benign prostate hyperplasia, polycythaemia or sleep apnoea. Assessment of response to treatment and a screen for adverse effects should be undertaken at 6–12 month intervals via symptomatic enquiry, rectal examination of the prostate and
measurement of prostate-specific antigen (PSA), haematocrit and testosterone levels. Dosage should be adjusted according to symptomatic and biochemical response, aiming for a testosterone level in the mid-normal range.
Fertility is not improved with androgen replacement therapy. In men with secondary hypogonadism, substitution
of testosterone replacement with gonadotrophin therapy can help initiate and maintain spermatogenesis. Men with primary hypogonadism will not respond to gonadotrophin therapy, and may require assisted conception via testicular sperm extraction and intra-cytoplasmic sperm injection (ICSI).

Gynaecomastia

Definition

Gynaecomastia is a condition of benign hyperplasia of the breast tissue in men and should be distinguished from simple adiposity. Gynaecomastia develops as a result of a relative excess of oestrogens over testosterone, either because of increased production or action of oestrogens, or reduced production or action of androgens (Figures 29.1 and 29.2).

Causes

  • Physiological Most commonly in the newborn or pubertal period. Around 50% of pubertal boys will have gynaecomastia at some stage, but this is usually self-limiting.
  • Drugs A common cause, whether prescribed or taken recreationally. Examples include anti-androgens (e.g. spironolactone), oestrogens, testosterone (stimulates aromatase), cannabis and opiates.
  • Hypogonadism (Chapter 28).
  • Tumours Oestrogen- or androgen-producing testicular or adrenal tumours. HCG-producing tumours, usually testicular but occasionally ectopic (e.g. lung).
  • Systemic illness Classically, liver cirrhosis (increased oestrogen and lower bioavailability of androgens due to high levels of SHBG) but also chronic renal failure.
  • Other conditions including obesity, thyrotoxicosis and androgen insensitivity.
    Many cases are idiopathic with no clear underlying cause.

Assessment

The history should elicit the duration and progression of gynaecomastia; recent and rapid onset should lead to clinical
suspicion of a tumour. Symptoms and signs of hypogonadism (Chapter 28) and systemic disease (endocrine, hepatic or
renal) should be sought in addition to a careful drug history. The breasts should be examined to confirm the presence of gynaecomastia and to document its extent. The testes must be palpated to exclude a tumour and to assess size (androgenic steroid abuse may, for example, lead to atrophy). Baseline blood tests should include measurement of 09.00 testosterone, oestradiol, LH and FSH, SHBG, HCG and LFTs. Depending on results, other tests may subsequently be required (e.g. tests for hypogonadism; Chapter 28, testicular ultrasound and chest X-ray if raised HCG, and abdominal CT or MRI if markedly raised oestradiol).

Treatment

If an underlying disorder is identified this should be treated and offending drugs should be stopped if possible. Physiological gynaecomastia is usually self-limiting and does not generally require treatment. In persistent cases where there is significant cosmetic concern, medical treatment with anti-oestrogens (e.g. tamoxifen) can be tried, although success is variable and surgery is usually preferred.

Infertility

Definition and aetiology

Infertility is defined as the inability to conceive after 1 year of unprotected intercourse. It is estimated that the chances of a couple conceiving are 85% after 1 year and 95% after 2 years (in women under the age of 35). Infertility is primary (no previous pregnancies) or secondary (previous pregnancy, regardless of outcome). A number of factors lead to difficulty in conceiving (Figure 30.1):

  • Age The prevalence of infertility rises significantly with advancing female age. Fertility rates fall moderately between age 35 and 39, and dramatically thereafter.
  • Anovulation This accounts for 20% of cases and is usually indicated by menstrual dysfunction: amenorrhoea, oligomenorrhoea or polymenorrhoea.
  • Tubal factors Pelvic infections (pelvic inflammatory disease; PID), most commonly caused by Chlamydia trachomatis, result in damage to the fallopian tubes in a significant number of women, and are often clinically ‘silent’.
  • Cervical mucus factors.
  • Male factors.

Evaluation of the infertile couple

History

Both the male and female partner needs to be evaluated. In some cases, such as amenorrhoea, azoospermia or bilateral tubal obstruction, the aetiology is obvious but in most couples the cause is less clear. The history should enquire about any previous pregnancies, previous gynaecological history, menstrual characteristics, sexually transmitted infections, medical illnesses, family history and drug history. In men, a history of previous testicular surgery, trauma or orchitis should be sought. Couples should also be questioned about the frequency and timing of sexual intercourse, and any symptoms of sexual dysfunction such as loss of libido, erectile dysfunction or dyspareunia (painful intercourse).

Examination

A general examination should include measurement of BMI, as women who have a normal BMI are more likely to conceive than those who are either under- or overweight. Signs of androgen excess (acne, hirsutism) suggests a diagnosis of PCOS (Chapter 26) while a pelvic examination can reveal nodules, tenderness or limited pelvic organ mobility in keeping with endometriosis. BMI should also be assessed in men, in addition to a search for features of hypogonadism (Chapter 28)

Investigations

General health screening should include measurement of blood pressure, BMI, urinalysis, cervical cytology and rubella immunity (Table 30.1). Other tests include the following:

  • Ovulation function Regular menstrual cycles are a sign of ovulation in 95% of cycles. A mid-luteal phase (day 21)
    progesterone level can help confirm the presence of ovulation. If periods are irregular then measurement of other hormones is necessary (prolactin, thyroid function, androgens; Chapter 25). Measurement of anti-Müllerian hormone levels can help predict ovarian reserve.
  • Tubal assessment Needed when ovulation status and semen analysis is normal, especially in women with a history of PID. Laparoscopy is the gold standard.
  • Uterine evaluation Transvaginal ultrasound helps assess uterine morphology and neighbouring structures.
  • Chlamydia serology The best initial screen for tubal disease.
  • Semen analysis Semen volume, sperm count, motility and morphology are assessed. Testosterone, FSH, LH and prolactin should be measured in men with oligospermia or azoospermia (absent sperm). Urological assessment is needed in azoosper-mic men with normal testosterone,

Management

  • Tubal and uterine disease Surgery can be considered for proximal tubal disease or uterine fibroids in selected patients.
  • Endometriosis Laparoscopic ablation or resection of endometriotic deposits plus adhesiolysis may be beneficial.
  • Ovulatory dysfunction Optimisation of BMI helps restore ovulatory cycles in women who are under- or overweight.
    Ovulation induction with pulsatile GnRH analogues or gonadotrophins can be offered to patients with hypogonadotrophic hypogonadism. Anti-oestrogens such as clomifene citrate are used first line to induce ovulation in women with PCOS whereas patients with hyperprolactinaemia are treated with dopamine agonists (Chapter 6).
  • Intra-uterine insemination Involves timed insemination of sperm into the uterus. Often undertaken after failed ovulation induction in women with patent tubes.
  • In vitro fertilisation (IVF) and ICSI IVF treatment involves a series of steps that include superovulation (ovulation induction), oocyte (egg) retrieval, IVF, embryo transfer and luteal phase support.
  • Oocyte donation Used in women with premature ovarian failure (e.g. Turner’s syndrome, oophorectomy, previous chemo-/ radiotherapy).
  • Male factor infertility Gonadotrophins or pulsatile GnRH analogue therapy can improve fertility in men with hypogonadotrophic hypogonadism (e.g. Kallmann’s syndrome; Chapter 28). Hyperprolactinaemia is treated with dopamine agonists. Surgery or percutaneous sperm aspiration can improve fertility in men with obstructive azoospermia.