The two commonest causes of primary amenorrhoea are Turner’s syndrome and constitutional delay (Fig. 5.2). Other causes include pregnancy, hypothalamic causes (stress, excessive exercise, anorexia), androgen insensitivity syndrome, hypothyroidism, primary ovarian failure and anatomical causes (uterine malformation, imperforate hymen and vaginal septum). Drugs that cause amenorrhoea are chemotherapeutic agents (damage to ovaries) or others such as phenothiazines, which are dopamine antagonists.

Figure 5.2 Causes of amenorrhoea in relation to the hypothalamopituitary–ovarian–endometrial axis. GnRH, gonadotrophin-releasing hormone; LH, luteinizing hormone; FSH, follicle-stimulating hormone; LNG-IUS, levonorgestrel-releasing intrauterine system.

Clinical features

A family history of female relatives with late onset of periods is suggestive of constitutional delay. Autoimmune disease or androgen insensitivity syndrome may also be suggested in the family history. Excessive exercise and any change in weight should be elicited. Chronic illnesses or medications should be asked about. An imperforate hymen or vaginal septum may present with a history of amenorrhoea and cyclical abdominal pain.

Examination

The important examination feature is the presence or absence of secondary sex characteristics such as breast development, pubic and axillary hair. Absence of such features by 14 years suggests ovarian dysgenesis (e.g. Turner’s), a hypothalamic cause or hypothyroidism.

The weight and height should be checked for calculation of body mass index.

Other features to note are signs of Turner’s syndrome (such as webbed neck and short stature), hypothyroidism or abnormal visual fields from a possible prolactinoma. Acne or hirsutism suggests androgen excess and clitoromegaly may suggest virilization or may represent ambiguous genitalia of congenital adrenal hyperplasia or an androgen-secreting tumour.

Investigations

Investigations should be initiated in a girl who has no periods by the age of 16 years if secondary sexual characteristics are present and at 14 if there is no secondary sex development.

A pregnancy test should be performed if there is a possibility of pregnancy. Thyroid function and prolactin levels should be checked. Serum gonadotrophin levels are high with low oestrogen in ovarian causes, such as Turner’s syndrome, previous chemotherapy or premature ovarian failure. Low gonadotrophins are found in hypothalamic causes such as weight-related and exercise-induced amenorrhoea. In PCOS, the testosterone and LH levels are high, with normal FSH.

Karyotype confirms the presence of Turner’s syndrome or other rare abnormalities, such as fragile X syndrome, and aids the diagnosis of androgen insensitivity.

Ultrasound scan should be arranged to confirm the presence of a uterus and exclude haematometra or haematocolpos.

In constitutional delay, the commonest cause of primary amenorrhoea, the examination and gonadotrophin results are normal.

Management

Girls with constitutional delay will menstruate spontaneously and reassurance should be given.

Other causes of primary amenorrhoea should be treated where possible; for example, thyroxine for hypothyroidism, bromocriptine or surgery for prolactinoma, hymenal division for haematocolpos. Exercise should be limited in those with exercise-induced amenorrhoea and weight gain encouraged if the body mass index is less than 19.

In causes such as Turner’s syndrome, androgen insensitivity and premature ovarian failure, extensive counselling is required for both the girl and her parents. Support groups exist for all these disorders and cover issues of self-image, sexuality and fertility. Osteoporosis should be prevented by long-term hormone replacement, usually in the form of the COCP.

Secondary amenorrhoea

The causes of amenorrhoea are illustrated in relation to the hypothalamopituitary–ovarian–endometrial axis in Figure 5.2.

After physiological causes, such as pregnancy, breastfeeding and contraceptives, the commonest causes are polycystic ovaries, hyperprolactinaemia and premature ovarian failure.

History

The questions to ask include:

Examination

Examination should be directed by the history, looking for signs of PCOS (obesity, hirsutism and acne) or endocrine disease such as hypothyroidism. If a prolactinoma is suspected then the visual fields should be checked.

All women should have body mass index calculated. A bimanual examination may be indicated, for example to check for uterine size in suspected haematometra.

Investigations

A pregnancy test is usually indicated in secondary amenorrhoea. A hormone profile should then generally indicate the diagnosis.

In PCOS, a raised LH and moderately high testosterone are found in the majority of women. A very high testosterone level indicates further investigation for a possible androgen-secreting tumour, for example from the ovary or adrenal gland.

Premature ovarian failure is associated with raised FSH (>10 IU/l) and LH and with low oestradiol.

Hypothyroidism is associated with low thyroxine and raised thyroid-stimulating hormone.

Serum prolactin should always be checked, but caution is needed in interpreting the result as a prolactin level up to 1000 mU/ml may be due to stress, breast examination, PCOS or the venepuncture itself. True hyperprolactinaemia is usually caused by a microprolactinoma or occasionally a macroadenoma. Computed tomography or magnetic resonance imaging of the pituitary fossa and formal visual field testing should be arranged in cases of suspected prolactinoma.

Pelvic ultrasound is helpful where haematometra is suspected.

If premature ovarian failure is confirmed by gonadotrophin levels, then karyotype and autoimmune tests should be arranged for genetic causes and associated autoimmune disease, respectively.

If Asherman’s syndrome is suspected from previous uterine evacuation, then a hysteroscopy is indicated.

Management

Management of secondary amenorrhoea depends on the cause of the problem. As with primary ovarian failure, counselling is an essential part of the management of women in whom the amenorrhoea is permanent, in view of the anxiety caused about fertility, sexuality and long-term health issues such as osteoporosis.

Polycystic ovaries

Treatment with a COCP will restore periods and should be used if the woman has had fewer than four periods per year. Co-cyprindiol (ethinyloestradiol with cyproterone acetate) has been used in the past, as cyproterone acetate acts as an antiandrogen, thus also improving hirsutism and acne. However, the incidence of thrombosis exceeds that with low-dose oestrogen preparations and, therefore, co-cyprindiol should only be used after appropriate counselling.

If obesity is a problem in these women, then weight loss usually restores periods and fertility. If the woman is trying to conceive, then ovulation may be induced with clomifene.

Premature ovarian failure (spontaneous or iatrogenic)

Hormone replacement therapy (HRT) for osteoporosis prevention is necessary and counselling support should be offered. Fertility is only a possibility by ovum donation and in vitro fertilization (IVF).

Anorexia- or exercise-related amenorrhoea

Clear advice about lifestyle and diet is essential to restore periods. Most women recommence menstruating once exercise is reduced or the body mass index is above 19. If a woman continues to be amenorrhoeic, then some form of hormone replacement with COCP or HRT is needed to prevent osteoporosis.

Prolactinoma

Prolactinoma is generally managed by endocrinologists with bromocriptine or cabergoline. Surgery is only indicated for macroadenomas or cases resistant to medication.

Hypothyroidism

Hypothyroidism should be treated with thyroxine replacement.

Asherman’s syndrome

Adhesions can be broken down hysteroscopically and a combination of an IUCD with a 3-month course of systemic oestrogen is necessary to prevent reformation. However, although periods may return, pregnancy is unlikely.

Contraceptive-related amenorrhoea

Intermenstrual and postcoital bleeding

Intermenstrual bleeding (vaginal bleeding not due to a regular menstrual period) and postcoital bleeding (bleeding after sexual intercourse) are almost always pathological.

Aetiology of intermenstrual and postcoital bleeding

Hormonal and contraception-related causes

Long-acting progestogens, the LNG-IUS and progesterone-only pill can all cause irregular bleeding, as can poor compliance with the COCP.

Uterine causes

The most important cause of intermenstrual bleeding and postcoital bleeding, especially in older women, is endometrial carcinoma. Other uterine causes are endometrial hyperplasia, endometrial polyps and pedunculated submucosal fibroids. Retained products of conception are an uncommon cause.

Cervical causes

Cervical carcinoma can present with intermenstrual or postcoital bleeding. More commonly, cervical ectropion, infection (Trichomonas, gonorrhoea) or endocervical polyps may be the cause of the irregular bleeding.

Vaginal causes

Candida, carcinoma and hypo-oestrogenic atrophy are vaginal causes of intermenstrual and postcoital bleeding.

Non-gynaecological causes

Rectal bleeding (e.g. from haemorrhoids) and urethral bleeding (e.g. from a caruncle) can be mistaken for vaginal bleeding.

Clinical features

The history should include the amount and timing of the bleeding, contraceptive use and any previous infections. The cervical smear history is important. Some risk factors may suggest a more likely cause. For example, obesity, diabetes and nulliparity are associated with endometrial hyperplasia and malignancy.

Examination

Careful examination of the anus, external genitalia and urethral orifice may reveal the site of bleeding. Speculum examination may show an ectropion, inflamed cervix or features suggestive of malignancy. Endocervical polyps may be visualized. Bimanual examination may show an enlarged uterus suggestive of fibroids or malignancy.

Investigations

Triple swabs should be taken for infection (high vaginal swab for Candida and Trichomonas, endocervical for gonorrhoea, endocervical for Chlamydia).

Cervical smear should be taken if it has not been performed within the last 3 years.

Colposcopy and cervical biopsy should be performed if there is suspicion of cervical malignancy.

Transvaginal ultrasound scan, preferably around day 5, may suggest endometrial thickening or a polyp.

Hysteroscopy should be arranged in women where no other cause has been found for the irregular bleeding and a biopsy should be taken.

Management

The management of intermenstrual and postcoital bleeding depends on the cause.

Sexually transmitted infections or Candida should be treated. Visible endocervical polyps should be removed in the outpatient clinic by grasping with polyp forceps and twisting repeatedly until the polyp is avulsed. Larger endocervical or intrauterine polyps or fibroids should be resected hysteroscopically. All specimens should be sent for histological analysis to confirm they are benign.

Continuous progestogens can be used for the treatment of endometrial hyperplasia. Oncological assessment is necessary if uterine, cervical or vaginal malignancy is diagnosed.

Cervical ectropion usually resolves by stopping the COCP, or it may be cauterized in the colposcopy unit, only after a normal smear.

For women taking a COCP in whom a cervical ectropion is not present, it is important to check that compliance is good and that there are no other factors influencing the effect, such as enzyme-inducing drugs or diarrhoea and vomiting. Otherwise, a biphasic or triphasic preparation can be considered, or a preparation containing a different progestogen or a lower oestrogen.

Premenstrual syndrome

One in three women experience some degree of premenstrual symptoms. In 3–5% these symptoms are severe, and when mood and behaviour symptoms dominate, the term ‘premenstrual dysphoric disorder (PMDD)’ is used.

Pathophysiology

Premenstrual syndrome and PMDD are poorly understood, but increased sensitivity to progesterone is thought to cause a fall in the concentration of neurotransmitters, including serotonin, hence the benefit of serotonin-specific reuptake inhibitors in treatment.

Clinical features

The symptoms of premenstrual syndrome always start after ovulation, worsen as menstruation approaches and resolve within the first few days of bleeding. Symptoms may be physical, emotional or behavioural.

Physical symptoms include breast swelling and discomfort, abdominal bloating, oedema, weight gain, headaches or deterioration in asthma, migraine or epilepsy. Emotional and behavioural symptoms include aggression, anger, irritability, tearfulness, low mood, anxiety, altered eating habits and disturbed sleep.

In severe cases, women may become violent or suicidal. Relationship difficulties and occupational problems are commonly reported.

Diagnosis

The diagnosis is made clinically with a symptom diary kept over a few months. The symptoms must be seen to occur in most months, develop in the luteal phase and resolve soon after the onset of menstruation. There must be at least 1 week without symptoms and if any symptoms persist throughout the menstrual cycle then an alternative diagnosis, such as anxiety or depression, is likely.

Treatment

Ovulation inhibition

Preventing ovulation with the COCP is effective for many women. Oestrogen may also be administered in other forms, for example as patches, as long as the endometrium is protected. The LNG-IUS is a useful method of protection for the endometrium as it acts locally on the endometrium with minimal systemic progestogen absorption.

Serotonin-specific reuptake inhibitors

There is good evidence that serotonin-specific reuptake inhibitors, particularly fluoxetine and sertraline, improve physical, emotional and behavioural symptoms of premenstrual syndrome and PMDD. Long-term treatment is generally needed, as symptoms tend to relapse after stopping.

Alternative treatments

Evening primrose oil has some benefit for reducing breast tenderness and pain. There is no evidence of benefit from vitamin B₆ (pyridoxine), though it may be an effective placebo treatment.

Progesterone treatment has no role in the treatment of premenstrual syndrome or PMDD.

Polycystic ovarian syndrome

Definition

The classic definition of PCOS (Stein–Leventhal syndrome) is a triad of obesity, oligomenorrhoea and infertility. ‘Polycystic ovaries’ is the term used to describe a typical appearance of ovaries on ultrasound scan.

PCOS is now known to involve a disturbance of metabolic function. There are no specific diagnostic criteria, but the diagnosis is made on a combination of any of the following features:

Figure 5.3 Schematic representation of normal and polycystic ovary.

Incidence

The typical appearance of polycystic ovaries is found in 20% of women on pelvic scan. Of these, 50% have other features suggestive of PCOS.

Aetiology

The aetiology of PCOS is poorly understood, but there is a genetic correlation.

Pathophysiology

Infrequent periods result from anovulation in most cycles. Greasy skin, acne and hirsutism arise from the androgen excess. The underlying metabolic disorder is insulin resistance (hyperinsulinaemia in the presence of normoglycaemia) and this accounts for the common symptom of obesity.

Presentation

Women may present with a history of subfertility or irregular periods. Others present with hirsutism, skin problems or obesity. Polycystic ovaries are also a common incidental finding on ultrasound scans for other indications.

Clinical features

The spectrum of clinical features is described above. The presentation of PCOS varies enormously between different women. For example, many women have normal body mass index despite the typical features of oligomenorrhoea, ultrasound features and abnormal androgen concentrations. Other women may have regular periods with obesity and abnormal lipids.

In PCOS, irregular periods are often very heavy or prolonged as they result from endometrial shedding after prolonged oestrogen priming without a progesterone-induced withdrawal bleed.

Examination

A general examination may reveal hirsutism, greasy skin, acne and obesity. Abdominal and pelvic examinations are usually unremarkable and the ovaries are not usually palpable.

Investigations

A hormone profile should be taken around day 5. The investigations usually show:

• LH greater than 10 IU/l

• Raised LH:FSH ratio

• Testosterone greater than 2.5 nmol/l

• Decreased sex hormone-binding globulin.

Serum FSH, thyroid function tests and prolactin levels are usually normal in women with PCOS.

Other causes of hyperandrogenism should be screened for if there are other virilizing features (such as clitoromegaly, voice changes or altered body habitus) or if the serum testosterone concentration is greater than 4.8 nmol/l. Such causes include adrenal or ovarian tumours, Cushing’s syndrome and atypical congenital adrenal hyperplasia.

Transvaginal ultrasound scan usually confirms the typical features of polycystic ovaries, but the diagnosis of PCOS is not dependent on this.

Management

Women with PCOS need a careful explanation of the diagnosis and its implications. Further management should be determined by the symptoms and in women with no symptoms reassurance alone is needed.

The COCP is the most effective method used to regulate periods. Oligomenorrhoeic or amenorrhoeic women with PCOS may be at risk of endometrial hyperplasia or malignancy from persistent oestrogen stimulation. In these women regular menstruation should be induced by the COCP or by a 14-day course of progesterone.

Hirsutism may be treated by local treatments, such as waxing, electrolysis and bleaching, though these are expensive and need repeating regularly. Oral and topical antibiotics may help with acne.

The COCP is also effective in women with hirsutism and acne, especially where contraception or regulation of periods is also desirable. A COCP containing cyproterone acetate, an antiandrogen with progestogenic effects (co-cyprindiol), helps to improve acne by 3 months and hirsutism by 6–9 months, as well as regulate menstruation. Extra cyproterone acetate, up to 100 mg daily, may be added if the COCP alone is not effective, but evidence for this is unclear. Co-cyprindiol has a higher associated risk of thrombosis than other low-dose pills and this should be explained to the woman. Spironolactone is an unlicensed treatment that may be of benefit in hirsutism by acting as an androgen receptor antagonist.

Weight loss may be difficult in women with PCOS, but is important for reducing long-term cardiovascular risks, self-image, menstruation and fertility. Referral to a dietician and exercise advice are helpful.

Ovarian stimulation with clomifene citrate or laparoscopic ovarian drilling is effective for PCOS-related subfertility. However, simple weight loss alone also has a dramatic effect on restoring ovulation.

Evidence suggests that metformin regulates ovulation, improves fertility and improves the lipid profile in women with PCOS. The presumed mechanism is that, by reducing insulin resistance, it breaks the chain of events that leads to the symptoms and signs of the disease. However, it is not licensed for these indications and no evidence is yet available to indicate whether it has a long-term benefit in preventing the metabolic consequences of PCOS. It is generally reserved for women who are significantly overweight and who have not been successful in reducing weight by diet control and exercise.

Contraception in polycystic ovarian syndrome

Women with PCOS may ovulate in some cycles, but not in others, so effective contraception should be used if pregnancy is not desirable.

Prognosis

The risk of type 2 diabetes developing in women with PCOS is significantly increased. Yearly screening for glycosuria and raised random blood glucose should be considered, though there is no evidence for the effectiveness of this yet.

Other cardiovascular disease risk factors are also more common in women with PCOS, such as hypertriglyceridaemia, reduced high-density lipoprotein cholesterol and obesity. Cerebrovascular accident (CVA) is more common, but mortality from cardiac disease has not been shown to be increased in these women.

Endometrial carcinoma is more common in women with PCOS. However, this may relate to obesity and the evidence is not clear that inducing a regular withdrawal bleed in these women reduces the malignancy risk.

Women with PCOS have a higher chance of miscarriage, but no effective treatment has been shown to reduce this.

Women with PCOS have an increased chance of developing gestational diabetes if they become pregnant. Screening with random blood glucose or glucose tolerance test should be considered for all PCOS women in pregnancy.

Infertility

Definitions

• Subfertility – failure to conceive after 1 year of regular unprotected sexual intercourse.

• Infertility – no chance of spontaneous conception, for example because of bilateral salpingectomy or azoospermia.

• Primary subfertility – the woman has never been pregnant.

• Secondary subfertility – the woman has had at least one pregnancy before.

Incidence

Thirty per cent of all women will become pregnant after 1 month of regular unprotected intercourse. The number of women becoming pregnant in each consecutive month then reduces so that only 10% of couples will not achieve pregnancy after 1 year (5% after 2 years).

Fifteen per cent of couples are referred for investigation or treatment for subfertility, usually after 1 year of trying, though many of these still conceive spontaneously while waiting for investigation or treatment. Some couples will be referred earlier if they are known to have fertility problems. Examples include women with previous salpingectomies or men with cystic fibrosis.

Age

Female fertility declines naturally with age, such that the chance of pregnancy at 35–39 years of age is half that at 19–26 years of age. Recently, male fertility has also been shown to decline with age, to a lesser extent.

Aetiology

Fifteen per cent of couples have more than one cause for their infertility. The causes of infertility are shown in Table 5.1.

Table 5.1 Causes of infertility

Male factor (30–50%):

Erectile problems (e.g. psychological or neurological disease)

Ejaculatory dysfunction (e.g. retrograde ejaculation after prostatic surgery)

Sperm dysfunction (motility, normality, survival)

Testicular failure (e.g. cryptorchidism, mumps orchitis, torsion, chemo- or radiotherapy, Klinefelter’s, hypogonadotrophic hypogonadism)

Genital tract obstruction (e.g. vasectomy, incidental ligation of vas deferens at hernia surgery, infection with gonorrhoea, Chlamydia or tuberculosis)

Congenital absence of the vas (e.g. cystic fibrosis)

Ovulatory problems (30%):

Polycystic ovary syndrome (70% of anovulatory infertility)

Hypogonadotrophic anovulation (e.g. excess exercise, anorexia, Sheehan’s, Kallman’s syndrome)

Hyperprolactinaemia (e.g. prolactinoma, drugs)

Genetic causes (e.g. Turner’s syndrome, androgen insensitivity)

Premature ovarian failure

Tubal problems (20%):

Infection (e.g. Chlamydia, gonorrhoea, pelvic inflammatory disease, tuberculosis)

Adhesions (e.g. surgery or endometriosis, but not unruptured appendicitis)

Previous ectopic pregnancy

Other causes:

Endometriosis (5%)

Fibroids (up to 10%)

Uterine anomalies (1%)

Unexplained infertility (25%)

History

A full medical history should be taken from both partners. Important questions for the woman are:

The partner should also be asked specifically:

Examination

A general gynaecological examination should be performed for all women, though commonly no abnormality is found. Body mass index should be calculated.

The man may be examined for the presence of both testes in the scrotum and the vas deferens should be palpated bilaterally. However, this is usually helpful only if semen analysis has shown oligozoospermia or azoospermia. If azoospermia is present, there may also be signs of hypoandrogenism (e.g. lack of body hair).

Investigations

Female investigations

Hormone profile

The following tests should be requested on all women complaining of subfertility:

• LH (day 2–5 of the menstrual cycle) – LH greater than 10 IU/l and a raised LH:FSH ratio suggests PCOS.

• FSH (day 2–5 of the menstrual cycle) – FSH greater than 10 IU/l suggests a poor prognosis as it is associated with poor ovarian reserve (ovarian failure) and a likely poor outcome from assisted conception, unless donor eggs are used.

• Progesterone (day 21 for a 28-day cycle, otherwise about 8 days before expected menstruation) – progesterone greater than 30 nmol/l suggests that ovulation has occurred.

• Testosterone – testosterone concentration 2.5–5 nmol/l is consistent with PCOS. If testosterone is greater than 5 nmol/l, then further investigation is needed for other causes of androgen excess.

• Prolactin – prolactin >1000 mU/ml suggests hyperprolactinaemia and if repeat test confirms this, then investigations for prolactinoma should be initiated. Prolactin levels less than 1000 mU/ml may be due to stress, exercise or venepuncture.

Blood tests

Full blood count should be checked to confirm that the woman is not anaemic.

Thyroid function tests are only indicated where there are other signs or symptoms of thyroid disease.

Rubella immunity should be confirmed in order that immunization can take place, if indicated, before pregnancy.

Transvaginal ultrasound scan

Ultrasound scan should identify fibroids or polyps. Other anatomical uterine anomalies, such as a uterine septum, may also be seen.

Further investigations

Tests for tubal patency

All tests of tubal patency should be performed in the first 10 days of the menstrual cycle to avoid disruption to a potential early pregnancy. Various tests are employed, as described below, depending on the skills of the clinicians and the likely diagnosis from the history. As all tests involve some degree of instrumentation of the uterus, prophylactic antibiotics should be given.

Hysterosalpingogram

Hysterosalpingogram involves contrast medium injected into the cervix and real-time X-ray to visualize its progress through the uterus and tubes. It demonstrates the shape of the uterine cavity as well as tubal patency and morphology.

Hystercontrastsalpingography

Hystercontrastsalpingography involves saline injection through the cervix and visualization with transvaginal ultrasound. It shows polyps and fibroids more clearly than hysterosalpingogram as well as demonstrating tubal patency.

Laparoscopy and dye

Laparoscopy is performed, under general anaesthetic, and methylene blue dye is injected through the cervix into the uterus. If the tubes are patent, the dye can be visualized as it fills the tubes and spills from the fimbrial ends into the peritoneal cavity. Any tubal blockage identified can be assessed for suitability for tubal microsurgery. The procedure also has the advantage of demonstrating and allowing immediate treatment of any endometriosis.

Postcoital test

The postcoital test provides little useful information.

Male investigations

Semen analysis

A semen sample must be given by masturbation without lubrication into a sterile pot and transported to the laboratory within 1 hour for analysis. If the man cannot masturbate then a coital specimen in a non-spermicidal condom may be sufficient. The man should not have ejaculated for at least 3 days prior to providing the specimen.

The normal values for semen analysis are given in Table 5.2.

Table 5.2 Normal values for semen analysis

Volume	2–5 ml
Count	>20 million per ml
Motile forms	>50% progressively mobile and >25% rapidly progressive
Normal forms	>15% normal shape

Semen deficiency definitions

• Teratozoospermia is an abnormally high number of abnormal forms.

• Asthenozoospermia is reduced sperm motility.

• Oligozoospermia is a reduced sperm count.

• Azoospermia is the absence of sperm in the ejaculate.

Abnormal sperm counts often consist of a reduced number of poorly motile sperm with excessive abnormal forms, rather than a single problem. If the result is abnormal, the sample should be repeated after 6 weeks. If there is a history of a recent serious illness then it may take 3–4 months for return of normal spermatogenesis and a normal semen analysis result.

Further investigations

Testicular biopsy will confirm whether azoospermia has an obstructive cause (mature sperm seen) or is due to testicular failure (Sertoli cell-only syndrome or maturation arrest).

LH and FSH can help diagnose hypogonadotrophic causes. Karyotype will identify Klinefelter’s (XXY) and Y chromosome microdeletions. Cystic fibrosis testing should be arranged in cases of obstructive azoospermia.

Management

The chance of successful spontaneous or assisted pregnancy relates to age, previous pregnancy, duration of subfertility, body mass and the cause of the problem.

Couples often feel they have failed in not achieving a pregnancy and need careful counselling for subfertility. Realistic pregnancy rates should be given with emphasis on the stress placed on couples and the treatment failure in many cases. Options, including donor insemination for sperm problems, ovum donation, adoption or accepting childlessness, are all difficult issues for couples to consider.

Sperm dysfunction

Any abnormal specimen should be repeated after 6 weeks to exclude illness as a cause. In the meantime, advice should include avoiding alcohol, nicotine, very hot baths or tight underpants, all of which are known to inhibit sperm quality. If the sperm quality does not improve, then referral can be made to an andrologist for further investigation. Testosterone injections stimulate spermatogenesis in hypogonadotrophic hypogonadism. Sperm may be retrieved from the testis in obstructive cases. This sperm may then be used for intracytoplasmic sperm injection (ICSI). ICSI is also very effective, even for poor sperm quality or oligozoospermia.

Reversal of vasectomy depends on the time since the operation, with almost no pregnancies if the procedure was more than 10 years earlier. However, early reversal results in sperm in the ejaculate in up to 90% of samples and pregnancy in up to 50% of couples after 2 years.

Tubal infertility

Some women will become pregnant spontaneously despite apparently non-patent tubes. However, most women with tubal infertility will need IVF to bypass the damaged tubes.

Surgical options are available for a few specific tubal problems. For example, open or laparoscopic salpingotomy or reanastomosis may be possible after previous sterilization and proximal tubal obstruction is sometimes helped by hysteroscopic cannulation of the tube. Severely damaged tubes and hydrosalpinges should be removed by bilateral salpingectomy to reduce the complications of IVF.

Anovulatory infertility

Where possible, the cause of anovulation should be treated. Prolactinomas are treated with 1.25 mg bromocriptine at night, gradually increased to 7.5 mg daily in divided doses, though much higher doses can be required. The serum prolactin level should be maintained below 1000 mU/ml for ovulation to return in 70–80% of women. Bromocriptine should then be discontinued once pregnancy is confirmed.

Cabergoline is an alternative treatment for hyperprolactinaemia, but should be discontinued at least 1 month prior to pregnancy due to theoretical risks of teratogenicity.

Other medication should be reviewed where this may be the cause of anovulation.

Women should be encouraged to maintain their body mass index at between 20 and 30 to maximize the chance of conception. Most underweight women will ovulate once their body mass index exceeds 20, but those who do not may need further GnRH pulsatile stimulation.

Polycystic ovarian syndrome

Weight loss is the simplest treatment for anovulatory women with PCOS and they should all have clear advice about improved diet and exercise.

Ovarian stimulation with clomifene results in a 40–60% conception rate after 6 months, though twins occur in 10% and triplets in 1%. Hyperstimulation also occurs in 1% of women taking clomifene. The clomifene dose is 50 mg daily from day 2 to 6 of the cycle. Day 21 progesterone is checked in the first cycle to confirm that ovulation has occurred. If ovulation has not occurred, then the dose is increased to 100 mg daily. The maximum course is 6 months due to fears of ovarian carcinoma from repeated stimulation. Those women who do not respond to clomifene may need FSH injections to stimulate ovulation.

Metformin also improves ovulation (20% pregnancy after 6 months), with no reported teratogenic effects. However, it is not licensed for this use.

Ovarian drilling (laparoscopic diathermy to make several holes in the ovaries) is another effective method of inducing ovulation in women with PCOS and does not result in hyperstimulation or increased risk of multiple pregnancy. There are, however, associated operative complications.

Endometriosis

Infertility with endometriosis does not necessarily relate to tubal obstruction, as many women will have normal tubal patency, but possibly impaired tubal function, limited fimbrial mobility or adhesions. Surgical treatment to ablate the endometriosis has been shown to improve fertility in moderate to severe endometriosis. Endometriomas should be drained or excised as they may inhibit follicular development and also increase the chance of infection at egg retrieval in IVF.

Women with minimal disease do not benefit from surgery and should be treated initially with intrauterine insemination (IUI).

IVF is the most effective treatment where the above measures have not been successful.

Fibroids

Submucosal fibroids may interfere with implantation and IVF cycles are 50% less successful in the presence of fibroids. Intracavity fibroids should, therefore, be removed hysteroscopically after shrinking with GnRH analogues. Laparoscopic or open myomectomy is performed for intramural fibroids where no other cause for the infertility has been identified.

Social factors

Alcohol, caffeine and smoking may reduce fertility in women and should be discouraged.

Unexplained infertility

Women with unexplained infertility should be offered superovulation and IUI. IVF is then indicated for those who have not responded to IUI. Women over 38 years may be offered IVF as a first-line treatment.

Assisted conception techniques

Assisted conception techniques aim to:

• Pharmacologically stimulate ovaries to produce several eggs.

• Prepare the semen by washing, and in ICSI selecting a highly motile normal form.

• Optimize fertilization by approximating the sperm and egg closely (IUI) or facilitating fertilization in vitro (IVF or ICSI).

Ovulation induction

Oral drugs such as clomifene and tamoxifen or parenteral drugs such as FSH can stimulate ovulation.

FSH can be ‘natural’, from the urine of postmenopausal women, or more commonly recombinant. The side effects are increased multiple pregnancy rates and ovarian hyperstimulation. Down-regulation of the pituitary–gonadal axis with GnRH analogues or antagonists prior to FSH stimulation reduces the chance of these side effects, but carries menopausal-type side effects itself.

The follicles are monitored during stimulation and eggs collected or ovulation triggered when the leading follicle reaches 18 mm. Ovulation is triggered by human chorionic gonadotrophin (hCG), which mimics the normal LH surge.

Intrauterine insemination

IUI involves placing a small volume of prepared motile sperm high in the uterine cavity on the day of ovulation. It bypasses cervical mucus, introduces sperm at the right time in the cycle and places them close to the fallopian tubes. It may be used in natural cycles or be combined with controlled ovarian stimulation (with gonadotrophins or clomifene). The success is 10–17% pregnancy per cycle and it is cheaper and much less invasive than IVF. If used as a first-line treatment, IUI probably prevents 20% of couples from having to move on to IVF.

Indications for IUI are mild sperm defects, unexplained infertility, failure to conceive with ovulation induction alone, ejaculatory failure or retrograde ejaculation.

In vitro fertilization

IVF involves ovulation induction with FSH, usually after GnRH down-regulation, to produce several eggs. Once the dominant follicle reaches 18 mm in diameter, maturation of the eggs is stimulated by injection of hCG 38–48 hours later; the eggs are then collected by ultrasound-guided aspiration, usually under sedation. Sperm is collected by masturbation and washed. Each egg is then cultured with a small sample of the washed sperm.

On the second or third day, at the four- to eight-cell stage, one to three embryos are transferred back into the uterus, via a transcervical cannula.

The pregnancy is supported with hCG injections or progesterone pessaries, tablets or injections as there is no corpus luteum to produce natural progesterone.

A pregnancy test is taken after 2 weeks and, if positive, an ultrasound scan is performed to confirm the presence of an intrauterine sac. Vaginal bleeding in the meantime usually implies failed implantation. Indications for IVF are severe tubal damage, endometriosis, bilateral salpingo-oophorectomy, unexplained infertility and mild male factor infertility.

Success rates are variable, up to 25–30% live birth rate per cycle, depending on the age of the mother, whether donated eggs are used and the number of embryos transferred. The overall national average success rate, however, is about 17%.

Complications of in vitro fertilization

Ovarian hyperstimulation

Ovarian hyperstimulation may occur with FSH or clomifene stimulation. It is more common when GnRH analogues have been used prior to stimulation, in women with PCOS and in successful implantations. The pathophysiology involves massively enlarged ovaries, extravasation of fluid causing ascites and haemoconcentration causing thrombosis.

Clinical features are:

• Mild ovarian hyperstimulation syndrome (OHSS) – abdominal discomfort

• Moderate OHSS – abdominal distension and pain, nausea, vomiting, constipation or diarrhoea, dark urine and oedema

• Severe OHSS – pulmonary oedema or thrombosis.

Management for mild OHSS is to increase the oral fluid intake and review regularly. For moderate OHSS, admission is indicated for daily weight and girth measurement, fluid balance monitoring, thromboprophylaxis and monitoring of liver function, albumin, electrolytes and haematocrit. Severe OHSS may need intravenous fluids and drainage of ascites or pleural effusions.

Multiple pregnancies

Multiple pregnancies are common after assisted conception. The risks of multiple pregnancies include maternal obstetric complications (e.g. pre-eclampsia), extreme prematurity, cerebral palsy and increased perinatal mortality. Strategies to prevent this include implantation of a maximum of two embryos, with cryopreservation of extra embryos for use in future cycles.

Ectopic pregnancy

Ectopic pregnancy occurs in about 4% of assisted conception pregnancies. Heterotopic pregnancies (simultaneous intrauterine and ectopic pregnancies) are also much more common and diagnosis (with a combination of clinical symptoms, biochemical markers and ultrasound) is difficult.

Intracytoplasmic sperm injection

ICSI is the injection of a single sperm into an oocyte. Similar egg retrieval methods are used as for IVF. The sperm may be from a semen sample or may be retrieved from the epididymis or testis in obstructive azoospermia. Indications for ICSI include severe oligozoospermia, severe sperm morphological abnormalities, poor motility and obstructive azoospermia.

The success rates are up to 20–30% live births per cycle where oligozoospermia is the only cause and the woman is under 35 years.

There is some evidence that sex chromosome anomalies, congenital abnormalities and developmental delay may be more common with ICSI.

Gamete intrafallopian transfer

Gamete intrafallopian transfer involves retrieval of eggs as for IVF and injection of the sperm and eggs directly into the fallopian tube under laparoscopic guidance. It has largely been replaced by IVF and ICSI and is not commonly used.

Alternative infertility options

Donor insemination, embryo donation and egg donation are all possible ways of achieving pregnancy in cases of failure of other methods. Surrogacy, where another woman carries the pregnancy in her uterus, using the partner’s sperm and either her own or the infertile woman’s egg, is also possible, but has no legal backing in the UK.

Acceptance of childlessness and adoption should also be discussed from an early stage.

Human Fertilisation and Embryology Authority

The Human Fertilisation and Embryology Authority (HFEA) regulates all assisted conception units in the UK. It licenses units involved in ICSI, IVF, preimplantation genetic diagnosis, embryo, egg or sperm donation and surrogacy, as well as storage of embryos and sperm (occasionally eggs) and research involving human embryos.

The HFEA also sets standards for assisted conception, which include consideration of the welfare of the potential child, information to be given to couples, counselling to be given, confidentiality issues and consent issues.

Ovarian failure

Ovarian function declines gradually from birth and the climax of this is the menopause, which normally occurs in the fifth or sixth decade. Some women experience earlier ovarian failure, which may be spontaneous or secondary to medical or surgical treatment.

Definitions

Menopause

Menopause is the permanent cessation of periods resulting from the loss of ovarian follicular activity.

The menopause can only be diagnosed retrospectively, 1 year after the last menstrual period.

The climacteric (menopause transition)

The climacteric is the time prior to the menopause, when menopausal symptoms are present and periods are usually irregular.

The average duration of such symptoms before cessation of periods is 4 years.

Premature ovarian failure

Premature ovarian failure is the cessation of periods due to ovarian failure under 40 years.

Age

The average age of the menopause is 51 years. Smoking reduces the age of menopause by 2 years. There is a genetic tendency, with daughters experiencing the menopause at about the same age as their mothers.

Pathophysiology

Women have a finite number of oocytes within the ovary, which undergo atresia with time. In the climacteric, failing ovarian follicular activity causes lower circulating oestrogen levels and thus higher levels of LH and FSH from the pituitary. Although ovarian oestrogenic hormone production falls, androstenedione continues to be produced by the ovarian stroma, which is converted peripherally to oestrogen, so measured oestradiol levels may remain high.

Bleeding is often irregular and prolonged as oestrogen induces endometrial proliferation, but anovulation means no progesterone to induce a regular bleed.

Clinical features of menopause

Symptoms, which commonly start about 4 years before the last period, are experienced by 75–80% of women. Irregular periods are one of the commonest features, with only 10% of women having a sudden cessation of periods. Other features of oestrogen deficiency are hot flushes (a feeling of heat, flushing and perspiration of the head, neck and chest), palpitations, night sweats, headaches, tiredness, sleep disturbance, depressed mood, irritability, loss of concentration, vaginal dryness, decreased libido and urinary tract infections. Thin skin, brittle nails and hair loss are also reported.

Psychosexual changes also occur relating to self-image, libido, loss of fertility and the ‘empty nest’. However, these symptoms have complex aetiology and may relate to ageing and relationship changes rather than low oestrogen levels.

Signs

Vaginal and labial atrophy may be recognizable on examination. However, other features such as thin skin and brittle nails may simply reflect the ageing process.

Investigations

Investigations are only indicated if there is diagnostic difficulty. FSH and LH are both raised. However, hormone levels fluctuate during the climacteric and women with very high gonadotrophin levels may still menstruate intermittently. Similarly, women with severe menopausal symptoms may have normal gonadotrophin levels at times.

Oestradiol measurement is not helpful.

Management

Hormone replacement therapy

Until recently, up to 60% of women had used HRT at some stage between the ages of 51 and 57. The current indications for treatment are symptom control and osteoporosis risk.

Symptom control

Oestrogen-containing systemic HRT, in the form of tablets, patches, gels or implants, improves hot flushes, vaginal dryness and urinary symptoms. Cognitive function, tiredness and mood symptoms also improve with systemic oestrogen, but this may relate to better sleep once the sweats and flushes have been treated. Systemic HRT may regulate irregular perimenopausal bleeding if no other pathology is present.

Topical oestrogens, in the form of creams, pessaries or rings, are only effective at reducing vaginal atrophy and urinary symptoms.

Low libido is sometimes improved with HRT, but counselling or androgen supplementation may be indicated.

Osteoporosis prevention

Bone density declines with age and this is accelerated by the menopause. Systemic HRT reduces this bone loss for the duration of the therapy.

Types of hormone replacement therapy

Oestrogen (oestradiol, oestrone, oestriol or conjugated equine oestrogens) is the active hormone in all HRT, but if the uterus is present then some form of progestogen is needed to prevent endometrial hyperplasia or malignancy from the unopposed oestrogen.

Sequential hormone replacement therapy

Sequential HRT consists of continuous oestrogen with an additional 12–14 days of progestogen every month to induce a withdrawal bleed. ‘Long cycle’ preparations use a progestogen to induce a bleed only every 3 months.

Continuous combined hormone replacement therapy

Continuous combined HRT (CCT) consists of continuous oestrogen and low-dose progestogen. The advantage of this regime is the absence of periods – women usually experience irregular bleeding for the first few months and are then bleed-free. However, CCT is only suitable for women who have stopped menstruating for at least 1 year or who are over 55 years. This is because persistent irregular bleeding is likely if the woman still has significant endogenous hormone production.

Unopposed oestrogen

Unopposed oestrogen preparations are only suitable in women without a uterus (generally after hysterectomy). They are not suitable for women who have had a resection of the endometrium for menorrhagia, as small islands of endometrial tissue may still be present.

Tibolone

Tibolone is a synthetic steroid with oestrogen, progestogen and androgen activity. It is used, like CCT, as a bleed-free preparation. An advantage is the improvement in libido for some women from the androgenic component.

Modes of administration

Oral

Daily HRT tablets are easy to take and there is a wide choice of preparations. However, some women may not remember to take them or may object to tablets and there is variable absorption between women.

Transdermal

Patches are the commonest transdermal preparation, with twice-weekly or weekly application. Disadvantages include variable absorption, skin irritation, possible dislodgement and the need to remember to change the patch. Transdermal gels are also available.

Implants

Oestradiol may be given as a subcutaneous implant under local anaesthetic every 6 months. The advantage is that there are no compliance issues and testosterone implants can be co-administered for libido problems. However, tachyphylaxis may occur, where the woman becomes less responsive to successive implants and experiences menopausal symptoms despite high blood levels of oestradiol. Other disadvantages are occasional infections at the wound site, difficulty with removal if side effects occur and the need to give a progestogen by a different route.

Topical

Oestrogen cream, pessaries or rings are very effective for urogenital symptoms. If long courses are required in women with a uterus, then to protect the endometrium a progestogen should also be administered.

Combined approach

Many different combinations of approaches may be used to administer HRT. For example, oestrogen patches may be used with 14 days of progesterone tablets each month, or oestrogen tablets may be used in a woman with the LNG-IUS, though it is not licensed for this use.

Side effects of hormone replacement therapy

Vaginal bleeding

Unwanted withdrawal bleeds may occur with sequential HRT and irregular bleeding can occur with CCT. This may be managed by altering the oestrogen or progestogen dose, changing to tibolone or considering an LNG-IUS.

Oestrogenic effects

Breast tenderness, nausea and leg cramps may occur with systemic oestrogen. Such symptoms often settle after a few months.

Progestogenic effects

Fluid retention, breast tenderness, headache, acne and greasy skin may occur. These may be intermittent with sequential regimes. Three-monthly sequential preparations, CCT or the LNG-IUS may improve the symptoms.

Weight gain

Weight gain is reported by some women taking HRT, but probably relates to age and lack of exercise rather than to HRT.

Contraindications to hormone replacement therapy

HRT is contraindicated in women with a history of endometrial cancer, undiagnosed vaginal bleeding, thromboembolic disease or thrombophilia and porphyria.

Relative contraindications are breast cancer, obesity, cardiovascular disease, diabetes, migraine and a family history of deep-vein thrombosis.

Malignant melanoma contains oestrogen receptors, but there is no current evidence to support avoidance of HRT in these women.

Risks of hormone replacement therapy

Breast cancer

There is an overall 26% increase in breast cancer in HRT users. This means an extra eight cases per 10 000 women (38 versus 30 cases). This should be seen in the context of a 1 in 9 background risk of breast cancer by the age of 74.

The risk increases by 2.3% for each year of HRT use (Table 5.3) and declines to a normal risk 5 years after stopping. The risk is higher for oestrogen and progestogen preparations than for oestrogen alone. The risk of breast cancer with tibolone is somewhere between that of oestrogen alone and that of combined preparations.

Table 5.3 Breast cancer cases per year of hormone replacement therapy (HRT) use

No HRT	45 cases per 1000 women
5-year HRT	47 cases per 1000 women
10-year HRT	51 cases per 1000 women
15-year HRT	57 cases per 1000 women

(Reproduced from Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52705 women with breast cancer and 108411 women without breast cancer. Lancet 1997; 350: 1047–1059, with permission.)

There is no evidence for an increased risk of recurrence if HRT is given after breast cancer and it is occasionally prescribed by specialists, depending on the need in terms of vasomotor or osteoporosis problems and the type of tumour.