Davidson’s_Principles_and_Practice_of_Internal_Mesicine_24th_Edition-718-722.pdf
Transcript
The reproductive system 667 Congenital thyroid disease Early treatment with levothyroxine is essential to prevent irreversible brain damage in children (cretinism) with congenital hypothyroidism. Routine screening of TSH levels in heel-prick blood samples obtained 5–7 days after birth (as part of...
The reproductive system 667 Congenital thyroid disease Early treatment with levothyroxine is essential to prevent irreversible brain damage in children (cretinism) with congenital hypothyroidism. Routine screening of TSH levels in heel-prick blood samples obtained 5–7 days after birth (as part of the Guthrie test) has revealed an incidence of approximately 1 in 3000, resulting from thyroid agenesis, ectopic or hypoplastic glands, or dyshormonogenesis. Congenital hypothyroidism is thus six times more common than phenylketonuria. It is now possible to start levothyroxine replacement therapy within 2 weeks of birth. Developmental assessment of infants treated at this early stage has revealed no differences between cases and controls in most children. LH Inhibin Sertoli cells in seminiferous tubules Several autosomal recessive defects in thyroid hormone synthesis have been described; the most common results from deciency of the intrathyroidal peroxidase enzyme. Homozygous individuals present with congenital hypothyroidism; heterozygotes present in the rst two decades of life with goitre, normal thyroid hormone levels and a raised TSH. The combination of dyshormonogenetic goitre and nerve deafness is known as Pendred syndrome. Most cases of Pendred syndrome are caused by mutations in the SLC26A4 gene, which encodes pendrin, the protein that transports iodide to the luminal surface of the follicular cell (see Fig. 20.3). Clinical practice in reproductive medicine is shared between several specialties, including gynaecology, urology, paediatric endocrinologists, psychiatry and endocrinology. The following section is focused on disorders managed by adult endocrinologists. Functional anatomy, physiology and investigations The physiology of male and female reproductive function is illustrated in Figures 20.14 and 20.15, respectively. Pathways for synthesis of sex steroids are shown in Figure 20.20 The male In the male, the testis serves two principal functions: synthesis of testosterone by the interstitial Leydig cells under the control of luteinising hormone (LH), and spermatogenesis by Sertoli cells under the control of follicle-stimulating hormone (FSH) (but also requiring adequate testosterone). Negative feedback suppression of LH is mediated principally by testosterone, while secretion of another hormone produced by the testis, inhibin, suppresses FSH. The axis can be assessed easily by a random blood sample for testosterone, LH and FSH. Testosterone levels are higher in the morning and Spermatogenesis Testosterone Facial, axillary and body hair growth Scalp balding Skin sebum production Penis and scrotal development Prostate development and function Laryngeal enlargement Muscle power Bone metabolism/epiphyseal closure Libido Aggression Thyroid hormone resistance The reproductive system FSH Testis Dyshormonogenesis This is a rare disorder in which the pituitary and hypothalamus are resistant to feedback suppression of TSH by T 3, sometimes due to mutations in the thyroid hormone receptor β gene or because of defects in monodeiodinase activity. The result is high levels of TSH, T 4 and T3, often with a moderate goitre that may not be noted until adulthood. Thyroid hormone signalling is highly complex and involves different isozymes of both monodeiodinases and thyroid hormone receptors in different tissues. For that reason, other tissues may or may not share the resistance to thyroid hormone and there may be features of thyrotoxicosis (e.g. tachycardia). This condition can be difcult to distinguish from an equally rare TSHproducing pituitary tumour (TSHoma; see Box 20.5); administration of TRH results in elevation of TSH in thyroid hormone resistance and not in TSHoma, but an MRI scan of the pituitary may be necessary to exclude a macroadenoma. Negative feedback Interstitial (Leydig) cells Fig. 20.14 Male reproductive physiology. (FSH = follicle-stimulating hormone; LH = luteinising hormone) therefore, if testosterone is marginally low, sampling should be repeated with the patient fasted at 0900 hrs. Testosterone is largely bound in plasma to sex hormone-binding globulin and this can also be measured to calculate the ‘free androgen index’ or the ‘bioavailable’ testosterone. Testicular function can also be tested by semen analysis. There is no equivalent of the menopause in men, although testosterone concentrations decline slowly from the fourth decade onwards. The female In the female, physiology varies during the normal menstrual cycle. FSH stimulates growth and development of ovarian follicles during the rst 14 days after the menses. This leads to a gradual increase in oestradiol production from granulosa cells, which initially suppresses FSH secretion (negative feedback) but then, above a certain level, stimulates an increase in both the frequency and amplitude of gonadotrophin-releasing hormone (GnRH) pulses, resulting in a marked increase in LH secretion (positive feedback). The mid-cycle ‘surge’ of LH induces ovulation. After release of the ovum, the follicle differentiates into a corpus luteum, which secretes progesterone. Unless pregnancy occurs during the cycle, the corpus luteum regresses and the fall in progesterone levels results in menstrual bleeding. Circulating levels of oestrogen and progesterone in pre-menopausal women are, therefore, critically dependent on the time of the cycle. The most useful ‘test’ of ovarian function is a careful menstrual history: if menses are regular, measurement of gonadotrophins and oestrogen is not necessary. In addition, ovulation can be conrmed by measuring plasma progesterone levels during the luteal phase (‘day 21 progesterone’). Cessation of menstruation (the menopause) occurs at an average age of approximately 50 years in high-income countries. In the 5 years before, there is a gradual increase in the number of anovulatory cycles and this is referred to as the climacteric. Oestrogen and inhibin secretion falls and negative feedback results in increased pituitary secretion of LH and FSH (both typically to levels above 30 IU/L (3.3 µg/L)). ALGRAWANY 20 668 ENDOCRINOLOGY Ovulation Follicular phase Luteal phase Feedback FSH LH LH FSH Ovary Inhibin Oestradiol Progesterone 0 Menses 7 14 21 Days after start of last menstrual period Oestradiol Primary 28 Oestradiol Oestradiol Oestradiol Progesterone Progesterone Dominant vesicular Follicle Mature Haemorrhagic Mature Regressing Corpus luteum Oestradiol Endometrial proliferation Genital development and lubrication Breast proliferation Bone epiphyseal closure and mineral content Brain Body fat distribution Skin sebum Progesterone Endometrial secretory change Decreased myometrial contractility Thermogenesis Breast swelling Fig. 20.15 Female reproductive physiology and the normal menstrual cycle. (FSH = follicle-stimulating hormone; LH = luteinising hormone) The pathophysiology of male and female reproductive dysfunction is summarised in Box 20.18 Presenting problems in reproductive disease Delayed puberty 20.18 Classication of diseases of the reproductive system Primary Secondary Hormone excess Polycystic ovary syndrome Granulosa cell tumour Leydig cell tumour Teratoma Pituitary gonadotrophinoma Hormone deciency Hypogonadism (see Box 20.19) Turner syndrome Klinefelter syndrome Hypopituitarism Kallmann syndrome (isolated GnRH deciency) Severe systemic illness, including anorexia nervosa Hormone hypersensitivity Idiopathic hirsutism Hormone resistance Androgen resistance syndromes Complete (‘testicular feminisation’) Partial (Reifenstein syndrome) 5α-reductase type 2 deciency Non-functioning tumours Ovarian cysts Carcinoma Teratoma Seminoma (GnRH = gonadotrophin-releasing hormone) Normal pubertal development is discussed in Chapter 33. Puberty is considered to be delayed if the onset of the physical features of sexual maturation has not occurred by a chronological age that is 2.5 standard deviations (SD) above the national average. In the UK, this is by the age of 14 in boys and 13 in girls. Genetic factors have a major inuence in determining the timing of the onset of puberty, such that the age of menarche (the onset of menstruation) is often comparable within sibling and mother–daughter pairs and within ethnic groups. However, because there is also a threshold for body weight that acts as a trigger for normal puberty, the onset of puberty can be inuenced by other factors, including nutritional status and chronic illness. Clinical assessment The differential diagnosis is shown in Box 20.19. The key issue is to determine whether the delay in puberty is simply because the ‘clock is running slow’ (constitutional delay of puberty) or because there is pathology in the hypothalamus/pituitary (hypogonadotrophic hypogonadism) or the gonads (hypergonadotrophic hypogonadism). A general history and physical examination should be performed with particular reference to previous or current medical disorders, social circumstances and family history. Body proportions, sense of smell and pubertal stage should be carefully documented and, in boys, the presence or absence of testes in the scrotum noted. Current weight and height may be plotted on centile charts, along with parental heights. Previous growth measurements in childhood, which can usually be obtained from health records, are extremely useful. Healthy growth usually follows a centile. Usually, children with constitutional delay have always been small but have maintained a normal growth velocity that is appropriate for bone age. Poor linear growth, with ‘crossing of the height centiles’, is more likely to be The reproductive system 669 20.19 Causes of delayed puberty and hypogonadism Constitutional delay Hypogonadotrophic hypogonadism Structural hypothalamic/pituitary disease (see Box 20.53) Functional gonadotrophin deciency: Chronic systemic illness (e.g. asthma, malabsorption, coeliac disease, cystic brosis, renal failure) Psychological stress Anorexia nervosa Excessive physical exercise Hyperprolactinaemia Other endocrine disease (e.g. Cushing’s syndrome, primary hypothyroidism) Isolated gonadotrophin deciency (Kallmann syndrome) Hypergonadotrophic hypogonadism Acquired gonadal damage: Chemotherapy/radiotherapy to gonads Trauma/surgery to gonads Autoimmune gonadal failure Mumps orchitis Tuberculosis Haemochromatosis Developmental/congenital gonadal disorders: Steroid biosynthetic defects Anorchidism/cryptorchidism in males Klinefelter syndrome (47,XXY, male phenotype) Turner syndrome (45,X, female phenotype) of the disease itself or secondary malnutrition), endocrine disorders and profound psychosocial stress. Isolated gonadotrophin deciency is usually due to a genetic abnormality that affects the synthesis of either GnRH or gonadotrophins. The most common form is Kallmann syndrome, in which there is primary GnRH deciency and, in most affected individuals, agenesis or hypoplasia of the olfactory bulbs, resulting in anosmia or hyposmia. If isolated gonadotrophin deciency is left untreated, the epiphyses fail to fuse, resulting in tall stature with disproportionately long arms and legs relative to trunk height (eunuchoid habitus). Cryptorchidism (undescended testes) and gynaecomastia are commonly observed in all forms of hypogonadotrophic hypogonadism. Hypergonadotrophic hypogonadism Hypergonadotrophic hypogonadism associated with delayed puberty is usually due to Klinefelter syndrome in boys and Turner syndrome in girls. Other causes of primary gonadal failure are shown in Box 20.19 Investigations 20.20 Delayed puberty Aetiology: in boys the most common cause is constitutional delay, whereas in girls there is inevitably a structural hypothalamic/pituitary abnormality or a factor that affects their function. Psychological effects: whatever the underlying cause, delayed puberty is often associated with substantial psychological distress. Investigations: a karyotype should be performed in all adolescents with hypergonadotrophic hypogonadism, to exclude Turner and Klinefelter syndromes, unless there is an obvious precipitating cause. Medical induction of puberty: if this is being considered, it needs to be managed carefully and carried out in a controlled fashion, to avoid premature fusion of the epiphyses. associated with acquired disease. Issues that are commonly encountered in the management of adolescents with delayed puberty are summarised in Box 20.20 Key measurements are LH and FSH, testosterone (in boys) and oestradiol (in girls). Chromosome analysis should be performed if gonadotrophin concentrations are elevated. If gonadotrophin concentrations are low, then the differential diagnosis lies between constitutional delay and hypogonadotrophic hypogonadism. A plain X-ray of the wrist and hand may be compared with a set of standard lms to obtain a bone age. Full blood count, renal function, liver function, thyroid function and coeliac disease autoantibodies (see p. 819) should be measured, but further tests may be unnecessary if the blood tests are normal and the child has all the clinical features of constitutional delay. If hypogonadotrophic hypogonadism is suspected, neuroimaging and further investigations are required (see Box 20.51). Management Puberty can be induced using low doses of oral oestrogen in girls (e.g. ethinylestradiol 2 µg daily) or testosterone in boys (testosterone gel or depot testosterone esters). Higher doses carry a risk of early fusion of epiphyses. This therapy should be given in a specialist clinic where the progress of puberty and growth can be carefully monitored. In children with constitutional delay, this ‘priming’ therapy can be discontinued when endogenous puberty is established, usually in less than a year. In children with hypogonadism, the underlying cause should be treated and reversed if possible. If hypogonadism is permanent, sex hormone doses are gradually increased during puberty and full adult replacement doses given when development is complete. Amenorrhoea Constitutional delay of puberty This is the most common cause of delayed puberty, but is a much more frequent explanation for lack of pubertal development in boys than in girls. Affected children are healthy and have usually been more than 2 SD below the mean height for their age throughout childhood. There is often a history of delayed puberty in siblings or parents. Since sex steroids are essential for fusion of the epiphyses, ‘bone age’ can be estimated by X-rays of epiphyses, usually in the wrist and hand; in constitutional delay, bone age is lower than chronological age. Constitutional delay of puberty should be considered as a normal variant, as puberty will commence spontaneously. However, affected children can experience signicant psychological distress because of their lack of physical development, particularly when compared with their peers. Hypogonadotrophic hypogonadism This may be due to structural, inammatory or inltrative disorders of the pituitary and/or hypothalamus (see Box 20.53). In such circumstances, other pituitary hormones, such as growth hormone, are also likely to be decient. ‘Functional’ gonadotrophin deciency is caused by a variety of factors, including low body weight, chronic systemic illness (as a consequence Primary amenorrhoea may be diagnosed in a female who has never menstruated; this usually occurs as a manifestation of delayed puberty but may also be a consequence of anatomical defects of the female reproductive system, such as endometrial hypoplasia or vaginal agenesis. Secondary amenorrhoea describes the cessation of menstruation in a female who has previously had periods. The causes of this common presentation are shown in Box 20.21. In non-pregnant women, secondary amenorrhoea is almost invariably a consequence of either ovarian or hypothalamic/pituitary dysfunction. Premature ovarian failure (premature menopause) is dened, arbitrarily, as occurring before 40 years of age. Rarely, endometrial adhesions (Asherman syndrome) can form after uterine curettage, surgery or infection with tuberculosis or schistosomiasis, preventing endometrial proliferation and shedding. Clinical assessment The underlying cause can often be suspected from associated clinical features and the patient’s age. Hypothalamic/pituitary disease and premature ovarian failure result in oestrogen deciency, which causes a variety of symptoms usually associated with the menopause (Box 20.22). A history of galactorrhoea should be sought. Signicant weight loss of ALGRAWANY 20 670 ENDOCRINOLOGY 20.21 Causes of secondary amenorrhoea Physiological Pregnancy Menopause Hypogonadotrophic hypogonadism (see Box 20.19) Ovarian dysfunction Hypergonadotrophic hypogonadism (see Box 20.19) Polycystic ovary syndrome Androgen-secreting tumours Uterine dysfunction Asherman syndrome 20.22 Symptoms of oestrogen deciency Vasomotor effects Hot ushes Sweating Psychological Anxiety Irritability Emotional lability Genitourinary Dyspareunia Urgency of micturition Vaginal infections any cause can cause amenorrhoea by suppression of gonadotrophins. Weight gain may suggest hypothyroidism, Cushing’s syndrome (if other discriminatory features are present), or very rarely, a hypothalamic lesion. Hirsutism, obesity and long-standing irregular periods suggest polycystic ovary syndrome (PCOS). The presence of other autoimmune disease raises the possibility of autoimmune premature ovarian failure. Investigations Pregnancy should be excluded in women of reproductive age by measuring urine or serum hCG. Serum LH, FSH, oestradiol, prolactin, testosterone, T4 and TSH should be measured and, in the absence of a menstrual cycle, can be taken at any time. Investigation of hyperprolactinaemia is described on page 697. High concentrations of LH and FSH with low or low-normal oestradiol suggest primary ovarian failure. Ovarian autoantibodies may be positive when there is an underlying autoimmune aetiology, and a karyotype should be performed in younger women to exclude mosaic Turner syndrome. Elevated LH, prolactin and testosterone levels with normal oestradiol are common in PCOS. Low levels of LH, FSH and oestradiol suggest hypothalamic or pituitary disease and a pituitary MRI is indicated. There is some overlap in gonadotrophin and oestrogen concentrations between women with hypogonadotrophic hypogonadism and PCOS. If there is doubt as to the underlying cause of secondary amenorrhoea, then the response to 5 days of treatment with an oral progestogen (e.g. medroxyprogesterone acetate 10 mg twice daily) can be assessed. In women with PCOS, the progestogen will cause maturation of the endometrium and menstruation will occur a few days after the progestogen is stopped. In women with hypogonadotrophic hypogonadism, menstruation does not occur following progestogen withdrawal because the endometrium is atrophic as a result of oestrogen deciency. If doubt persists in distinguishing oestrogen deciency from a uterine abnormality, the capacity for menstruation can be tested with 1 month of treatment with cyclical oestrogen and progestogen (usually administered as a combined oral contraceptive pill). Assessment of bone mineral density by dual X-ray absorptiometry (DXA, see Ch. 26) may be appropriate in patients with low androgen and oestrogen levels. Management Where possible, the underlying cause should be treated. For example, women with functional amenorrhoea due to excessive exercise and low weight should be encouraged to reduce their exercise and regain some weight. The management of structural pituitary and hypothalamic disease is described on page 693 and that of PCOS on page 673. In oestrogen-decient women, replacement therapy may be necessary to treat symptoms and/or to prevent osteoporosis. Women who have had a hysterectomy can be treated with oestrogen alone but those with a uterus should be treated with combined oestrogen/progestogen therapy, since unopposed oestrogen increases the risk of endometrial cancer. Cyclical hormone replacement therapy (HRT) regimens typically involve giving oestrogen on days 1–21 and progestogen on days 14–21 of the cycle, and this can be conveniently administered as the oral contraceptive pill. If oestrogenic side-effects (uid retention, weight gain, hypertension and thrombosis) are a concern, then lower-dose oral or transdermal HRT may be more appropriate. The timing of the discontinuation of oestrogen replacement therapy is still a matter of debate. In post-menopausal women, HRT has been shown to relieve menopausal symptoms and to prevent osteoporotic fractures but is associated with adverse effects, which are related to the duration of therapy and to the patient’s age. In patients with premature menopause, HRT should be continued up to the age of around 50 years, but continued beyond this age only if there are continued symptoms of oestrogen deciency on discontinuation. Management of infertility in oestrogen-decient women is described below. Male hypogonadism The clinical features of both hypo- and hypergonadotrophic hypogonadism include loss of libido, lethargy with muscle weakness and decreased frequency of shaving. Patients may also present with gynaecomastia, infertility, delayed puberty, osteoporosis or anaemia of chronic disease. The causes of hypogonadism are listed in Box 20.19. Mild hypogonadism may also occur in older men, particularly in the context of central adiposity and the metabolic syndrome. Postulated mechanisms are complex and include reduction in sex hormone-binding globulin by insulin resistance and reduction in GnRH and gonadotrophin secretion by cytokines or oestrogen released by adipose tissue. Testosterone levels also fall gradually with age in men (see Box 20.24) and this is associated with gonadotrophin levels that are low or inappropriately within the ‘normal’ range. There is an increasing trend to measure testosterone in older men, typically as part of an assessment of erectile dysfunction and lack of libido. Investigations Male hypogonadism is conrmed by demonstrating a low fasting 0900-hr serum testosterone level. The distinction between hypo- and hypergonadotrophic hypogonadism is by measurement of random LH and FSH. Patients with hypogonadotrophic hypogonadism should be investigated as described for pituitary disease on page 692. Patients with hypergonadotrophic hypogonadism should have the testes examined for cryptorchidism or atrophy, and a karyotype should be performed (to identify Klinefelter syndrome). Management Testosterone replacement is clearly indicated in younger men with signicant hypogonadism to prevent osteoporosis and to restore muscle power and libido. Debate exists as to whether replacement therapy is of benet in mild hypogonadism associated with ageing and central adiposity, particularly in the absence of structural pituitary/hypothalamic disease or other pituitary hormone deciency. In such instances, a therapeutic trial of testosterone therapy may be considered if symptoms are present (e.g. low libido and erectile dysfunction) and the serum testosterone is consistently low, but the benets of therapy must be carefully weighed against the potential for harm. Routes of testosterone administration are shown in Box 20.23. First-pass hepatic metabolism of testosterone is highly efcient, so bioavailability of ingested preparations is poor. Doses of systemic testosterone can be titrated against symptoms; circulating testosterone The reproductive system 671 20.23 Options for androgen replacement therapy Route of administration Preparation Dose Frequency Comments Intramuscular Testosterone undecanoate 1000 mg Every 3 months Testosterone enanthate 50–250 mg Every 3–4 weeks Smoother prole than testosterone enantate, with less frequent injections Produces peaks and troughs of testosterone levels that are outside the physiological range and may be symptomatic Testosterone gel 50–100 mg Daily Transdermal Stable testosterone levels; transfer of gel can occur following skinto-skin contact with another person 20.24 Gonadal function in old age 20.25 Causes of infertility Post-menopausal osteoporosis: a major public health issue due to the high incidence of associated fragility fractures, especially of hip. Hormone replacement therapy: should be prescribed only above the age of 50 for the short-term relief of symptoms of oestrogen deciency. Sexual activity: many older people are sexually active. ‘Male menopause’: does not occur, although testosterone concentrations do fall with age. Testosterone therapy in mildly hypogonadal men may be of benet for body composition, muscle and bone. Large randomised trials are required to determine whether benets outweigh potentially harmful effects on the prostate and cardiovascular system. Androgens in older women: hirsutism and balding occur. In those rare patients with elevated androgen levels, this may be pathological, e.g. from an ovarian tumour. levels may provide only a rough guide to dosage because they may be highly variable (Box 20.23). Testosterone therapy can aggravate prostatic carcinoma; prostate-specic antigen (PSA) should be measured before commencing testosterone therapy in men older than 50 years and monitored annually thereafter. Haemoglobin concentration should also be monitored, as androgen replacement can cause polycythaemia. Testosterone replacement inhibits spermatogenesis; treatment for fertility is described below. Some important aspects of gonadal function in older women and men are summarized in Box 20.24 Female factors (35%–40%) Ovulatory dysfunction: Polycystic ovary syndrome Hypogonadotrophic hypogonadism (see Box 20.19) Hypergonadotrophic hypogonadism (see Box 20.19) Tubular dysfunction: Pelvic inammatory disease (chlamydia, gonorrhoea) Endometriosis Previous sterilisation Previous pelvic or abdominal surgery Cervical and/or uterine dysfunction: Congenital abnormalities Fibroids Treatment for cervical carcinoma Asherman syndrome Male factors (35%–40%) Reduced sperm quality or production: Y chromosome microdeletions Varicocele Hypergonadotrophic hypogonadism (see Box 20.19) Hypogonadotrophic hypogonadism (see Box 20.19) Tubular dysfunction: Varicocele Congenital abnormality of vas deferens/epididymis Previous sexually transmitted infection (chlamydia, gonorrhoea) Previous vasectomy Unexplained or mixed factors (20%–35%) Infertility Infertility affects around 1 in 7 couples of reproductive age, often causing psychological distress. The main causes are listed in Box 20.25. In women, it may result from anovulation or abnormalities of the reproductive tract that prevent fertilisation or embryonic implantation, often damaged Fallopian tubes from previous infection. In men, infertility may result from impaired sperm quality (e.g. reduced motility) or reduced sperm number. Azoospermia or oligospermia is usually idiopathic but may be a consequence of hypogonadism (see Box 20.19). Microdeletions of the Y chromosome are increasingly recognised as a cause of severely abnormal spermatogenesis. In many couples more than one factor causing subfertility is present, and in a large proportion no cause can be identied. Clinical assessment A history of previous pregnancies, relevant infections and surgery is important in both men and women. A sexual history must be explored sensitively, as some couples have intercourse infrequently or only when they consider the woman to be ovulating, and psychosexual difculties are common. Irregular and/or infrequent menstrual periods are an indicator of anovulatory cycles in the woman, in which case causes such as PCOS should be considered. In men, the testes should be examined to conrm that both are in the scrotum and to identify any structural abnormality, such as small size, absent vas deferens or the presence of a varicocele. Investigations Investigations should generally be performed after a couple has failed to conceive despite unprotected intercourse for 12 months, unless there is an obvious abnormality like amenorrhoea. Both partners need to be investigated. The male partner needs a semen analysis to assess sperm count and quality. Home testing for ovulation (by commercial urine dipstick kits, temperature measurement, or assessment of cervical mucus) is not recommended, as the information is often counterbalanced by increased anxiety if interpretation is inconclusive. In women with regular periods, ovulation can be conrmed by an elevated serum progesterone concentration on day 21 of the menstrual cycle. Transvaginal ultrasound can be used to assess uterine and ovarian anatomy. Tubal patency may be examined at laparoscopy or by hysterosalpingography (HSG; a radio-opaque medium is injected into the uterus and should normally outline the Fallopian tubes). In vitro assessments of sperm survival in cervical mucus may be done in cases of unexplained infertility but are rarely helpful. Management Couples should be advised to have regular sexual intercourse, ideally every 2–3 days throughout the menstrual cycle. It is not uncommon for ‘spontaneous’ pregnancies to occur in couples undergoing investigations for infertility or with identied causes of male or female subfertility. ALGRAWANY 20
