Category Archives: Endocrinology.

Tall stature

The commonest causes are hereditary (two tall parents!), idiopathic (constitutional) or early development. It can occasionally be due to thyrotoxicosis. Other causes include chromosomal abnormalities (e.g. Klinefelter’s syndrome, Marfan’s syndrome) or metabolic abnormalities. G H excess is a very rare cause and is usually clinically apparent.

Acromegaly

This is due to a pituitary tumour in almost all cases. Hyperplasia due to GHRH excess is rare.

CLINICAL FEATURES

Symptoms and signs of acromegaly . One-third of patients present with changes in appearance, one-quarter with visual field defects or headaches; in the remainder the diagnosis is made by an alert observer in another clinic, e.g. diabetic, hypertension, dental, dermatology.

INVESTIGATIONS

GH LEVELS are normally very low «1 mU litre:”) in adults except during stress or as occasional spikes but, unless levels are always below 1 mU litre “, one cannot exclude the diagnosis.
GLUCOSE TOLERANCE TEST is diagnostic. Acromegalies fail to suppress GH below 2 mU litre’:’ and some show a paradoxical rise; about 25% of acromegalies have a diabetic glucose tolerance test.
IGF-l LEVELS. A single plasma level of IGF-l reflects mean 24-hour GH levels and is useful in diagnosis.
LATERAL SKULL X-RAYS: abnormal in 90% as the tumours are relatively large.
VISUAL FIELDS: field defects are common.
HIGH-RESOLUTION CT SCANS are virtually never normal;
MRI often gives even better definition of tumour extent and anatomy, particularly where surgery is contemplated.
PITUITARY FUNCTION: partial or complete anterior hypopituitarism is common.
PROLACTIN: mild to moderate hyperprolactinaemia occurs in 30% of patients.

MANAGEMENT AND TREATMENT

Untreated acromegaly results in markedly reduced survival with most deaths from heart failure, coronary artery disease and hypertension related causes. Treatment is therefore indicated in all except the elderly or those with minimal abnormalities. The general pros and cons of surgery, radiotherapy and medical treatment.
Preferred treatment is controversial and complete cure is often slow, if possible at all. The choice lies between:
TRANS-SPHENOIDAL SURGERY with subsequent radiotherapy if excision is incomplete or if GH has not been normalized after surgery. Many authorities would give postoperative radiotherapy in nearly all cases, as the tumours frequently recur.
TRANS FRONTAL SURGERY for big tumours with pressure effects. Postoperative radiotherapy is again usually given as excision is virtually never complete.
EXTERNAL RADIOTHERAPY (takes 1-10+ years to be effective), possibly plus bromocriptine or octreotide.
OCTREOTI DE. The synthetic analogue of somatostatin (GHRIH, p.796) called octreotide is now the treatment of choice in resistant cases, and as a short-term treatment while other modalities become effective. It has to be given by subcutaneous injection in doses of 50-200 ILg 8-hourly but is associated with mild steatorrhoea and an increased incidence of gallstones. It is extremely expensive.
BROMOCRIPTINE ALONE, usually reserved for the elderly and frail. It can be given to shrink tumours prior to definitive therapy or to control symptoms and persisting GH secretion. It is probably only effective in mixed growth-hormone producing (somatotroph) and prolactin producing (mammotroph) tumours. The dose is 10-60 mg daily (higher than for prolactinomas) but should start slowly (see Hyperprolactinaemia). It has largely been replaced by octreotide. Progress can be assessed by mean GH levels and by IGF- 1 measurements. When present hypopituitarism should be corrected and concurrent diabetes and/or hypertension should be treated conventionally; both usually improve with treatment of the acromegaly. It is not yet clear by how much the cardiac prognosis is improved by energetic treatment. There appears to be an excess of large bowel carcinoma in acromegaly.

The signs of acromegaly. Bold type indicates signs of greater discriminant value.

The signs of acromegaly. Bold type indicates signs
of greater discriminant value.

The Growth AXIS

Physiology and control of growth hormone

GH is the pituitary factor responsible for stimulation of body growth in humans. Its secretion is stimulated by GHRH, released into the portal system from the hypothalamus; it is also under inhibitory control by GHRIH (somatostatin). GH stimulates the hepatic production of an intermediate (IGF-1, previously known as somatomedin C) that actually stimulates growth. Plasma levels of IGF-l, however, reflect local growth activity poorly, partly as there are multiple IGF-binding proteins (IGFBP). The metabolic actions of the system are:
• Increasing collagen and protein synthesis
• Promoting retention of calcium, phosphorus and nitrogen, necessary substrates for anabolism
• Opposing the action of insulin GH release is intermittent and mainly nocturnal, especially during REM sleep. The frequency and size of GH pulses increase during the growth spurt of adolescence and decline thereafter. Acute stress and exercise both stimulate GH release while, in the normal subject, hyperglycaemia suppresses it.

The control of growth hormone

The control of growth hormone

Disorders of sexual differentiation.

Disorders of sexual differentiation.

Normal growth

Factors other than GH involved in linear growth in the human are:
GENETIC. Children of two short parents will probably be short.
NUTRITIONAL. Adequate nutrients must be available; impaired growth can result from inadequate dietary intake or small-bowel disease (e.g. coeliac disease).
GENERAL HEALTH. Any serious systemic disease in childhood is likely to reduce growth (e.g. renal failure).
INTRAUTERINE GROWTH RETARDATION. These infants often grow poorly in the long term, while infants with simple prematurity usually catch up.
EMOTIONAL DEPRIVATION AND PSYCHOLOGICAL FACTORS. These can impair growth by complex, poorly understood mechanisms, possibly involving temporarily decreased GH secretion. The relevant aspects of history and examination in the assessment of problems.

Assessment of growth

Charts showing ranges of height and weight for normal British children are available (Fig. 16.17); other national data are available. Height must be measured very carefully, ideally at the same time of day on the same instrument by the same observer. In general, there are three overlapping phases of growth: infantile (0-2 years), which appears largely substrate (food) dependent; childhood (age 2 years to puberty), which is largely GH dependent; and the adolescent ‘growth spurt’, dependent on GH and sex hormones.
More important than current height is height velocity, which requires at least two measurements some months apart and, ideally, multiple serial measurements. This is a rate of current growth (em per year), while attained height is largely dependent upon previous growth. Standard deviation scores (SDS) based on the degree of deviation from age-sex norms are widely used by experts-these and growth velocities are far more sensitive than simple charts in assessing growth. The approximate future height of a child (‘midparental height’) can be simply predicted from the parental heights. For a boy, this is [(Maternal height +13 ern (5 inches) + Paternal height)/2] and for a girl [(Paternal height -13 em (5 inches) + Maternal height)/2].
Thus, with a father of 5 ft 10 inches and mother of 5 ft 1 inch, the predicted heights are 5 ft 8 inches for a son and 5 ft 3 inches for a daughter.

History

Pregnancy records
Rate of growth (home/school records, e.g. heights on kitchen door)
Comparison with peers at school and siblings
Change in appearance (old photos)
Change in shoe/glove/hat size or frequency of ‘growing out’
Age of appearance of pubic hair, breasts, menarche

Physical signs

Evidence of systemic disease
Body habitus, Size, relative weight, proportions (span versus height)
Skin thickness, Interdental separation
Facial features
Spade hands/feet
Grading of secondary sexual characteristics

GROWTH FAILURE-SHORT STATURE

When children or their parents complain of short stature particular attention should focus on:
• Intrauterine growth retardation, weight and gestation at birth
• Possible systemic disorder-any system but especially small-bowel disease
• Evidence of skeletal, chromosomal or other congenital abnormalities
• Endocrine status-particularly primary hypothyroidism
• Dietary intake and use of drugs, especially steroids for asthma
• Emotional, psychological, family and school problems
School, general practitioner, clinic and home records of height and weight should be obtained if possible to allow growth-velocity calculation. If unavailable, such data must be obtained prospectively. A child with normal growth velocity is unlikely to have significant endocrine disease. However, low growth velocity without apparent systemic cause requires further investigation. Sudden cessation of growth suggests major physical disease; if no gastrointestinal, respiratory, renal or skeletal abnormality is apparent, then a cerebral tumour or hypothyroidism are lilceliest. Consistently slow-growing children require full endocrine assessment.
Features of the commoner causes of growth failure are given in Table 16.21. Where constitutional delay is clearly shown and symptoms require intervention then very low dose sex steroids in 3-6 month courses will usually induce acceleration of growth.

A height chart for boys.

A height chart for boys.

INVESTIGATION

Systemic disease having been excluded, the following should be undertaleen:
THYROID FUNCTION TESTS: serum TSH and T4 to exclude hypothyroidism.
GH STATUS: basal levels are of little value, though urinary GH measurements may prove to be of some value in screening. Overnight repeated sampling is optimal but the GH response to Bovril, exercise, clonidine, arginine and insulin are all used; a normal peale response is >20 mU litre “. The ‘gold standard’ test has been the insulin tolerance test (lIT), but this should only be performed in specialist centres for safety reasons. ASSESSMENT OF BONE AGE: non-dominant hand and wrist X-rays allow assessment of bone age by comparison with standard charts (Tanner, Greulich and Pyle).

TREATMENT

SYSTEMIC ILLNESS should be treated.
PRIMARY HYPOTHYROIDISM: replace with thyroxine 0.05-0.2 mg daily.
GH INSUFFICIENCY: human GH (collected from pituitaries) was previously used but was withdrawn as cases of Creutzfeld-Iakob disease were reported. It has been superseded by very expensive recombinant GH, which is given as nightly injection in doses of 10- 20 U m? of body surface area. Treatment should be supervised in expert centres.
The place of GH treatment in so-called ‘short normal’ children has still not been adequately defined. In Turner’s syndrome large doses of GH are needed combined with oxandrolone, a growth-stimulating synthetic sex steroid.
GROWTH HORMONE EXCESSGIGANTISM AND ACROMEGALY GH stimulates skeletal and soft-tissue growth. GH excess therefore produces gigantism in children (if acquired before epiphyseal fusion) but acromegaly in adults .

Clinical features of common causes of short stature.

Clinical features of common causes of short
stature.

ORAL CONTRACEPTION

The combined oestrogen-progestogen pill is widely used for contraception and has a low failure rate « 1 per 100 woman-years). ‘Pills’ contain 20-50 J.Lgof oestrogen, usually ethinyloestradiol, together with a variable amount of one of several progestogens.
The mechanism of action is twofold:
Suppression by oestrogen of gonadotrophins, thus preventing follicular development, ovulation and luteinization 2 Progestogen effects on cervical mucus, making it hostile to sperm, and on tubal motility and the endometrium Side-effects of these preparations; most of the serious ones are rare and are less common on modern 20-30 J.Lgoestrogen pills.
While some problems require immediate cessation of the pill, the importance of other milder side-effects must be judged against the hazards of pregnancy occurring with inadequate contraception, especially if other effective methods are not practicable or acceptable. It is clear, however, that the hazards of the combined pill are greater in women over 35 years, especially in smokers and those with other risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemias). The ‘mini-pill’ (progestogen only) is less effective but is often suitable where oestrogens are contraindicated. A progesterone antagonist, mifepristone, has recently been introduced which, in combination with a prostaglandin analogue, induces abortion of pregnancy up to 9 weeks’ gestation. It prevents progesteroneinduced inhibition of uterine contraction.

General

Weight gain
Loss of libido
Pigmentation (chloasma)
Breast tenderness
Increased growth rate of some malignancies
Cardiovascular
Increased blood pressure”
Deep vein thrombosis’
Myocardial infarction
Stroke
Gastrointestinal
Nausea and vomiting
Abnormal liver biochemistry’
Gallstones increased
Hepatic tumours
Nervous system
Headache
Migraine’
Depression>
Malignancy
Possible increase in cancer of the breast
Gynaecological
Amenorrhoea
‘Spotting’
Cervical erosion
Haematological
Increased dotting tendency
Endocrine/metabolic
Impaired glucose tolerance
Worsened lipid profile
Drug interactions (reduced contraceptive effect due to enzyme induction)
Antibiotics
Barbiturates
Phenytoin
Carbamazepine
Rifampicin
‘Common reasons for stopping oral contraceptives.

SUBFERTILITY

This term, kinder than infertility, is defined as the inability of a couple to conceive after 1 year of unprotected intercourse. Investigation requires the combined skills of gynaecologist, endocrinologist and, ideally, andrologist. Both partners must be considered and every aspect of the physiology critically examined.

CAUSES

MALE FACTOR. About 30–40% of couples have a major identifiable male factor.
FEMALE FACTORS. Female tubal problems account for perhaps 20%; a similar proportion have ovulatory disorders.
UNCOMMON CAUSES. Inadequate intercourse, hostile cervical mucus and vaginal factors are uncommon (5%).
‘IDIOPATHIC’-15% have no apparent explanation.
BOTH PARTNERS. A significant proportion have both male and female problems.
The major factors involved in subfertility and their investigation. SCMC, sperm-cervical mucus contact test.

CLINICAL ASSESSMENT

Both partners should be seen, not just the woman, and the following factors checked: THE MAN: previous testicular damage (e.g. orchitis, trauma, undescended testes), urethral symptoms and venereal problems, local surgery and use of alcohol and drugs. A semen analysis early in the investigations is essential.
THE WOMAN: previous pelvic infection, regularity of periods, previous surgery, alcohol intake and smoking. Adequacy of body weight.
TOGETHER: frequency and adequacy of intercourse, use of lubricants.
Examination should include an assessment of secondary sexual characteristics, body habitus and general health. In men, size and consistency of the testes are important, plus exclusion of a varicocele. In women, vaginal examination allows a check on the uterus and ovaries.

The major factors involved in subfertility and their investigation.

The major factors involved in subfertility and their investigation.

INVESTIGATION

Appropriate tests for particular defects.

TREATMENT

Counselling of both partners is essential. Any defect(s) found should be treated if possible. Ovulation can usually be induced by exogenous hormones if simpler measures fail, while in vitro fertilization (IVF) and similar techniques are becoming more widely used, especially where there is tubal blockage, oligospermia or ‘idiopathic subfertility’ .

DISORDERS OF SEXUAL DIFFERENTIATION

An individual’s sex can be defined in several ways:
CHROMOSOMAL SEX. The normal female is 46XX, the normal male 46XY. The Y chromosome confers male sex; if it is not present, development follows female lines.
GONADAL SEX. This is obviously determined predominantly by chromosomal sex but requires normal embryological development.
PHENOTYPIC sex=-the normal physical appearance and characteristics of male and female body shape. This in turn is a manifestation of gonadal sex and subsequent sex hormone production.
SOCIAL SEX (GENDER) -heavily dependent on phenotypic sex and normally assigned on appearance of the external genitalia at birth. SEXUAL ORIENTATION-heterosexual, homosexual (male/male or female/female) or bisexual (both sexes).
Recent studies suggest that there may be some element of genetic determination of homosexuality. Disorders of sexual differentiation are rare but may affect chromosomal, gonadal, endocrine and phenotypic development.

Hirsuties

PATHOPHYSIOLOGY

The extent of hair growth varies between individuals, families and races, being more extensive in the Mediterranean and Asian populations. Soft vellous hair on the face and elsewhere is not sex-hormone dependent, nor is hair on the forearm or lower leg. Hair in the beard, moustache, breast, chest, axilla, abdominal midline, pubic and thigh areas is sex-hormone dependent. Any excess in the latter regions is thus usually a mark of increased ovarian or adrenal androgen production. Hair has a long growing cycle with spontaneous variations and clinical changes are therefore slow.
Oestrogens are converted to androgens in adipose tissue, which presumably explains the frequent coexistence of hirsuties and obesity without definable endocrine disease.

Differential diagnosis and investigation of amenorrhoea.

Differential diagnosis and investigation of
amenorrhoea.

CLINICAL FEATURES

The complaint is common and often accompanied by severe anxiety and social stress. Important questions are:
AGE AND SPEED OF ONSET. Rapid progression and prepubertal or late onset suggest a more serious cause.
ACCOMPANYING VIRILIZATION (clitoromegaly, frontal balding, male phenotype, greasy skin, acne). This implies substantial androgen excess.
MENSTR VA TION. The greater the disruption the more likely a serious cause.

CAUSES AND INVESTIGATION

These are summarized.

TREATMENT

The underlying cause should be removed in the rare instances where this is possible (e.g. drugs, adrenal or ovarian tumours). Other therapy is either local or systemic.

Conditions causing hirsuties.

Conditions causing hirsuties.

Local therapy

Plucking, bleaching, depilatory cream or wax and shaving may all help and are underused. Waxing is of especial value where the ‘bikini area’ is causing the concern. Electrolysis is slow and expensive.

Systemic therapy

Oestrogens (e.g. oral contraceptives) reduce free androgens by increasing SHBG levels when these are low. Prednisolone given in a reverse circadian manner (5 mg at night, 2.5 mg in the morning) may rarely improve hirsuties in polycystic ovarian syndrome when given alone, though is more effective in restoring regular menstruation. Cyproterone acetate (50-200 mg daily). is an antiandrogen but is also teratogenic and a weak glucocorticoid and progestogen. Given continuously it produces amenorrhoea, and so is normally given for days 1-14 of each cycle. In women of childbearing age, contraception is essential. Other agents of doubtful efficacy include spironolactone, bromocriptine and cimetidine.

Polycystic ovarian syndrome

PATHOPHYSIOLOGY

This very common condition, originally known in its severe form as the Stein-Leventhal syndrome, is characterized by multiple ovarian cysts and by excess androgen production from the ovaries and adrenals, although whether the basic defect is in the ovary, adrenal or pituitary, remains unknown. The ovarian cysts represent arrested follicular development.

CLINICAL FEATURES

It is a common cause of amenorrhoea/oligomenorrhoea, hirsuties or acne, usually beginning shortly after menarche. It is sometimes associated with marked obesity, but weight may be normal. Mild virilization occurs in severe cases.
Recent studies have shown an association of polycystic ovarian syndrome with menstrual disturbance and hypertension and hyperlipidaemia; it appears that insulin resistance may form part of the mechanism of the syndrome.

INVESTIGATION

The most accurate investigation is ovarian ultrasound, although a skilled observer is necessary and some apparently normal women show the abnormality. The typical ultrasonic features are those of a thickened capsule, multiple 3-5 mm cysts and a hyperechogenic stroma. Biochemically there are increased free androgens, though total testosterone may be normal. SHBG is low. The LH : FSH ratio is usually raised (>2: I) but the FSH is normal or low. Mild hyperprolactinaemia is common but rarely exceeds 1500 mU litre.”.

Polycystic ovary on a transvaginal scan

Polycystic ovary on a transvaginal scan

TREATMENT

This depends upon whether the aim is to produce fertility, regularize periods or reduce hirsuties.
REVERS  CIRCADIAN RHYTHM, prednisolone (2.5 mg in the morning,S mg on retiring) to suppress pituitary production of ACTH upon which adrenal androgens partly depend. Regular ovulatory cycles often ensue; hirsuties seldom respond to this treatment alone, but acne frequently does. Steroid instruction and a card must be supplied.
OESTROGENS/ORAL CONTRACEPTIVES FOR HIRSUTIES.
CYPROTERONE as above. For fertility, in addition to prednisolone:
CLOMIPHENE 50-200 mg daily from days 2-6 of cycle (or tamoxifen 10-40 mg daily) plus HCG 5000 U i.m. on day 12/13. This can occasionally cause ovarian hyperstimulation and specialist supervision is essential.
WEDGE RESECTION OR LASER SURGERY OF THE OVARY-rarely.

Hyperprolactinaemia

Mildly increased prolactin levels (400-600 mU litre:’) may be physiological, pathological or secondary to drug therapy (Table 16.19), while higher levels require a diagnosis. Not all patients with galactorrhoea have hyperprolactinaemia, but the other causes are poorly understood Cnormoprolactinaemic galactorrhoea’).

CLINICAL FEATURES

Hyperprolactinaemia per se usually presents with:
• Galactorrhoea, spontaneous or expressible (60% of cases)
• Oligomenorrhoea or amenorrhoea
• Decreased libido in both sexes
• Decreased potency
• Sub fertility
• Symptoms or signs of oestrogen or androgen deficiency-in the long term osteoporosis may result, especially in women
• In the peripubertal patient, as delayed or arrested puberty Additionally, headaches and/or visual field defects may be present if there is a pituitary tumour (more common in men).

Physiological
Sleep (REM) phase
Pregnancy
Suckling
Nipple stimulation
Stress
Coitus
Pathological
Production by tumours
Prolactinomas
Occurs in some acromegalies
Interference with stalk
Any hypothalamidpituitary tumour
Idiopathic hyperprolactinaemia
Polycystic ovarian syndrome
Primary hypothyroidism
Chest wall injury
Renal failure
Liver failure
Drug-induced
Dopamine antagonists (e.g. metoclopramide and phenothiazines)
Oestrogens
Opiates
Cimetidine
Methyldopa
Reserpine

INVESTIGATION

Once physiological and drug causes have been excluded:
AT LEAST THREE PROLACTIN LEVELS SHOULD BE MEASURED. Mean levels of >2000-3000 mU litre-I suggest a prolactinoma
A GOOD QUALITY SKULL X-RAY should be obtained.
VISUAL FIELDS should be checked.
ANTERIOR PITUITARY FUNCTION should be assessed if there is any clinical evidence of hypopituitarism or radiological evidence of tumour. Hypothyroidism must be excluded.
MRI OF THE PITUITARY is necessary (if available) if there is an obvious tumour, and desirable if not. MRI is more sensitive than CT though the latter should be used if MRI is not available.
Macroprolactinoma refers to tumours above 10 mm in diameter, microprolactinoma to smaller ones. The size of tumour may affect the choice of treatment.

TREATMENT

Treatment is dependent upon circumstances and facilities. Hyperprolactinaemia should be reduced with bromocriptine, a dopamine agonist. Initial doses shouldbe small (e.g. 1 mg) and taken during food, beginning at  bedtime. The dose should be gradually increased, usually to 2.5 mg three times daily, judged on clinical response and prolactin levels. Maintenance doses are 2.5-15 mg daily in divided doses. Side-effects include nausea and vomiting, dizziness and syncope, constipation and cold peripheries. Newer agents include lisuride. If a tumour is present this is likely to shrink with bromocriptine. Definitive therapy is controversial and will depend upon the size of the tumour, the patient’s wish for fertility and local facilities.
TRANS-SPHENOIDAL SURGERY often restores normoprolactinaemia but there is a considerable late recurrence rate (50% at 5 years). Bromocriptine may produce hardening of the tumour and surgery should not be delayed beyond 2-3 months’ treatment. RADIOTHERAPY is only slowly effective and can sometimes cause eventual hypopituitarism. It should, however, be used after surgery in larger turnours, especially where families are complete.
SMALL TUMOURS in asymptomatic patients without hypogonadism may need only observation.
RARELY, TUMOURS ENLARGE DURING PREGNANCY to produce headaches and visual defects. Bromocriptine should be restarted.
MICROPROLACTI OMAS. There is some evidence that some microprolactinomas may not recur after several years of dopamine agonist therapy.

Disorders of sex and reproduction

CLINICAL FEATURES

A detailed history and examination of all systems is required.

Tests of gonadal function

The patient and partner are their own best assay for gonadal endocrine function. A man having regular satisfactory intercourse or a woman with regular ovulatory periods is most unlikely to have significant endocrine disease, assuming the history is accurate (check with the partner!). When symptoms are present, much can be deduced by basal measurements of the gonadotrophins, oestrogens/ testosterone and prolactin:

Low TESTOSTERONE OR OESTRADIOL WITH HIGH GO ADOTROPHINS indicates primary gonadal disease.
Low LEVELS OF LH/FSH AND TESTOSTERONE/OESTRADI0L imply hypothalamic-pituitary disease.
CONFIRMATION OF NORMAL FEMALE REPRODUCTIVE ENDOCRINOLOGY requires the demonstration of ovulation-this is achieved by measurement of luteal phase serum progesterone and/or by serial ovarian ultrasound in the follicular phase.
COMPLETE DEMONSTRATION OF NORMAL MALE AND FEMALE FUNCTION requires a pregnancy-in the male, in the first instance there should be a healthy sperm count (20-200 X 106/ml), good motility (>60% Grade 1) and few abnormal forms «20%).
HYPERPROLACTINAEM IA can be confirmed or excluded by direct measurement of preferably two to three samples. Levels may increase with stress; ideally, a cannula should be inserted and samples taken through it 30 min later.
THE CLOMIPHENE TEST examines hypothalamic negative feedback. Clomiphene is a competitive oestrogen antagonist that binds to, but does not activate, oestrogen receptors, thus inducing a rise in gonadotrophin secretion in the normal subject. More detailed tests are indicated.

Tests of gonadal function.

Tests of gonadal function.

DISORDERS IN THE MALE

Hypogonadism

CLINICAL FEATURES

Male hypogonadism may be a presenting complaint or an incidental finding, e.g. during investigation for subfertility. The testes may be small and soft. Except with sub fertility, the complaints are usually of androgen deficiency rather than deficiency of semen production. Sperm only makes up a very small proportion of seminal fluid volume. Causes of male hypogonadism.

General
Maintenance of libido
Deepening of voice
Fronto-temporal balding
Facial, axillary and limb hair
Pubic hair
Maintenance of male pattern
Testes and scrotum
Maintenance of testicular size/consistency
Rugosity of scrotum
Maintenance of erectile and ejaculatory function
Stimulation of spermatogenesis
Skeletal
Epiphyseal fusion
Maintenance of muscle bulk

INVESTIGATION

Testicular disease may be initially apparent but basal levels of testosterone, LH and FSH should be measured. These will allow the distinction between primary gonadal (testicular) failure and hypothalamic-pituitary disease to be made. Biopsy of the testes may be indicated, though rarely yields a treatable cause. Skull radiology, pituitary CT scan, prolactin levels and other pituitary function tests may be needed. Depending on the causes, semen analysis, chromosomal analysis (e.g. to exclude Klinefelter’s syndrome) and bone age estimation may be required.

TREATMENT

The cause can rarely be reversed. Replacement therapy should be commenced. Primary gonadal failure should be treated with androgens. Patients with hypothalamic-pituitary disease may be given LH and FSH (Pergonal) or pulsatile LHRH if fertility is required, otherwise they should receive androgen replacement. Special instances of hypogonadism include:
CRYPTORCHIDISM. By the age of 5 years both testes should be in the scrotum. After that age the germinal epithelium is increasingly at risk; lack of descent by puberty is associated with infertility. Surgical exploration and orchidopexy are usually undertaken but a short trial of HCG occasionally induces descent: an HCG test with a testosterone response 72 hours later excludes anorchia. Intra-abdominal testes have an increased risk of developing malignancy; if presentation is after puberty, orchidectomy is advised.
KLINEFELTER’S SY DROME (seminiferous tubule dysgenesis). This chromosomal disorder (47XXY) affecting 1 in 1000 males involves loss of both Leydig cells and seminiferous tubular dysgenesis. Patients usually present with poor sexual development, small or undescended testes, gynaecomastia or infertility. They are sometimes mentally retarded. Clinical examination shows small pea-size but firm testes, usually gynaecomastia and often signs of androgen deficiency. Confirmation is by chromosomal analysis. Treatment is androgen replacement therapy, though if the patient is mentally subnormal this should be used carefully. No treatment is possible for the abnormal seminiferous tubules and infertility.

Androgen replacement therapy.

Androgen replacement therapy.

ISOLATED DEFICIENCY OF LHRH OR LH/FSH
(Kallmann’s syndrome). Also known as hypogonadotrophic hypogonadism, this is often associated with decreased sense of smell (anosmia), and sometimes with other bony (cleft-palate), renal and cerebral abnormalities (e.g. colour blindness). It is often familial and is usually X-linked; the genetic defect has recently been identified. Management is that of secondary hypogonadism; fertility is possible.
OLIGOSPERMIA OR AZOOSPERMIA. These may be secondary to androgen deficiency and corrected by replacement but more often they result from primary testicular diseases in which case they are rarely treatable.
AZOOSPERMIA WITH NORMAL TESTICULAR SIZE AND LOW FSH LEVELS suggests a vas deferens block.

Lack of libido and impotence

Many patients with impotence have no definable organic cause. A careful history of physical disease, related symptoms, stress and psychological factors, together with drug and alcohol abuse, must be taken. The presence of nocturnal emissions and frequent satisfactory morning erections largely excludes endocrine disease as a cause. True erectile difficulty may be psychological, neurogenic, vascular, endocrine or related to drugs. Vascular disease may be more common than realized and is often associated with vascular problems elsewhere. The endocrine causes are those of hypogonadism (above) and can be excluded by normal testosterone, gonadotrophin and prolactin levels. Autonomic neuropathy, most commonly from diabetes mellitus, is a common partial, if not total, identifiable cause. Many drugs can be responsible-cannabis, diuretics, metoclopramide, bethanidine/guanethidine, methyldopa and f3-blockers all produce impotence. Psychogenic impotence is frequently a diagnosis of exclusion, though complex tests of penile vasculature and function are now available in some centres. Apart from cessation of the offending drug, methods  of treatment include vacuum condoms, intracavernosal injections of papaverine and phentolamine, penile implants and vacuum expanders; specialist advice is essential.
If no organic disease is found, or if there is clear evidence of psychological problems, the couple should receive psychosexual counselling.

Gynaecomastia

Gynaecomastia is development of breast tissue in the male.
Pubertal gynaecomastia occurs in perhaps 50% of normal boys, often asymmetrically. It usually resolves spontaneously within 6-18 months but after this duration may require surgical removal, as fibrous tissue will have been laid down. The cause is thought to be relative oestrogen excess.
In the older male, gynaecomastia requires a full assessment to exclude potentially serious underlying disease, such as bronchial carcinoma and testicular turn ours (e.g. Leydig cell tumour). Drug effects are common (especially digoxin and spironolactone) and once these are excluded most cases have no definable cause. Surgical removal is occasionally necessary.

Physiological
Neonatal
Pubertal
Old age
Hyperthyroidism
Liver disease
Oestrogen-producing tumours (testis. adrenal)
HCG-producing tumours (testis. lung)
Starvation/refeeding
Carcinoma of breast
Drugs
Oestrogenic
Oestrogens
Digitalis
Cannabis
Diamorphine
Antiandrogens
Spironolactone
Cimetidine
Cyproterone
Others
Gonadotrophins
Cytotoxics

DISORDERS IN THE FEMALE

Hypogonadism

Impaired ovarian function, whether primary or secondary, will lead both to oestrogen deficiency and abnormalities of the menstrual cycle. The latter is very sensitive to disruption, cycles becoming anovulatory and irregular before disappearing altogether. Symptoms will depend on the age at which the failure develops. Thus, before puberty, primary amenorrhoea will occur, possibly with delayed puberty; if after puberty, secondary amenorrhoea and possibly hypogonadism will result. Oestrogen deficiency The physiological effects of oestrogins and symptomsl signs of deficiency.

Amenorrhoea

Absence of periods or markeclly irregular infrequent periods (oligomenorrhoea) are a common presentation, often the earliest, of female gonadal disease.  Important factors in clinical assessment of such patients.

Effects of oestrogens and consequences of oestrogen deficiency.

Effects of oestrogens and consequences of
oestrogen deficiency.

factors in clinical assessment of such patients.
PREGNANCY. This must a/wars be considered.
GENITAL TRACT ABNORMALITIES, such as imperforate hymen, should be remembered, especially in primary amenorrhoea.
WEIGHT-RELATED AMENORRHOEA. A minimum body weight is necessary for regular menstruation. While anorexia nervosa is the extreme form, this condition is common and may be seen at weights within the ‘normal’ range. Many of these subjects may have additional minor endocrine disease (e.g. polycystic ovarian disease) but restoration of body weight toabove the 50th centile is often helpful. Similar problems  occur with intensive physical training in athletes and dancers.
HYPOTHALAMIC AMENORRHOEA. Some dispute the existence of this condition, linking all amenorrhoea to low weight or increased stress. A few patients, however, do appear to have defective cycling mechanisms without apparent explanation.
HYPOTHYROIDISM results in increased TRH which timulates prolactin secretion.
SEVERE ILL ESS, even in the absence of weight loss.
AFTER STOPPING THE CONTRACEPTIVE PILL.

History

Pregnant
Age of onset
Age of menarche, if any
Sudden or gradual onset
General health
Weight, absolute and changes in recent past
Stress Gob, life-style, exams, relationships)
Excessive exercise
Drugs
Hirsuties, acne, virilization
Headaches/visual symptoms
Sense of smell
Past history of pregnancies
Past history of gynaecological surgery

Examination

General health
Body shape and skeletal abnormalities
Weight and height
Hirsuties and acne
Evidence of virilization
Maturity of secondary sexual characteristics
Galactorrhoea
Normality of vagina, cervix and uterus

INVESTIGATION

Basal levels of FSH, LH, oestrogen and prolactin allow initial distinction between primary gonadal and hypothalamic- pituitary causes (Table 16.17). Ovarian biopsy is necessary to confirm the diagnosis of primary ovarian failure. Subsequent investigations.

TREATMENT

Treatment is that of the cause wherever possible (e.g. hypothyroidism, low weight, stress, excessive exercise). Primary ovarian disease is rarely treatable except in the rare condition of ‘resistant’ ovary, where high-dose Pergonal can occasionally lead to folliculogenesis. Hyperprolactinaemia should be corrected. Polycystic ovarian syndrome is discussed in detail below.

The menopause

The menopause, or cessation of periods, naturally occurs about the age of 45-55 years. During the late forties, FSH initially, and then LH concentrations begin to rise, probably as follicle supply diminishes. Oestrogen levels fall and the cycle becomes disrupted. Most women notice irregular scanty periods coming on over a variable period, though in some sudden amenorrhoea or menorrhagia occur. Eventually the menopausal pattern of low oestradiollevels with grossly elevated LH and FSH (usually >50 and >25 Ulitre-I, respectively) is established. Menopause may also occur surgically, with radiotherapy to the ovaries and with ovarian disease (e.g. premature menopause). Features of oestrogen deficiency are hot flushes, which occur in most women and can be disabling, vaginal dryness and atrophy of the breasts. There may also be vague symptoms of loss of libido, loss of self-esteem, non-specific aches and pains, irritability, depression, loss of concentration and weight gain. Women show loss of bone density (osteoporosis, see p.426) and the premenopausal protection from ischaemic heart disease disappears.

TREATMENT

Some of the usual hazards of oestrogens apply (see below)but most physicians are now treating symptomatic  patients much more widely and some recommend the widespread use of HRT, though still much less widely than in the USA. Current evidence suggests that, when given with a progestogen, the benefits of HRT far outweigh the small risks, unless there are clear contraindications. The overall benefits may be summarized as follows:
SYMPTOMATIC IMPROVEMENT in many, but not all, menopausal symptoms for the majority of women. Oestrogen-deficient symptoms respond well to oestrogen replacement, the vaguer symptoms generally, but not always, less well. Vaginal symptoms respond to local oestrogen preparations.
REDUCTION IN ISCHAEMIC HEART DISEASE and cerebrovascular disease mortality-blood pressure falls in the majority.
PROTECTION AGAINST FRACTURES OF WRIST, SPINE AND HIP, secondary to osteoporosis, at least where HR T is used before the age of 60 years when loss of bone mass is maximal. This is due to predominant protection of trabecular rather than cancellous bone. In HR T oestrogen should be given cyclically with a progestogen (if the uterus is present) to prevent endometrial carcinoma from unopposed oestrogen action. Apart from individual risks from oestrogen therapy (e.g. migraine, thrombosis) -and even with these the effect of HR T may not parallel those of the ‘pill’: the oestrogen dose is much smaller and does not guarantee contraception- the main concerns have been induction of cancer of the uterus or breast. Given with a progestogen, the risk of uterine cancer is not significantly increased, while the data on breast carcinoma are conflicting. There is of course the inconvenience of withdrawal bleeds, unless a hysterectomy has been performed. The preferred route of administration has been oral, but oestrogen implants and skin patches are now also widely used. The length of treatment with HR T is controversial.

The control of prolactin secretion.

The control of prolactin secretion.

Premature menopause

The commonest cause of early menopause in the twenties and thirties is ovarian failure which is usually autoimmune in nature. HR T should be given, as the risk of osteoporosis and premature ischaemic heart disease far outweigh the risks.
The ageing male In the male there is no sudden ‘change of life’. However, there is a progressive loss in sexual function with reduction in morning erections and frequency of intercourse. The age of onset varies widely but overall testicular volume diminishes and gonadotrophin levels gradually rise. If premature hypogonadism is present for any reason, replacement testosterone therapy should be given to prevent osteoporosis. A new agent, finasteride, which is an inhibitor of Sa-reductase, is now used in benign prostatic hypertrophy. It prevents the conversion of testosterone to dihydrotestosterone which causes local prostatic hyperplasia.

Physiology of prolactin secretion

The hypothalamic-pituitary control of prolactin secretion is illustrated. It is under tonic dopamine inhibition, while other factors
known to increase prolactin secretion (e.g. TRH) are probably of less importance. Prolactin stimulates milk secretion but also reduces gonadal activity. It decreases LHRH pulsatility at hypothalamic level and, to a lesser extent, blocks the action of LH on the ovary or testis, producing hypogonadism. These actions may be clinically important.

History
libido
Potency
Frequency of intercourse
Menstruation-relation of symptoms to cycle
Breasts (? galactorrhoea)
Hirsuties
Physical signs
Evidence of systemic disease
Secondary sexual characteristics
Genital size (testes. ovaries. uterus)
Clitoromegaly
Breast development. gynaecomastia
Galactorrhoea
Extent/distribution of hair

Reproduction and sex

Normal physiology of the female and male reproductive systems will first be considered, followed by their common disorders.

Delayed puberty

Over 95% of children show signs of pubertal development by age 14 years. In its absence, investigation should begin by age 15 years. Causes of hypogonadism (below) are clearly relevant but most cases represent constitutional delay:
IN CONSTITUTIONAL DELAY, pubertal development, bone age and stature should be in parallel. A family history may confirm that other family members did the same.
IN BOYS, testicular volume >5 rnl indicates the onset of puberty. A rising serum testosterone is an earlier clue. IN GIRLS, the breast bud is the first sign. Ultrasound allows accurate assessment of ovarian and uterine development.
BASAL LH/F SH LEVELS may identify the site of a defect, and LHRH tests can indicate the stage of early puberty.
IF ANY PROGRESSION AT ALL IS EVIDENT CLINICALLY, observation is usually indicated.
LOW-DOSE SHORT-TERM SEX HORMONE THERAPY to induce puberty is possible when delay is great and problems are serious (e.g. severe teasing at school). Specialist assessment is advisable. Until 8 weeks the sexes share a common development, with a primitive genital tract including the Wolffian and Miillerian ducts. There are additionally a primitive perineum and primitive gonads. In the presence of a Y chromosome the potential testis develops while the ovary regresses. In the absence of a Y chromosome, the potential ovary develops and related ducts form a uterus and the upper vagina. Production of Miillerian inhibitory factor from the early ‘testis’ produces atrophy of the Mullerian duct, while, under the influence of testosterone and dihydrotestosterone, the Wolffian duct differentiates into an epididymus, vas deferens, seminal vesicles and prostate. Androgens induce transformation of the perineum to include a penis, penile urethra and scrotum containing the testes, which descend in response to androgenic stimulation. At birth testicular volume is 0.5-1 mI. Definitions Relevant terminology.

PHYSIOLOGY

The male

An outline of the hypothalamic-pituitary-testicular axis.
1 Pulses of LHRH (GnRH) are released from the hypothalamus and stimulate LH and FSH release from the pituitary.
2 LH stimulates testosterone production from Leydig cells of the testis.
3 Testosterone acts systemically to produce male secondary sexual characteristics, anabolism and the maintenance of libido. It also acts locally within the testis to aid spermatogenesis. Both testosterone and oestrogen circulate largely bound to sex hormone-binding globulin (SHBG).
4 FSH stimulates the Sertoli cells in the seminiferous tubules to produce mature sperm and the feedback hormone inhibin.
S Testosterone feeds back on the hypothalamus/pituitary to inhibit LHRH secretion.
6 Inhibin causes feedback on the pituitary to decrease FSH secretion.
The secondary sexual characteristics of the male for which testosterone is necessary are the growth of pubic, axillary and facial hair, enlargement of the external genitalia, deepening of the voice, sebum secretion, muscle growth and frontal balding.

(a) Male and (b) female hypothalamic-pituitarygonadal axes.

(a) Male and (b) female hypothalamic-pituitarygonadal axes.

Definitions in reproductive medicine.

Definitions in reproductive medicine.

The female

The female situation is more complex.
1 In the adult female, higher brain centres impose a menstrual cycle of 28 days upon the activity of hypothalamic GnRH.
2 Pulses of GnRH, at about 2-hour intervals, stimulate release of pituitary LH and FSH.
3 LH stimulates ovarian androgen production.
4 FSH stimulates follicular development and arornatase activity (an enzyme required to convert ovarian androgens to oestrogens). FSH also stimulates inhibin from ovarian stromal cells. Inhibin, in turn, inhibits FSH release.
S Although many follicles are ‘recruited’ for development in early folliculogenesis, by day 8-10 a ‘leading’ follicle is selected for development into a mature Graafian follicle.
6 Oestrogens show a double feedback action on the pituitary, initially inhibiting gonadotrophin secretion (negative feedback), but later high-level exposure results in increased GnRH secretion and increased LH sensitivity to GnRH (positive feedback), which leads to the mid-cycle LH surge inducing ovulation from the leading follicle.
7 The follicle then differentiates into a corpus luteum, which secretes both progesterone and oestradiol during the second half of the cycle (luteal phase).
8 Oestrogen initially and then progesterone cause uterine endometrial proliferation in preparation for possible implantation; if implantation does not occur, the corpus luteum regresses and progesterone secretion and inhibin levels fall allowing increased GnRH and FSH secretion so that the endometrium is shed (menstruation).
9 If implantation and pregnancy follow, human chorionic gonadotrophin (HCG) production from the corpus luteum maintains corpus luteum function till 10- 12 weeks, by which time the placenta will be making sufficient oestrogens and progesterone to support itself.
10 Oestrogen circulates largely bound to SHBG .
Oestrogens also induce secondary sexual characteristics, especially development of the breast and nipples, vaginal and vulval growth and pubic hair development. They also induce growth and maturation of the uterus and tubes. They do not, however, usually increase breast size in other circumstances.

Hormonal and follicular changes during the normal menstrual cycle.

Hormonal and follicular changes during the normal menstrual cycle.

Puberty

The mechanisms initiating puberty remain poorly understood but are thought to result from withdrawal of central inhibition of GnRH release. LH and FSH are both low in the prepubertal child. In early puberty, FSH begins to rise first, initially in nocturnal pulses; this is followed by a rise in LH with a subsequent increase in testosterone/oestrogen levels. The milestones of puberty in the two sexes.
In boys, pubertal changes begin between 10 and 14 years and are complete between IS and 17 years. The genitalia develop, testes enlarge and the area of pubic hair increases. Peak height velocity is reached between ages 12 and 17 years during stage 4 of testicular development. Full spermatogenesis occurs comparatively late. In girls, even ts start a year earlier. Breast bud enlargement begins at ages 9-13 years and continues to 12-18 years. Pubic hair growth commences at ages 9-14 years and is completed at 12-16 years. Menarche occurs relatively late (age II-IS years) but peak height velocity is reached much earlier than in boys (age 10-13 years). Growth is completed earlier than in boys.

The age of development of features of puberty.

The age of development of
features of puberty.

Precocious puberty

Development of menarche (girls) or secondary sexual characteristics (boys) before the age of 9 years is premature, and may take the following forms: IDIOPATHIC (TRUE) PRECOCITY, commoner in girls. This is a diagnosis of exclusion with no apparent cause for premature breast or pubic hair development, and an early growth spurt; it may be normal and run in families. Treatment has been with cyproterone acetate, an anti-androgen with progestational activity, but longacting LHRH analogues causing suppression of gonadotrophin release with reduced sex hormone production have largely superseded cyproterone: these may be given by nasal spray, by subcutaneous injection or preferably by implant.
CEREBRAL PRECOCITY. Many causes of hypothalamic disease, especially tumours, may present in this way. In boys this must be rigorously excluded.
FORBES-ALBRIGHT SYNDROME, usually in girls, with precocity, polyostotic fibrous dysplasia and skin pigmentation (cafe-au-lait).
PREMATURE THELARCHE is early breast development alone, usually transient between ages 2 and 4 years. It may regress or persist till puberty.
PREMATURE ADRENARCHE is early development of pubic hair without significant other changes, usually after age 5 years and commoner in girls.

 Delayed puberty

Over 95% of children show signs of pubertal development by age 14 years. In its absence, investigation should begin by age 15 years. Causes of hypogonadism are clearly relevant but most cases represent constitutional delay:
IN CONSTITUTIONAL DELAY, pubertal development, bone age and stature should be in parallel. A family history may confirm that other family members did the same.
IN BOYS, testicular volume >5 rnl indicates the onset of puberty. A rising serum testosterone is an earlier clue. IN GIRLS, the breast bud is the first sign. Ultrasound allows accurate assessment of ovarian and uterine development.
BASAL LH/F SH LEVELS may identify the site of a defect, and LHRH tests can indicate the stage of early puberty.
IF ANY PROGRESSION AT ALL IS EVIDENT CLINICALLY, observation is usually indicated.
LOW-DOSE SHORT-TERM SEX HORMONE THERAPY to induce puberty is possible when delay is great and problems are serious (e.g. severe teasing at school). Specialist assessment is advisable.

TREATMENT

This depends on the type and size of tumour and is discussed in more detail in the relevant sections (acromegaly, prolactinoma). In general therapy has three aims:

1 Removal/control of tumour
(a) Surgery-usually via the trans-sphenoidal route is the treatment of choice. Large tumours are removed via the open transfrontal route. Radiotherapy is given if the tumour is incompletely removed.
(b) Radiotherapy-external three-beam technique, or occasionally via implant of yttrium needles. Used when surgery is impracticable as it rarely abolishes tumour mass.
(c) Medical-octreotide or bromocriptine sometimes shrinks specific types of tumour.
2 Reduction of excess hormone secretion. Usually obtained by surgical removal but sometimes by medical treatment, e.g. bromocriptine or octreotide alone. Prolactinomas respond with significant tumour shrinkage to bromocriptine. Acromegaly, however, responds less well. ACTH secretion usually cannot be controlled by medical means.
3 Replacement of hormone deficiencies.
Small turn ours producing no significant symptoms, pressure or endocrine effects may be observed with regular clinical, visual field, imaging and endocrine assessments.

Comparisons of primary treatment for pituitary tumours.

Comparisons of primary treatment for pituitary
tumours.

Hypopituitarism

PATHOPHYSIOLOGY

Deficiency of hypothalamic releasing hormones or of pituitary trophic hormones may be either selective or multiple. There are, for example, rare congenital isolated deficiencies of LH/FSH and ACTH, some of which may be autoimmune in nature.
Multiple deficiencies usually result from tumour growth or other destructive lesions. With the latter there is generally a progressive loss of anterior pituitary function in the order shown from left to right in Fig. 16.6. GH and gonadotrophins, LH before FSH, are usually first affected. Rather than prolactin deficiency, hyperprolactinaemia occurs relatively early because of loss of tonic inhibitory control by dopamine. TSH and ACTH are usually last to be affected. Panhypopituitarism refers to deficiency of all anterior pituitary hormones; it is most commonly caused by pituitary turn ours, surgery or radiotherapy. Vasopressin and oxytocin secretion will only be significantly affected if the hypothalamus is involved, either by a hypothalamic tumour or by major suprasellar extension of a pituitary lesion.

Disorders causing hypopituitarism; pituitary and hypothalamic tumours are the commonest.

CLINICAL FEATURES

Symptoms and signs depend upon the extent of hypothalamicand/or pituitary deficiencies. Loss of libido, amenorrhoea and impotence are symptoms of gonadotrophin and thus gonadal deficiencies, while hyperprolactinaemia may cause galactorrhoea and hypogonadism. GH deficiency is clinically ‘silent’ except in children, though new evidence suggests markedly impaired wellbeing in adults. Secondary hypothyroidism and adrenal failure lead to tiredness, slowness of thought and action, and mild hypotension. Long-standing panhypopituitarism may give the classical picture of pallor with hairlessness (‘alabaster skin’).

Particular syndromes related to hypopituitarism include:
KALLMANN’S SYNDROME (isolated gonadotrophin deficiency, which leads to hypogonadism);
One sex-linked form has been shown to be due to abnormality of a cell adhesion molecule.
SHEEHAN’S SYNDROME. This situation, now rare, is pituitary infarction following postpartum haem orrhage.
PITUITARY APOPLEXY. A pituitary tumour may infarct or haemorrhage into itself. This may produce severe headache sometimes followed by acute lifethreatening hypopituitarism.
THE ‘EMPTY SELLA’ SYNDROME. This is sometimes due to a defect in the diaphragma and extension of the subarachnoid space (cisternal herniation) or may follow spontaneous infarction of a tumour. All or most of the sella turcica may be devoid of apparent pituitary tissue, but, despite this, pituitary function is usually normal, the pituitary being eccentrically placed and flattened against the floor or roof of the fossa.

Causes of hypopituitarism.

Causes of hypopituitarism.

INVESTIGATION

Each axis of the hypothalamic-pituitary system may require separate investigation. The presence of normal gonadal function (ovulatory/menstruation or normal libido/erections) suggests that multiple defects of anterior pituitary function are unlikely.
Tests range from the simple basal levels, e.g. T. for the thyroid axis, to stimulatory tests for the pituitary, and tests of feedback for the hypothalamus. The insulin tolerance test is now less widely used, as basal 0900 h cortisol levels above 500 nmol litre'” reliably indicate an adequate reserve and levels below 100 nrnol litre'” predict an inadequate response. The intravenous Synacthen test, though indirect, has proved to be an adequate indicator of hypothalamic-pituitary adrenal status.

TREATMENT

Steroid and thyroid hormones are essential for life. Both may be given as oral replacement drugs, aiming to restore the patient to clinical and biochemical normality. Sex hormone production may be replaced with androgens and oestrogens for symptomatic control; if necessary, human chorionic gonadotrophin (HCG, mainly LH) and metrotrophin (Pergonal) or urofollitrophin (Metrodin, mainly FSH) can be given if fertility is desired. Pulsatile GnRH (luteinizing hormone releasing hormone, LHRH) therapy is sometimes used where there is residual pituitary function but is expensive and timeconsuming. GH therapy may be given if necessary in the growing child and also produces substantial changes in body composition, work capacity and psychological well-being in acquired GH deficiency in the adult; long-term safety is not yet established and therapy may cost £4000-10000 per annum-at present it is only used in clinical trials. Two important warnings are necessary: Thyroid replacement should not commence until normal glucocorticoid function has been demonstrated or replacement steroid therapy initiated.
2 Glucocorticoid deficiency may mask impaired urine concentrating ability, diabetes insipidus only becoming apparent after steroid replacement.

Tests for hypothalamic-pituitary (HP) function.

Tests for hypothalamic-pituitary (HP) function.

Replacement therapy for hypopituitarism.

Replacement therapy for hypopituitarism.

Weight, exercise and stress

These are important factors in hypothalamic-pituitary function. Anorexia nervosa, the ‘slimming disease’ commonly affecting young females, is associated with major functional hypopituitarism. This often presents as amenorrhoea, without which the diagnosis is extremely unlikely. Anorexia is an extreme example, but more marginal degrees of underweight are a cause of secondary amenorrhoea and oligomenorrhoea, and are often unrecognized as a cause of sub fertility. Similar effects are seen in female athletes undergoing heavy training with menstrual irregularity that invariably reverts to normal when training stops. Stress, though difficult to define, also affects endocrine function, especially menstruation. Emotional deprivation in childhood is an important cause of growth retardation and may be mediated by reduced GH secretion.

Presentations of Hypothalamic and Pituitary Disease

Pituitary space-occupying lesions and tumours

Pituitary tumours are the commonest cause of pituitary disease and, as with most endocrine disease, problems may be caused by excess hormone secretion, by local effects of a tumour or inadequate production of hormone by the remaining normal pituitary, hypopituitarism.

Nomenclature and biochemistry of hypothalamic, pituitary and peripheral hormones.

Nomenclature and biochemistry of hypothalamic, pituitary and peripheral hormones.

Hypothalamic releasing hormones and the pituitary trophic hormones.

Hypothalamic releasing hormones and the pituitary
trophic hormones.

Processing of the ACTH

Processing of the ACTH

INVESTIGATION

Investigation of a possible or proven tumour thus follows three lines:
1 Is there a tumour? How big is it and what local anatomical effects is it exerting? Pituitary and hypothalamic space-occupying lesions, hormonally active or not, can cause symptoms by infiltration of, or pressure on:
• The visual pathways, with field defects and visual loss
• The cavernous sinus, with III, IV and VI cranial nerve lesions
• Bony structures and the meninges surrounding the fossa, with headache
• Hypothalamic centres: altered appetite, obesity, thirst, somnolence/wakefulness or precocious puberty
• Interruption of cerebrospinal fluid (CSF) flow leading to hydrocephalus
• Rarely, invasion of the sphenoid sinus causing CSF rhinorrhoea.

Investigations include:
LATERAL SKULL X-RAYS may show enlargement of the fossa. This is a common incidental finding and requires further investigation.
VISUAL FIELDS. These should be plotted formally by automated computer perimetry, Goldmann perimetry and/or by confrontation at the bedside using a small red pin as target. Common defects are upper temporal quadrantanopias and bitemporal hemianopias. Subtle defects may also be revealed by delay or attenuation of visual evoked potentials (VEP).
MRI OF THE PITUITARY, when and where available, is superior to high-resolution CT scanning with reconstruction.
2 Is there a hormonal excess? There are three major conditions that may be caused by tumour or hyperplasia. (a) GH excess, leading to acromegaly or gigantism. These are usually acidophil adenomas. (b) Prolactin excess (prolactinoma or hyperprolactinaemia). Histologically these are chromophobe adenomas; many of these appear to result from an abnormal G protein in the pituitary receptor.
(c) Cushing’s disease and Nelson’s syndrome (excess ACIH secretion)-basophil adenomas or hyperplasia. The clinical features of acromegaly and Cushing’s disease or hyperprolactinaemia are usually, but not always, obvious. Hyperprolactinaemia may be clinically ‘silent’. Tumours producing LH, FSH or ISH are very rare. Some apparently ‘non-functioning’ turnours, which are common and usually chromophobe adenomas, may produce the a-subunit of LH, FSH and ISH.
3 Is there a deficiency of any hormone? Clinical examination may give clues; thus, short stature in a child with a pituitary tumour is likely to be due to GH deficiency. A slow, lethargic adult with pale skin is likely to be ISH and/or ACIH deficient. Milder deficiencies may not be obvious, and require specific testing.
The differential diagnosis of apparent pituitary adenomas additionally includes craniopharyngioma, a usually cystic hypothalamic tumour arising from Rathke’s pouch that often mimicks an intrinsic pituitary lesion. Though presenting at any age, it is the commonest tumour in children and is often calcified.
Less common are cysts of Rathke’s pouch, meningiomas, gliomas, chondromas, pinealomas and carotid artery aneurysms masquerading as turn ours. Secondary deposits occasionally present as apparent pituitary tumours, often presenting as diabetes insipidus.

Characteristics of pituitary tumours.

Characteristics of pituitary tumours.

(a) MRI of pituitary fossa showing tumour with suprasellar extension.

(a) MRI of pituitary fossa showing tumour with
suprasellar extension.

Central Control of Endocrine Function

Anatomy

Many peripheral hormone systems are controlled by the hypothalamus and pituitary. The hypothalamus is sited at the base of the brain around the third ventricle and above the pituitary stalk, which leads down to the pituitary itself, carrying the hyophyseal-pituitary portal blood supply.
The important anatomical relationships of the hypothalamus and pituitary include the optic chiasm just above the pituitary fossa; any expanding lesion from the pituitary or hypothalamus can thus produce visual field defects by pressure on the chiasm. The pituitary is itself encased in a bony box; any lateral, anterior or posterior expansion must cause bony erosion. Upward expansion of the gland through the diaphragma sellae is termed ‘suprasellar extension’. The normal fossa is of very variable size but a true lateral X-ray should show a welldefined outline with a single floor. The commonest cause  of apparent abnormality is a poorly aligned film.
Embryologically, the anterior pituitary is formed from Rathke’s pouch (endodermal) which meets an outpouching of the third ventricular floor to become the posterior pituitary.

MRI of a sagittal section of the brain showing the pituitary fossa

MRI of a sagittal section of the brain showing the
pituitary fossa

Physiology

Hypothalamus

This contains many vital centres for such functions as appetite, thirst, thermal regulation and sleep/waking. It acts as an integrator of many neural and endocrine inputs to control the release of releasing factors. Amongst other important influences it plays a role in the circadian rhythm, menstrual cyclicity, stress, exercise and mood. From the hypothalamus the portal system runs down the stalk through which releasing factors are transported to the pituitary.

Anterior pituitary

Releasing or inhibitory hormones produced in the hypothalamus travel down the portal system and stimulate or inhibit specific cells within the pituitary. These cells then stimulate or inhibit the synthesis and release of trophic hormones, which in turn stimulate the peripheral glands. This pattern is illustrated. Many hormones are under dual control of stimulatory and inhibitory hypothalamic factors. For example: GROWTH HORMO E RELEASE is stimulated by growth hormone releasing hormone (GHRH) but inhibited by somatostatin (growth hormone release inhibitory hormone, GHRIH).

TSH RELEASE is stimulated by TRH but partially inhibited by somatostatin.
SOME HORMONES have a dual stimulatory control, e.g. corticotrophin releasing factor (CRF) and vasopressin are endogenous stimulators of ACTH release. Uniquely, prolactin is under predominant inhibitory dopaminergic control with some stimulatory TRH control.

Posterior pituitary

This, in contrast, acts merely as a storage organ. Antidiuretic hormone (ADH, vasopressin) and oxytocin, both nonapeptides, are synthesized in the supraoptic and paraventricular nuclei in the anterior hypothalamus. They are then transported along a single axon and stored in the posterior pituitary. This means that damage to the stalk or pituitary alone does not prevent synthesis and release of ADH and oxytocin. ADH; oxytocin produces milk ejection and uterine myometrial contraction.
Synthetic hypothalamic hormones and their antagonists are now available for testing of endocrine function and for treatment.
Endorphins and the ACTH families of peptides Some but not all of the endorphins (ENDogenous mORPHINe) are derived from part of the ACTH precursor molecular (Fig. 16.7). This scheme demonstrates some of the complex processing of pituitary peptides including the role of a ‘prohorrnone’, proopiomelanocortin, from which the major hormone, ACTH, is split. Pigmentation in humans is due to ACTH and l3-lipotrophin, not from a- and l3-melanocyte stimulating hormone (MSH) which are not found in humans.
The endorphins have opioid activity and are thought to be mediators of stress-induced analgesia. They have also been found within the gut but their physiological role remains uncertain. The hypothalamus also contains large amounts of other neuropeptides such as natriuretic factor, bombesin and vasoactive intestinal peptide (VIP) that can also alter pituitary hormone secretion.