Chapter 38 Hypothalamic, pituitary and sex hormones

• Many of the pituitary hormones and their hypothalamic releasing factors are used in diagnosis or therapy.

• The main therapeutic use of pituitary hormones is of growth hormone (anterior pituitary) and those from the posterior pituitary: oxytocin and vasopressin.

• Vasopressin (antidiuretic hormone) is used both for its vasoconstrictor effect (in the treatment of oesophageal varices) and for its antidiuretic action.

• The main hypothalamus–pituitary target organ axis for therapeutic intervention is that controlling reproductive hormones, especially in women.

• Suppression of oestrogen and/or androgen production is used in the treatment of tumours stimulated by these: breast and prostate.

• Therapy in women is used to suppress ovulation (contraceptives), to stimulate ovulation (fertility treatment) or to mimic ovarian endocrine function (post-menopausal hormone replacement therapy, HRT).

Figure 38.1 shows the hypothalamo-pituitary axes. The hypothalamus and pituitary glands form the centre of the ‘endocrine orchestra’. We will here describe the hypothalamic releasing hormones, and the anterior and posterior pituitary gland hormones, and drugs that are used to manipulate these axes.

Fig. 38.1 Hormones produced in the anterior pituitary and the hypothalamic hormones that regulate their secretion. ACTH, adrenocorticotrophic hormone; ADH, antidiuretic hormone; CRH, corticotropin releasing hormone; FSH, follicle stimulating hormone; GH, growth hormone; GHRH, growth hormone releasing hormone; GnRH, gonadotrophin releasing hormone; TRH, thyrotrophin releasing hormone; TSH, thyroid stimulating hormone; VIP, vasoactive intestinal peptide.

These hormones, analogues (agonists) and antagonists can be used:

• To analyse the functional integrity of endocrine control systems.

• As replacement in hormone deficiency states.

• To modify malfunction of endocrine systems.

• To alter normal function where this is inconvenient, e.g. contraception.

The scope of the specialist endocrinologist continues to increase in amount and in complexity and only an outline is appropriate here.

Hypothalamic and anterior pituitary hormones

The hypothalamus releases a number of locally active hormones that stimulate or inhibit pituitary hormone release (see Fig. 38.1).

The t_½ of the polypeptide and glycoprotein hormones listed below is 5–30 min; they are digested if swallowed.

Growth hormone is approved for treatment of children with short stature due not just to growth hormone deficiency, but also to Turner’s syndrome, renal failure, small size for gestational age, Prader–Willi syndrome ¹ and, most recently, idiopathic short stature. Treatment is continued until closure of the epiphyses. Subsequent treatment into adulthood is also warranted where UK National Institute for Health and Clinical Excellence (NICE) guidelines are fullfilled. Growth hormone therapy should be confined to specialist clinics.

The use of growth hormone in adults varies among different countries. In the UK, treatment is limited to growth hormone-deficient patients with severely impaired quality of life. Treatment improves exercise performance, increases lean body mass and overall quality of life. A low starting dose of 0.27 mg s.c. daily is used, and adjusted at 4–6 week intervals according to clinical response and IGF-1 levels. It is recommended by NICE that treatment be discontinued in patients when quality of life improves by fewer than seven points on the Adult Growth Hormone Deficiency Assessment (AGHDA) scale.

Adverse effects include increases in weight, blood pressure, and blood glucose and lipid levels. These should be monitored together with plasma haemoglobin A1c (HbA1c).

In acromegaly, excess growth hormone causes diabetes, hypertension and arthritis. The former two lead to a two-fold excess in cardiovascular mortality. Surgery is the treatment of choice. Growth hormone secretion is reduced by octreotide, lanreotide and other somatostatin analogues, and to a lesser degree by bromocriptine and cabergoline. If surgery fails (nadir growth hormone during oral glucose tolerance test > 1 microgram/L) somatostatin analogues should be used. These bind to somatostatin receptors 2 and 5 to inhibit growth hormone production. About 60% of patients respond to somatostatin analogues.

Pegvisomant

is a growth receptor antagonist. It binds to the receptor and prevents activation and production of IGF-1. As a result growth hormone increases with pegvisomant treatment, which is a specialist indication for the treatment of acromegaly in patients with inadequate response to pituitary surgery or radiation, and to somatostatin analogues.

Gonadotrophin releasing hormone (GnRH),

gonadorelin, releases luteinising hormone (LH) and follicle stimulating hormone (FSH). It has a use in the assessment of pituitary function. In hypogonadotrophic hypogonadal men, GnRH may be used to induce spermatogenesis and fertility. Pulsatile subcutaneous GnRH administration via a catheter attached to a mini-pump evokes secretion of gonadotrophins (LH and FSH) and is used to treat infertility. But continuous use evokes tachyphylaxis owing to down-regulation of its receptors, i.e. gonadotrophin release and therefore gonadal secretions are reduced.

Longer-acting analogues, e.g. buserelin, goserelin, nafarelin, deslorelin and leuprorelin, are used to suppress androgen secretion in prostatic carcinoma. Other uses may include endometriosis, precocious puberty and contraception.

Cetrorelix and ganirelix are luteinising hormone releasing hormone antagonists, which inhibit the release of gonadotrophins. They are used in the treatment of infertility by assisted reproductive techniques

All of these drugs need to be administered by a parenteral route. Their use should generally be in the hands of a specialist endocrinologist, oncologist or gynaecologist.

Follicle stimulating hormone (FSH)

stimulates development of ova and of spermatozoa. It is prepared from the urine of post-menopausal women; menotrophin also contains a small amount of LH, and urofollitrophin is FSH alone. They are used in female and male hypothalamic hypophyseal infertility as an alternative to GnRH treatment. Pulsatile GnRH is more likely to result in development and ovulation of a single follicle than FSH. Recombinant FSH subunits (follitrophin α or β) are available for in vitro fertilisation.

Chorionic gonadotrophin

(human chorionic gonadotrophin, HCG) is secreted by the placenta and is obtained from the urine of pregnant women. Its predominant action is that of luteinising hormone (LH), which induces progesterone production by the corpus luteum in women, and in the male it is involved in spermatogenesis and gonadal testosterone production. It is also used to trigger ovulation in induction protocols, for corpus luteum support. In males, HCG is used in diagnostic tests of ambiguous genitalia; if HCG fails to induce testicular descent in pre-pubertal males, there is time for surgery to achieve a fully functioning testis. In older boys, HCG may be used to induce puberty where this is delayed.

Prolactin

is secreted by the lactotroph cells of the anterior pituitary gland. Its control is by tonic hypothalamic inhibition through dopamine, which in turn acts on D₂ receptors of the lactotrophs. Its main physiological function is stimulation of lactation. Supra-physiological levels of prolactin inhibit gonadotrophin releasing hormone and gonadotrophin release as well as gonadal steroidogenesis.

Hyperprolactinaemia may be caused by drugs with antidopaminergic actions: antiemetics, major tranquillisers, second-generation neuroleptics, monoamine oxidase (MAO) inhibitors, tricyclic antidepressants and, to a lesser extent, oestrogens.

Hyperprolactinaemia may occur in primary hypothyroidism, in pituitary stalk disconnection or prolactin-secreting adenomas. Medical treatment is with bromocriptine started at 0.625 mg by mouth nightly, and titrated weekly to a maximum of 20 mg in divided doses. Cabergoline may be preferred as a more specific dopamine agonist than bromocriptine, which is taken once weekly, titrated from 500 micrograms to 2 mg. Higher doses (up to 6 mg weekly) are necessary only in the treatment of macroprolactinomas. Quinagolide is anther dopamine agonist; the dose is 25–150 micrograms at bedtime.

In pregnancy, the dopamine agonists are discontinued in microadenomas, where the risk of enlargement is small. Treatment should continue for macroadenomas because the risk of enlargement is much higher, 15–30%. Both bromocriptine and cabergoline are safe to use, although cabergoline is not licensed in pregnancy. Much higher doses of cabergoline (e.g. 4 mg daily or 28 mg weekly) have been associated with cardiac fibrosis, although this has not been reported in many groups of prolactinoma patients. Nevertheless, the UK regulatory agency (MHRA) advises cardiac valve monitoring for patients on any dose of cabergoline.

Trans-sphenoidal surgery in a specialist unit is an alternative to medical therapy in patients who do not tolerate, or are resistant to, dopamine agonists.

Hypopituitarism

In hypopituitarism there is a partial or complete deficiency of hormones secreted by the anterior and posterior lobe of the pituitary, although the latter is less common. Patients suffering from severe hypopituitarism may present in coma, in which case treatment is as for severe acute adrenal insufficiency. Maintenance therapy is required, using hydrocortisone, thyroxine, estradiol and progesterone (in women) and testosterone (in men), growth hormone and desmopressin, where indicated.

Posterior pituitary hormones and analogues

Vasopressin: antidiuretic hormone (ADH)

Vasopressin is a nonapeptide (t_½ 20 min) with two separate G-protein-coupled target receptors responsible for its two roles. The V₁ receptor on vascular smooth muscle cells is coupled to calcium-ion entry and is not usually stimulated by physiological concentrations of the hormone. The V₂ receptor is coupled to adenylyl cyclase, and regulates opening of the water channel, aquaporin, in cells of the renal collecting duct.

Secretion of the antidiuretic hormone is stimulated by any increase in the osmotic pressure of the blood supplying the hypothalamus and by a variety of drugs, notably nicotine. Secretion is inhibited by a fall in blood osmotic pressure and by alcohol.

In large non-physiological doses (pharmacotherapy) vasopressin causes contraction of all smooth muscle, raising the blood pressure and causing intestinal colic. The smooth muscle stimulant effect provides an example of tachyphylaxis (frequently repeated doses give progressively less effect). It is not only inefficient when used to raise the blood pressure, but also dangerous, as it causes constriction of the coronary arteries and sudden death has occurred following its use.

For replacement therapy of pituitary diabetes insipidus the longer acting analogue desmopressin is used.

Desmopressin

Desmopressin (des-amino-D-arginine vasopressin, DDAVP) has two major advantages: the vasoconstrictor effect has been reduced to near insignificance and the duration of action with nasal instillation, spray or subcutaneous injection, is 8–20 h (t_½ 75 min) so that, using it once to twice daily, patients are not inconvenienced by polyuria and nocturia.

Desmopressin is available as oral or sublingual tablets, nasal spray and injection. The adult dose for intranasal administration is 10–20 micrograms daily. The dose for children is about half that for adults. The bioavailability of intranasal DDAVP is 10%. It is also the only peptide for which an oral formulation is currently available, albeit with a bioavailability of only 1%. Tablets of DDAVP are prescribed initially at 200–600 micrograms daily in three divided doses. The main complication of DDAVP is hyponatraemia, which can be prevented by allowing the patient to develop some polyuria for a short period during each week. The dose requirement for DDAVP may decrease during intercurrent illness. It is therefore important to review the need for DDAVP daily in critically ill patients.

Nephrogenic diabetes insipidus, as is to be expected, does not respond to antidiuretic hormone.

In bleeding oesophageal varices, use is made of the vasoconstrictor effect of vasopressin (as terlipressin, a vasopressin prodrug); see page 564.

In haemophilia, desmopressin can enhance blood concentration of factor VIII.

Felypressin is used as a vasoconstrictor with local anaesthetics.

Enuresis: see page 313.

Diabetes insipidus: vasopressin deficiency

Diabetes insipidus (DI) is characterised by persistent production of excess dilute urine (> 40 mL/kg every 24 h in adults and > 100 mL/kg every 24 h in children). DI is classified as cranial or nephrogenic. Cranial causes of DI are genetic, developmental or idiopathic. Acquired causes are head injury, surgery to the hypothalamic–pituitary region, tumours, inflammatory conditions such as granulomatous and infectious disease, vascular causes and external radiotherapy. Nephrogenic DI has a larger number of causes including drugs (lithium, demeclocycline) and several diseases affecting the renal medulla. The DNA sequencing of the receptor and aquaporins has also allowed identification of mutations in these that cause congenital DI.

Desmopressin replacement therapy

is the first choice. Thiazide diuretics (and chlortalidone) also have paradoxical antidiuretic effect in diabetes insipidus. That this is not due to sodium depletion is suggested by the fact that the non-diuretic thiazide, diazoxide, also has this effect. It is probable that changes in the proximal renal tubule result in increased reabsorption and in the delivery of less sodium and water to the distal tubule, but the mechanism remains incompletely elucidated. Some cases of the nephrogenic form, which is not helped by antidiuretic hormone, may be benefited by a thiazide.

Carbamazepine 200 mg once or twice daily is marginally effective in partial pituitary diabetes insipidus, because it acts on the kidney, potentiating the effect of vasopressin on the renal tubule.

Syndrome of inappropriate antidiuretic hormone secretion (SIADH)

A variety of tumours, e.g. oat-cell lung cancer, can make vasopressin, and they are not, of course, subject to normal homeostatic mechanisms. SIADH also occurs in some central nervous system (CNS) and respiratory disorders (infection). Dilutional hyponatraemia follows, i.e. low plasma sodium with an inappropriately low plasma osmolality and high urine osmolality. When plasma sodium approaches 120 mmol/L, treatment should be with fluid restriction (e.g. 500 mL/day). Treatment is primarily of the underlying disorder accompanied by fluid restriction. Chemotherapy to the causative tumour or infection is likely to be the most effective treatment. Demeclocycline, which inhibits the renal action of vasopressin, is useful. Initially 0.9–1.2 g is given daily in divided doses, reduced to 600–900 mg daily for maintenance. V₂ receptor antagonists (the vaptans) are also now available and are licensed for such patients. There is no evidence of these drugs being any more effective than a carefully supervised fluid restriction, and at present conivaptan and tolvaptan are difficult to justify on grounds of cost and safety. It is also important to note that rapid correction of hyponatraemia can lead to central pontine myelinolysis, and that care must therefore be taken with these drugs.

Emergency treatment of hyponatraemia

Whereas most patients with a serum sodium concentration exceeding 125 mmol/L are asymptomatic, those with lower values may have symptoms, especially if the disorder has developed rapidly. These may be mild (headache, nausea) or severe (vomiting, disorientation). Complications are catastrophic: seizures, coma, permanent brain damage, respiratory arrest, brainstem herniation and death. Optimal treatment requires balancing the risks of hypotonicity against those of therapy, the most feared being central pontine myelinolysis. Infusion of isotonic or hypertonic saline is therefore reserved for extreme emergencies, associated with stupor, and undertaken with great caution.

The rate of correction must not exceed 0.5 mmol/L/h until the plasma sodium is 120–125 mmol/L. Over-correction (to plasma sodium > 130 mmol/L) is unnecessary and potentially harmful. The predicted increase in plasma sodium per litre of infusate can be estimated from the formula:

Body water is a fraction of body-weight in kilograms, being 0.6 in children and non-elderly men, 0.5 in elderly men and non-elderly women, and 0.45 in elderly women.

Oxytocin

See page 631.

Sex (gonadal) hormones and antagonists: steroid hormones

Steroid hormone receptors

(for gonadal steroids and adrenocortical steroids) are complex proteins inside the target cell. The steroid penetrates, binds to the receptor and translocates into the cell nucleus, which is the principal site of action and where RNA synthesis occurs. Compounds that occupy the receptor without causing translocation into the nucleus or the replenishment of receptors act as antagonists, e.g. spironolactone to aldosterone, cyproterone to androgens, clomifene to oestrogens.

Selectivity

Many synthetic analogues, although classed as, e.g. androgen, anabolic steroid, progestogen, are non-selective and bind to several types of receptor as agonist, partial agonist, antagonist. The result is that their effects are complex. The selective oestrogen receptor modulators (SERMS) may be antagonists to the oestrogen receptors in the breast, while being agonists in bone. Tamoxifen and raloxifene are such SERMS, which therefore increase bone density (as normal oestrogen does) but reduce the risk of breast cancer (by blocking the breast receptor to estradiol) (see also below).

Pharmacokinetics

Steroid sex hormones are well absorbed through the skin (factory workers need protective clothing) and the gut. Most are subject to extensive hepatic metabolic inactivation (some so much that oral administration is ineffective or requires very large doses, if a useful amount is to pass through the liver and reach the systemic circulation).

There is some enterohepatic recirculation, especially of oestrogen, and this may be interrupted by severe diarrhoea, with loss of efficacy. Some non-steroidal analogues are metabolised more slowly. Sustained-release (depot) preparations are used. The hormones are carried in the blood extensively bound to sex hormone binding globulin. In general the plasma t_½ relates to the duration of cellular action, which is implied in the recommended dosage schedules.

Androgens

Testosterone is the predominant natural androgen secreted by the Leydig cells of the testis; in a normal adult male testosterone production amounts to 4–9 mg/24 h. It circulates highly bound to a hepatic glycoprotein called sex hormone binding globulin (65%) and loosely bound to albumin (33%). Only 1–2% of circulating testosterone is unbound and freely available to tissues. It is converted by hydroxylation to the active dihydrotestosterone (DHT). Testosterone is necessary for normal spermatogenesis, for the development of the male secondary sex characteristics, sexual potency and for the growth, at puberty, of the genital tract.

Protein anabolism is increased by androgens, i.e. androgens increase the proportion of protein laid down as tissue, especially muscle and (combined with training, increase strength). Growth of bone is promoted, but the rate of closure of the epiphyses is also hastened, causing short stature in cases of precocious puberty or of androgen overdose in the course of treating hypogonadal children.

Indications for androgen therapy

Indications for testosterone treatment are primary testicular failure such as a result of bilateral anorchia, Klinefelter’s (XXY) karyotype, surgery, chemotherapy and radiotherapy, or secondary testicular failure as a result of hypothalamic–pituitary disease.

Other conditions that require testosterone treatment are delayed puberty in boys aged 16 years or older, angioneurotic oedema and adrenal insufficiency in females.

Testosterone replacement improves libido and overall sexual performance in hypogonadal men. Its effect on erectile response to sexual arousal is less clear and sildenafil and its analogues are more appropriate for patients complaining of erectile dysfuntion.

Preparations and choice of androgens

Testosterone given orally is subject to extensive hepatic first-pass metabolism (see p. 86) and it is therefore usually given by other routes. Androgens are available for oral, buccal, transdermal or depot administration.

Oral preparations

Testosterone undecanoate is highly lipophilic. When given orally it is absorbed through the intestinal lymphatics, thereby bypassing otherwise extensive hepatic first-pass metabolism. Yet bioavailability is poor and variable. The t_½ is short and the dose is 40–120 mg three times daily. It is converted to DHT before being absorbed, so monitoring should be by measuring DHT, not testosterone levels.

Mesterolone is a DHT derivative.

Parenteral preparations

Sustanon is a mixed testosterone ester preparation normally given 2–4 weekly by deep intramuscular injection; the usual dose is 250 mg (range 100–250 mg). Other preparations, testosterone enanthate and testosterone epionate, are given at 1–2-week intervals. These preparations are widely used and have a good safety profile. Their main disadvantage is fluctuation of plasma testosterone concentrations, causing swings of mood and well-being. But testosterone undecanoate (1000 mg in 4 mL castor oil given by a depot intramuscular injection) achieves stable physiological concentrations lasting for 3 months.

Transdermal preparations

Patches are available for scrotal and non-scrotal sites; they provide stable pharmacokinetics and are an alternative to painful injections. Absorption is superior at the scrotum because of its high skin vascularity. High concentrations of DHT are achieved because 5α-reductase is present in scrotal skin.

Non-scrotal patches are applied to the skin of the upper arms, back, abdomen and thighs.

Local skin reactions occur in 10% of cases and they are secondary to absorption enhancers. Application of corticosteroid ointment improves tolerability. Patches must be changed every 24 h.

Transdermal gels are hydroalcoholic gels for delivering testosterone transdermally. They are applied daily on the skin of the arms and torso. Showering must be avoided for 6 h, as well as intimate skin contact with others, as transfer of testosterone may occur.

Buccal preparations

These are available in a sustained-release form. A tablet is placed in the small depression above the incisor tooth twice daily. Testosterone is absorbed and delivered into the superior vena cava, thereby bypassing hepatic first-pass metabolism. Steady-state testosterone and DHT concentrations are achieved in 24 h.

Testosterone implants

Pellets of crystallised testosterone are implanted subcutaneously under local anaesthesia by a small incision in the anterior abdominal wall, using a trocar and cannula. Three implanted pellets (total 600 mg) give hormone replacement for about 6 months. There is an approximately 10% risk of extrusion of the pellets; infection and haemorrhage are uncommon.

Adverse effects

Increased libido may lead to undesirable sexual activity, and virilisation is undesired by most women. Androgens have a weak salt and water retaining activity, which is not often clinically important. Liver injury (cholestatic) can occur, particularly with 17α-alkyl derivatives (ethylestrenol, danazol, oxymetholone); it is reversible but these agents should be avoided in hepatic disease. As androgens are contraindicated in carcinoma of the prostate, monitoring during treatment includes regular measurement of prostate specific antigen (PSA). Haemoglobin should also be monitored to avoid polycythaemia.

Effects on blood lipids are complex and variable, and the balance may be to disadvantage.

In patients with malignant disease of bone, androgen administration may be followed by hypercalcaemia. The less virilising androgens are used to promote anabolism and are discussed below.

Antiandrogens (androgen antagonists)

Oestrogens and progestogens are physiological antagonists to androgens. But compounds that compete selectively for androgen receptors have been made.

Cyproterone

Cyproterone is a derivative of progesterone; its combination of structural similarities and differences results in the following:

• Competition with testosterone for receptors in target peripheral organs (but not causing feminisation as do oestrogens); it reduces spermatogenesis even to the level of azoospermia (reversing over about 4 months after the drug is discontinued); abnormal sperm occurs during treatment.

• Competition with testosterone in the CNS, reducing sexual drive and thoughts, and causing impotence.

• Some agonist progestogenic activity on hypothalamic receptors, inhibiting gonadotrophin secretion, which also inhibits testicular androgen production.

Uses

Cyproterone is used for reducing male hypersexuality, and in prostatic cancer and severe female hirsutism. A formulation of cyproterone plus ethinylestradiol (Dianette, which contains only 2 mg of cyproterone acetate) is offered for this latter purpose as well as for severe acne in women; this preparation acts as an oral contraceptive but does not have a UK licence, and should not be used primarily for this purpose.

Flutamide and bicalutamide are non-steroidal antiandrogens available for use in conjunction with the gonadorelins (e.g. goserelin) in the treatment of prostatic carcinoma.

Finasteride and dutasteride (see p. 462), which inhibit conversion of testosterone to dihydrotestosterone, have localised antiandrogen activity in tissues where dihydrotestosterone is the principal androgen; they are therefore useful drugs in the treatment of benign prostatic hypertrophy.

Spironolactone (see p. 563) also has antiandrogen activity and may help hirsutism in women (as an incidental benefit to its diuretic effect). Androgen secretion may be diminished by continued use of a gonadorelin (LHRH) analogue (see p. 597).

Ketoconazole

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