Karim Meeran
Synopsis
• 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 t½ of the polypeptide and glycoprotein hormones listed below is 5–30 min; they are digested if swallowed.
Corticotropin releasing hormone (CRH)
is a hypothalamic polypeptide that has diagnostic use. It increases secretion of adrenocorticotrophin (ACTH) in Cushing's disease secondary to pituitary ACTH-secreting adenoma. It is also used to stimulate ACTH secretion during bilateral inferior petrosal sinus sampling, a procedure carried out in specialist centres to determine the cause of Cushing's syndrome. It has no therapeutic use.
Adrenocorticotrophic hormone (ACTH)
(Corticotropin). Is used in the short and long synacthen tests to make a diagnosis of Addison's disease. The standard test uses 250 micrograms either i.v. or i.m.
Thyrotrophin releasing hormone (TRH)
is a tripeptide amide formed in the hypothalamus and controlled by free plasma T4 and T3 concentration. It has been synthesised and has been used in the past to test the capacity of the pituitary to release thyroid stimulating hormone (TSH), to determine whether hypothyroidism is due to primary thyroid gland failure or secondary to pituitary hypothalamic lesion, and in the differential diagnosis of borderline or subclinical thyrotoxicosis. Current sensitive assays for TSH make this role redundant. The TRH test is still used to differentiate between TSHomas (TSH-producing tumours, where the response to TRH is flat) and thyroid hormone resistance (where there is an exuberant response to TRH). It is also a potent prolactin releasing factor and can thereby be useful in detecting normal pituitary function.
Thyroid stimulating hormone (TSH) thyrotrophin,
a glycoprotein of the anterior pituitary, controls the synthesis and release of thyroid hormone from the gland, and also the uptake of iodide. There is a negative feedback of thyroid hormones on both the hypothalamic secretion of TRH and pituitary secretion of TSH.
Recombinant TSH is now used in the treatment of thyroid cancer. A dose of TSH is administered just before a tracer dose of radioiodine in such patients. A high level of TSH is required to stimulate uptake of radioiodine into any TSH responsive tissue. This was previously achieved by stopping thyroxine replacement, and rendering the patient profoundly hypothyroid for several weeks, causing high levels of endogenous TSH. This unpleasant treatment is no longer required with the advent of recombinant TSH.
Sermorelin
is an analogue of the hypothalamic growth hormone releasing hormone (somatorelin); it is used in a diagnostic test for growth hormone secretion from the pituitary.
Growth hormone release inhibiting hormone, somatostatin, occurs in other parts of the brain as well as in the hypothalamus, and also in some peripheral tissues, e.g. pancreas, stomach. In addition to the action implied by its name, it inhibits secretion of thyrotrophin, insulin, gastrin and serotonin. Somatostatin is a 14 amino acid hypothalamic peptide. It inhibits growth hormone secretion.
Octreotide
is a synthetic analogue of somatostatin having a longer action (t½ 1.5 h). It is administered subcutaneously two or three times daily; a depot formulation is available for deep intramuscular injection once a month. Lanreotide is much longer acting than octreotide, and is administered intramuscularly twice a month. Uses of the somatostatin analogues include acromegaly, carcinoid (serotonin-secreting) tumours and other rare tumours of the alimentary tract. An unlicensed use of octeotride is the termination of variceal bleeding (see p. 548). Radiolabelled somatostatin is used to localise, and in higher doses to treat, metastases from neuroendocrine tumours which often bear somatostatin receptors. Both octreotide and lanreotide are now available as a monthly slow-release preparation.
Growth hormone, somatrophin
(Genotropin, Humatrope) is a biosynthetic form (191 amino acids) of growth hormone prepared by recombinant DNA technology, as is somatrem. Naturally occurring human growth hormone was extracted from cadaver pituitaries and its supply was therefore limited. In 1985 the use of natural growth hormone was terminated because of the risk of transmitting Creutzfeldt–Jacob disease, the fatal prion infection. Growth hormone acts on many organs to produce a peptide insulin-like growth factor IGF-1 (somatomedin), which causes muscle, bone and other tissues to increase growth, i.e. protein synthesis, and the size and number of cells.
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 syndrome1 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 (t½ 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 (t½ 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 t½ 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 t½ 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 (antifungal) interferes with androgen and corticosteroid synthesis by inhibiting several of the cytochrome P450 enzymes involved in steroid biosynthesis and may be used in prostatic carcinoma and Cushing's syndrome (400 mg twice daily).
Metyrapone inhibits one enzyme on the cortisol and aldosterone synthetic pathway, 11 hydroxylase, and is therefore also used in the treatment of Cushing's syndrome while awaiting definitive surgical (either bilateral adrenalectomy or transphenoidal pituitary hypophysectomy) treatment.
Anabolic steroids
(See also above.)
Androgens are effective protein anabolic agents, but their clinical use for this purpose is limited by the amount of virilisation that women will tolerate. Attempts made to separate anabolic from androgenic action have been only partially successful and all anabolic steroids also have androgenic effects.
They benefit some patients with aplastic anaemia.
Nandrolone 50 mg is given by deep intramuscular injection every 3 weeks. Hereditary angioedema (lack of inhibition of the complement Cl esterase) may be prevented by danazol.
Anabolic steroids can prevent the calcium and nitrogen loss in the urine that occurs in patients bedridden for a long time, and have been used in the treatment of some severe fractures. The use of anabolic steroids in conditions of general wasting despite nutritional support may be justifiable in extreme debilitating disease, such as severe ulcerative colitis, and after major surgery. In the later stages of malignant disease they may make the patient feel and look less wretched.
Anabolic steroids do not usefully counter the unwanted catabolic effects of the adrenocortical hormones.
None of these agents is free from virilising properties in high doses; acne and greasy skin may be the early manifestation of virilisation (see also, Adverse effects of androgens, p. 593, and Drugs and sport, p. 141).
Oestrogens have only a modest anabolic effect.
Administration of anabolic steroids should generally be intermittent in courses of 3–12 weeks with similar steroid-free intervals, to reduce the occurrence of unwanted effects, especially liver injury.
Oestrogens
Estrone and estradiol are both natural oestrogens. Oestrogens are responsible for the development of normal secondary sex characteristics in women, uterine growth, thickening of vaginal mucosa and the ductal breast system.
Pharmacokinetics
See page 682.
Preparations of oestrogens
The dose varies according to whether replacement of physiological deficiencies is being carried out (replacement therapy) or whether pharmacotherapy is being used.
• Ethinylestradiol (t½ 13 h) is a synthetic agent of first choice for pharmacological uses (mainly contraceptive, female hypogonadism and menstrual disorders); it is effective by mouth, dose 20–50 micrograms/day.
• Estradiol and estriol are orally active mixed natural oestrogens, dose 1–2 mg/day.
• Conjugated oestrogens (Premarin) are orally active mixed natural oestrogens containing 50–65% estrone obtained from the urine of pregnant mares, dose 0.625–1.25 mg.
• Estropipate (piperazine estrone sulphate) is an orally active synthetic conjugate.
• Diethylstilbestrol (stilboestrol) is the first synthetic oestrogen; it is used (rarely) in prostatic cancer, and occasionally in post-menopausal women with breast cancer.
Choice of oestrogen
Ethinylestradiol, or its methylated derivative mestranol (synthetic), is a satisfactory first choice for pharmacotherapy. The weaker endogenous oestrogens, estradiol, estriol and estrone (natural), or the conjugated equine oestrogens (CEE) are preferable for physiological replacement. It remains uncertain whether all oestrogens have exactly similar hormonal and non-hormonal effects, including adverse effects.
Selective oestrogen receptor modulators (SERMS) combine oestrogenic and antioestrogenic properties (raloxifene and tibolone). Raloxifene has antioestrogenic effects on breast and endometrium, but oestrogenic effects on bone and is used for prevention and treatment of osteoporosis. It reduces risk of invasive breast cancer but increases risk of stroke and thromboembolism. It has no effect on vasomotor symptoms. Tibolone is licensed for short-term treatment of osteoporosis.
Oestrogen formulations and routes of administration
Oral
This is an easy and effective route but is subject to the first-pass effect through the liver, and higher doses are needed in comparison to other formulations.
Transdermal
formulations are in the form of patches and gels. This route may eliminate the risk of thrombosis associated with oral oestrogen.
Subcutaneous implants
Crystalline pellets inserted into the anterior wall or buttock release hormone over several months. Used in women who undergo oophorectomy and hysterectomy, they are usually repeated at 6 months and tachyphylaxis may be a problem.
Vaginal (ring, cream, tablet or pessary)
Low-dose oestrogen therapy is delivered for treatment of urogenital symptoms. If used for long periods, i.e. more than 2 years, progesterone should be added to avoid endometrial hyperplasia.
Others
A nasal spray is available. It delivers 300 micrograms of estradiol daily.
Indications for oestrogen therapy
Replacement therapy in hypo-oestrogenaemia
This term refers to decreased oestrogen production due to ovarian disease, or to hypothalamic–pituitary disease (hypogonadotrophic hypogonadism). Treatment is by cyclic oestrogen (estradiol 1–2 mg, conjugated oestrogens 0.625/1.25 mg daily or ethinylestradiol 20–30 micrograms continuously) plus a progestogen, medroxyprogesterone 2.5–10 mg daily for the last 10–14 days of oestrogen treatment. An alternative treatment is the oral contraceptive (p. 607).
Post-menopausal hormone replacement therapy (HRT)
HRT refers to the use of oestrogen treatment in order to reverse or prevent problems due to the loss of ovarian hormone secretion after the menopause, whether physiological or induced. The tissues sensitive to oestrogen include brain, bone, skin, cardiovascular and genitourinary. The goal of HRT is to reduce the vasomotor symptoms of oestrogen loss (hot flushes, sleeplessness and vaginal dryness) without causing disorders that may be more common with oestrogen treatment such as breast and endometrial cancer.
All types of HRT (oestrogen with or without progestogen) are effective at reducing the hot flushes experienced by more than 50% of post-menopausal women. The benefit is most during the first year of treatment when 75% of women report a reduced likelihood. By year 3 of treatment the reduction in frequency decreases by 65% in comparison to placebo. The other major value of HRT is the relief of vaginal dryness. Vaginal administration is the most effective route for treatment of dyspareunia and related symptoms. Urinary incontinence does not respond to HRT.
The clinical evidence base for prescribing HRT has changed since the publication of trials showing excess risks of breast cancer and stroke that outweigh small benefits in reduction of fractures and risk of colonic cancer. HRT should not be used in the treatment of osteoporosis or for prevention of coronary heart disease.
Preparations used for HRT
There are three types of regimen:
1. Women without a uterus take continuous oestrogen alone.
2. Women with a uterus require oestrogen combined with progestogen to prevent endometrial proliferation and risk of endometrial cancer.
• In the commonest, ‘sequential’, regimen women take oestrogen without a break and add a progestogen from day 12–14 to day 28 of each cycle (different preparations vary in the exact length of progestogen prescribing). The first course is started on the first day of menstruation (if present), and 28-day cycles of treatment follow thereafter without interval.
• In the ‘continuous’ regimen (appropriate only for women who have been amenorrhoeic for more than 1 year) fixed-dose combinations of oestrogen and progestogen are taken without a break. Continuous combination HRT regimens will eventually induce amenorrhoea in most women, thereby eliminating one of the major deterrents to HRT use, withdrawal bleeding.
Calendar packs are available. The oral preparations, Prempak-C and Femoston, use, respectively, conjugated oestrogen and estradiol as their oestrogen. Oral progestogens include dihydrogesterone, medroxyprogesterone, norgestrel and norethisterone. Individual progestogens can be given orally in combination with an oestrogen, as subcutaneous depot injection or by transdermal patch. Some patches provide both hormones but obviously lack the facility for doses to be separately titrated to provide the minimum necessary to prevent both flushing and (if undesired) withdrawal bleeding.
An alternative to oestrogen therapy is tibolone 2.5 mg, which is a synthetic oral steroid with weak oestrogenic, progestogenic and androgenic properties. Its main adverse effect is vaginal bleeding, which needs investigation if persistent. Vasomotor menopausal symptoms may occasionally be helped by low doses of clonidine (Dixarit).
Contraception
HRT in routine use does not provide contraception and any potentially fertile woman who requires HRT should take appropriate precautions. A woman is considered potentially fertile for 2 years after her last menstrual period if she is under 50 years of age, and for 1 year if she is aged over 50 years. A woman who is under 50 years and free of all risk factors for venous and arterial disease can use a low-oestrogen combined oral contraceptive pill to provide both relief of menopausal symptoms and contraception; it is recommended that the oral contraceptive be stopped at 50 years of age as there are more suitable alternatives.
Adverse effects of HRT
The commonest reasons for withdrawal are irregular or withdrawal bleeding and breast pain. Concerns about musculoskeletal symptoms and weight gain have not been substantiated in the long-term trials. Transdermal patches were associated with skin reactions but as the alcohol content has been reduced in the newer formulations the incidence has been reduced.
The more serious complications are venous thromboembolism and cancer of the endometrium or breast. These risks are small in absolute terms, particularly so for the risks of cancer during the first 5 years of treatment.
For venous thromboembolism, the excess risk is 4 per 1000 woman-years, which may be considered clinically insignificant except in women with predisposing factors, e.g. previous personal or family history of thromboembolism, or recent surgery.
The risk of carcinoma of the endometrium is increased two-fold during 5 years, rising to seven-fold with longer treatment. Because endometrial cancer is uncommon, the absolute risk is about one-tenth that of thromboembolic disease; the risk subsides over 5–10 years after stopping treatment.
Carcinoma of the breast can occur with any type of HRT. Some 45 in every 1000 women aged 50 years will have breast cancer over the next 20 years, rising by only 2, 6 and 12 cases, respectively, for women who take HRT for 5, 10 or 15 years. A family history of breast cancer does not increase the risks from HRT.
The risk of gallstones may be increased up to two-fold. HRT does not increase risk of ovarian cancer.
Blood lipids: the effect of oestrogens is on balance favourable, but the addition of a progestogen (unless gestodene or desogestrel) reverses the balance.
Contraindications
to oestrogen therapy include recent arterial or venous thromboembolic disease, and history of oestrogen-dependent neoplasm, e.g. breast cancer. Hypertension, liver disease or gallstones, migraine, diabetes, uterine fibroids or endometriosis may all be made worse by oestrogen. These are very variable, and are not absolute contraindications.
Anti-oestrogens
Selective antagonists of the oestrogen receptor are used either to induce gonadotrophin release in anovulatory infertility or to block stimulation of oestrogen receptor-positive carcinomas of the breast.
Clomifene
is structurally related to diethylstilbestrol; it is a weak oestrogen agonist having less activity than natural oestrogens, so that its occupation of receptors results in antagonism, i.e. it is a partial agonist. Clomifene blocks hypothalamic oestrogen receptors so that the negative feedback of natural oestrogens is prevented and the pituitary responds by increased secretion of gonadotrophins, which may induce ovulation.
Clomifene is administered during the early follicular phase of the menstrual cycle (50 mg daily on days 2–6) and is successful in inducing ovulation in about 85% of women. Multiple ovulation with multiple pregnancy may occur and this is its principal adverse effect, which can be limited by using ultrasonography. There have been reports of an increased incidence of ovarian carcinoma following multiple exposure, and the number of consecutive cycles for which clomifene may be used to stimulate ovulation should be limited to 12.
Cyclofenil
acts similarly to clomifene.
Tamoxifen
is a non-steroidal competitive oestrogen antagonist on target organs. Although available for anovulatory infertility (20 mg daily on days 2, 3, 4 and 5 of the cycle), its main use now is in the treatment of oestrogen-dependent breast cancer (see p. 518). Treatment with tamoxifen delays the growth of metastases and increases survival; if tolerated it should be continued for 5 years.
Tamoxifen is also the hormonal treatment of choice in women with oestrogen receptor-positive metastatic breast cancer. Approximately 60% of such patients respond to initial hormonal manipulation, whereas less than 10% of oestrogen receptor-negative tumours respond.
Severe adverse effects are unusual with tamoxifen but patients with bony metastases may experience an exacerbation of pain, sometimes associated with hypercalcaemia; this reaction commonly precedes tumour response. Amenorrhoea commonly develops in pre-menopausal women. Patients should be told of the small risk of endometrial cancer and encouraged to report relevant symptoms early. They can be reassured that the benefits of treatment far outweigh the risks. Tamoxifen is now considered a SERM (see above).
Progesterone and progestogens
Progesterone (t½ 5 min) is produced by the corpus luteum and converts the uterine epithelium from the proliferative to the secretory phase. It is thus necessary for successful implantation of the ovum and is essential throughout pregnancy, in the last two-thirds of which it is secreted in large amounts by the placenta. It acts particularly on tissues that are sensitised by oestrogens. Some synthetic progestogens are less selective, having varying oestrogenic and androgenic activity, and these may inhibit ovulation, though not very reliably. Progestogens are of two principal kinds:
• Progesterone and its derivatives: dydrogesterone, hydroxyprogesterone, medroxyprogesterone (t½ 28 h).
• Testosterone derivatives: norethisterone and its prodrug ethynodiol (t½ 10 h), levonorgestrel, desogestrel, gestodene, gestronol, norgestimate.
Drospirenone is a derivative of the synthetic aldosterone antagonist, spironolactone (see p. 563). It therefore has antimineralocorticoid activity, reducing salt retention and blood pressure. It also exhibits partial antiandrogenic activity, about 30% of that of cyproterone acetate. It is available as a combination with ethinylestradiol for use as a contraceptive.
Most progestogens can virilise directly or by metabolites (except progesterone and dydrogesterone), and fetal virilisation to the point of sexual ambiguity has occurred with vigorous use during pregnancy (see also Contraception, p. 608).
Megestrol is used only in cancer; it causes tumours in the breasts of beagle dogs.
Uses
The clinical uses of progestational agents are ill defined, apart from contraception, the menopause and post-menopausal hormone replacement therapy (see above).
Other possible uses include: menstrual disorders, e.g. menorrhagia, endometriosis, dysmenorrhoea and premenstrual syndrome (doubtful efficacy), breast and endometrial cancer.
Preparations
Available progestogens (some used only in combined formulations) include:
• Oral: norethisterone, dydrogesterone, gestodene, desogestrel, levonorgestrel, megestrol, medroxyprogesterone.
• Suppositories or pessaries: progesterone.
• Injectable: progesterone, hydroxyprogesterone, medroxyprogesterone.
Adverse effects
of prolonged use include virilisation (see above), raised blood pressure and an adverse trend in blood lipids. Gestodene, desogestrel and norgestimate may have less affinity for androgen receptors and therefore fewer unfavourable effects on blood lipids; the first two of these may have a higher risk of thrombosis.
Antiprogestogens
Menstruation (in its luteal phase) is dependent on progesterone, and uterine bleeding follows antagonism of progesterone. Pregnancy is dependent on progesterone (for implantation, endometrial stimulation, suppression of uterine contractions and placenta formation), and abortion follows progesterone antagonism in early pregnancy.
Mifepristone
is a pure competitive antagonist at progesterone and glucocorticoid receptors. Clinical trials of oral use in hospital outpatients have shown it to be safe and effective in terminating pregnancy. Efficacy is enhanced if its use is followed by vaginal administration of a prostaglandin (gemeprost) to produce uterine contractions (the success rate is raised from 85% to more than 95%).
Adverse effects of the combined treatment include nausea and vomiting, dizziness, asthenia, abdominal pain; uterine bleeding may be heavy. Mifepristone also offers the opportunity for mid-trimester terminations. These are likely to become more frequent with rise in the number of inherited syndromes amenable to antenatal diagnosis at this stage.
Guidelines may vary in detail and the following are general regimens:
• For gestation of up to 1 week where the fetus is deemed viable, mifepristone 600 mg by mouth followed 36–48 h later by gemeprost 1 mg by vagina.
• For mid-trimester medical abortion (13–24 weeks), mifepristone 600 mg by mouth followed 36–48 h later by gemeprost 1 mg every 3 h by vagina to a maximum of 5 mg.
Other progesterone derivatives
Danazol (Danol) is a derivative of the progestogen, ethisterone. It has partial agonist androgen activity and is described as an ‘impeded’ androgen; it has little progestogen activity. It is a relatively selective inhibitor of pituitary gonadotrophin secretion (LH, FSH) affecting the surge in the mid-menstrual cycle more than basal secretion. This reduces ovarian function, which leads to atrophic changes in endometrium, both uterine and elsewhere (ectopic), i.e. endometriosis. In males it reduces spermatogenesis. Unwanted androgenic effects occur in women (acne, hirsutism and, rarely, enlargement of the clitoris).
It is used chiefly for: endometriosis, fibrocystic mastitis, gynaecomastia, precocious puberty, menorrhagia and hereditary angioedema (see p. 611).
Gestrinone
is similar.
Fertility regulation
Infertility
Depending on the cause, the following agents, already described, are used:
For women,
ovulation induction:
• Hypothalamic hormone: gonadorelin (p. 597).
• Anterior pituitary hormones: follicle stimulating hormone (p. 597); chorionic gonadotrophin (p. 597).
• Anti-oestrogens: such as clomifene. (p. 605).
• Cabergoline for hyperprolactinaemia (p. 363).
For men,
induction of spermatogenesis: the same agents as for ovulation are used.
Polycystic ovary syndrome (PCOS)
The diagnosis requires at least two of the following features:
• Polycystic ovaries.
• Oligo-ovulation or anovulation.
• Clinical and/or biochemical evidence of androgen excess.
Management of PCOS includes:
• Treatment of infertility. Induction of ovulation can be accomplished in 75–80% of women with PCOS by the use of anti-oestrogens, typically clomifene citrate. More recent data indicate that metformin (see below) may improve ovulation rates in women with PCOS when given alone or in combination with clomifene.
• Menstrual regulation in those who do not desire pregnancy. A low-dose combined oral contraceptive (containing ethinylestradiol, 20–35 micrograms) may be the most convenient form of treatment, although cyclical progestogen is a reasonable alternative. Norgestimate and desogestrel are the preferred progestins, having virtually no androgenic properties.
• Treatment of associated symptoms of hyperandrogenism. Management of hirsutism usually involves cosmetic treatment to remove unwanted hair and, in more severe cases, antiandrogen therapy. The most commonly used antiandrogen is cyproterone acetate. This also has progestogenic activity and can be combined with ethinylestradiol to provide cycle control in addition to management of hyperandrogenic symptoms. Drospirenone (see above) is ideal in PCOS because of its antiandrogen and antimineralocorticoid properties. Spironolactone can be used at high doses, 100–200 mg. Flutamide is a potent non-steroidal antiandrogen that is effective in the treatment of hirsutism. Concern about inducing hepatocellular dysfunction has limited its use.
• Prevention of the possible long-term consequences of the metabolic disturbance characteristic of anovulatory women with PCOS.
Calorie restriction in obese women with PCOS improves insulin sensitivity and glucose tolerance, and leads to resumption of spontaneous ovulatory cycles and normal fertility in many cases. Metformin may be a safe and effective means of improving metabolic profile in both lean and obese women with PCOS.
Contraception by drugs and hormones
The requirements of a successful hormonal contraceptive are stringent, for it will be used by millions of healthy people who wish to separate sexual relations from physical reproduction. The following represent the ideal:
• It must be extremely safe as well as highly effective.
• Its action must be quick in onset and quickly and completely reversible, even after years of continuous use.
• It must not affect libido.
The fact that alternative methods are less reliable implies that their use will lead to more unwanted pregnancies with their attendant inconvenience, morbidity and mortality, and this must be taken into account in deciding what risks of hormonal contraception are acceptable.
Hormonal contraception in women
comprises:
• Oestrogen and progestogen (combined and phased administration).
• Progestogen alone.
Combined contraceptives (the ‘pill’)
Combined oestrogen–progestogen
oral contraceptives (COCP) have been used extensively since 1956. The principal mechanism is inhibition of ovulation through suppression of LH surge by hypothalamus and pituitary. In addition the endometrium is altered, so that implantation is less likely and cervical mucus becomes more viscous and impedes the passage of the spermatozoa.
The combination is conveniently started on the first day of the cycle (first day of menstruation) and continued for 21 days (this is immediately effective, inhibiting the first ovulation). It is followed by a period of 7 days when no pill is taken, and during which bleeding usually occurs. Thereafter, regardless of bleeding, a new 21-day course is begun, and so on, i.e. active tablets are taken daily for 3 weeks out of 4. For easy compliance, some combined pills are packaged so that the woman takes one tablet every day without interruption (21 active then 7 dummy).
In some instances, the course is not started on the first day of menstruation but on the second to the fifth day (to give a full month between the menses at the outset). An alternative method of contraception should then be used until the seventh pill has been taken, as the first ovulation may not have been suppressed in women who have short menstrual cycles.
The pill should be taken at about the same time (to within 12 h) every day to establish a routine. The monthly bleeds that occur 1–2 days after the cessation of active hormone administration are hormone withdrawal bleeds not natural menstruation. They are not an essential feature of oral contraception, but women are accustomed to monthly bleeds and they provide monthly reassurance of the absence of pregnancy.
Numerous field trials have shown that progestogen–oestrogen combinations, if taken precisely as directed, are the most reliable reversible contraceptive known. (The only close competitors are depot progestogens and progestogen-releasing intrauterine devices.)
Important aspects
Subsequent fertility
After stopping the pill, fertility that is normal for the age the woman has now reached is restored, although conception may be delayed for a few months longer in younger, and for as much as a year in older, users than if other methods had been used.
Effect on an existing pregnancy
Although progestogens can masculinise the female fetus, the doses for contraception are so low that risk of harming an undiagnosed pregnancy is extremely small, probably less than 1 in 1000 (the background incidence of birth defects is 1–2%).
Carcinomas
of the breast and cervix are slightly increased in incidence;2 the incidence of hepatoma (very rare) is increased. The risk to life seems to be less than that of moderate smoking (10 cigarettes/day) and than that of a normal pregnancy, as the risks of pulmonary embolus are higher in a normal pregnancy. The risk of carcinoma of the ovary and endometrium is substantially reduced. The overall incidence of cancer is unaltered.
The effect on menstruation
(it is not true menstruation, see above) is generally to regularise it, and often to diminish blood loss, but amenorrhoea can occur. In some women ‘breakthrough’ intermenstrual bleeding occurs, especially at the outset, but this seldom persists for more than a few cycles. Premenstrual tension and dysmenorrhoea are much reduced.
Libido
is greatly subject to psychosocial influences, and removal of fear of pregnancy may permit enthusiasm for the first time. It is likely that direct pharmacological effect (reduction) is rare. There is evidence that the normal increase in female-initiated sexual activity at time of ovulation is suppressed.
Cardiovascular complications
The incidence of venous thromboembolism is increased in pill users. It is lowest in the 20–35-microgram pill and rises progressively with the 50- and 100-microgram preparations; it is not known whether there is any difference between doses of 20 and 35 micrograms. The small increase in hypertension, cerebrovascular events and acute myocardial infarction is confined principally to smokers.
Increased arterial disease also appears to be associated with the type of progestogen in the combined pill. The ‘third-generation’ pills (see below) appear to carry a higher risk of venous thrombosis, but may have a lower risk of arterial thrombosis because their lower androgen activity leads to slightly higher high-density lipoprotein (HDL) levels than older pills. The progestogen-only pill does not significantly affect coagulation.
Major surgery
(in patients taking oestrogen–progestogen contraceptives and post-menopausal hormone replacement therapy). Because of the added risk of venous thromboembolism (surgery causes a fall in antithrombin levels), oral contraceptives should be withdrawn, if practicable, 4 weeks before all lower limb operations or any major elective surgery (and started again at the first menstruation to occur more than 2 weeks after surgery). But increase in clotting factors may persist for many weeks and there is also the risk of pregnancy to be considered. An alternative for emergencies is to use low molecular weight heparin (although this may not reverse all the oestrogenic effects on coagulation) and other means (mechanical stimulation of venous return) to prevent postoperative thrombosis.
Plasma lipoproteins
may be adversely affected; least where the progestogen is desogestrel or low-dose norethisterone.
Plasma proteins
Oestrogens cause an increase in proteins, particularly the globulins that bind hydrocortisone, thyroxine and iron. As a result, the total plasma concentration of the bound substances is increased, although the concentration of free and active substance remains normal. This can be misleading in diagnostic tests, e.g. of thyroid function. This effect on plasma proteins passes off about 6 weeks after cessation of the oestrogen.
Other adverse effects
Often more prominent at the outset and largely due to oestrogen, these include: nausea and, rarely, vomiting; breast discomfort, fluid retention, headache (including increase in migraine), lethargy, abdominal discomfort, vaginal discharge or dryness. Depression may occur but most depression in pill users is not due to the contraceptive.
The above account gives rise to guidelines for use:
Absolute contraindications
include:
• A personal history of thromboembolic venous, arterial or cardiac disease, or severe or multiple risk factors for these.
• Transient cerebral ischaemic attacks without headache.
• Infective hepatitis, until 3 months after liver function test results have become normal, and other liver disease including disturbances of hepatic excretion, e.g. cholestatic jaundice, Dubin–Johnson and Rotor syndromes.
• Migraine, if there is a typical aura, focal features, or if it is severe and lasts for more than 72 h despite treatment, or is treated with an ergot derivative (use with caution is acceptable if there is no aura, focal features, or if it is controlled with a 5-HT1 receptor agonist).
• Carcinoma of the breast or genital tract, past or present.
• Other conditions including: systemic lupus erythematosus, porphyria, following evacuation of a hydatidiform mole (until urine and plasma gonadotrophin concentrations are normal), undiagnosed vaginal bleeding.
Relative contraindications
or uses with caution, include:
• Family history of venous thromboembolism, arterial disease or a known prothrombotic condition, e.g. factor V Leiden (pretreatment coagulation investigation is advised).
• Diabetes mellitus, which may be precipitated or become more difficult to control (avoid if there are diabetic complications).
• Hypertension (avoid if blood pressure exceeds 160/100 mmHg).
• Smoking more than 40 cigarettes per day (15 cigarettes/day enhances the risks of circulatory disease three-fold, and constitutes an absolute contraindication for women over 35 years).
• Age over 35 years (avoid if older than 50 years).
• Obesity (avoid if body mass exceeds 39 kg/m2).
• Long-term immobility, e.g. due to leg plaster, confinement to bed.
• Breast feeding (until weaning or for 6 months after birth).
Duration of use
does not enhance risks of itself. The increase in risk with increased duration of use is due to increasing age. The approaching menopause presents an obvious problem. Cyclical bleeding will continue to occur under the influence of the drugs even after the natural menopause. Thus the only way of deciding whether contraception can be permanently abandoned is by discontinuing it (and using another technique) for 3 months annually to see whether natural menstruation is resumed, or by stopping the combined pill for 1 month and measuring luteinising hormone (LH)/follicle stimulating hormone (FSH) concentration in the blood, which indicates the state of pituitary function.
Benefits additional to contraception
Menses are accompanied by less premenstrual tension and dysmenorrhoea. When oestrogen is combined with the antiandrogen cyproterone acetate as the progestogenic agent Dianette, the combined pill is useful treatment for acne in young women.
Formulations of oestrogen–progestogen combination
Oestrogen:
ethinylestradiol or mestranol.
Progestogen:
• Second generation: norethisterone, levonorgestrel.
• Third generation: desogestrel, gestodene, norgestimate.
Combined oral contraceptives
are defined as second or third generation by the progestogen component (first-generation progestogens are obsolete). Those containing a fixed amount of oestrogen and progestogen in each active tablet are termed ‘monophasic’. Other pills employ variable ratios between oestrogen and progestogen, in two (biphasic) or three (triphasic) periods within the menstrual cycle. The dose of progestogen is low at the beginning and higher at the end, the oestrogen remaining either constant or rising slightly in mid-cycle. The objective is to achieve effective contraception with minimal distortion of natural hormonal rhythms.
The advantages claimed for these techniques are diminished adverse metabolic changes, e.g. blood lipids, and a particularly reliable monthly bleeding pattern without loss of contraceptive efficacy. Preparations include BiNovum, TriNovum, Logynon.
It is now appreciated that the earlier preparations had much more oestrogen than was necessary for efficacy. It seems probable that 20 micrograms is about the limit below which serious loss of efficacy can be expected. Indeed, in patients whose hepatic enzymes are likely to be induced, e.g. those taking antiepileptic or some antirheumatic drugs, it is advisable to use a preparation containing 50 micrograms oestrogen or more to avoid loss of efficacy due to increased oestrogen metabolism (elimination of breakthrough bleeding is a guide to adequacy of dose).
Choice of oestrogen–progestogen combination
There is a wide choice of formulations, with the dose of ethinylestradiol varying from 20 to 35 micrograms. In general, users should be prescribed the lowest total hormone dose that suits them (good cycle control and minimal unwanted effects) and should make a start with the first preparation given above, recognising that compliance is particularly important with the 20-microgram dose.
Common problems
Missed pill
The following refers to the combined pill (see later for the progestogen-only pill):
• If an omitted dose is remembered within 12 h, it should be taken at once and the next dose at the usual time, and all should be well.
• If more than 12 h have elapsed, the above procedure should be followed but an additional barrier method of contraception should be used for 7 days. Although the protective effect of cervical mucus returns within 48 h, this 7-day period is needed to ensure effective suppression of an ovulation that may have been initiated by the missed pill.
Intercurrent gut upset
If vomiting occurs more than 3 h after a pill, behave as for a missed pill (above). The hormones are rapidly absorbed and only severe diarrhoea would interfere significantly with efficacy. In case of doubt, it would be prudent to use a barrier method during and for 7 days after the episode.
Changing of preparation
If a woman is unhappy on one preparation she may be changed to another containing a different dose of oestrogen and/or progestogen. The new preparation should start the day after she has finished a cycle on the previous preparation. If this is done no extra risk of pregnancy occurs.
Breakthrough bleeding
(bleeding on days of active pill taking) can mean that a higher dose of oestrogen or progestogen is required. Note that missed or late pills, drug interaction (see below) or sexually transmitted infection, e.g. due to chlamydia, can also cause breakthrough bleeding.
Progestogen-only contraception
Progestogen-only pills (POPs) are indicated where oestrogen is contraindicated (see above, p. 603) and in lactating women. Progestogens render cervical mucus less easily penetrable by sperm and induce a premature secretory change in the endometrium so that implantation does not occur. Older POPs became unreliable if not taken at the same time of day, because their effect on cervical mucus wears off after 3 h and their additional action to inhibit ovulation occurs in only 40% of cycles. There is also liability to breakthrough bleeding.
A newer POP containing 75 micrograms desogestrel inhibits ovulation in 97–99% of cycles, resulting in an efficacy similar to that of the COCP. A further advantage of the newer POP is that no extra contraceptive cover is required if the exact time of dose is missed, provided the delay is no more than 12 h. Ectopic pregnancy may be more frequent due to a fertilised ovum being held up in a functionally depressed fallopian tube.
Medroxyprogesterone acetate and its metabolites are excreted in breast milk, so women who breast feed should wait until 6 weeks postpartum before starting Depo-Provera, when the infant's enzyme system should be more mature. Norethisterone enantate 200 mg (Noristerat) is shorter-acting than Depo-Provera, 8 weeks, and is used to provide contraception after administration of the rubella vaccine, and until a partner's vasectomy has taken effect. It can also be used in the longer-term but only on a ‘named patient’ basis.
Subdermal implantations that release hormone for several years are in use; they can be removed surgically if adverse effects develop or pregnancy is desired. For example, a flexible rod containing etonorgestrel (Implanon) inserted into the lower surface of the upper arm provides contraception for 3 years (2 years for overweight women because they have lower blood concentrations). The rod must be removed when its effective period has elapsed.
Two depot injections of intramuscular progestogen are available, equal in efficacy to the combined pill. Medroxyprogesterone (Depo-Provera) (t½ 28 h) is a sustained-release (aqueous suspension) deep intramuscular injection given 3-monthly. When injected between day 1 and day 5 of the menstrual cycle, contraception starts immediately. If given after day 5, a barrier contraceptive is needed for 7 days.
Postcoital (‘morning after pill’) and emergency contraception
The overall risk of pregnancy following a single act of unprotected intercourse on any day in the menstrual cycle is 2–4%. The risk from a single act is highest (20–30%) in the days before and just after ovulation. Pregnancy may be prevented before implantation by disrupting the normal hormonal arrangements; the mode of action is probably by delaying or preventing ovulation or by preventing implantation of the fertilised ovum.
Progestogen-only treatment
is preferred. Levonorgestrel 1500 micrograms is taken within 72 h of unprotected sexual intercourse. It can be taken more than once in a cycle, if required, and there is no upper limit to how many times it can be taken in a year. Contraindications to hormonal emergency contraception include current or suspected pregnancy, unprotected sexual intercourse more than 72 h earlier, and sensitivity to the components of the progestogen-only preparation. Some women complain of nausea and vomiting, which responds best to domperidone.
Drug interaction with steroid contraceptives
Particularly now that the lowest effective doses are in use there is little latitude between success and failure if absorption, distribution and metabolism are disturbed. Any additional drug-taking must be looked at critically lest it reduces efficacy.
Enzyme induction
The rifamycins, rifampicin and rifabutin, are potent inducers of hepatic drug-metabolising enyzmes. The classic example of failure with the combined pill is breakthrough bleeding and pregnancy in young women being treated with rifampicin for tuberculosis, or meningitis including eradication of the carrier state. The enhanced metabolism of the steroids results in contraceptive failure.
Antiepileptics (phenytoin and carbamazepine but not sodium valproate) create a similar risk. Indeed, all drugs that induce metabolising enzymes (see p. 93), whether prescribed or self-administered (alcohol, tobacco smoking), constitute a risk to contraceptive efficacy and prescribing should be specifically reviewed for the effect.
Broad-spectrum antimicrobials, e.g. ampicillin, doxycycline, can reduce the efficacy of combined oral contraceptives by diminishing the bacterial flora that metabolise ethinylestradiol in the large bowel and make it available for recycling. Additional contraceptive measures should be taken during a short course of antimicrobial, and for 7 days thereafter. When the course is long, i.e. more than 3 weeks, the bacteria have time to recover by developing resistance, and additional precautions are unnecessary after the first 14 days.
Hypothalamic/pituitary hormone approach to contraception
(See gonadorelin.)
Other methods of contraception
Copper intrauterine devices
are widely used and highly effective (> 99% at 1 year) for 5 years, and some for 10 years. They are especially useful in the over-40s, in whom oral contraceptives may become progressively contraindicated and for whom one IUD will last into the menopause. The IUD prevents implantation of the fertilised ovum, and has an additional antifertilisation effect enhanced by the toxic effect of copper ions on the gametes.
The intrauterine levonorgestrel system
Mirena is used as a contraceptive, as a medical treatment for idiopathic menorrhagia and as the progestogen component of hormone replacement therapy. It is popular because of reduced dysmenorrhoea and lighter menses. Mirena contains 52 mg levonorgestrel surrounded by a Silastic capsule, and releases 20 micrograms/day over 5 years, after which the device should be changed.
Vaginal preparations,
used to immobilise or kill (spermicide) spermatozoa, are used to add safety to various mechanical contraceptives. They are very unreliable and should be used alone only in an emergency. Substances used include non-oxinols (surfactants that alter the permeability of the sperm lipoprotein membrane) as pessary, gel or foam.
Oil-based lubricants
cause failure of rubber condoms and contraceptive diaphragms; many ‘lubricants’, e.g. hand or baby creams, wash off readily, but are nevertheless oil-based. Barrier contraceptive devices made of polyurethane, e.g. the female condom (Femidom), are not so affected.
Risks of contraception in relation to benefit
Despite the small risk of thromboembolism, the death rate from taking oral contraceptives is less than that pregnancy.
Menstrual disorders
Amenorrhoea,
primary or secondary, requires specialist endocrinological diagnosis. Where the cause is failure of hormone production, cyclical replacement therapy is indicated.
Menorrhagia
can be associated with both ovulatory and anovulatory ovarian cycles. It is important to distinguish the menstrual consequences of each cycle. Ovulatory ovarian cycles give rise to regular menstrual cycles, whereas anovulatorycycles result in irregular menstruation or, extremely, amenorrhoea. This distinction is critical in management.
Both ovulatory and anovulatory cycles can give rise to excessive menstrual loss in the absence of any other abnormality, so-called dysfunctional uterine bleeding. Endocrine disorders do not cause excessive menstrual loss, with the exception of the endocrine consequences of anovulation. Equally, haemostatic disorders are rare causes of menorrhagia. One consequence of excessive menstrual loss is iron deficiency anaemia. In the Western world, menorrhagia is the commonest cause of iron deficiency anaemia.
Medical treatment of menorrhagia is either non-hormonal or hormonal therapy. As there is no hormonal defect, the use of hormonal therapy does not correct an underlying disorder but merely imposes an external control of the cycle. For many women, cycle control is as important an issue as the degree of menorrhagia.
The two main first-line treatments for menorrhagia associated with ovulatory cycles are non-hormonal, namely tranexamic acid (an antifibrinolytic) and a non-steroidal anti-inflammatory drug (NSAID), e.g. mefenamic acid500 mg when the blood loss becomes heavy, followed by 250 mg three times daily for 3 days. The effectiveness of these treatments has been shown in randomised trials and reported in systematic reviews of treatment. Tranexamic acid reduces menstrual loss by about a half and NSAIDs reduce it by about a third. Both have the advantage of being taken only during menstruation itself and are particularly useful in women who either do not require contraception or do not wish to use a hormonal therapy. They are also of value in treating excessive menstrual blood loss associated with the use of non-hormonal intrauterine contraceptive devices.
Hormonal therapy should be regarded as a third-choice treatment only in women not requiring contraception as a parallel objective. Progestogens are effective only when given for 21 days in each cycle. Combined oral contraceptives are useful for anovulatory bleeding as they impose a cycle. The levonorgestrel releasing intrauterine system (Mirena) is advocated as an alternative to surgery.
The timing of menstruation
Sometimes there are pressing reasons to prevent menstruation at the normal time but obviously this cannot be done at the last moment.
Menstruation can be postponed by giving oral norethisterone 5 mg three times daily, starting 3 days before the expected onset; bleeding occurs 2–3 days after withdrawal. Users of the combined oral contraceptive pill (having a 7-day break) can simply continue with active pills where they would normally stop for 7 days.
Although there is no evidence that harm follows such manoeuvres, it is obviously imprudent to practise them frequently.
Note. These uses of progestogen should not be undertaken if there is any possibility of pregnancy.
Endometriosis
Medical treatments for endometriosis have focused on the hormonal alteration of the menstrual cycle in an attempt to produce a pseudo-pregnancy, pseudo-menopause or chronic anovulation. Each of these situations is believed to cause a suboptimal milieu for the growth and maintenance of endometrium and, by extension, of implants of endometriosis. Danazol 600–800 mg/day causes anovulation by attenuating the mid-cycle surge of luteinising hormone secretion, inhibiting multiple enzymes in the steroidogenic pathway, and increasing plasma free testosterone concentrations.
Medroxyprogesterone causes the decidualisation of endometrial tissue, with eventual atrophy.
Adverse effects occur at low (20–30 mg/day) or high (100 mg/day) dose, and include abnormal uterine bleeding, nausea, breast tenderness, fluid retention and depression. These resolve after the discontinuation of the drug.
Gestrinone 5–10 mg/week is an antiprogestational steroid that causes a decline in the concentrations of oestrogen and progesterone receptors, and a 50% decline in plasma estradiol concentrations. Androgenic adverse effects, such as a deepening of the voice, hirsutism and clitoral hypertrophy, are potentially irreversible. A combination of an oestrogen and a progestogen induces a hormonal pseudo-pregnancy. The oral contraceptive is used either continuously or cyclically (21 active pills followed by 7 days of placebo). Both regimens are effective; the amenorrhea of continuous administration is advantageous for women with dysmenorrhoea.
Gonadotrophin releasing hormone (GnRH) agonists diminish the secretion of follicle stimulating hormone and luteinising hormone, resulting in hypogonadotrophic hypogonadism, endometrial atrophy and amenorrhoea. The GnRH agonist can be given intranasally, subcutaneously or intramuscularly, with a frequency of administration ranging from twice daily to every 3 months. The unwanted effects are the menopausal-type symptoms of hypo-oestrogenism (such as transient vaginal bleeding, hot flushes, vaginal dryness) and can be prevented by concurrent administration of HRT in post-menopausal doses.
Although most treatments for endometriosis are directed at the hormones themselves, the symptoms can be also treated directly. NSAIDs such as diclofenac, ibuprofen and mefenamic acid are often given to relieve the pain associated with endometriosis. These drugs are frequently the first-line treatment in women with pelvic pain whose cause has not yet been proved to be endometriosis.
Dysmenorrhoea
is due to uterine contractions resulting from excess prostaglandins in the uterus during ovulatory cycles. It can be treated by suppressing ovulation (using the combined pill or norethisterone), or by using inhibitors of prostaglandin synthesis, e.g. aspirin, indometacin, naproxen. The analgesic prostaglandin synthase inhibitor (NSAID) may need to be given for several days before menstruation, or only at the time of the pain.
Premenstrual tension syndrome
may be due to an imbalance of natural oestrogen and progesterone secretion, but knowledge of the syndrome remains imprecise. Psychosocial factors can be important. Placebo effects are strong. Drugs are not necessarily the preferred treatment.
Cyclical breast pain
or mastalgia, when severe, may respond to continuous use of gamolenic acid (Efamast) by mouth; it is an essential unsaturated fatty acid for cell membranes (patients have low concentrations); it may act by reducing cellular uptake of prolactin and ovarian hormones. Danazol and bromocriptine also help.
Myometrium
Oxytocics, i.e. drugs that hasten childbirth, and prostaglandins induce uterine contractions. They are used to induce abortion, to induce or augment labour, and to minimise blood loss from the placental site.
Oxytocics
Oxytocin
is a peptide hormone of the posterior pituitary gland. It stimulates the contractions of the pregnant uterus, which becomes much more sensitive to it at term. Patients with posterior pituitary disease (diabetes insipidus) can go into labour normally.
Oxytocin is released reflexly from the pituitary following suckling (also by manual stimulation of the nipple) and produces an almost immediate contraction of the myoepithelium of the breast; it can be used to enhance milk ejection (nasal spray). The only other clinically important effect is on the blood pressure, which may fall if an overdose is given.
Synthetic oxytocin (Syntocinon) is pure and is not contaminated with vasopressin as is the natural product, which is obsolete.
Oxytocin is used intravenously in the induction of labour and sometimes for uterine inertia, haemorrhage or during abortion. It produces, almost immediately, rhythmic contractions with relaxation between, i.e. it mimics normal uterine activity.
The decision to use oxytocin requires special skill. It has a t½ of 6 min and is given by intravenous infusion using a pump (see below); it must be closely supervised; the dose is adjusted by results; overdose can cause uterine tetany and even rupture. The utmost care is required.
Oxytocin is structurally close to vasopressin and it is no surprise that it also has antidiuretic activity (see p. 454). Serious water intoxication can occur with prolonged intravenous infusions, especially where accompanied by large volumes of fluid. The association of oxytocin with neonatal jaundice appears to be due to increased erythrocyte fragility causing haemolysis.
Oxytocin has been supplanted by the ergot alkaloid, ergometrine, as prime treatment of postpartum haemorrhage.
Ergometrine
is used to contract the uterus. It is an α-adrenoceptor and dopamine receptor agonist and acts almost immediately when injected intravenously. The uterus is stimulated at all times, but is much more sensitive in late pregnancy (see also ergotamine, p. 297).
Ergometrine and oxytocin differ in their actions on the uterus. In moderate doses, oxytocin produces slow generalised contractions with full relaxation in between; ergometrine produces faster contractions superimposed on a tonic contraction. High doses of both substances produce sustained tonic contraction. It will be seen, therefore, that oxytocin is more suited to induction of labour and ergometrine to the prevention and treatment of postpartum haemorrhage, the incidence of which is reduced by its routine prophylactic use (generally intramuscularly).
There are advantages in a mixture of oxytocin and ergometrine (Syntometrine).
Prostaglandins
(For a general account of the prostaglandins see Ch. 16.)
Prostaglandins that soften the uterine cervix (by an action on collagen) and have a powerful oxytocic effect include:
Dinoprost
(prostaglandin F2α; PGF2α) (Prostin F2 alpha) and dinoprostone (prostaglandin E2; PGE2) (Prostin E2). They are used to induce labour and to terminate pregnancy, including missed or partial abortion and in the treatment of hydatidiform mole; they are given by intra- or extra-amniotic injection, by vaginal tablet, or intracervical gel, by intravenous infusion or by mouth. Their safe and effective use (including choice of route) requires special skill.
Adverse effects include vomiting, diarrhoea, headache, pyrexia and local tissue reaction.
Gemeprost
(prostaglandin E1 analogue) (Cervagem) is used intravaginally to soften the cervix before operative procedures in the first trimester of pregnancy and for abortion, alone and in combination with an antiprogestogen (mifepristone, see p. 606).
Carboprost
(prostaglandin F2 analogue) is used for postpartum haemorrhage (resistant to ergometrine and oxytocin) for its oxytocin action. It is highly effective. Adverse effects include hypertension, asthma and pulmonary oedema.
Induction of abortion
Gemeprost, administered vaginally as pessaries, is the preferred prostaglandin for the medical induction of late therapeutic abortion. Gemeprost ripens and softens the cervix before surgical abortion, particularly in primigravida. Misoprostol by mouth or by vaginal administration, or gemeprost, may be given to induce medical abortion (an unlicensed indication in the UK). Pretreatment with mifepristone(see p. 606) can facilitate the process, by sensitising the uterus to the prostaglandin so that abortion occurs in a shorter time and with a lower dose of prostaglandin.
Induction and augmentation of labour
Oxytocin is administered by slow intravenous infusion as below, usually in conjunction with amniotomy, and dinoprostone by vaginal tablets, pessaries and vaginal gels. Misoprostol may be used orally or vaginally to induce labour (an unlicensed indication in the UK).
The UK National Institute for Health and Clinical Excellence has recommended that:
• Dinoprostone is preferable to oxytocin for induction of labour in women with intact membranes, regardless of parity or cervical favourability.
• Dinoprostone and oxytocin are equally effective for the induction of labour in women with ruptured membranes, regardless of parity or cervical favourability.
• Intravaginal dinoprostone preparations are preferable to intracervical preparations.
• Oxytocin should not be started for 6 h following administration of vaginal prostaglandins.
• When used to induce labour, the recommended dose of oxytocin by intravenous infusion is initially 0.001–0.002 units/min, increased at intervals of at least 30 min until a maximum of three to four contractions occurs every 10 min (0.012 units/min is often adequate); the maximum recommended rate is 0.032 units/min (licensed max. 0.02 units/min).
Prevention and treatment of uterine haemorrhage
Bleeding due to incomplete abortion can be controlled with ergometrine and oxytocin (Syntometrine) given intramuscularly. Their combination is more effective in early pregnancy than either drug alone.
For the routine management of the third stage of labour ergometrine 500 micrograms with oxytocin 5 units (Syntometrine 1 mL) is given by intramuscular injection on delivery of the anterior shoulder or, at the latest, immediately after the baby is delivered. In pre-eclampsia, oxytocin may be given alone by intramuscular injection. These regimens are also used for the treatment of postpartum haemorrhage. The same drugs may be given i.v. for excessive uterine bleeding caused by uterine atony. Carboprost is an alternative for haemorrhage unresponsive to ergometrine and oxytocin.
Uterine relaxants
β2-Adrenoceptor agonists relax the uterus and are given by i.v. infusion by obstetricians to inhibit premature labour, e.g. isoxsuprine, terbutaline, ritodrine, salbutamol. Their use is complicated by the expected cardiovascular effects, including tachycardia, hypotension. Less easy to explain, but more devastating on occasion to the patient, is severe left ventricular failure. The combination of fluid overload (due to the vehicle) and increased oxygen demand by the heart are possible factors; the risk is higher in multiple pregnancy, pre-existing cardiac disease or maternal infection. It is important to administer the β2 agonist with minimum fluid volume using a syringe pump with 5% dextrose (not saline) as diluent, and to monitor the patient closely for signs of fluid overload.
The dose of ritodrine for i.v. administration is: initially 50 micrograms/min, increased gradually according to response by 50 micrograms/min every 10 min until contractions stop or maternal heart rate reaches 140 beats per min; continue for 12–48 h after contractions cease (usual rate 150–350 micrograms/min).
Guide to further reading
Amin A. New drugs for hyponatraemia: evidence is lacking that they are better than cheaper standard treatment. Br. Med. J.. 2011;342:559–560.
Banerjee A., Wynne K., Tan T., et al. High dose cabergoline therapy for resistant macroprolactinoma during pregnancy. Clin. Endocrinol. (Oxf.). 2009;70:812–813.
Barrett-Connor E.L., Mosca L., Collins P., et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N. Engl. J. Med.. 2006;355:125–137.
Coombs N.J., Taylor R., Wilcken N., Boyages J. Hormone replacement therapy and breast cancer: estimate of risk. Br. Med. J.. 2005;331:347–349.
Jayasena C.N., Wujanto C., Donaldson M., et al. Measurement of basal growth hormone (GH) is a useful test of disease activity in treated acromegalic patients. Clin. Endocrinol. (Oxf).. 2008;68:36–41.
Martin N.M., Dhillo W.S., Banerjee A., et al. Comparison of the dexamethasone-suppressed corticotropin-releasing hormone test and low-dose dexamethasone suppression test in the diagnosis of Cushing's syndrome. J. Clin. Endocrinol. Metab.. 2006;91:2582–2586.
Martin N.M., Tan T., Meeran K. Dopamine agonists and hyperprolactinaemia. Br. Med. J.. 2009;338:b381.
Melmed S. Medical progress: acromegaly. N. Engl. J. Med.. 2006;355:2558–2573.
Peterson H.B., Curtis K.M. Long-acting methods of contraception. N. Engl. J. Med.. 2005;353:2169–2175.
1 An inherited condition that gives rise to obesity, decreased muscle tone, poor large muscle strength, decreased mental capacity, and sex glands that produce few or no hormones.
2 A meta-analysis of 54 studies concluded that use of the COCP was associated with a relative risk of 1.24, which disappears over 10 years after stopping the COCP. A higher relative risk in women who started taking the COCP at a young age is explained by the lower background rate and there is little added effect from long-term COCP ingestion. (Collaborative Group on Hormonal Factors in Breast Cancer. Lancet 1996; 347:1713–1727).