Fig. 43.1 Control mechanisms for the release of growth hormone, gonadotropins and prolactin from the anterior pituitary.
For control of other hormones, see Ch. 41 (thyroid) and Ch. 44 (adrenocorticotropic hormones). Oestrogen effects on gonadotropin-releasing hormone (GnRH) are shown as both positive and negative because oestrogen suppresses luteinizing hormone (LH) secretion in the early follicular phase but enhances secretion around ovulation (Ch. 45). The actions of drugs are shown by red arrows. Gonadorelin is a synthetic GnRH and buserelin and goserelin are GnRH analogues. Pulsatile administration of GnRH or its analogues enhances LH/follicle-stimulating hormone (FSH). On continuous administration, they downregulate the GnRH receptors, inhibiting LH/FSH release, an effect produced more rapidly by GnRH antagonists (cetrorelix, ganirelix). Somatropin is synthetic growth hormone, and octreotide and lanreotide are somatostatin analogues that suppress growth hormone release. For details of dopamine (DA) agonists, see Ch. 24. GHRH, growth hormone-releasing hormone; HMG, human menopausal gonadotropins (menotrophin); HCG, human chorionic gonadotropin; IGF-1 insulin-like growth factor 1; SST, somatostatin (also called GHRIH, growth hormone release-inhibiting hormone); ? = regulating hormone not yet established. Note: dopamine stimulates growth hormone release in healthy individuals, but paradoxically in acromegaly it inhibits release.
GH is released in pulses repeatedly throughout the day and night. Like other peptide hormones, GH binds to cell surface receptors and activates adenylyl cyclase, and has direct metabolic effects on several tissues. In addition it produces other effects via the production of insulin-like growth factor 1 (IGF-1, a somatomedin). IGF-1 is synthesised by the liver in response to GH stimulation, and is highly protein bound in plasma.
The effects of GH are anabolic in relation to protein metabolism, especially in skeletal muscle leading to increased muscle mass, and in epiphyseal cartilage, where the proliferating effects stimulate bone growth. These actions are mediated by IGF-1. IGF-1 also has effects on the liver via the insulin receptor, and promotes hepatic gluconeogenesis. However, GH has an opposing direct effect on carbohydrate metabolism, reducing glucose uptake by skeletal muscle and adipose tissue, creating an insulin-resistant state (Box 43.1).
Box 43.1 Effects of growth hormone
Anabolic effects on protein synthesis in muscle
Increases bone growth, mineralisation and Ca2+ retention
Stimulates growth of most internal organs
Reduces liver uptake of glucose and promotes gluconeogenesis
The effect of GH on fat is catabolic, with a direct action on adipocytes that promotes lipolysis and reduces lipogenesis.
Growth hormone for therapeutic use
Somatropin has several therapeutic uses in children, which include:
to improve linear growth in children with proven GH deficiency (who usually lack GHRH; pituitary dwarfism),
To be effective, the hormone must be given before the closure of the epiphyses in long bones. Treatment should be stopped if growth velocity does not increase by at least 50% from baseline.
Adult GH deficiency may warrant treatment with somatropin if all the following criteria are fulfilled:
Pharmacokinetics: Somatropin is usually given by subcutaneous injection, although the intramuscular route can be used. Plasma concentrations fluctuate widely following both routes, although the latter gives more stable levels because of slower uptake into the circulation. Somatropin has a very short half-life (0.5 h), but the plasma concentration of IGF-1 is much more constant due to its high protein binding. As a consequence, three doses of somatropin per week give good clinical results, although daily dosing is often used.
Acromegaly
Acromegaly results from excessive production of GH, almost always by an adenoma in the anterior pituitary which also secretes prolactin in one-third of cases (Fig. 43.1). The most common clinical features arise from excessive growth of bone and soft tissue. Complex metabolic consequences include insulin resistance with diabetes mellitus and hypertension.
The morbidity and mortality of acromegaly vary according to its severity. Untreated acromegalic individuals have a life expectancy approximately half that of people without acromegaly, due to an excess incidence of cardiovascular and respiratory disease and of carcinoma of the colon. Acromegaly is therefore usually treated actively.
Drugs for acromegaly
Mechanisms of action and uses: The synthetic derivatives of SST are both more potent and longer-acting inhibitors of GH secretion than the native compound. They are selective for the SST receptor subtypes that are highly expressed on GH-secreting adenomas. Like SST, they also inhibit the release of gastro-entero-pancreatic peptide hormones, such as insulin, glucagon, cholecystokinin, gastrin and vasoactive intestinal peptide (VIP), via intestinal SST receptors, which generate intracellular cAMP and modulate Ca2+ influx into the cell. These actions make SST analogues useful also for the treatment of a variety of conditions associated with excess secretion of gut hormones.
Uses of SST analogues include:
management of other endocrine tumours, for example carcinoid tumours (to reduce flushing and diarrhoea), VIPoma (to reduce diarrhoea) and glucagonoma (to improve the characteristic necrolytic rash),
management of medullary thyroid tumours (lanreotide) and prevention of complications following pancreatic surgery (octreotide),
Pharmacokinetics: Octreotide is given by subcutaneous injection. It has a short half-life (1–2 h) but suppresses GH secretion for up to 8 h so it is used three times daily. A depot preparation is available in which octreotide is adsorbed onto microspheres; given by deep intramuscular injection it has a duration of action of about 4 weeks. The depot is used once control has been achieved by the use of the conventional formulation. Lanreotide also has a short half-life (1–2 h) and is formulated as a sustained-release preparation given by subcutaneous or intramuscular injection every 1–4 weeks.
Gastrointestinal upset is common, especially anorexia, nausea, vomiting, abdominal pain, bloating and diarrhoea. It usually resolves with continued treatment.
Gallstones, due to suppression of cholecystokinin secretion with decreased gallbladder motility. In addition, an increase in bowel transit time alters colonic flora and makes bile salts more lithogenic.
Growth hormone receptor antagonist:
Mechanism of action: Pegvisomant is a pegylated synthetic analogue of GH that acts as a highly selective GH receptor antagonist.
Pharmacokinetics: Pegvisomant is given by subcutaneous injection. The mechanism of its clearance is unknown; the half-life is very long (6 days).
Dopamine receptor agonists: In healthy people, dopaminergic receptor stimulation increases the secretion of GH, but in acromegaly there is a paradoxical decrease. Bromocriptine was originally used to treat acromegaly, but the clinical response was unpredictable and control of plasma IGF-1 was achieved in only about 20% of cases. It has been superseded by better-tolerated drugs such as cabergoline, which adequately suppress IGF-1 concentrations in about 40% of people with acromegaly. Further details of these drugs can be found in Ch. 24.
Treatment of acromegaly
Surgery by the trans-sphenoidal route is the usual treatment of choice, sometimes followed by external radiotherapy if the tumour is large.
Three groups may be suitable for drug treatment:
those in whom an excess of GH persists despite surgery and radiotherapy; after radiotherapy the plasma GH concentration can take 1–2 years to fall,
SST analogues are the first-line treatment, with pegvisomant used when there is intolerance or failure to respond. Cabergoline is sometimes used with a SST analogue when there is resistance to other treatments. The effectiveness of treatment is monitored by the plasma concentration of IGF-1.
Adrenocorticotropic hormone
Adrenocorticotropic hormone (ACTH; corticotropin) is a single-chain polypeptide with 39 amino acids, of which the 24 that form the N-terminal region are essential for full biological activity. It promotes steroidogenesis in adrenocortical cells by occupying cell surface receptors and stimulating adenylyl cyclase. Release of ACTH occurs in response to the hypothalamic peptide corticotropin-releasing hormone (CRH). CRH secretion is pulsatile and has a diurnal rhythm, with maximal release in the morning around the time of waking (see further detail in Ch. 44). The release of CRH is affected by other factors, including chemical (e.g. antidiuretic hormone, opioid peptides), physical (e.g. heat, cold, injury) and psychological influences. The main inhibitory influence on ACTH release is negative feedback control by circulating glucocorticoids. This occurs at both hypothalamic and pituitary levels. Adrenal androgens, although stimulated by ACTH, play no part in feedback control.
ACTH for therapeutic use
ACTH preparations of animal origin have been replaced by a less allergenic synthetic peptide analogue, tetracosactide, which consists of the active N-terminal amino acids 1–24 of the ACTH molecule.
Pharmacokinetics: There are two formulations of tetracosactide:
a rapid-acting form that increases steroidogenesis for about an hour and is suitable for tests of adrenocortical function. In adrenal insufficiency there is a subnormal or no rise of plasma cortisol 30 min after intramuscular or intravenous injection of tetracosactide,
Once absorbed into the circulation, tetracosactide is metabolised rapidly with a very short half-life (0.2 h).
Prolactin
Prolactin is a glycoprotein similar in structure to GH but secreted by distinct cells in the anterior pituitary (Fig. 43.1). The major hypothalamic control mechanism is inhibition by dopamine via D2 receptors on the prolactin-secreting cells of the anterior pituitary (Ch. 45). Thyrotropin-releasing hormone (or TRH) is involved in stimulating prolactin release, and oestrogen increases prolactin production. The main target tissue for prolactin is the breast, which secretes milk in response to prolactin if the mammary glands have been primed by ovarian and other hormones. At delivery, the maternal plasma prolactin concentration is high. Release of further prolactin continues as long as suckling continues. A high plasma concentration of prolactin suppresses follicle-stimulating hormone (FSH) release from the pituitary and leads to a failure of ovarian follicle growth. This may explain the relative subfertility of women who are breastfeeding.
Prolactin has other functions, including producing sexual gratification after intercourse and contributing to maturation of the fetal lung and proliferation of oligodendrocytes that form the neural myelin sheath.
Hyperprolactinaemia
Persistent hyperprolactinaemia is usually caused by a microadenoma of the anterior pituitary or by the action of dopamine receptor antagonist drugs such as phenothiazines (Ch. 21). In younger women hyperprolactinaemia can produce amenorrhoea, infertility and signs and symptoms of oestrogen deficiency (e.g. vaginal dryness and dyspareunia, galactorrhoea and osteoporosis). In men it may cause hypogonadism. Withdrawal of a provoking drug should be considered. For a microadenoma, a dopamine D2 receptor agonist such as cabergoline (Ch. 24) can be used to suppress prolactin secretion. Pituitary surgery may be considered for treatment failure.
Gonadotropin-releasing hormone
Gonadotropin-releasing hormone (GnRH) is a decapeptide that is synthesised in the hypothalamus and is transported by neuronal axons to the pituitary. It is then released in pulses into the capillaries of the pituitary-portal circulation and positively controls the synthesis and release of both luteinizing hormone (LH) and FSH from the anterior pituitary (Fig. 43.1). The cell surface receptors for GnRH are G-protein-linked and are found widely in the body, although their role is poorly understood, as well as on the gonadotropic cells in the anterior pituitary. These receptors are upregulated by repeated stimulation with GnRH, but pulsatile exposure is essential to maintain responsiveness. Low-frequency pulses stimulate FSH release, and high-frequency pulses stimulate LH release. In males, pulse frequency remains constant, whereas in females it varies through the menstrual cycle with a surge just before ovulation (see Ch. 45).
There is rapid tolerance to constant-rate infusions of GnRH because of downregulation of cell surface receptors. Therapeutic administration of GnRH can mimic pulsatile stimulation or produce receptor downregulation, and these have different clinical uses, as described below. There is negative feedback control of GnRH release via neural pathways and sex steroids (Fig. 43.1).
GnRH-related products for therapeutic use
Synthetic GnRH (gonadorelin): Synthetic GnRH is available for assessing hypothalamic-pituitary function and is given as a subcutaneous or intravenous injection. Unwanted effects are unusual, but include nausea, headaches and abdominal pain.
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