Table 2-46. Causes of vaginal discharge

Infective	Non-infective
Candida albicans	Cervical polyps
Trichomonas vaginalis	Neoplasms
Bacterial vaginosis	Retained products (e.g. tampons)
Neisseria gonorrhoeae	Chemical irritation
Chlamydia trachomatis
Herpes simplex

Table 2-47. Causes of urethral discharge

Infective	Non-infective
Neisseria gonorrhoeae	Physical or chemical trauma
Chlamydia trachomatis	Urethral stricture
Mycoplasma genitilium	Non-specific (aetiology unknown)
Ureaplasma urealyticum
Trichomonas vaginalis
Herpes simplex virus
Human papillomavirus (meatal warts)
Urinary tract infection (rare)
Treponema pallidum (meatal chancre)

Table 2-48. Causes of genital ulceration

Infective	Non-infective
Syphilis:
Primary chancre	Behçet’s syndrome
Secondary mucous patches	Toxic epidermal necrolysis
Tertiary gumma	Stevens-Johnson syndrome
Chancroid
Lymphogranuloma venereum	Carcinoma
Donovanosis	Trauma
Herpes simplex:
Primary
Recurrent
Herpes zoster

HORMONAL ACTIVITY

Hormones are chemical messengers produced by a variety of specialized secretory cells. They may be transported in the blood to a distant site of action (the classic ‘endocrine’ effect) or act directly upon nearby cells (’paracrine’ activity). In the hypothalamus, elsewhere in the brain and in the gastrointestinal tract there are many such cells secreting hormones, some of which have true endocrine or paracrine activity, while others behave more like neurotransmitters or neuromodulators. At the molecular level there is little difference in the way cellular activity is regulated between classical neurotransmitters that act across synaptic clefts, intercellular factors acting across gap junctions, classic endocrine and paracrine activity and a variety of other chemical messengers involved in cell regulation – such as cytokines, growth factors and interleukins; progress in basic cell biology has revealed the biochemical similarities in the messengers, receptors and intracellular post-receptor mechanisms underlying all these aspects of cell function.

Synthesis, storage and release of hormones

Hormones may be of several chemical structures: polypeptide, glycoprotein, steroid or amine. Hormone release is the end-product of a long cascade of intracellular events. In the case of polypeptide hormones, neural or endocrine stimulation of the cell leads to increased transcription from DNA to a specific mRNA, which is in turn translated to the peptide product. This is often in the form of a precursor molecule that may itself be biologically inactive. This ‘prohormone’ may be further processed before being packaged into granules, in the Golgi apparatus. These granules are then transported to the plasma membrane before release, which is itself regulated by a complex combination of intracellular regulators. Hormone release may be in a brief spurt caused by the sudden stimulation of granules, often induced by an intracellular Ca2+-dependent process, or it may be ‘constitutive’ (immediate and continuous secretion).

Plasma transport

Most classical hormones are secreted into the systemic circulation where they travel to have effects elsewhere in the body. In contrast, hypothalamic releasing hormones are released into the pituitary portal system so that much higher concentrations of the releasing hormones reach the pituitary than occur in the systemic circulation.

Many hormones are bound to proteins within the circulation. In most cases, only the free (unbound) hormone is available to the tissues and thus biologically active. This binding serves to buffer against very rapid changes in plasma levels of the hormone, and some binding protein interactions may also be involved in the active regulation of hormone action. Many tests of endocrine function often measure total rather than free hormone, since binding proteins are frequently altered in disease states. Binding proteins comprise both specific, high-affinity proteins of limited capacity, such as thyroxine-binding globulin (TBG) and other less-specific low-affinity ones, such as prealbumin and albumin. The clinically relevant binding proteins are shown in Table 18.1.

Hormone action and receptors

Hormones act by binding to specific receptors in the target cell, which may be at the cell surface and/or within the cell. Most hormone receptors are proteins with complex tertiary structures, parts of which complement the tertiary structure of the hormone to allow highly specific interactions, while other parts are responsible for the effects of the activated receptor within the cell. Many hormones bind to specific cell-surface receptors where they trigger internal messengers, while others bind to nuclear receptors which interact directly with DNA. Cell-surface receptors usually contain hydrophobic sections which span the lipid-rich plasma membrane, while nuclear receptors contain characteristic amino-acid sequences to bind nuclear DNA (e.g. so-called ‘zinc fingers’, see p. 167) as in the glucocorticoid receptor.

In order to achieve their intracellular effects, hormone receptors interact with a variety of other regulatory factors within the cell membrane, in the cytosol or within the nucleus of the cell. In each case, binding of the hormone to its receptor results in a conformational change in the structure of the receptor, which may result in a number of possible outcomes which are illustrated in

- activation of, or modified binding to, other regulatory factors within the cell membrane or cytosol (e.g. binding of transmembrane receptors to the cell-membrane G-proteins, thereby activating the stimulatory or inhibitory effects of the latter on other intracellular mediators)
- activation of enzyme activity in the receptor or its regulatory factors (e.g. receptor adenylate cyclase, other protein kinases, phospholipase C) to generate a variety of intracellular ’second messengers’ (e.g. cAMP, cGMP, phosphatidylinositol metabolites, calmodulin) which usually form a complex, branching and interacting intracellular cascade of enzyme activation and inhibition and/or mobilization of intracellular stores of ions (primarily calcium)
- altered binding of the receptor to DNA or to nuclear transcription factors in order to stimulate or inhibit transcription of one or more genes
- altered activity of cell-membrane channels or transporters (e.g. for glucose, potassium or for other ions)
- dimerization of the receptor, or internalization of some cell-surface receptors.

These immediate effects of hormone binding may then cause rapid alterations in cell-membrane ion transport or intracellular calcium concentrations, or slower responses such as DNA, RNA and protein synthesis.
In each case, binding of the hormone to its receptor is the first step in a complex cascade of interrelated intracellular events which eventually lead to the overall effects of that hormone on cellular function.

Common ’second messengers’ involved in these cascades include cyclic AMP (for adrenocorticotrophic hormone (ACTH), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and parathyroid hormone (PTH)), a calcium-phospholipid system (for thyrotrophin-releasing hormone (TRH), vasopressin and angiotensin II), tyrosine kinase and other intracellular kinases (for insulin and insulin-like growth factor-1 (IGF-1)) and membrane-bound phosphoinositide pathways.

The sensitivity and/or number of receptors for a hormone are often decreased after prolonged exposure to a high hormone concentration, the receptors thus becoming less sensitive (’downregulation’, e.g. angiotensin II receptors, β-adrenoceptors). The reverse is true when stimulation is absent or minimal, the receptors showing increased numbers or sensitivity (’upregulation’).
Abnormal receptors are an occasional, though rare, cause of endocrine disease (see p. 1041), but are recognized and characterized more frequently owing to advances in molecular endocrinology.
Control and feedback

Most hormone systems are controlled by some form of feedback; an example is the hypothalamic-pituitary-thyroid axis (Fig. 18.1).
TRH (thyrotrophin-releasing hormone) is secreted in the hypothalamus and travels via the portal system to the pituitary where it stimulates the thyrotrophs to produce thyroid-stimulating hormone (TSH).
TSH is secreted into the systemic circulation where it stimulates increased thyroidal iodine uptake and thyroxine (T4) and triiodothyronine (T3) synthesis and release.

Serum levels of T3 and T4 are thus increased by TSH; in addition, the conversion of T4 to T3 (the more active hormone) in peripheral tissues is stimulated by TSH.

T3 and T4 then enter cells where they bind to nuclear receptors and promote increased metabolic and cellular activity.
Levels of T3 (from the blood and from local conversion of T4) are sensed by receptors in the pituitary and possibly the hypothalamus. If they rise above normal, TRH and TSH production is suppressed, leading to reduced T3 and T4 secretion.
Peripheral T3 and T4 levels thus fall to normal.

If, however, T3 and T4 levels are low (e.g. after thyroidectomy), increased amounts of TRH and thus TSH are secreted, stimulating the remaining thyroid to produce more T3 and T4; blood levels of T3 and T4 may be restored to normal, although at the expense of increased TSH drive, reflected by a high TSH level (’compensated euthyroidism’). Conversely, in thyrotoxicosis when factors other than TSH itself are maintaining high T3 and T4 levels, the same mechanisms lead to suppression of TSH secretion.
This is known as a ‘negative feedback’ system, referring to the effect of T3 and T4 on the pituitary and hypothalamus, which represents the most common mechanism for regulation of circulating hormone levels. There are also ‘positive feedback’ systems, classically seen in the regulation of the normal menstrual cycle (p. 1050).

Patterns of secretion

Hormone secretion is continuous or intermittent. The former is shown by the thyroid hormones, where T4 has a half-life of 7-10 days and T3 of about 6-10 hours. Levels over the day, month and year show little variation.
In contrast, secretion of the gonadotrophins, LH and FSH, is normally pulsatile, with major pulses released every 1-2 hours depending on the phase of the menstrual cycle. Continuous infusion of LH to produce a steady equivalent level does not produce the same result (e.g. ovulation in the female) as the intermittent pulsatility, and may indeed produce downregulation. Thus a long-acting superactive gonadotrophin-releasing hormone (GnRH) analogue, such as buserelin, produces downregulation of the GnRH receptors and subsequent very low androgen or oestrogen levels, which are clinically valuable both in carcinoma of the prostate in men and in ovulation-induction regimens in infertile women. In contrast, pulsatile GnRH administration can produce normal menstrual cyclicity, ovulation and fertility in women with hypothalamic amenorrhoea but intact pituitary LH and FSH stores.

Circadian means changes over the 24 hours of the day-night cycle and is best shown for the pituitary-adrenal axis. Figure 18.2 shows plasma cortisol levels measured over 24 hours – levels are highest in the early morning and lowest overnight. Additionally, cortisol release is pulsatile, following the pulsatility of pituitary ACTH. Thus ‘normal’ cortisol levels vary during the day and great variations can be seen in samples taken only 30 minutes apart (Fig. 18.2). The circadian (light-dark) rhythm is seen in reverse with the pineal hormone, melatonin, which shows high levels during dark. Melatonin may be involved in entraining other hormonal rhythms and systems to the current light-dark cycle, but there is no known clinical syndrome related to abnormalities of this hormone, though a synthetic preparation is widely used for ‘jet-lag’ (p. 1033).

Other regulatory factors

Stress. Physiological ’stress’ and acute illness produce rapid increases in ACTH and cortisol, growth hormone (GH), prolactin, epinephrine (adrenaline) and norepinephrine (noradrenaline). These can occur within seconds or minutes.
Sleep. Secretion of GH and prolactin is increased during sleep, especially the rapid eye movement (REM) phase.
Feeding and fasting. Many hormones regulate the body’s control of energy intake and expenditure and are therefore profoundly influenced by feeding and fasting. Thus, secretion of insulin is increased and growth hormone decreased after ingestion of food, and secretion of a number of hormones is altered during prolonged food deprivation.

All these factors must be considered when attempting to measure hormone levels in normal individuals and in patients with disease. For example, cortisol levels will often be high and fail to suppress during standard tests in a patient who is severely stressed by serious illness, and growth hormone will usually be low in postprandial individuals during the daytime.