Category Archives: Endocrinology.

An introduction to endocrine disease

EPIDEMIOLOGY

The commonest endocrine disorders, excluding diabetes mellitus , are:
THYROID DISORDERS, affecting four to eight new patients per primary care physician per year. Most common problems are thyrotoxicosis, primary hypothyroidism and goitre.
SUBFERTILITY, affecting 5-10% of all couples, often with an endocrine component, and increasingly treatable.
MENSTRUAL DISORDERS AND EXCESSIVE HAIR GROWTH IN YOUNG WOMEN, particularly polycystic ovary syndrome.

OSTEOPOROSIS, especially in postmenopausal women, is of increasing importance in fracture of the femur and premature death and disability.
PRIMARY HYPERPARATHYROIDISM, affecting about 0.1% of the population.
CHILDREN WITH SHORT STATURE OR DELAYED PUBERTY.
While most other endocrine conditions are very uncommon, they often affect young people and are usually curable or completely controllable with appropriate therapy. Hormones are also widely used therapeutically:
ORAL CONTRACEPTIVE PILL, the choice of perhaps 25-30% of women aged 18-35 years using contraception.

HORMONE REPLACEMENT

(oestrogens ± progestogens) women.
CORTICOSTEROID THERAPY is widely used in nonendocrine disease such as asthma.

Body size and shape

Short stature
Tall stature
Excessiveweight or weight gain
loss of weight
‘Metabolic’ effects
Tiredness
Weakness
Increased appetite
Decreased appetite
Polydipsialthirst
Polyuria/nocturia
Tremor
Palpitation
Anxiety
Local effects
Swelling in the neck
Carpal tunnel syndrome
Bone or muscle pain
Protrusion of eyes
Visual loss (acuity and/or fields)
Headache

Reproduction/sex

Lossor absence of libido
Impotence
Oligomenorrhoea/amenorrhoea
Subfertility
Galactorrhoea
Gynaecomastia
Delayed puberty
Precocious puberty
Skin
Hirsuties
Hair thinning
Pigmentation
Dry skin
Excesssweating

SYMPTOMS

Common endocrine presenting symptoms , which demonstrates the many effects that hormonal abnormalities can produce. Hormones produce widespread effects upon the body; focal symptoms are less common than with other systems. Many endocrine symptoms are diffuse and vague, and the differential diagnosis is often wide.

HISTORY AND EXAMINATION

A detailed history including the past, family and social history should be taken. Physical signs are listed under the relevant systems. A full drug history is mandatory as endocrine problems are quite often iatrogenic. Specific points about endocrine disease As with other systems, endocrine diseases may be congenital or acquired and can be caused by a variety of pathologies. However, several forms of illness are commoner than in other systems.

Autoimmune disease

Organ-specific autoimmune diseases have now been shown for every major endocrine organ.

They are characterized by the presence of specific antibodies in the serum, often present years before clinical symptoms are evident. The conditions are usually commoner in women and have a strong genetic component, often with an identical-twin concordance rate of 50% and with HLA associations (see individual diseases). Several of the autoantigens have now been identified

Past history

Necessarydetails may include:
Previous pregnancies (ease of conception, postpartum haemorrhage).
Relevant surgery (e.g. thyroidectomy, orchidopexy) Radiation (e.g. to neck, gonads, thyroid) Drug exposure (e.g. chemotherapy, sex hormones, oral contraceptives).
In childhood, developmental milestones and growth Family history Family history of:
Autoimmune disease
Endocrine disease
Essential hypertension
Diabetes
Family details of:
Height
Weight
Body habitus
Hair growth
Age of sexual development

SocIal history

Detailed records of alcohol intake (e.g. in subfertility, obesity) Drug abuse (e.g. cannabis and subfertility) Full details of occupation, e.g. accessto drugs, chemicals Diet. e.g. salt. liquorice, iodine.

Drugs and endocrine disease.

Drugs and endocrine disease.

Endocrine tumours

Hormone-secreting tumours occur in all endocrine organs, most commonly pituitary, thyroid and parathyroid. Fortunately, they are more commonly benign than malignant. While often considered to be ‘autonomous’, that is independent of the physiological control mechanisms, many do show evidence of feedback occurring at a higher ‘set-point’ than normal (e.g. ACTH secretion from a pituitary basophil adenoma).

The molecular basis of some of these tumours is now understood, e.g. an abnormal G protein in prolactinomas and abnormalities on chromosome 11 in multiple endocrine neoplasia (MEN) type 1 tumours and on chromosome 10 in MEN type 2A.

Types of autoimmune disease

Types of autoimmune disease

Enzymatic defects

The biosynthesis of most hormones involves many stages. Deficient or abnormal enzymes can lead to absent or reduced production of the terminal hormone. In general, severe deficiencies present early in life with obvious signs; partial deficiencies usually present later with mild signs or are only evident under stress. An example of an enzyme deficiency is congenital adrenal hyperplasia (CAH). Again the molecular basis is now known for several abnormalities, particularly for CAH where the coding gene is on the short arm of chromosome 6, and affected patients have defects such as point mutations or deletions.

Receptor abnormalities

Hormones work by activating cellular receptors. There are rare conditions in which hormone secretion and control are normal but the receptors are defective: thus, if androgen receptors are defective, normal levels of androgen will not produce masculinization (e.g. testicular feminization). There are also a number of rare syndromes of diabetes and insulin resistance from receptor abnormalities other examples include nephrogenic diabetes insipidus and pseudohypoparathyroidism.

Biological rhythms

The most important rhythms are circadian and menstrual.
Circadian changes mean changes over the 24 hours of the day-night cycle and is best shown for the glucocorticoid cortisol axis. 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 (stippled areas) vary during the day and great variations can be seen in samples take only 30 min apart. The circadian (lightdark) rhythm is seen in reverse with the pineal hormone, melatonin, which shows high levels during dark, though there is no clear clinical role for this.
The menstrual cycle is the best example of a longer (28-day) biological rhythm.

Plasma cortisol levels during a 24-hour period.

Plasma cortisol levels during a 24-hour period.

Other regulatory factors

STRESS. Though difficult to define, stress can produce rapid increases in ACTH and cortisol, growth hormone (GH), prolactin, adrenaline and 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.

Testing endocrine function

Ideally, cellular levels of hormones would be measured, but this is currently impossible. Body fluids are the normal substitute and are usually an excellent approximation, but it must be remembered that they do not always reflect the current tissue action of the relevant hormone.

Blood levels

Assays for all important hormones are now available. Obviously the time, day and condition of measurement may make great differences to hormone levels. The method and timing of samples will depend upon the characteristics of the endocrine system involved. BASAL LEVELS are especially useful for systems with long half-lives, e.g. T. and T3• These vary little over the short term and random samples are therefore satisfactory. BASAL SAMPLES may also be satisfactory if interpreted with respect to normal ranges for the time of day/month, diet or posture concerned. Examples are FSH, oestrogen and progesterone and aldosterone. All relevant details must be recorded or the data may prove uninterpretable.
STRESS-RELATED HORMONES (e.g. catecholamines, prolactin, GH, ACTH and cortisol) may require samples to be taken via an indwelling needle some time after venepuncture; otherwise, high levels may be artefactual.

Urine collections

24-Hour collections have the advantage of providing an ‘integrated mean’ of a day’s secretion but are often incomplete or wrongly timed. They also vary with sex and body size or age. Written instructions should be provided. Saliva is sometimes used for steroid estimations, especially in children.

Stimulation and suppression tests

These are valuable in instances of hormone deficiency or excess:
WHERE SECRETORY CAPACITY OF A GLAND IS DAMAGED, maximal stimulation by the trophic hormone will give a diminished output. Thus, in the Synacthen (SYNthetic-ACTH-en) test for adrenal reserve, subject A shows a normal response (stippled area); subject B with primary hypoadrenalism (Addison’s disease) demonstrates an impaired cortisol response to ACTH.
A PATIENT WITH A HORMONE-PRODUCING TUMOUR usually fails to show normal negative feedback. A patient with Cushing’s disease (excess pituitary ACTH) will thus fail to suppress ACTH and cortisol production when given a dose of synthetic steroid, as would normal subjects. the response of a normal subject (A) given 1 mg dexamethasone at midnight; cortisol is suppressed the following morning. Subject B with Cushing’s disease shows inadequate suppression.
The detailed protocol for each test must be followed exactly, since even slight differences in technique will produce variations in results. Details of commoner tests are given in the Appendix.

a) Short ACTH stimulation test showing a normal response

a) Short ACTH stimulation test showing a normal
response

Measurement of hormone concentrations

Circulating levels of most hormones are very low (10-‘_ 10-12 mol litre:”) and cannot be measured by simple chemical techniques. Radioimmunoassay (RIA), previously by far the most common technique in endocrine assays, is being rapidly supplanted by immunoradiometric type assays (IRMA). These are increasingly being automated and using non-radioactive end-points such as colorimetric. Other techniques include high pressure liquid chromatography (HPLC). RIA has limitations; in particular the immunological activity of a hormone, as used in developing the antibody, may not necessarily correspond to biological activity, and the increasing stringency of Health and Safety requirementshas led to a search for methods not involving  radioactivity.
RIA is, however, widely being replaced by IRMAs. These rely on highly specific antibodies (usually monoclonal) that are themselves labelled rather than labelling the hormone concerned. Usually employing a solid-phase system, the principles are otherwise similar to those of RIA, requiring incubation and separation of bound and free fractions, except that the ‘signal’ is obviously proportional to the amount of substance present (i.e. this is a saturation analysis). The label need not be a radioactive label, but may involve a fiuorimetric, colorimetric, chemiluminescent or enzymatic end-point.

Hormone action and receptors

Hormones act at the cell surface and/or within the cell. Many hormones bind to specific cell-surface receptors where they trigger internal messengers. Cell surface receptors are a family of ‘G proteins’ which bind the hormone on the cell surface and then activate socalled ‘second messengers’ via GTP. The second messengers 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, and  tyrosine kinase for insulin and insulin-like growth factor- 1 (IGF-l). These then cause rapid alterations in cellmembrane ion transport or slower responses such as DNA, RNA and protein synthesis. Some hormones act by activation of the membrane-bound phosphoinositide pathways.
Others, especially steroids, enter most cells of the body where they act on intracellular protein receptors, often altering the activity of intracellular enzymes by phosphorylation or dephosphorylation.
Steroid hormone-receptor complexes are usually transported into the nucleus, where they interact with D A to regulate gene transcription, and thus protein synthesis. The characteristics of different hormone systems.
The sensitivity and/or number of receptors for a hormone is often decreased after prolonged exposure to a high hormone concentration, the receptors thus becoming less sensitive (‘down-regulation’) e.g. angiotensin II receptor, f3-adrenoceptor. The reverse is true when stimulation is absent or minimal, the receptors showing increased numbers or sensitivity (‘up-regulation’). Abnormal receptors are an occasional, though very rare, cause of endocrine.

Plasma hormones with important binding proteins.

Plasma hormones with important binding
proteins.

a) Binding of hormone to cellular surface receptor with subsequent release of a second messenger, here cAMP,

a) Binding of hormone to
cellular surface receptor with subsequent release of a second messenger, here cAMP,

Control and feedback

Most hormone systems are controlled by some form of feedback; an example is the hypothalamic-pituitarythyroid axis.
I TRH 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).
2 TSH is secreted into the systemic circulation where it stimulates increased thyroidal iodine uptake and thyroxine (T.) and tri-iodothyronine (T,) synthesis and release.
3 Serum levels of T, and T, are thus increased by TSH; in addition, the conversion of T, to T, (the more active hormone) in peripheral tissues is stimulated by TSH. 4 T. and T3 then enter cells where they bind to nuclear receptors and promote increased metabolic and cellular activity.
5 Blood levels of T3 and T. are sensed by receptors in the pituitary and possibly the hypothalamus. If they rise above the normal range, TRH and TSH production is suppressed, leading to less T. and T3 secretion. 6 Peripheral T3/T. levels thus fall to normal. 7 If, however, T3 and T. levels are low (e.g. post thyroidectomy), increased amounts of TRH and thus TSH are secreted, stimulating the remaining thyroid to produce more T3 and T.; blood levels of T./T3 may be restored to normal, although at the expense of increased TSH drive, reflected by a high TSH level (‘compensated euthyroidism’).

This is known as a ‘negative feedback’ system, referring to the effect of T. and T3 on the pituitary and hypothalamus. There are also positive feedback systems, classically seen in the regulation of the normal menstrual cycle.

Characteristics of different hormone systems.

Characteristics of different hormone systems.

The hypothalamic-pituitary-thyroid feedback system.

The hypothalamic-pituitary-thyroid feedback system.

Patterns of secretion

Hormone secretion may be continuous or intermittent. The former is shown by the thyroid hormones, where T. has a half-life of 7-10 days and T3 of about 6-10 hours. Levels over the day, month and year show very little variation. In contrast, secretion of the gonadotrophins, LH and FSH, is normally pulsatile, with major pulses released every 2 hours or so. 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 down-regulation and amenorrhoea. Thus the long-acting superactive gonadotrophin releasing hormone (GnRH) analogue buserelin produces down-regulation 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 infertility in women. Pulsatile GnRH administration on the other hand can produce normal menstrual cyclicity, ovulation and fertility in women with hypothalamic amenorrhoea but intact pituit ary LH and FSH stores.

Endocrinology

Introduction

Hormones are chemical messengers produced by a variety of specialized secretory cells. They may be transported to a distant site of action (the classical ‘endocrine’ effect) or may 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. The distinction between neurotransmitters that act across synaptic clefts, intercellular factors acting across gap junctions and classical endocrine and paracrine activity is becoming increasingly blurred. There are also many chemical messengers involved in cell regulation such as cytokines, growth factors and interleukins.

Synthesis. storage and release of hormones

Hormones may be of several chemical structures: polypeptide, glycoprotein, steroid or amine. In the case of polypeptides, neural or endocrine stimulation of the specific mRNA increases the synthesis of its hormone product. This is often in the form of a precursor molecule that may itself be biologically inactive. This ‘prohorrnone’ may be further processed before being packaged into granules, in the Golgi apparatus. These granules are then transported to the plasma membrane before release. This 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 hormones are secreted into the systemic circulation but, in the hypothalamus, they are released into the pituitary portal system. Much higher concentrations of the releasing factors thus reach the pituitary than occur in the systemic circulation.

Many hormones are bound to proteins within the circulation. Only the free (unbound) hormone is available to the tissues and thus biologically active. The binding serves to buffer against very rapid changes in plasma levels of the hormone. This principle is important in interpreting many tests of endocrine function, which 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 most important and clinically relevant binding proteins.