Clinical presentation of endocrine disease

History

Hormones produce widespread effects in the body, and states of hormonal deficiency or excess typically present with symptoms that are generalized, diffuse and nonspecific. Symptoms of tiredness, weakness or lack of energy or drive and changes in appetite or thirst are common presentations. Other typical ‘hormonal’ symptoms include changes in body size and shape, problems with libido and potency, periods or sexual development, and changes in the skin (dry, greasy, acne, bruising, thinning or thickening) and hair (loss or excess). The differential diagnosis is often wide but endocrine disorders should be always considered when assessing a patient with any of these common complaints.

The past, family and social history is essential for making the diagnosis, planning appropriate management and interpreting results of borderline hormonal blood tests.

The past history should include previous surgery or radiation involving endocrine glands, menstrual history, pregnancy and growth and development in childhood.

A full drug history will exclude common iatrogenic endocrine problems (Table 19.1).

A family history of autoimmune disease, endocrine disease including tumours, diabetes and cardiovascular disease is frequently relevant, and knowledge of family members’ height, weight, body habitus, hair growth and age of sexual development may aid interpretation of the patient’s own symptoms.

Table 19.1 Drugs and endocrine disease

Common endocrine conditions

The most common endocrine disorders, excluding obesity (Ch. 5) and diabetes mellitus (Ch. 20), are:

While most other endocrine conditions are uncommon, they often affect young people and are usually curable or completely controllable with appropriate therapy.

Aetiology of endocrine disease

Aetiological mechanisms common to many endocrine disorders include:

Autoimmune disease

Organ-specific autoimmune diseases can affect every major endocrine organ (Table 19.2). They are characterized by the presence of specific antibodies in the serum, often present years before clinical symptoms are evident, are usually more common 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 been identified.

Table 19.2 Types of autoimmune disease affecting endocrine organs

Endocrine tumours

Most endocrine tumours are benign, although a cytological or histological diagnosis may be needed if there is clinical or radiological suspicion of malignancy. Clinical presentation depends on whether the tumour is functional or non-functional, the latter presenting only as a mass clinically or on imaging. Palpable thyroid nodules are common, and mass effects are a frequent presentation of pituitary adenomas, but the increased use of high-resolution ultrasound and detailed cross-sectional imaging has revealed a very high prevalence of asymptomatic, incidentally-discovered thyroid, adrenal and pituitary lesions, commonly termed ‘incidentalomas’ (see p. 989).

Functional tumours cause their effects via excess secretion of the relevant hormone. While often considered to be ‘autonomous’, i.e. independent of the physiological control mechanisms, many functional tumours do show evidence of feedback occurring at a higher ‘set-point’ than normal (e.g. ACTH secretion from a pituitary basophil adenoma). This is relevant in the dynamic assessment of endocrine diseases such as in the differential diagnosis of Cushing’s syndrome.

Endocrine adenomas typically present in a single gland, although rarer multiple endocrine neoplasia (MEN) syndromes exist due to very specific mutations of a single gene, such as the mutations of the RET proto-oncogene in MEN 2 or the MEN1 gene mutation in MEN 1 (see p. 997).

Enzyme defects

The biosynthesis of most hormones involves many stages. Deficient or abnormal enzymes can lead to absent or reduced production of the secreted 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), where the molecular basis has also been identified as mutations or deletions of the gene encoding the relevant enzymes (see p. 987).

Receptor abnormalities

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 (see p. 1006); other examples include nephrogenic diabetes insipidus, pseudohypoparathyroidism and thyroid hormone resistance which can cause an unusual pattern of thyroid blood results.

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’ is then 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 is ‘constitutive’ (immediate and continuous secretion).

Plasma transport

Most classical hormones are secreted into the systemic circulation. 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 are also involved in the active regulation of hormone action. Many tests of endocrine function measure total rather than free hormone, which can give rise to difficulties in interpretation when binding proteins are altered in disease states or by drugs.

Binding proteins comprise both specific, high-affinity proteins of limited capacity, such as thyroxine-binding globulin (TBG), cortisol-binding globulin (CBG), sex-hormone-binding globulin (SHBG) and IGF-binding proteins (e.g. IGF-BP3) and other less specific, low-affinity ones, such as prealbumin and albumin.

Hormone action and receptors

Hormones act by binding to specific receptors in the target cell. Most hormone receptors are proteins with complex tertiary structures. The structure of the hormone-binding domain of the receptor complements the tertiary structure of the hormone, while changes in other parts of the receptor in response to hormone binding are responsible for the effects of the activated receptor within the cell. The structure of common hormones and their receptors is described under individual hormone axes.

Hormone receptors are broadly divided into:

Abnormal receptors are an occasional cause of endocrine disease (see p. 43).

Control and feedback

Most hormone systems are under tight regulatory control (typically by the hypothalamo-pituitary (HP) axis) by a system known as negative feedback. An example of the negative feedback system in the hypothalamo-pituitary-thyroid axis is demonstrated in Figure 19.2 and described here:

Figure 19.2 The hypothalamic-pituitary-thyroid axis. Pituitary TSH is secreted in response to hypothalamic TRH and stimulates secretion of T₄ and T₃ from the thyroid. T₄ and T₃ have actions in peripheral tissues and exert negative feedback on pituitary and hypothalamus.

Primary and secondary gland failure

It is useful in clinical endocrinology to distinguish between ‘primary’ disease of the end-organ gland (e.g. due to auto-immune destruction, atrophic change, infiltration or surgical removal of the gland), and ‘secondary’ disorders of the same axis caused by disease of the pituitary gland. An understanding of the negative feedback system is key to interpreting endocrine blood results and diagnosing the site of the disease process in clinical practice. In general terms:

Hormone resistance

In certain situations, receptor abnormalities can give rise to abnormal negative feedback due to hormone resistance, which can lead to an unusual pattern of blood results. For example, thyroid hormone resistance, due to mutations in the thyroid hormone receptor, is characterized by an elevation in thyroid hormones with a non-suppressed TSH. With this pattern of thyroid results, the clinician should also consider the rare diagnosis of a TSH secreting pituitary tumour.

Measurement of hormones

Hormones are measured in routine clinical practice by biochemical assays in the laboratory. It is possible to measure pituitary trophic hormones and the hormones produced by the end-organ glands, but hypothalamic hormones are not routinely measured in practice because of their low concentration and local action within the hypothalamo-pituitary axis. Circulating levels of most hormones are very low (10⁻⁹– 10⁻¹² mol/L) and cannot be measured by simple chemical techniques. Hormones are therefore usually measured by immunoassays, which rely on highly specific polyclonal or monoclonal antibodies, which bind to the hormone being measured during the assay incubation. This hormone-antibody interaction is measured by use of labelled hormone after separation of bound and free fractions (Fig. 19.3).

Figure 19.3 Principles of measurement of hormone levels in plasma by immunoassay (precise details vary with different assays and manufacturers). Immunoassays use two antibodies specific to the hormone being measured – one typically attached to a solid phase and one labelled antibody in the liquid phase. (a) High hormone levels in plasma: large amount of hormone binds to antibody on solid phase – large amount of labelled antibody linked to solid phase via molecules of the hormone. (b) Low hormone levels in plasma: less hormone, and therefore less labelled antibody, is linked to the solid phase. Label (radioactive, chemiluminescent, enzymatic or fluorescent) can be measured in either solid or liquid phase after separation of phases; levels of label will be proportional to the amount of hormone in the sample.

Immunoassays are sensitive but have limitations. In particular, the immunological activity of a hormone, as used in developing the antibody, may not necessarily correspond to biological activity and there may be false positive and negative results. The patient’s blood may also contain heterophile antibodies which interact with the animal antibodies used in the assay, and result in falsely low or high values. When there is a discrepancy between endocrine blood results and the clinical presentation, the clinician must question the validity of an endocrine result, and a close relationship with the relevant laboratory is essential. It may be necessary for the sample to be measured in a different laboratory using an alternative antibody, or to measure hormones in ways other than by immunoassay. Examples of alternative techniques to accurately quantify and characterize hormone levels include equilibrium dialysis, high-pressure liquid chromatography (HPLC) and, increasingly, mass spectroscopy.

Patterns of hormonal secretion

Hormone secretion can be continuous or intermittent, for example:

Biological rhythms

Circadian means changes over the 24 hours of the day–night cycle and is best shown for the pituitary–adrenal axis. Figure 19.4 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.

Figure 19.4 Plasma cortisol levels during a 24-hour period. Note both the pulsatility and the shifting baseline. Normal ranges for 09:00 hours (180–700 nmol/L) and 24:00 hours (<100 nmol/L; must be taken when asleep) are shown in the orange boxes. Purple shading shows sleep.

The menstrual cycle is an example of a longer and more complex (28-day) biological rhythm (see p. 972).

Other regulatory factors

Stress. Physiological ‘stress’ and acute illness produce rapid increases in ACTH and cortisol, growth hormone (GH), prolactin, adrenaline (epinephrine) and noradrenaline (norepinephrine). 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. 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.

Pituitary space-occupying lesions and tumours

Pituitary tumours (Table 19.4) are the most common cause of pituitary disease, and the great majority of these are benign pituitary adenomas, usually monoclonal in origin. Problems are caused by:

Table 19.4 Characteristics of common pituitary and related tumours

Investigations (of a possible or proven mass)

Is there a tumour?

If there is, how big is it and what local anatomical effects is it exerting? Pituitary and hypothalamic space-occupying lesions, hormonally active or not, can cause symptoms by pressure on, or infiltration of:

the visual pathways, with field defects and visual loss (most common)

the cavernous sinus, with III, IV and VI cranial nerve lesions

bony structures and the meninges surrounding the fossa, causing headache

hypothalamic centres: altered appetite, obesity, thirst, somnolence/wakefulness or precocious puberty

the ventricles, causing interruption of cerebrospinal fluid (CSF) flow leading to hydrocephalus

the sphenoid sinus with invasion causing CSF rhinorrhoea.

Investigations

MRI of the pituitary. MRI is superior to CT scanning (Fig. 19.8) and will readily show any significant pituitary mass. Small lesions within the pituitary fossa on MRI consistent with small pituitary microadenomas are very common (10% of normal individuals in some studies). Such small lesions are sometimes detected during MRI scanning of the head for other reasons – so-called ‘pituitary incidentalomas’.

Visual fields. These should be plotted formally by automated computer perimetry or Goldmann perimetry, but clinical assessment by confrontation using a small red pin as target is also sensitive and valuable. Common defects are upper temporal quadrantanopia and bitemporal hemianopia (see p. 1073).

Figure 19.8 (a) Coronal MRI of pituitary, showing a left-sided lucent intrasellar microadenoma (arrowed). The pituitary stalk is deviated slightly to the right. (b) Coronal MRI of pituitary, showing macroadenoma with moderate suprasellar extension, and lateral extension compressing left cavernous sinus. The top of the adenoma is compressing the optic chiasm (arrowed). (c) Sagittal MRI of head, showing a pituitary macroadenoma with massive suprasellar extension (arrows).

Is there a hormonal excess?

There are three major conditions usually caused by secretion from pituitary adenomas which will show positive immunostaining for the relevant hormone:

Prolactin excess (prolactinoma or hyperprolactinaemia): histologically, prolactinomas are ‘chromophobe’ adenomas (a description of their appearance on classical histological staining)

GH excess (acromegaly or gigantism): somatotroph adenomas, usually ‘acidophil’, and sometimes due to specific G-protein mutations (see p. 945)

excess ACTH secretion (Cushing’s disease and Nelson’s syndrome): corticotroph adenomas, usually ‘basophil’.

Many tumours are able to synthesize several pituitary hormones, and occasionally more than one hormone is secreted in clinically significant excess (e.g. both GH and prolactin).

The clinical features of acromegaly, Cushing’s disease or hyperprolactinaemia are usually (but not always) obvious, and are discussed on pages 953, and 957. Hyperprolactinaemia may be clinically ‘silent’. Tumours producing LH, FSH or TSH are well described but very rare.

Some common pituitary tumours, usually ‘chromophobe’ adenomas, cause no clinically apparent hormone excess and are referred to as ‘non-functioning’ tumours. Laboratory studies such as immunocytochemistry or in situ hybridization show that these tumours may often produce small amounts of LH and FSH or the α-subunit of LH, FSH and TSH, and occasionally ACTH.

Is there a deficiency of any hormone?

Clinical examination may give clues; thus, short stature in a child with a pituitary tumour is likely to be due to GH deficiency. A slow, lethargic adult with pale skin is likely to be deficient in TSH and/or ACTH. Milder deficiencies may not be obvious, and require specific testing (see Table 19.7).

Table 19.7 Tests for hypothalamic-pituitary (HP) function

Differential diagnosis of pituitary or hypothalamic masses

Although pituitary adenomas are the most common mass lesion of the pituitary (90%), a variety of other conditions may also present as a pituitary or hypothalamic mass and form part of the differential diagnosis.

Other tumours

Craniopharyngioma (1–2%), a usually cystic hypothalamic tumour, often calcified, arising from Rathke’s pouch, often mimics an intrinsic pituitary lesion. It is the most common pituitary tumour in children but may present at any age.

Craniopharyngioma: a partially cystic pituitary and suprasellar mass. (a) Sagittal, (b) coronal MRI.

Uncommon tumours include meningiomas, gliomas, chondromas, germinomas and pinealomas. Primary pituitary carcinomas are very rare, but occasionally prolactin and ACTH secreting tumours can present in an aggressive manner which may require chemotherapy in addition to conventional treatment. Secondary deposits occasionally present as apparent pituitary tumours, typically presenting with headache and diabetes insipidus.

Meningioma involving pituitary fossa showing typical ‘dural tail’.

Hypophysitis and other inflammatory masses

A variety of inflammatory masses occur in the pituitary or hypothalamus. These include rare pituitary-specific conditions (e.g. autoimmune [lymphocytic] hypophysitis, giant cell hypophysitis, postpartum hypophysitis) or pituitary manifestations of more generalized disease processes (sarcoidosis, Langerhans’ cell histiocytosis, Wegener’s granulomatosis). These lesions may be associated with diabetes insipidus and/or an unusual pattern of hypopituitarism.

Other lesions

Carotid artery aneurysms may masquerade as pituitary tumours and must be diagnosed before surgery. Cystic lesions may also present as a pituitary mass, including arachnoid and Rathke cleft cysts.

Hypopituitarism

Clinical features

Symptoms and signs depend upon the extent of hypothalamic and/or pituitary deficiencies, and mild deficiencies may not lead to any complaint by the patient. In general, symptoms of deficiency of a pituitary-stimulating hormone are the same as primary deficiency of the peripheral endocrine gland (e.g. TSH deficiency and primary hypothyroidism cause similar symptoms due to lack of thyroid hormone secretion).

Secondary hypothyroidism and adrenal failure both lead to tiredness and general malaise.

Hypothyroidism causes weight gain, slowness of thought and action, dry skin and cold intolerance.

Hypoadrenalism causes mild hypotension, hyponatraemia and ultimately cardiovascular collapse during severe intercurrent stressful illness.

Gonadotrophin and thus gonadal deficiencies lead to loss of libido, loss of secondary sexual hair, amenorrhoea and erectile dysfunction.

Hyperprolactinaemia may cause galactorrhoea and hypogonadism.

GH deficiency causes growth failure in children and impaired wellbeing in some adults.

Weight may increase (due to hypothyroidism, see above) or decrease in severe combined deficiency (pituitary cachexia).

Longstanding panhypopituitarism gives the classic picture of pallor with hairlessness (‘alabaster skin’).

Particular syndromes related to hypopituitarism are:

Kallmann’s syndrome. This syndrome is isolated gonadotrophin (GnRH) deficiency (p. 976).This syndrome arises due to mutations in the KAL1 gene which is located on the short (p) arm of the X chromosome. Kallmann’s is classically characterized by anosmia because the KAL1 gene provides instructions to make anosmin, which has a role in development of both the olfactory system as well as migration of GnRH secreting neurones.

Septo-optic dysplasia. This is a rare congenital syndrome (associated with mutations in the HESX1 gene) presenting in childhood with a clinical triad of midline forebrain abnormalities, optic nerve hypoplasia and hypopituitarism.

Sheehan’s syndrome is due to pituitary infarction following postpartum haemorrhage and is rare in developed countries.

Pituitary apoplexy. A pituitary tumour occasionally enlarges rapidly owing to infarction or haemorrhage. This may produce severe headache, double vision and sudden severe visual loss, sometimes followed by acute life-threatening hypopituitarism. Often pituitary apoplexy can be managed conservatively with replacement of hormones and close monitoring of vision, although if there is a rapid deterioration in visual acuity and fields, surgical decompression of the optic chiasm may be necessary.

Pituitary apoplexy, showing a bright area of haemorrhage at the top of a pituitary adenoma. (a) Sagittal, (b) coronal.

The ‘empty sella’ syndrome. An ‘empty sella’ is sometimes reported on pituitary imaging. This is sometimes due to a defect in the diaphragma and extension of the subarachnoid space (cisternal herniation) or may follow spontaneous infarction or regression of a pituitary tumour. All or most of the sella turcica is devoid of apparent pituitary tissue, but, despite this, pituitary function is usually normal, the pituitary being eccentrically placed and flattened against the floor or roof of the fossa.

FURTHER READING

Rajasekaran S, Vanderpump M, Baldeweg S et al UK guidelines for the management of pituitary apoplexy. Clin Endocrinol 2011; 74:9–20.

Physiology and control of growth hormone (GH) (Fig. 19.9)

GH is the pituitary factor responsible for stimulation of body growth in humans. Its secretion is stimulated by GHRH, released into the portal system from the hypothalamus; it is also under inhibitory control by somatostatin. A separate GH stimulating system involves a distinct receptor (GH secretogogue receptor), which interacts with ghrelin (see p. 259). It is not known how these two systems interact but because ghrelin is synthesized in the stomach, it suggests a nutritional role for GH.

Figure 19.9 The control of growth hormone (GH) and insulin-like growth factor-1 (IGF-1). Pituitary GH is secreted under dual control of growth hormone-releasing hormone (GHRH) and somatostatin and stimulates release of IGF-1 in liver and elsewhere. IGF-1 has peripheral actions including bone growth and exerts negative feedback to hypothalamus and pituitary.

The metabolic actions of the system are:

GH release is intermittent and mainly nocturnal, especially during REM sleep. The frequency and size of GH pulses increase during the growth spurt of adolescence and decline thereafter. Acute stress and exercise both stimulate GH release while, in the normal subject, hyperglycaemia suppresses it.

IGF-1 may, in addition, play a major role in maintaining neoplastic growth. A relationship has been shown between circulating IGF-1 concentrations and breast cancer in premenopausal women and prostate cancer in men.

Assessment of growth

Charts showing normal centiles of height and weight are essential to monitor growth; they are available for normal British children (Fig. 19.10) and many other national and ethnic groups. Height must be measured, ideally at the same time of day on the same instrument by the same observer.

Figure 19.10 A height chart for boys. Child A illustrates the course of a child with hypopituitarism, initially treated with cortisol and thyroxine, but showing growth only after growth hormone treatment. Child B shows the course of a child with constitutional growth delay without treatment.

Height velocity is more helpful than current height. It requires at least two measurements some months apart and, ideally, multiple serial measurements. Height velocity is the rate of current growth (cm per year), while the current attained height is largely dependent upon previous growth. Standard deviation scores (SDS) based on the degree of deviation from age–sex norms are widely used. Computer programs also allow calculation of many of these indices.

The approximate future height of a child (‘mid-parental height’) can be simply predicted from the parental heights. For a boy, this is:

and for a girl:

Thus, with a father of 180 cm and mother of 154 cm, the predicted heights are 174 cm for a son and 160 cm for a daughter.

Anatomy

The thyroid gland consists of two lateral lobes connected by an isthmus. It is closely attached to the thyroid cartilage and to the upper end of the trachea, and thus moves on swallowing. It is often palpable in normal women.

Embryologically it originates from the base of the tongue and descends to the middle of the neck. Remnants of thyroid tissue can sometimes be found at the base of the tongue (lingual thyroid) and along the line of descent. The gland has a rich blood supply from superior and inferior thyroid arteries.

The thyroid gland consists of follicles lined by cuboidal epithelioid cells. Inside is the colloid (the iodinated glycoprotein thyroglobulin) which is synthesized by the follicular cells. Each follicle is surrounded by basement membrane, between which are parafollicular cells containing calcitonin-secreting C cells.

Physiology

Synthesis.

The thyroid synthesizes two hormones:

Triiodothyronine (T₃), which acts at the cellular level

L-thyroxine (T₄), which is the prohormone.

Inorganic iodide is trapped by the gland by an enzyme dependent system, oxidized and incorporated into the glycoprotein thyroglobulin to form mono- and diiodotyrosine and then T₄ and T₃ (Fig. 19.16).

Figure 19.16 Synthesis and metabolism of the thyroid hormones. Tg, thyroglobulin.

More T₄ than T₃ is produced, but T₄ is converted in some peripheral tissues (liver, kidney and muscle) to the more active T₃ by 5′-monodeiodination; an alternative 3′-monodeiodination yields the inactive reverse T₃ (rT₃). The latter step occurs particularly in severe non-thyroidal illness (see below).

In plasma, more than 99% of all T₄ and T₃ is bound to hormone-binding proteins (thyroxine-binding globulin, TBG; thyroid-binding prealbumin, TBPA; and albumin). Only free hormone is available for action in the target tissues, where T₃ binds to specific nuclear receptors within target cells. Many drugs and other factors affect TBG; all may result in confusing total T₄ levels in blood, and most laboratories therefore now measure free T₄ levels.

Control of the hypothalamic-pituitary-thyroid axis. Thyrotrophin-releasing hormone (TRH), a peptide produced in the hypothalamus, stimulates the pituitary to secrete thyroid-stimulating hormone (TSH) (see Fig. 19.2). TSH in turn stimulates growth and activity of the thyroid follicular cells via the G-protein coupled TSH membrane receptor (see Table 19.3). The T₃ and T₄ subsequently secreted into the circulation by follicular cells exert negative feedback on the hypothalamus, as described on page 941.

Circulating T₄ is peripherally deiodinated to T₃ which binds to the thyroid hormone nuclear receptor (TR) on target organ cells to cause modified gene transcription. There are two TR receptors (TR-α and TR-β) and the tissue-specific effects of T₃ are dependent upon the local expression of these TR receptors. TR-α knockout mice show poor growth, bradycardia and hypothermia, whilst TR-β knockout mice show thyroid hyperplasia and high T₄ levels in the presence of inappropriately normal circulating TSH, suggesting a role for the latter receptors in thyroid hormone resistance (see p. 967).

Physiological effects of thyroid hormones. The physiological effects of thyroid hormones are summarized in Table 19.12.

Table 19.12 Physiological effects of thyroid hormone

Target	Effect
Cardiovascular system	Increases heart rate and cardiac output
Bone	Increases bone turnover and resorption
Respiratory system	Maintains normal hypoxic and hypercapnic drive in respiratory centre
Gastrointestinal system	Increases gut motility
Blood	Increases red blood cell 2,3-BPGa facilitating oxygen release to tissues
Neuromuscular function	Increases speed of muscle contraction and relaxation and muscle protein turnover
Carbohydrate metabolism	Increases hepatic gluconeogenesis/glycolysis and intestinal glucose absorption
Lipid metabolism	Increases lipolysis and cholesterol synthesis and degradation
Sympathetic nervous system	Increases catecholamine sensitivity and β-adrenergic receptor numbers in heart, skeletal muscle, adipose cells and lymphocytes Decreases cardiac α-adrenergic receptors

a 2,3-BPG, 2,3-bisphosphoglyceric acid.

Dietary iodine requirement. Globally, dietary iodine deficiency is a major cause of thyroid disease, as iodine is an essential requirement for thyroid hormone synthesis. The recommended daily intake of iodine should be at least 140 µg, and dietary supplementation of salt and bread has reduced the number of areas where ‘endemic goitre’ still occurs (see below).

FURTHER READING

Colao A, et al. A 12 month Phase 3 study of Pasireotide in Cushing’s disease. New Engl J Med 2012; 366:914–924.

SIGNIFICANT WEBSITE

International Council for the Control of Iodine Deficiency Disorders: http://www.iccidd.org

Pathophysiology

Underactivity of the thyroid is usually primary, from disease of the thyroid, but may be secondary to hypothalamic-pituitary disease (reduced TSH drive) (Table 19.14). Primary hypothyroidism is one of the most common endocrine conditions with an overall UK prevalence of over 2% in women, but under 0.1% in men; lifetime prevalence for an individual is higher – perhaps as high as 9% for women and 1% for men with mean age at diagnosis around 60 years. The worldwide prevalence of subclinical hypothyroidism varies from 1% to 10%.

Table 19.14 Causes of hypothyroidism

Clinical features (Fig. 19.17)

Hypothyroidism produces many symptoms. The alternative term ‘myxoedema’ refers to the accumulation of mucopolysaccharide in subcutaneous tissues. The classic picture of the slow, dry-haired, thick-skinned, deep-voiced patient with weight gain, cold intolerance, bradycardia and constipation makes the diagnosis easy. Milder symptoms are, however, more common and hard to distinguish from other causes of nonspecific tiredness. Many cases are detected on biochemical screening.

Figure 19.17 Hypothyroidism: symptoms and signs. Bold type indicates symptoms or signs of greater discriminant value. A history from a relative is often revealing. Symptoms of other autoimmune disease may be present.

Special difficulties in diagnosis may arise in certain circumstances:

Investigation of primary hypothyroidism

Serum TSH is the investigation of choice; a high TSH level confirms primary hypothyroidism. A low free T₄ level confirms the hypothyroid state (and is also essential to exclude TSH deficiency if clinical hypothyroidism is strongly suspected and TSH is normal or low).

Thyroid and other organ-specific antibodies may be present. Other abnormalities include the following:

Treatment

Replacement therapy with levothyroxine (thyroxine, i.e. T₄) is given for life. The starting dose will depend upon the severity of the deficiency and on the age and fitness of the patient, especially their cardiac performance: 100 µg daily for the young and fit, 50 µg (increasing to 100 µg after 2–4 weeks) for the small, old or frail. People with ischaemic heart disease require even lower initial doses, especially if the hypothyroidism is severe and longstanding. Most physicians would then begin with 25 µg daily and perform serial ECGs, increasing the dose at 3- to 4-week intervals if angina does not occur or worsen and the ECG does not deteriorate. Occasional patients develop ‘thyrotoxic’ (hyperthyroid) symptoms despite normal fT4 levels if dose if increased too rapidly.

Monitoring. The aim is to restore T₄ and TSH to well within the normal range. Adequacy of replacement is assessed clinically and by thyroid function tests after at least 6 weeks on a steady dose. If serum TSH remains high, the dose of T₄ should be increased in increments of 25–50 µg with the tests repeated at 6–8 weeks intervals until TSH becomes normal. Complete suppression of TSH should be avoided because of the risk of atrial fibrillation and osteoporosis. The usual maintenance dose is 100–150 µg given as a single daily dose. An annual thyroid function test is recommended – this is usually performed in the primary care setting, often assisted and prompted by district ‘thyroid registers’.

Clinical improvement on T₄ may not begin for 2 weeks or more, and full resolution of symptoms may take 6 months. The necessity of lifelong therapy must be emphasized and the possibility of other autoimmune endocrine disease developing, especially Addison’s disease or pernicious anaemia, should be considered. During pregnancy, an increase in T₄ dosage of about 25–50 µg is often needed to maintain normal TSH levels, and the necessity of optimal replacement during pregnancy is emphasized by the finding of reductions in cognitive function in children of mothers with elevated TSH during pregnancy.

A few people with primary hypothyroidism complain of incomplete symptomatic response to T₄ replacement. Combination T₄ and T₃ replacement has been advocated in this context, but randomized clinical trials show no consistent benefit in quality of life symptoms.

Relapse

About 50% of patients will relapse after a course of carbimazole or PTU, mostly within the following 2 years but occasionally much later. Long-term antithyroid therapy is then used or surgery or radiotherapy is considered (see below). Most patients (90%) with hyperthyroidism have a diffuse goitre but those with large single or multinodular goitres are unlikely to remit after a course of antithyroid drugs and will usually require definitive treatment. Severe biochemical hyperthyroidism is also less likely to remain in remission.

Toxicity

The major side-effect of drug therapy is agranulocytosis that occurs in approximately 1 in 1000 patients, usually within 3 months of treatment. All patients must be warned to seek immediate medical attention for a white blood cell count if they develop unexplained fever or sore throat – written information is essential. Rashes are more frequent and usually require a change of drug. If toxicity occurs on carbimazole, PTU may be used and vice-versa; side-effects are only occasionally repeated on the other drug.

Thyroid crisis or ‘thyroid storm’

This rare condition, with a mortality of 10%, is a rapid deterioration of hyperthyroidism with hyperpyrexia, severe tachycardia, extreme restlessness, cardiac failure and liver dysfunction. It is usually precipitated by stress, infection or surgery in an unprepared patient, or radioiodine therapy. With careful management it should no longer occur and most cases referred as ‘crisis’ are simply severe but uncomplicated thyrotoxicosis.

Treatment is urgent. Propranolol in full doses is started immediately together with potassium iodide, antithyroid drugs, corticosteroids (which suppress many of the manifestations of hyperthyroidism) and full supportive measures. Control of cardiac failure and tachycardia is also necessary.

Occasionally, hyperthyroidism can lead to a thyrotoxic cardiomyopathy which causes ischaemic changes on a 12-lead ECG which reverse after reversion to euthyroidism.

Thyrotoxic cardiomyopathy: ECG showing marked lateral T-wave inversion.

Hyperthyroidism in pregnancy and neonatal life

Since hyperthyroidism typically affects young women, pregnancies, both planned and unplanned, inevitably occur during antithyroid treatment. PTU is usually the preferred antithyroid drug during pregnancy or in any woman planning pregnancy, due to rare reports of congenital abnormalities with carbimazole which have not been described with PTU.

The high level of HCG found in normal pregnancy is a weak stimulator of the TSH receptor, commonly causing suppressed TSH with slightly elevated fT₄/fT₃ in the first trimester which may be associated with hyperemesis gravidarum. True maternal hyperthyroidism occurring de novo during pregnancy is however uncommon and usually mild. Diagnosis can be difficult because of the overlap with symptoms of normal pregnancy and misleading thyroid function tests, although TSH is largely reliable. The pathogenesis is almost always Graves’ disease.

Thyroid-stimulating immunoglobulin (TSI) crosses the placenta to stimulate the fetal thyroid. Carbimazole and PTU (see below) also cross the placenta, but T₄ does so poorly, so a ‘block-and-replace’ regimen is contraindicated. The smallest dose necessary of PTU (see above) is used and the fetus must be monitored. If necessary (high doses needed, poor patient compliance or drug side-effects), surgery can be performed, preferably in the second trimester. Radioactive iodine is absolutely contraindicated.

The fetus and maternal Graves’ disease

Any mother with a history of Graves’ disease may have circulating TSI. Even if she is euthyroid after surgery or RAI, the immunoglobulin may still be present to stimulate the fetal thyroid, and the fetus can thus become hyperthyroid.

Any such patient should therefore be monitored during pregnancy. Fetal heart rate provides a direct biological assay of fetal thyroid status, and monitoring should be performed at least monthly. Rates above 160/minute are strongly suggestive of fetal hyperthyroidism, and maternal treatment with PTU and/or propranolol is used. Direct measurement of TSHR-Ab may be helpful to predict neonatal thyrotoxicosis in this situation. To prevent a euthyroid mother becoming hypothyroid, T₄ may be given as this does not easily cross the placenta. Sympathomimetics, used to prevent premature labour, are contraindicated as they may provoke fatal tachycardia in the fetus. The paediatrician should be informed and the infant checked immediately after birth – overtreatment with PTU or carbimazole can cause fetal goitre. Breast-feeding while on usual doses of carbimazole or PTU appears to be safe.

Hyperthyroidism may also develop in the neonatal period as TSI has a half-life of approximately 3 weeks. Manifestations in the newborn include irritability, failure to thrive and persisting weight loss, diarrhoea and eye signs. Thyroid function tests are difficult to interpret as neonatal normal ranges vary with age.

Untreated neonatal hyperthyroidism is probably associated with hyperactivity in later childhood.

Thyroid hormone resistance

Thyroid hormone resistance is an inherited condition caused by an abnormality of the thyroid hormone receptor. Mutations to the receptor (TR β) result in the need for higher levels of thyroid hormones to achieve the same intracellular effect. As a result, the normal feedback control mechanisms (see Fig. 19.2, p. 941) result in high blood levels of T₄ with a normal TSH in order to maintain a euthyroid state. This has two consequences:

Long-term consequences of hyperthyroidism

Long-term follow-up studies of hyperthyroidism show a slight increase in overall mortality, which affects all age groups, is not fully explained and tends to occur in the first year after diagnosis. Thereafter, the only long-term risk of adequately treated hyperthyroidism appears to be an increased risk of osteoporosis. People with persistently suppressed TSH levels have an increased likelihood of developing atrial fibrillation which may predispose to thromboembolic disease.

Pathophysiology

The ophthalmopathy of Graves’ disease is due to a specific immune response that causes retro-orbital inflammation (Fig. 19.19). Swelling and oedema of the extraocular muscles lead to limitation of movement and to proptosis which is usually bilateral but can sometimes be unilateral. Ultimately increased pressure on the optic nerve may cause optic atrophy. Histology of the extraocular muscles shows focal oedema and glycosaminoglycan deposition followed by fibrosis. The precise autoantigen which leads to the immune response remains to be identified, but it appears to be an antigen in retro-orbital tissue with similar immunoreactivity to the TSH receptor.

Figure 19.19 Model of the Initiation of Thyrotrophin-Receptor Autoimmunity in Graves’ Ophthalmopathy and Its Consequences.Thyrotrophin receptor is internalized and degraded by antigen-presenting cells that present thyrotrophin-receptor peptides, in association with major histocompatibility complex (MHC) class II antigens, to helper T cells. These cells become activated, interact with autoreactive B cells through CD154-CD40 bridges, and secrete interleukin-2 and interferon-γ. These cytokines induce the differentiation of B cells into plasma cells that secrete anti-thyrotrophin-receptor antibodies. Anti-thyrotrophin-receptor antibodies recognize the thyrotrophin receptor on orbital fibroblasts and, in conjunction with the secreted type 1 helper T cytokines interferon-γ and tumour necrosis factor (TNF), initiate the tissue changes characteristic of Graves’ ophthalmopathy. These antibodies stimulate the thyrotrophin receptor on thyroid follicular epithelial cells, leading to hyperplasia and increased production of the thyroid hormones triiodothyronine (T₃) and thyroxine (T₄). IL, interleukin; IFN, interferon.

(Adapted from Bahn RS 2010 Graves’ ophthalmology. N Engl J Med 362:726–738.)

Eye disease is a manifestation of Graves’ disease and can occur in patients who may be hyperthyroid, euthyroid or hypothyroid. Thyroid dysfunction and ophthalmopathy usually occur within two years of each other although sometimes a gap of many years is seen. TSH receptor antibodies are almost invariably found in the serum but their role in the pathogenesis is becoming clearer (Fig. 19.19). Ophthalmopathy is more common and more severe in smokers.

Clinical features

The clinical appearances are characteristic (Fig. 19.18) but thyroid eye disease demonstrates a wide range of severity. A high proportion of people with Graves’ disease notice some soreness, painful watering or prominence of the eyes, and the ‘stare’ of lid retraction is relatively common. More severe proptosis occurs in a minority of cases, and limitation and discomfort of eye movement and visual impairment due to optic nerve compression are relatively uncommon. Proptosis and lid retraction may limit the ability to close the eyes completely so that corneal damage may occur. There is periorbital oedema and conjunctival oedema and inflammation.

Eye manifestations do not parallel the degree of biochemical thyrotoxicosis, or the need for antithyroid therapy, but exacerbation of eye disease is more common after radioiodine treatment (15% versus 3% on antithyroid drugs). Sight is threatened in only 5–10% of cases, but the discomfort and cosmetic problems cause great patient anxiety.

Investigations

Few investigations are necessary if the appearances are characteristic and bilateral. TSH, fT₃ and fT₄ are measured.

There are a variety of grading systems but none is universally accepted. It is essential to clearly document eye movements and the degree of oedema and inflammation. The exophthalmos should be measured to allow progress to be monitored. MRI or CT of the orbits will exclude retro-orbital space-occupying lesions, show enlarged muscles and oedema, and may show a taut optic nerve due to raised intra-orbital pressure.

Treatment

If the patient is thyrotoxic this should be treated, but this will not directly result in an improvement of the ophthalmopathy, and hypothyroidism must be avoided as it may exacerbate the eye problem. Smoking should be stopped. Treatment of the eyes may be either local or systemic, and always requires close liaison between specialist endocrinologist and ophthalmologist:

Clinical features

Goitres are present on examination in up to 9% of the population. Most commonly a goitre is noticed as a cosmetic defect by the patient or by friends or relatives. The majority are painless, but pain or discomfort can occur in acute varieties. Large goitres can produce dysphagia and difficulty in breathing, implying oesophageal or tracheal compression.

A small goitre may be more easily visible (on swallowing) than palpable. Clinical examination should record the size, shape, consistency and mobility of the gland as well as whether its lower margin can be demarcated (thus implying the absence of retrosternal extension). A bruit may be present. Associated lymph nodes should be sought and the tracheal position determined if possible. Examination should never omit an assessment of the patient’s clinical thyroid status.

Specific enquiry should be made about any medication, especially iodine-containing preparations, and possible exposure to radiation.

Particular points of note are:

Assessment

There are two major aspects of any goitre: its pathological nature and the patient’s thyroid status.

The nature can often be judged clinically. Goitres (Table 19.17) are usually separable into diffuse and nodular types, the causes of which differ.

Table 19.17 Goitre: causes and types

Nodular goitres

Multinodular goitre

Most common is the multinodular goitre, especially in older patients. The patient is usually euthyroid but may be hyperthyroid or borderline with suppressed TSH levels but normal free T₄ and T₃. Multinodular goitre is the most common cause of tracheal and/or oesophageal compression and can cause laryngeal nerve palsy. It may also extend retrosternally.

Tc scan showing multinodular goitre, with predominant involvement of the left lobe of the thyroid (anterior view with arrowed anatomical marker at the sternal notch).

The classical ‘multinodular goitre’ is usually readily apparent clinically, but it should be noted that modern, high-resolution ultrasound frequently reports multiple small nodules in glands which are clinically diffusely enlarged and associated with autoimmune thyroid disease. These nodules are also found in up to 40% of the normal population.

Solitary nodular goitre

Such a goitre presents a difficult problem of diagnosis. Malignancy should be of concern in any solitary nodule – however, the majority of such nodules are cystic or benign and, indeed, may simply be the largest nodule of a multinodular goitre. The diagnostic challenge is to identify the small minority of malignant nodules, which require surgery, from the majority of benign nodules, which do not. Sometimes a history of rapid enlargement, associated lymph nodes or pain may suggest an aggressive malignancy, but most thyroid cancers are painless and slow-growing so that investigations are paramount. Risk factors for malignancy include previous irradiation, longstanding iodine deficiency and occasional familial cases.

Solitary toxic nodules are quite uncommon and may be associated with T₃ toxicosis.

Fibrotic goitre (Riedel’s thyroiditis)

Fibrotic goitre is a rare condition, usually producing a ‘woody’ gland. It is associated with other midline fibrosis and is often difficult to distinguish from carcinoma, being irregular and hard. Clinical clues include systemic symptoms of inflammation and elevation in inflammatory markers; it has been shown to be an IgG₄-related disease.

Investigations

Clinical findings will dictate appropriate initial tests:

Retrosternal goitre showing deviation and compression of trachea on a CT scan.

FNA reduces the necessity for surgery, but there is a 5% false-negative rate, which must be borne in mind (and the patient appropriately counselled). Continued observation is required when an isolated thyroid nodule is assumed to be benign without excision.

Treatment

Embryology

Up to 8 weeks of gestation the sexes share a common development, with a primitive genital tract including the Wolffian and Müllerian ducts. There are additionally a primitive perineum and primitive gonads.

Production of Müllerian inhibitory factor from the early ‘testis’ produces atrophy of the Müllerian duct, while, under the influence of testosterone and dihydrotestosterone, the Wolffian duct differentiates into an epididymis, vas deferens, seminal vesicles and prostate. Androgens induce transformation of the perineum to include a penis, penile urethra and scrotum containing the testes, which descend in response to androgenic stimulation. At birth, testicular volume is 0.5–1 mL.

Physiology

The male

An outline of the hypothalamic-pituitary-gonadal axis is shown in Figure 19.20.

1. Pulses of gonadotrophin-releasing hormone (GnRH) are released from the hypothalamus and stimulate LH and FSH release from the pituitary. LH and FSH are composed of two glycoprotein chains (α and β subunits). The α subunits are identical and are shared with TSH, whilst the β subunit confers specific biological activity.

2. LH stimulates testosterone production from Leydig cells of the testis.

3. Testosterone acts via nuclear androgen receptors which interact with coregulatory proteins to produce the appropriate tissue responses: male secondary sexual characteristics, anabolism and the maintenance of libido. It also acts locally within the testis to aid spermatogenesis. Testosterone circulates largely bound to sex hormone-binding globulin (SHBG) (see p. 942). Testosterone feeds back on the hypothalamus/pituitary to inhibit GnRH secretion.

4. FSH stimulates the Sertoli cells in the seminiferous tubules to produce mature sperm and the inhibins A and B.

5. Inhibin feeds back to the pituitary to decrease FSH secretion. Activin, a related peptide, counteracts inhibin.

Figure 19.20 Male and female hypothalamic-pituitary-gonadal axes. LH and FSH are secreted in pulses in response to hypothalamic GnRH and have differential effects on the gonads (see text). Testosterone and oestrogens have multiple peripheral effects and exert negative feedback on LH secretion. Inhibin exerts negative feedback on FSH secretion.

The secondary sexual characteristics of the male. for which testosterone is necessary are the growth of pubic, axillary and facial hair, enlargement of the external genitalia, deepening of the voice, sebum secretion, muscle growth and frontal balding.

The female

Female physiology is more complex (Figs 19.20, 19.21).

1. In the adult female, higher brain centres impose a menstrual cycle of 28 days upon the activity of hypothalamic GnRH.

2. Pulses of GnRH, at about 2-hour intervals, stimulate release of pituitary LH and FSH.

3. LH stimulates ovarian androgen production by the ovarian theca cells.

4. FSH stimulates follicular development and aromatase activity (an enzyme required to convert ovarian androgens to oestrogens) in the ovarian granulosa cells. FSH also stimulates release of inhibin from ovarian stromal cells, which inhibits FSH release. Activin counteracts inhibin (Fig. 19.20).

5. Although many follicles are ‘recruited’ for development in early folliculogenesis, by day 8–10 a ‘leading’ (or ‘dominant’) follicle is selected for development into a mature Graafian follicle.

6. Oestrogens have a double feedback action on the pituitary (Fig. 19.20). Initially they inhibit gonadotrophin secretion (negative feedback), but later high-level exposure results in increased GnRH secretion and increased LH sensitivity to GnRH (positive feedback), which leads to the mid-cycle LH surge inducing ovulation from the leading follicle (Fig. 19.21).

7. The follicle then differentiates into a corpus luteum, which secretes both progesterone and oestradiol during the second half of the cycle (luteal phase).

8. Oestrogen initially and then progesterone cause uterine endometrial proliferation in preparation for possible implantation; if implantation does not occur, the corpus luteum regresses and progesterone secretion and inhibin levels fall so that the endometrium is shed (menstruation) allowing increased GnRH and FSH secretion.

9. If implantation and pregnancy follow, human chorionic gonadotrophin (HCG) production from the trophoblast maintains corpus luteum function until 10–12 weeks of gestation, by which time the placenta will be making sufficient oestrogen and progesterone to support itself.

Figure 19.21 Hormonal and follicular changes during the normal menstrual cycle.

Secondary sexual characteristics of the female. These are induced by oestrogens, especially development of the breast and nipples, vaginal and vulval growth and pubic hair development. Oestrogens also induce growth and maturation of the uterus and fallopian tubes. They circulate largely bound to SHBG.

FURTHER READING

Carel JC, Léger J. Precocious puberty. N Engl J Med 2008; 358:2366–2377.

Puberty

The mechanisms initiating puberty are poorly understood but are thought to result from withdrawal of central inhibition of GnRH release. Environmental and physical factors are involved in the timing of puberty (including body fat changes, physical exercise) as well as genetic factors (e.g. a G protein-coupled receptor gene, GPR54) required for pubertal maturation. Kisspeptin is the endogenous ligand for kisspeptin receptor KISSIR formerly known as GPR54 and this peptide is believed to play a crucial role in the regulation of GnRH production and the timing of puberty.

LH and FSH are both low in the prepubertal child. In early puberty, FSH begins to rise first, initially in nocturnal pulses; this is followed by a rise in LH with a subsequent increase in testosterone/oestrogen levels. The milestones of puberty in the two sexes are shown in Figure 19.22.

Figure 19.22 The age of development of features of puberty. Stages and testicular size show mean ages, and all vary considerably between individuals. The same is true of height spurt, shown here in relation to other data. Numbers 2–5 indicate stages of development.

In boys, pubertal changes begin at between 10 and 14 years and are complete at between 15 and 17 years. The genitalia develop, testes enlarge and the area of pubic hair increases. Peak height velocity is reached between ages 12 and 17 years during stage 4 of testicular development. Full spermatogenesis occurs comparatively late.

In girls, events start a year earlier. Breast bud enlargement begins at age 9–13 years and continues to 12–18 years. Pubic hair growth commences at ages 9–14 years and is completed at 12–16 years. Menarche occurs relatively late (age 11–15 years) but peak height velocity is reached earlier (at age 10–13 years), and growth is completed much earlier than in boys.

The menopause

The menopause, or cessation of periods, naturally occurs at about the age of 45–55 years. During the late 40s, FSH initially, and then LH concentrations begin to rise, probably as follicle supply diminishes. Oestrogen levels fall and the cycle becomes disrupted. Most women notice irregular scanty periods coming on over a variable period, though in some sudden amenorrhoea or menorrhagia occurs. Eventually the menopausal pattern of low oestradiol levels with grossly elevated LH and FSH levels (usually >50 and >25 U/L, respectively) is established. Premature menopause may also occur surgically, with radiotherapy to the ovaries and with ovarian disease.

The ageing male

In the male, there is no sudden ‘change of life’. However, there is a progressive loss in sexual function with reduction in morning erections and frequency of intercourse.

The age of onset varies widely. Typically, overall testicular volume diminishes and sex hormone-binding globulin (SHBG) and gonadotrophin levels gradually rise, but other men present with low or borderline testosterone without elevation of LH/FSH. Low testosterone certainly increases the risk of osteoporosis and in some studies is associated with increased cardiovascular risk, but it remains unclear to what extent general symptoms of lack of energy, drive, muscle strength and general wellbeing may relate to these hormonal changes. Loss of libido and erectile dysfunction are common symptoms even when hormones are normal, and long-term outcome studies of testosterone replacement are still awaited. Therefore, the decision to offer testosterone replacement to an ageing male is currently based on full clinical and biochemical assessment and full discussion of potential risks (including prostate disease) as well as benefits. If testosterone is unequivocally low (<7 pmol/L) most authorities would recommend replacement. However, few would treat if testosterone is >12 pmol/L with normal LH/FSH. Clinically, a large proportion of cases are in the borderline range (7–12 pmol/L), which can lead to difficulties in reaching a firm diagnosis.