Chapter 19 Endocrine disease

Introduction

The pituitary gland and hypothalamus

Presentations of pituitary and hypothalamic disease

Growth and abnormal stature

Normal growth

Growth failure: short stature

Tall stature

Pituitary hypersecretion syndromes

Acromegaly and gigantism

Hyperprolactinaemia

Cushing’s syndrome

Hypersecretion of other pituitary hormones

Goitre (thyroid enlargement)

Thyroid carcinoma

Reproduction and sex

Clinical features of disorders of sex and reproduction

Disorders in the male

Disorders in the female

Subfertility

Disorders of sexual differentiation

The adrenal axis

The adrenal cortex

The adrenal medulla

The thirst axis

Disorders of calcium metabolism

Other endocrine disorders

Diseases of many glands

Ectopic hormone secretion

Introduction

The endocrine system consists of glands that exert their actions at distant parts of the body via the production of biologically active hormones secreted into the bloodstream. Unlike the neurological system, which produces an immediate response, the endocrine system typically has a slower and longer lasting effect on the body. The main endocrine glands are the pituitary, thyroid, adrenals, gonads, parathyroids and pancreas and the common endocrine problems seen in clinical practice are shown in Figure 19.1. The pituitary gland, a pea-sized structure situated at the base of the brain, plays a key role in the control and feedback mechanisms of the endocrine system and has been termed the ‘conductor of the endocrine orchestra’.

Figure 19.1 The major endocrine organs and common endocrine problems.

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

Examination

A full general examination is essential to endocrine assessment because endocrine disorders affect all organ systems. Weight, height, body mass index (BMI), blood pressure and general habitus should all be documented, together with presence or absence of specific signs of deficiency or excess of individual hormone axes (signs of hyper- or hypo-thyroidism, acromegaly, Cushing’s).

In people with suspected pituitary disease, visual fields and adjacent cranial nerves should be assessed clinically. In thyroid disease, presence of goitre or thyroid eye disease should be documented. Skin changes may give clinical clues, including pigmentation (Addison’s and Nelson’s), vitiligo (autoimmune endocrinopathies), acanthosis nigricans (polycystic ovary syndrome (PCOS) and diabetes), skin thinning (Cushing’s, hypogonadism) or thickening (acromegaly, PCOS) and bruising and striae (Cushing’s). Hirsutism is a key sign in women and signs of hair loss from the head (following a change in thyroid function, androgen excess in women or normal virilization in men) or from the body, axillary and pubic areas (hypogonadism) may occur in both sexes.

In children, height and pubertal status are an essential part of the clinical examination.

Specific clinical signs associated with particular endocrine diseases are discussed in detail in the appropriate sections.

Aetiology of endocrine disease

Aetiological mechanisms common to many endocrine disorders include:

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

Hormonal activity

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:

Cell surface or membrane receptors: typically transmembrane receptors which contain hydrophobic sections spanning the lipid-rich plasma membrane and which trigger internal cellular messengers (see also p. 18)

Nuclear receptors which typically bind hormones and translocate them to the nucleus where they bind hormone response elements of nuclear DNA via characteristic amino-acid sequences (e.g. so-called ‘zinc fingers’, see p. 27).

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

Mechanisms of hormone-receptor action

Common structural mechanisms of hormone-receptor action are illustrated in Figure 2.9 (p. 25) and include:

G-protein coupled receptors (7-transmembrane or serpentine receptors). These bind hormones on their extracellular domain and activate the membrane G-protein complex with their intracellular domain. The activated complex may then:

stimulate cyclic AMP (cAMP) generation by adenylate cyclase – activating further intracellular kinases and leading to phosphorylation

activate phospholipase C (PLC) leading to generation of inositol 1,4,5-triphosphate (IP₃) and release of intracellular calcium – in turn leading to calmodulin-dependent kinase activity and phosphorylation

lead to diacylglycerol (DAG) activation of C-kinase and subsequent protein phosphorylation.

Most peptide hormones act via G-protein coupled receptors.

Dimeric transmembrane receptors, from several receptor superfamilies, bind hormone in their extracellular components (sometimes causing the dimerization of the receptor monomer) and directly phosphorylate intracellular messengers via their intracellular components, leading to a variety of intracellular activation cascades. Growth hormone, prolactin and insulin-like growth factor-1 (IGF-1) act via this type of receptor.

Lipid-soluble molecules pass through the cell membrane and typically bind with their nuclear receptors in the cell cytoplasm before translocation of the activated hormone-receptor complex to the nucleus where it binds to nuclear DNA, often in combination with a multi-component complex of promoters, inhibitors and transcription factors. This interaction usually leads to increased transcription of the relevant gene product. Steroid and thyroid hormones act via this type of receptor.

Hormone release and binding to receptors. The activation of intracellular kinases, phosphorylation, release of intracellular calcium and other ‘second messenger’ pathways and the direct stimulation of DNA transcription results in some or all of the following:

Stimulation or release of pre-formed hormone from storage granules

Stimulation or synthesis of hormone and other cellular components

Opening or closing of ion or water channels in the cell membrane (e.g. calcium channels or aquaporin water channels)

Activation or deactivation of other DNA binding proteins leading to stimulation or inhibition of DNA transcription.

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.

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’).

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:

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 by the thyroid and the synthesis and release of thyroxine (T₄) and triiodothyronine (T₃).

Serum levels of T₃ and T₄ are 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 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 fall to normal.

If, however, T₃ and T₄ levels are low, for example after thyroidectomy, increased amounts of TRH and TSH are secreted, stimulating the remaining thyroid to produce more T₃ and T₄; blood levels of T₃ and T₄ may be restored to normal, 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.

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:

‘Primary’ hormone deficiency due to a disease process in the endocrine end-organ (thyroid, adrenal or gonad) will lead to a loss of negative feedback and subsequent elevation in the corresponding anterior pituitary hormone. Conversely, an abnormal hormone excess due to a disease process in the primary endocrine gland, or excess amount of exogenous hormone, will lead to increased negative feedback and suppression of the corresponding pituitary hormones.

In ‘secondary gland failure’ there are low or ‘inappropriately normal’ levels of the pituitary trophic hormone in the face of a low end-organ hormone level. For example, if a patient has low circulating free T₃ (fT₃) and T₄ levels in the context of a low TSH, pituitary disease should be suspected. Equally, the presence of a non-suppressed plasma ACTH in the context of Cushing’s syndrome implies that the pituitary rather than the adrenal itself is the cause.

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.

Hormone binding proteins

Many hormones are transported in the bloodstream from the primary gland to their distant target organ attached to a specific binding protein (p. 940). It is more helpful to measure the free hormone rather than total bound hormone level, as this is the part that is biologically active. Some modern assays attempt to measure the free hormone level directly (e.g. free T₄) and are therefore a more accurate reflection of biological activity, although there are often technical problems with this approach and many assays still measure total hormone level.

Cortisol, which is bound to cortisol binding globulin (CBG), and testosterone, which is bound to sex hormone binding globulin (SHBG), are still usually measured in their total form and can be affected by alterations in binding protein levels. In women who are pregnant or on the combined oral contraceptive pill, high oestrogen levels may lead to an elevation in CBG which can overestimate cortisol and give the false impression of hypercortisolaemia. In people with diabetes mellitus or other insulin-resistant states which may lower SHBG levels, low total testosterone levels may give the false impression of androgen deficiency. Conversely, hyperthyroidism or oestrogen excess can cause an elevation in SHBG, leading to apparently high total testosterone levels. As with all endocrine results, the data need to be interpreted in the clinical context.

Patterns of hormonal secretion

Hormone secretion can be continuous or intermittent, for example:

Continuous secretion is shown by the thyroid hormones, with a half-life of 7–10 days for T₄ and 6–10 hours for T₃, and with little variation in levels over the day, month and year

Pulsatile secretion is the normal pattern for the gonadotrophins, LH and FSH, with major pulses released every 1–2 hours depending on the phase of the menstrual cycle. Growth hormone is also secreted in a pulsatile fashion, with undetectable levels in between pulses. A single measurement is therefore not helpful to diagnose GH deficiency or excess.

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.

Testing endocrine function

Endocrine function is assessed by measurement of hormone levels in blood (or more precisely in plasma or serum) and sometimes in other body fluids on samples obtained basally and in response to stimulation and suppression tests.

Basal blood levels

Assays for all clinically relevant pituitary and end-organ hormones are available.

The time, day and condition of measurement make great differences to hormone levels, and the method and timing of samples therefore depends upon the characteristics of the endocrine system involved. There are also sex, developmental and age differences.

Basal levels are especially useful for systems with long half-lives (e.g. T₄ and T₃, IGF-1, androstenedione, SHBG). These vary little over the short term and random samples are therefore satisfactory.

Basal samples for many hormones need to be interpreted with respect to normal ranges for the time of day/month, diet or posture concerned. Hormones with a marked circadian rhythm (testosterone in men, cortisol, ACTH, 17αOH-progesterone) must be measured at appropriate time of day (typically at 08:00 to 10:00 but, e.g. at 24:00 to demonstrate normal low levels of cortisol at this time). LH/FSH, oestrogen and progesterone vary with time of menstrual cycle and renin/aldosterone vary with sodium intake, posture and age. For these hormones, all relevant details must be recorded or the results may prove uninterpretable.

Stress-related hormones

Measurement of stress-related hormones may be problematic either because the patient is stressed by hospital attendance or venepuncture, leading to falsely high levels (e.g. catecholamines, prolactin where sampling via an indwelling needle some time after initial venepuncture may be required) or because low levels in a non-stressed individual are unable to confirm an adequate reserve required for normal physiological stress (cortisol and GH).

Urine collections

Collections over 24 hours have the advantage of providing an ‘integrated mean’ of a day’s secretion but in practice are often incomplete or wrongly timed. They also vary with sex and body size or age. Written instructions should be provided for the patient to ensure accurate collection. Examples of hormones measured in this way are catecholamines and urinary free cortisol levels.

Saliva

Saliva is sometimes used for steroid estimations, especially in children or for samples taken at home. Midnight salivary cortisol levels are increasingly used for the diagnosis of Cushing’s syndrome due to the practical difficulties in obtaining a midnight blood sample.

Stimulation and suppression tests

These tests are used when basal levels give equivocal information. In general, stimulation tests are used to confirm suspected deficiency, and suppression tests to confirm suspected excess of hormone secretion. These tests are valuable in many instances.

For example, where the secretory capacity of a gland is damaged, maximal stimulation by the trophic hormone will give a diminished output. Thus, in the short ACTH stimulation test for adrenal reserve (Box 19.1, Fig. 19.5a), the healthy subject shows a normal response while the subject with primary hypoadrenalism (Addison’s disease) demonstrates an impaired cortisol response to tetracosactide (an ACTH analogue).

Box 19.1

Short ACTH (tetracosactide) stimulation test

Indication

Diagnosis of Addison’s disease

Screening test for ACTH deficiency

Procedure

Intravenous cannula for sampling

Any time of day, but best at 09:00 hours; non-fasting

Tetracosactide 250 µg, i.v. or i.m. at time 0

Measure serum cortisol at time 0 and time +30 min

Normal response

30 min cortisol >600 nmol/L ^a

– (400–600 nmol/L borderline and may indicate deficiency)

^a Precise cortisol normal ranges are variable between laboratories and assays – appropriate local reference ranges must be used.

Figure 19.5 Short ACTH stimulation and dexamethasone tests. (a) This test shows a normal response in a healthy subject and a decreased response in a patient with Addison’s disease. (b) Dexamethasone suppression tests in a normal subject and in a patient with Cushing’s disease showing inadequate suppression.

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, in contrast to normal subjects. Figure 19.5b shows the response of a normal subject given dexamethasone 1 mg at midnight; cortisol is suppressed the following morning. The subject with Cushing’s disease shows inadequate suppression.

The detailed protocol for each test must be followed exactly, since differences in technique will produce variations in results.

The pituitary gland and hypothalamus

Anatomy

Most peripheral hormone systems are controlled by the hypothalamus and pituitary. The hypothalamus is sited at the base of the brain around the third ventricle and above the pituitary stalk, which leads down to the pituitary itself, carrying the hypophyseal-pituitary portal blood supply.

The anatomical relations of the hypothalamus and pituitary (Fig. 19.6) include the optic chiasm just above the pituitary fossa; any expanding lesion from the pituitary or hypothalamus can thus produce visual field defects by pressure on the chiasm. Such upward expansion of the gland through the diaphragma sellae is termed ‘suprasellar extension’. Lateral extension of pituitary lesions may involve the vascular and nervous structures in the cavernous sinus and may rarely reach the temporal lobe of the brain. The pituitary is itself encased in a bony box, therefore any lateral, anterior or posterior expansion must cause bony erosion.

Figure 19.6 MR image of a sagittal section of the brain, showing the pituitary fossa and adjacent structures.

(By kind permission of Dr Martin Jeffree.)

Embryologically, the anterior pituitary is formed from an upgrowth of Rathke’s pouch (ectodermal) which meets an outpouching of the third ventricular floor which becomes the posterior pituitary. This unique combination of primitive gut and neural tissue provides an essential link between the rapidly responsive central nervous system and the longer-acting endocrine system. Several transcription factors – LHX3, HESX1, PROP1, POU1F1 – are responsible for the differentiation and development of the pituitary cells. Mutation of these produces pituitary disease.

Physiology

Hypothalamus

This contains many vital centres for such functions as appetite, thirst, thermal regulation and sleeping/waking. It acts as an integrator of many neural and endocrine inputs to control the release of pituitary hormone-releasing factors. It plays a role in the circadian rhythm, menstrual cyclicity, and responses to stress, exercise and mood.

Hypothalamic neurones secrete pituitary hormone-releasing and -inhibiting factors and hormones (Table 19.3) into the portal system which run down the stalk to the pituitary. As well as the classical hormones illustrated in Figure 19.7, the hypothalamus also contains large amounts of other neuropeptides and neurotransmitters such as neuropeptide Y, vasoactive intestinal peptide (VIP) and nitric oxide that can also alter pituitary hormone secretion.

Table 19.3 Hormones and receptors of the hypothalamic–pituitary axis

Figure 19.7 Hypothalamic releasing hormones and the pituitary trophic hormones. See the text for an explanation.

Synthetic hypothalamic hormones and their antagonists are available for the testing of many aspects of endocrine function and for treatment.

Anterior pituitary

The majority of anterior pituitary hormones are under predominantly positive control by the hypothalamic releasing hormones apart from prolactin, which is under tonic inhibition by dopamine. Pathological conditions interrupt the flow of hormones between the hypothalamus and pituitary gland and therefore cause deficiency of most hormones but oversecretion of prolactin. There are five major anterior pituitary axes: the gonadotrophin axis, the growth axis, prolactin, the thyroid axis and the adrenal axis.

Posterior pituitary

The posterior pituitary is neuro-anatomically connected to specific hypothalamic nuclei, and acts merely as a storage organ. Antidiuretic hormone (ADH, also called vasopressin) and oxytocin, both nonapeptides, are synthesized in the supraoptic and paraventricular nuclei in the anterior hypothalamus. They are then transported along the axon and stored in the posterior pituitary (Fig. 19.7). This means that damage to the stalk or pituitary alone does not prevent synthesis and release of ADH and oxytocin. ADH is discussed on page 991; oxytocin produces milk ejection and uterine myometrial contraction.

Presentations of pituitary and hypothalamic disease

Diseases of the pituitary can cause under- or overactivity of each of the hypothalamo-pituitary-end-organ axes which are under the control of this gland. The clinical features of the syndromes associated with such altered pituitary function, e.g. Cushing’s syndrome, can be the presenting symptom of pituitary disease or of end-organ disease and are discussed later. First, however, we look at clinical features of pituitary disease which are common to all hormonal axes.

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:

local effects of a tumour

excess hormone secretion

the result of inadequate production of hormone by the remaining normal pituitary, i.e. hypopituitarism.

Table 19.4 Characteristics of common pituitary and related tumours

Tumour or condition	Usual size	Most common clinical presentation
Prolactinoma	Most <10 mm (microprolactinoma)	Galactorrhoea, amenorrhoea, hypogonadism, erectile dysfunction
	Some >10 mm (macroprolactinoma)	As above plus headaches, visual field defects and hypopituitarism
Acromegaly	Few mm to several cm	Change in appearance, visual field defects and hypopituitarism
Cushing’s disease	Most small: few mm (some cases are hyperplasia)	Central obesity, cushingoid appearance (local symptoms rare)
Nelson’s syndrome	Often large: >10 mm	Post-adrenalectomy, pigmentation, sometimes local symptoms
Non-functioning tumours	Usually large: >10 mm	Visual field defects; hypopituitarism (microadenomas may be incidental finding)
Craniopharyngioma	Often very large and cystic (skull X-ray abnormal in >50%; calcification common)	Headaches, visual field defects, growth failure (50% occur below age 20; about 15% arise from within sella)

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

Treatment

Treatment depends on the type and size of tumour (Table 19.5). In general, therapy has three aims:

Table 19.5 Comparisons of primary treatments for pituitary tumours

Treatment method	Advantages	Disadvantages
Surgical
Trans-sphenoidal adenomectomy or hypophysectomy	Relatively minor procedure Potentially curative for microadenomas and smaller macroadenomas	Some extrasellar extensions may not be accessible Risk of CSF leakage and meningitis
Transcranial (usually transfrontal)	Good access to suprasellar region	Major procedure; danger of frontal lobe damage High chance of subsequent hypopituitarism
Radiotherapy
External (40–50 Gy)	Non–invasive Reduces recurrence rate after surgery	Slow action, often over many years Not always effective Possible late risk of tumour induction
Stereotactic	Precise administration of high dose to lesion	Long-term follow-up data limited
Medical
Dopamine agonist therapy (e.g. bromocriptine, cabergoline)	Non-invasive; reversible	Usually not curative; significant side-effects in minority Concerns about fibrotic reactions
Somatostatin analogue therapy (octreotide, lanreotide)	Non-invasive; reversible	Usually not curative; gallstones; expensive
Growth hormone receptor antagonist (pegvisomant)	Highly selective	Usually not curative; very expensive

Removal/control of tumour

Surgery via the trans-sphenoidal route is usually the treatment of choice. Very large tumours are occasionally removed via the open transcranial (usually transfrontal) route.

Radiotherapy – by conventional linear accelerator or newer stereotactic techniques – is usually employed when surgery is impracticable or incomplete, as it controls but rarely abolishes tumour mass. The conventional regimen involves a dose of 45 Gy, given as 20–25 fractions via three fields. Stereotactic techniques use either a linear accelerator or multiple cobalt sources (‘gamma-knife’).

Medical therapy with somatostatin analogues and/or dopamine agonists sometimes causes shrinkage of specific types of tumour (see p. 954) and if successful can be used as primary therapy.

Reduction of excess hormone secretion

Reduction is usually obtained by surgical removal but sometimes by medical treatment. Useful control can be achieved with dopamine agonists for prolactinomas or somatostatin analogues for acromegaly, but ACTH secretion usually cannot be controlled by medical means. Growth hormone antagonists are also available for acromegaly (p. 955).

Replacement of hormone deficiencies

Replacement of hormone deficiencies, i.e. hypopituitarism, is discussed below (see Table 19.8).

Table 19.8 Replacement therapy for hypopituitarism

Axis	Usual replacement therapies
Adrenal	Hydrocortisone 15–40 mg daily (starting dose 10 mg on rising/5 mg lunchtime/5 mg evening)
Adrenal	(Normally no need for mineralocorticoid replacement)
Thyroid	Levothyroxine 100–150 µg daily
Gonadal
Male	Testosterone intramuscularly, orally, transdermally or implant
Female	Cyclical oestrogen/progestogen orally or as patch
Fertility	HCG plus FSH (purified or recombinant) or pulsatile GnRH to produce testicular development, spermatogenesis or ovulation
Growth	Recombinant human GH used routinely to achieve normal growth in children
Growth	Also advocated for replacement therapy in adults where GH has effects on muscle mass and wellbeing
Thirst	Desmopressin 10–20 µg one to three times daily by nasal spray or orally 100–200 µg three times daily
Thirst	Carbamazepine, thiazides and chlorpropamide are very occasionally used in mild diabetes insipidus
Breast (prolactin inhibition)	Dopamine agonist (e.g. cabergoline, 500 µg weekly)

Small tumours producing no significant symptoms, pressure or endocrine effects may be observed with appropriate clinical, visual field, imaging and endocrine assessments.

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.

Deficiency of hypothalamic releasing hormones or of pituitary trophic hormones can be selective or multiple. Thus isolated deficiencies of GH, LH/FSH, ACTH, TSH and vasopressin (ADH) are all seen, some cases of which are genetic and congenital and others sporadic and autoimmune or idiopathic in nature.

Multiple deficiencies usually result from tumour growth or other destructive lesions. There is generally a progressive loss of anterior pituitary function. GH and gonadotrophins are usually first affected. Hyperprolactinaemia, rather than prolactin deficiency, occurs relatively early because of loss of tonic inhibitory control by dopamine. TSH and ACTH are usually last to be affected.

Panhypopituitarism refers to deficiency of all anterior pituitary hormones; it is most commonly caused by pituitary tumours, surgery or radiotherapy. Vasopressin (ADH) and oxytocin secretion will be significantly affected only if the hypothalamus is involved by a hypothalamic tumour or major suprasellar extension of a pituitary lesion, or if there is an infiltrative/inflammatory process. Posterior pituitary deficiency is rare in an uncomplicated pituitary adenoma.

Genetics of hypopituitarism

Specific genes are responsible for the development of the anterior pituitary involving interaction between signalling molecules and transcription factors. For example, mutations in PROP1 and POU1F1 (previously PIT-1) prevent the differentiation of anterior pituitary cells (precursors to somatotroph, lactotroph, thyrotroph and gonadotroph cells), leading to deficiencies of GH, prolactin, TSH and GnRH. In addition, novel mutations within GH and GHRH receptor genes have been identified which may explain the pathogenesis of isolated GH deficiency in children. Despite these advances, most cases of hypopituitarism do not have specific identifiable genetic causes.

Causes

Disorders causing hypopituitarism are listed in Table 19.6. Pituitary and hypothalamic tumours, and surgical or radiotherapy treatment, are the most common.

Table 19.6 Causes of hypopituitarism

Congenital	Traumatic
Isolated deficiency of pituitary hormones (e.g. Kallmann’s syndrome) POU1F1 (Pit-1), Prop1, HESX1 mutations	Skull fracture through base Surgery, especially transfrontal Perinatal trauma
	Infiltrations
Infective	Sarcoidosis Langerhans’ cell histiocytosis Hereditary haemochromatosis Hypophysitis Postpartum Giant cell
Basal meningitis (e.g. tuberculosis) Encephalitis Syphilis
Vascular
Pituitary apoplexy Sheehan’s syndrome (postpartum necrosis) Carotid artery aneurysms
	Others
	Radiation damage Fibrosis Chemotherapy Empty sella syndrome
Immunological	‘Functional’
Autoimmune (lymphocytic) hypophysitis Pituitary antibodies	Anorexia nervosa Starvation Emotional deprivation
Neoplastic
Pituitary or hypothalamic tumours
Craniopharyngioma
Meningiomas
Gliomas
Pinealoma
Secondary deposits, especially breast
Lymphoma

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.

Investigations

Each axis of the hypothalamic-pituitary system requires separate investigation. However, the presence of normal gonadal function (ovulation/menstruation or normal libido/erections) suggests that multiple defects of anterior pituitary function are unlikely.

Tests range from the simple basal levels (e.g. free T₄ for the thyroid axis), to stimulatory tests for the pituitary, and tests of feedback for the hypothalamus (Table 19.7). Assessment of the hypothalamic-pituitary-adrenal axis is complex: basal 09:00 hours cortisol levels above 400 nmol/L usually indicate an adequate reserve, while levels below 100 nmol/L predict an inadequate stress response. In many cases basal levels are equivocal and a dynamic test is essential: the insulin tolerance test (Box 19.2) is widely regarded as the ‘gold standard’ but the short ACTH stimulation test (Box 19.1), though an indirect measure, is used by many as a routine test of hypothalamic-pituitary-adrenal status. Occasionally, the difference between ACTH deficiency and normal HPA axis can be subtle, and the assessment of adrenal reserve is best left to an experienced endocrinologist.

Box 19.2