Endocrine disease

Chapter 19 Endocrine disease




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’.





Clinical presentation of endocrine disease






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.







Hormonal activity






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).




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:



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:



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:







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).



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:







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.










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).




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.



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






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:



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)








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







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.






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).



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.



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.




Treatment




image Steroid and thyroid hormones are essential for life. Both are given as oral replacement drugs, as in primary thyroid and adrenal deficiency, aiming to restore the patient to clinical and biochemical normality (Table 19.8) and levels are monitored by routine hormone assays. Note: Thyroid replacement should not commence until normal glucocorticoid function has been demonstrated or replacement steroid therapy initiated, as an adrenal ‘crisis’ may otherwise be precipitated.


image Sex hormones are replaced with androgens and oestrogens, both for symptomatic control and to prevent long-term problems related to deficiency (e.g. osteoporosis).


image When fertility is desired, gonadal function is stimulated directly by human chorionic gonadotrophin (HCG, mainly acting as LH), purified or biosynthetic gonadotrophins, or indirectly by pulsatile gonadotrophin-releasing hormone (GnRH – also known as luteinizing hormone-releasing hormone, LHRH); all are expensive and time-consuming and should be restricted to specialist units.


image GH therapy is given in the growing child, under the care of a paediatric endocrinologist. In adult GH deficiency, GH therapy also produces improvements in body composition, work capacity and psychological wellbeing, together with reversal of lipid abnormalities associated with a high cardiovascular risk, and often results in significant symptomatic benefit in some cases. NICE recommends GH replacement for people with severe GH deficiency and significant quality of life impairment. It is expensive and in the UK costs £2500–6000 per annum.


image Glucocorticoid deficiency may mask impaired urine concentrating ability, diabetes insipidus only becoming apparent after steroid replacement because steroids are required for excretion of free water.

Stay updated, free articles. Join our Telegram channel

Apr 1, 2017 | Posted by in GENERAL & FAMILY MEDICINE | Comments Off on Endocrine disease

Full access? Get Clinical Tree

Get Clinical Tree app for offline access