Pituitary and Hypothalamic Disorders

Question 1

What is the anatomy of the pituitary gland and the hypothalamus

Answer 1

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 detects 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.

Question 2

What is the physiology of the hypothalamus

Answer 2

This contains many vital centres for such functions as appe-tite, 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 pitui-tary. 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.
Synthetic hypothalamic hormones and their antagonists are available for the testing of many aspects of endocrine function and for treatment.

Question 3

What is the physiology of the posterior pituitary

Answer 3

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 oversecre-tion of prolactin. There are five major anterior pituitary axes: the gonadotrophin axis, the growth axis, prolactin, the thyroid axis and the adrenal axis.

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 hypotha-lamus. They are then transported along the axon and stored in the posterior pituitary (Fig. 19.7). This means that damage

Question 4

Describe pituitary tumors

Answer 4

Pituitary tumours 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.

Question 5

What are some investigations made in a pituitary tumor

Answer 5

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 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 Goldman 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.
Is there a hormonal excess?
There are three major conditions usually caused by secretion from pituitary adenomas which will show positive immuno-staining 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

excess ACTH secretion (Cushing’s disease and
Nelson’s syndrome): corticotroph adenomas, usually
‘basophil’.
Many tumours are able to synthesize several pituitary hor-mones, 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. Hyperprolactinae-mia 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 a-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 defi-ciency. 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

Question 6

What is the treatment for pituitary tumors

Answer 6

Treatment depends on the type and size of tumor. In general, therapy has three aims:

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

Question 7

What are the differential diagnosis for pituitary or hypothalamic tumors

Answer 7

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.
• 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.

Question 8

Describe hypophysitis and its associated inflammatory masses

Answer 8

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.

Question 9

What is hypopituitarism

Answer 9

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.

Question 10

What is panhypopituitarism

Answer 10

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.

Question 11

What are some symptoms of hypopituitarism

Answer 11

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’).

Question 12

What is the genetics of hypopituitarism

Answer 12

Specific genes are responsible for the development of the anterior pituitary involving interaction between signaling 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 GnH. 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.

Question 13

What are the causes of hypopituitarism

Answer 13

Pituitary and hypothalamic tumours, and surgical or radiotherapy treatment, are the most common.

Question 14

Mention some syndromes associated with hypopituitarism

Answer 14

Kallmann’s syndrome
Septo-optic dysplasia
Sheehan’s syndrome
Pituitary apoplexy
The ‘empty sella’ syndrome

Question 15

What is Kallman’s syndrome

Answer 15

This syndrome is isolated gonado-trophin (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.

Question 16

What is septo-optic dysplasia

Answer 16

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

Question 17

What is Sheehan’s syndrome

Answer 17

This is due to pituitary infarction following postpartum hemorrhage and is rare in developed countries.

Question 18

What is pituitary apoplexy

Answer 18

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.

Question 19

What is the ‘empty sella’ syndrome

Answer 19

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.

Question 20

What are some investigations to make in hypopituitarism

Answer 20

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 Ta 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 mol/L usually indicate an adequate reserve, while levels below 100 mol/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. Occa-sionally, 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.

Question 21

How is hypopituitarism treated

Answer 21

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

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.
• 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.
• 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.

Question 22

What is the physiology and control of the growth hormone

Answer 22

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 (G 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.
• GH acts by binding to a specific (single transmembrane)
receptor located mainly in the liver (Table 19.3). This induces an intracellular phosphorylation cascade involving the JAK/STAT (Janus kinase/signal transducing activators of transcription) pathway (p. 32). STAT proteins are translocated from the cytoplasm into the cell nucleus and cause GH-specific effects by binding to nuclear DNA.
• IGF-1 (insulin-like growth factor-1), a somatomedin stimulates growth and its hepatic secretion is stimulated by a tissue-specific effect of GH on the liver. There are multiple IGF-binding proteins (IGF-BP) in plasma
- IGF-BP3 can be measured clinically to improve assessment of GH status, particularly in children.
The metabolic actions of the system are:
• Increasing collagen and protein synthesis
• Promoting retention of calcium, phosphorus and nitrogen, necessary substrates for anabolism
• Opposing the action of insulin (a ‘counter-regulatory’ hormone effect).
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.

Question 23

What are some factors other than growth hormone involved in linear growth in humans

Answer 23

• Genetic factors. Children of two short parents will probably be short and vice-versa.
• Nutritional factors. Adequate nutrients must be available. Impaired growth can result from inadequate dietary intake or small bowel disease (e.g. coeliac disease).
• General health. Any serious systemic disease in childhood is likely to reduce growth (e.g. chronic kidney disease or chronic infection).
• Intrauterine growth retardation. These infants often grow poorly in the long term, while infants with simple prematurity usually catch up. There is some evidence that low birthweight may predispose to hypertension, diabetes and other health problems in later adult life (p. 195).
• Emotional deprivation and psychological factors.
These can impair growth by complex, poorly understood mechanisms, probably involving temporarily decreased
GH secretion.
In general, there are three overlapping phases of growth: infantile (0-2 years), which appears largely substrate (food) dependent; childhood (age 2 years to puberty), which is largely GH dependent; and the adolescent ‘growth spurt’ dependent on GH and sex hormones.

Question 24

How do you assess for growth

Answer 24

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.
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:
(Maternal height + 14 cm (5.5 inches) + Paternal height) /2
and for a girl:
(Paternal height - 14 cm (5.5 inches) + Maternal height)/2
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.

Question 25

When children or their parents complain of short stature, particular attention should focus on

Answer 25

Intrauterine growth retardation, weight and gestation at birth
• Possible systemic disorders - any system, but especially small bowel disease
• Evidence of skeletal, chromosomal or other congenital
abnormalities
• Endocrine status - particularly thyroid
• Dietary intake and use of drugs, especially steroids for asthma
• Emotional, psychological, family and school problems.
School, general practitioner, clinic and home records of height and weight should be obtained if possible to allow growth-velocity calculation. If unavailable, such data must be obtained prospectively.
A child with normal growth velocity is unlikely to have significant endocrine disease and the commonest cause of short stature in this situation is pubertal or ‘constitutional’ delay. However, low growth velocity without apparent systemic cause requires further investigation. Sudden cessation of growth suggests major physical disease; if no gastrointes-tinal, respiratory, renal or skeletal abnormality is apparent, then a cerebral tumour or hypothyroidism is likeliest.
Consistently slow-growing children require full endocrine assessment. Features of the more common causes of growth failure are given in Table 19.9.
Around the time of puberty, where constitutional delay is clearly shown and symptoms require intervention, then very-low-dose sex steroids in 3- to 6-month courses will usually induce acceleration of growth.

Question 26

What are some investigations to make if short stature is suspected

Answer 26

Thyroid function tests: serum TSH and free T4 to exclude hypothyroidism
• GH status. Basal levels are of little value. Dynamic tests include the GH response to insulin (the ‘gold standard’;
Box 19.2), glucagon, arginine, exercise and clonidine.
Tests should only be performed in centres experienced in their use and interpretation. Normal responses depend on test and GH assay used Blood levels of IGF-1 (insulin-like growth factor-1) and IGF-BP3 (binding protein 3) may provide evidence of GH undersecretion
• Assessment of bone age. Non-dominant hand and wrist X-rays allow assessment of bone age by comparison with standard charts
•Karyotyping in females. Turner’s syndrome (p. 978) is associated with short stature. It is thought that this is due to a defect in the short stature homeobox (SHOX) gene which has a role in non-GH mediated growth.

Question 27

How do you treat short stature

Answer 27

Systemic illness should be treated and primary hypothyroidism treated with levothyroxine.
For GH insufficiency, recombinant GH (somatropin) is given as nightly injections in doses of 0.17-0.35 mg/kg per week, with dose adjustments made according to clinical response and IGF-1 levels. Treatment is expensive and should be supervised in expert centres.
GH treatment in so-called ‘short normal’ children has not been shown to produce any worthwhile increase in final height. In Turner’s syndrome (see p. 983) large doses of GH are effective in increasing final height, especially in combination with appropriate very-low-dose estrogen replacement.
Familial cases of resistance to GH owing to an abnormal GH receptor (Laron-type dwarfism) are well described. They are very rare but may respond to therapy with synthetic IGF-1 (mecasermin).

Question 28

What are the most common causes for tall stature

Answer 28

The most common causes are hereditary (two tall parents!), idiopathic (constitutional) or early development. It can occasionally be due to hyperthyroidism. Other causes include chromosomal abnormalities (e.g. Klinefelter’s syndrome, Marfan’s syndrome) or metabolic abnormalities. GH excess is a very rare cause and is usually clinically obvious.

Question 29

What are some pituitary hypersecretion syndromes

Answer 29

Acromegaly and gigantism
Hyperprolactinaemia
Cushing’s syndrome
Nelson’s syndrome
Hypersecretion of other pituitary hormones

Question 30

What is acromegaly and gigantism

Answer 30

Growth hormone stimulates skeletal and soft tissue growth.
GH excess therefore produces gigantism in children (if acquired before epiphyseal fusion) and acromegaly in adults.
Both are due to a GH secreting pituitary tumour (somatotroph adenoma) in almost all cases. Hyperplasia due to ectopic GHRH excess is very rare. Overall incidence is approximately
3-4/million per year and the prevalence is 50-80/million world-wide. Acromegaly usually occurs sporadically, although gene mutations can rarely give rise to familial acromegaly, typically the AIP gene in familial isolated pituitary adenoma.

Question 31

What are some clinical features of acromegaly and gigantism

Answer 31

Symptoms and signs of acromegaly are shown in Figure
19.11. One-third of patients present with changes in appear-ance, one-quarter with visual field defects or headaches; in the remainder the diagnosis is made by an alert observer in another clinic, e.g. GP, diabetic, hypertension, dental, derma-tology. Sleep apnoea is common and requires investigation and treatment if there are suggestive symptoms (see p. 818).
Sweating, headaches and soft tissue swelling are particularly useful symptoms of persistent growth hormone secretion.
Headache is very common in acromegaly and may be severe even with small tumours; it is often improved after surgical cure or with somatostatin analogues.

Question 32

What are some investigations to make in hypopituitarism

Answer 32

GH levels may exclude acromegaly if undetectable but a detectable value is non-diagnostic taken alone.
Normal adult levels are <0.5 Mg/L for most of the day except during stress or a ‘GH pulse’.
• A glucose tolerance test is diagnostic if there is no suppression of GH. Acromegalics fail to suppress GH below 0.3 ug/L and some show a paradoxical rise; about 25% of acromegalics have a positive diabetic glucose tolerance test.
• IGF-1 levels are almost always raised in acromegaly - a single plasma level of IGF-1 reflects mean 24-hour GH levels and is useful in diagnosis. A normal IGF-1 together with random growth hormone <1 ug/L may be taken to exclude acromegaly if the diagnosis is clinically unlikely.
• Visual field examination: defects are common, e.g. bitemporal hemianopia.
• MRI scan of pituitary if above tests abnormal. This will almost always reveal the pituitary adenoma.
• Pituitary function: partial or complete anterior hypopituitarism is common
• Prolactin: mild to moderate hyperprolactinaemia occurs in 30% of patients (see Fig. 19.13). In some, the adenoma secretes both GH and prolactin.

Question 33

What is the management and treatment for acromegaly and gigantism

Answer 33

Untreated acromegaly results in markedly reduced survival.
Most deaths occur from heart failure, coronary artery disease and hypertension-related causes. In addition, there is an increase in deaths due to neoplasia, particularly large bowel tumours (some specialist centres advocate regular colonoscopy to detect and remove colonic polyps to reduce the risk of colonic cancer). Treatment is therefore indicated in all except the elderly or those with minimal abnormalities. The aim of therapy is to achieve a mean growth hormone level below 2.5 Mg/L; this is not always ‘normal’ but has been shown to reduce mortality to normal levels and is therefore considered a ‘safe’ GH level. A normal IGF-1 is also a goal of therapy. Occasionally there can be discordance between GH and IGF-1 levels, which can create management dilemmas.
When present, hypopituitarism should be corrected (see p.
950) and concurrent diabetes and/or hypertension should be treated conventionally; both usually improve with treatment of the acromegaly.
The general advantages and disadvantages of surgery, radiotherapy and medical treatment are discussed on page
947. Progress can be assessed by monitoring GH and IGF-1 levels.
• Surgery. Trans-sphenoidal surgery is the appropriate first-line therapy. It will result in clinical remission in a majority of cases (60-90%) with pituitary microadenoma, but in only 50% of those with macroadenoma. Very high preoperative GH and IGF-1 levels are also poor prognostic markers of surgical cure. Surgical success rates are variable and highly dependent upon experience, and a specialist pituitary surgeon is essential. Transfrontal surgery is rarely required except for massive macroadenomas. There is approximately a 10% recurrence rate.

Pituitary radiotherapy. External radiotherapy is normally used after pituitary surgery fails to normalize GH levels rather than as primary therapy. It is often combined with medium-term treatment with a somatostatin analogue, dopamine agonist or GH antagonist because of the slow biochemical response to radiotherapy, which may take 10 years or more and is often associated with hypopituitarism which makes it unattractive in patients of reproductive age. Stereotactic radiotherapy is used in some centres.
• Medical therapy. There are three receptor targets for the treatment of acromegaly: pituitary somatostatin receptors and dopamine (D2) receptors and growth hormone receptors in the periphery.
- Somatostatin receptor agonists. Octreotide and lanreotide are synthetic analogues of somatostatin
(p. 951) that selectively act on somatostatin receptor subtypes (SST2 and SST5), which are highly expressed in growth-hormone-secreting tumours.
These drugs were used as a short-term treatment whilst other modalities become effective, but now are sometimes used as primary therapy. They reduce GH and IGF levels in most patients but not all achieve treatment targets. Both drugs are typically administered as monthly depot injections and are generally well tolerated but are associated with an increased incidence of gallstones and are expensive.
- Dopamine agonists. Dopamine agonists act on D2 receptors (p. 878) and can be given to shrink tumours prior to definitive therapy or to control symptoms and persisting GH secretion; they are probably most effective in mixed growth-hormone-producing (somatotroph) and prolactin-producing (mammotroph) tumours. Typical doses are bromocriptine 10-60 mg daily or cabergoline 0.5 mg daily (higher than for prolactinomas). Given alone they reduce GH to ‘safe’ levels in only a minority of cases - but they are useful for mild residual disease or in combination with somatostatin analogues. Drugs with combined somatostatin and dopamine receptor activity are under development.
- Growth hormone antagonists. Pegvisomant (a genetically modified analogue of GH) is a GH receptor antagonist which has its effect by binding to and preventing dimerization of the GH receptor. It does not lower growth hormone levels or reduce tumour size but has been shown to normalize IGF-1 levels in 90% of patients. It is given by a daily injection and its main role at the present time is treatment of patients in whom GH and IF levels cannot be reduced to safe levels with somatostatin analogues alone, surgery or radiotherapy.