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Nussey S, Whitehead S. Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers; 2001.

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Endocrinology: An Integrated Approach.

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Chapter 7The pituitary gland

Chapter objectives

Knowledge of


Anatomical and functional connections of the hypothalamo-pituitary axis


The causes of hypopituitarism, their investigation and treatment


The control of post-natal growth and its abnormalities


The pathophysiology of pituitary adenomas and their treatment


The regulation of circadian rhythms


The pathophysiology of obesity


The physiological regulation of water balance

“‘Do you know who made you?’

‘Nobody as I knows on,’ said the child, with a short

laugh …‘I ‘spect I grow'd’.”

Uncle Tom's Cabin, Harriet Beecher Stowe.

The pituitary gland sits below the brain in a midline pocket or fossa of the sphenoid bone known as the sella turcica, imaginatively named by anatomists because of its likeness to a Turkish horse saddle. Embryologically, anatomically and functionally the human gland is divided into two lobes. The anterior lobe constitutes two thirds of the volume of the gland and the posterior lobe one third. As with all other endocrine glands, symptoms arise as the result of either hypo- or hypersecretion of hormones.

Clinical Case 7.1

The Neurosurgeons referred a 31-year-old man to the Endocrine team. Until some 3 years previously, he had been an international level canoeist but his abilities began to deteriorate gradually, despite the attentions of his coach. He fell from the national rankings. He only came to medical attention because as a computer programmer he had noted deteriorating visual acuity. An optician reported a bitemporal field defect and recommended neurosurgical referral. MR scan showed a large suprasellar tumor (Box 7.1) that was removed by transsphenoidal surgery. Histologically, it was reported to be a craniopharyngioma. On post-operative examination, he was found to be grossly hypothyroid and hypogonadal and these were confirmed using biochemical tests. His serum free-T4 was 4 pmol/l (NR 10–24 pmol/l), TSH 0.9 mU/l (NR 0.5–4.0 mU/l) and testosterone <0.5 nmol/l (NR 9–25 nmol/l).

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Box 7.1

MR scan of Clinical Case 7.1. Coronal scans Sagittal scans

The clinical features of secondary hypothyroidism and hypogonadism are discussed in detail, but to understand the clinical presentation of this particular case requires knowledge of both the anatomy and the embryology of the pituitary gland.

Anatomical and functional connections of the hypothalamo-pituitary axis

The posterior part of the pituitary gland (the neural lobe or neurohypophysis) is embryologically and anatomically continuous with the hypothalamus, an area of gray matter in the basal part of the forebrain surrounding the third ventricle (Box 7.2). Neurons in the hypothalamus project directly to the posterior pituitary gland and approximately 100 000 axons form the hypophyseal nerve tract (Box 7.3). The posterior pituitary gland is thus formed from axons and nerve terminals of hypothalamic neurons; hormones stored in the terminals are released into the general circulation in response to electrical excitation. Surrounding the nerve terminals are modified astrocytes known as pituicytes and these cells appear to have an important role in the local control of hormone release.

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Box 7.2

Diagram of the anatomy and embryology of the pituitary gland. Abbreviations: MB, mammillary body; OC, optic chiasm * Originating from pharyngeal endoderm (see Box 3.21)

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Box 7.3

Anatomy of the functional connections between the hypothalamus and pituitary gland. Abbreviations: AL, anterior lobe; PL, posterior lobe; OC, optic chiasm; MB, mammillary body

The anterior lobe (or adenohypophysis) is anatomically distinct from the hypothalamus (Box 7.2) and consists of a collection of endocrine cells. Originally three different cell-types were identified according to their ability to take up general histological stains; these were chromophobes, acidophils and basophils (Box 7.4). Newer immunohistochemical techniques allow classification of cells by their specific secretory products. About 50% of adeno-hypophyseal secretory cells are somatotrophs (synthesizing somatotrophin or GH), 10–25% lactotrophs (making prolactin), 15–20% corticotrophs (ACTH), 10–15% gonadotrophs (LH and FSH), and 3–5% thyrotrophs (TSH). Some cells, usually chromophobes, do not stain with any of the antibodies to the various anterior pituitary hormones although electron microscopy reveals that these cells contain secretory granules.

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Box 7.4

Hormone secretions of the anterior lobe of the pituitary gland and their control.

Whilst the anterior pituitary gland is not anatomically connected with the hypothalamus, it is functionally connected with this part of the brain (Box 7.3). Nerve cells in the hypothalamus secrete neurohormones that, via a system of hypophyseal portal vessels in the median eminence, act on the endocrine cells of the anterior lobe to stimulate or inhibit their synthesis and secretion.

Within the hypothalamus, there are discrete groups of nerve cells, termed nuclei, arranged bilaterally around the third ventricle (Box 7.5). Those concerned with hormone secretions from the pituitary gland tend to be distributed more medially whilst those concerned with autonomic functions, such as temperature regulation, food intake and satiety and sympathetic stimulation of adrenomedullary secretions, tend to be located more laterally.

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Box 7.5

Diagram of the anatomy of the hypothalamo-pituitary axis showing the major hypothalamic nuclei and the pituitary gland, enclosed in dura mater, sitting within the sella turcica and outside the blood-brain barrier. Abbreviations: AHA, anterior (more...)

The pituitary gland maintains its anatomical and functional connections with the brain yet sits outside the blood-brain barrier (Box 7.5). The anterior part of the sella turcica is the tuberculum sellae which is flanked by wing-like projections of the sphenoid bone known as the anterior clinoid processes. The posterior part, known as the dorsum sellae, is flanked by the posterior clinoid processes. These clinoid processes are the points of attachment of the diaphragma sellae, a reflection of the dura mater surrounding the brain. In this way, the entire pituitary gland is surrounded by dura such that the arachnoid membrane, and thus the cerebrospinal fluid, cannot enter the sella turcica.

As a whole, the hypothalamus is bound rostrally (towards the nose) by the optic chiasm, caudally by the mammillary bodies, laterally by the optic tracts and dorsolaterally by the thalamus. Clinically, (and demonstrated by Clinical Case 7.1), it is noteworthy that the optic chiasm lies about 5 mm above the diaphragm sellae and anterior to the pituitary stalk, though there is some anatomical variability. Thus, it is clear that any mass lesion of sufficient size in the area of the pituitary gland will cause visual field defects. The tumor in Clinical Case 7.1 was a craniopharyngioma and an understanding of the origin of this tumor requires more detailed knowledge of the embryology of the pituitary gland.

Embryology of the pituitary gland

The anterior lobe of the gland develops from an evagination of ectodermal cells of the oropharynx in the primitive gut and its anlage is recognizable at 4–5 weeks gestation. The evagination is known as Rathke's pouch (Boxes 3.21 and Box 7.2) and it is eventually pinched off from the oral cavity and becomes separated by the sphenoid bone of the skull. The lumen of the pouch is reduced to a small cleft whilst the upper portion of the pouch surrounds the neural stalk and forms the pars tuberalis. This, together with the anterior lobe, is called the adenohypo-physis. When some cells from Rathke's pouch are left behind, forming tumors, these are craniopharyngiomas.

The posterior lobe develops from neural crest cells as a downward evagination of the floor of the third ventricle of the brain (Box 7.2). The lumen of this pouch closes as the sides fuse to form the neural stalk while the upper portion of the pouch forms a recess in the floor of the third ventricle known as the median eminence. The neural stalk together with the median eminence form the infundibular stem and this, together with the posterior lobe, is collectively termed the neurohypophysis.

The cleft-like remnant of Rathke's pouch demarcates the boundary between the anterior and posterior lobes of the pituitary gland. In some animals, but not in humans, cells in this area form an anatomically distinct intermediate lobe and secrete a hormone (melanocyte-stimulating hormone, MSH) that stimulates melanocytes in the skin and, thus, alters skin color (see Box 4.30). In humans, these cells become interspersed with cells of the anterior pituitary gland and secrete hormones derived from pro-opiomelanocortin, notably ACTH. The hypothalamo-pituitary axis is established by 20 weeks gestation and in the adult the gland weighs 500–900 mg and measures about 15 × 10 × 16 mm.

Pituitary morphogenesis and the development of different cell types involves a number of genes that code for transcription factors and their sequential expression is now known to be crucial. They involve the sequential expression of at least five homeobox genes and also the actions of a number of inductive signals from the diencephalon (Box 7.6).

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Box 7.6

Transcription factors involved in pituitary gland development. Pit-I- termed POU1F1 in newer terminology. Expression begins about the 14th day of fetal development (in the mouse) and continues throughout life.


The size of the craniopharyngioma of Clinical Case 7.1 produced damage to the anterior pituitary gland and the optic chiasm. Such tumors are rare with only a few hundred cases in the UK presenting each year, and usually in patients under the age of 20 years. They are nearly always cystic (sometimes lobulated) and filled with oily green fluid that has a characteristic appearance on MR scan. They may also calcify and appear as suprasellar calcification on a plain skull X-ray. There is some normal anatomical variability in the position of the optic chiasm (Box 7.7) and it is clear that the clinical presentation of such tumors depends on local anatomy and the structures damaged. For example, occasionally tumors extend into the cavernous sinuses and damage eye movements due to palsy of the left 3rd (occulomotor), 4th (trochlear) or 6th (abducens) cranial nerves (see Clinical Case 7.4).

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Box 7.7

Diagram to illustrate the normal variation in the position of the optic chiasm (OC) relative to that of the pituitary gland.

The usual treatment for craniopharyngiomas is surgical with post-operative radiotherapy recommended for any residual tumor. Medical treatment involves the replacement of missing hormones. The role of the adenohypophysis in regulating the functions of the various endocrine organs is discussed in Chapters 3, 4 and 6.

In most circumstances, it is not the trophic anterior pituitary gland hormones that are replaced but those of the target tissues. Thus, thyroxine (not TSH), hydrocortisone (not ACTH), testosterone (not LH) were given to Clinical Case 7.1 with improvement in his symptoms. However, when seen in the out-patient department at follow-up it was noted that since initiating endocrine replacement he had started to pass large volumes of urine and to complain of intense thirst. In addition, he was always lacking energy and, although he could keep up with a full-time sedentary job, he went to bed early at about 9 p.m. and had virtually no social life. The pathophysiological explanation for the appearance of these new symptoms is explored in more detail on page 327.

Blood supply of the hypothalamo-pituitary axis

The importance of the blood supply of the axis is demonstrated by the next clinical case of Sheehan's syndrome.

Clinical Case 7.2

A 26-year-old Afro-Caribbean woman had given birth to a 3.8 kg baby boy at 39 weeks gestation. Though the antenatal progress had been unremarkable, the delivery had been difficult, necessitating the use of obstetric forceps and complicated by a very large post-partum hemorrhage. As a Jehovah's Witness she had refused blood transfusion and, since bleeding continued and despite all other measures, she had required an emergency hysterectomy. Several times during the operation her systolic blood pressure had been measured at 50 mm Hg. The post-operative period had been complicated by a transient period of renal failure but after a further 2 weeks she was discharged. She bottle fed her son because she had failed to lactate. Her 6 week postnatal assessment had been unnoteworthy but 3 months later she was referred to the Endocrine team as she had developed hot flushes.

The blood supply to the hypothalamo-pituitary axis is complex but defines the functional relationship between the hypothalamus and adenohypo-physis. Any interruption of blood flow impairs the hypothalamic control of adenohypophyseal secretions. The hypothalamus receives its blood supply from the circle of Willis whilst the neurohypophysis and adenohypophysis receive blood from the inferior and superior hypophyseal arteries respectively (Box 7.8). The capillary plexus of the inferior hypophyseal artery drains into the dural sinus although some of these capillaries in the neural stalk form ‘short’ portal veins that drain into the anterior pituitary gland.

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Box 7.8

Diagrammatic representation of the blood supply and venous drainage of the median eminence and pituitary gland.

This constitutes only a small fraction of the circulation of the anterior lobe, which is one of the best vascularized mammalian tissues. The major portion of the circulation arises from the ‘long’ portal veins. These are formed from the capillary network of the superior hypophyseal arteries that invest the nerve endings of the neurosecretory cells in the median eminence. Thus, the hypothalamic releasing and inhibiting hormones are released into these hypophyseal portal veins, through which they are transported to the endocrine cells of the anterior pituitary lobe. Here, the portal veins form a secondary capillary network into which the hormones of the anterior pituitary are secreted. The capillaries in the hypophyseal portal system are fenestrated improving the delivery of hormones to the adenohypophyseal cells. The venous channels from the anterior pituitary gland drain into the cavernous sinuses and, thence, into the superior and inferior petrosal sinuses and into the jugular vein (Box 7.8).

Sheehan's syndrome

During pregnancy, there is an approximately 50% increase in the volume of the pituitary gland. This is primarily due to hyperplasia of the lactotrophs that secrete prolactin to prepare the breasts for lactation. Thus, whilst the volume of the pituitary increases, the fossa in which the pituitary gland sits does not increase to accommodate this growth. A sudden fall in blood pressure after an event such as a post-partum hemorrhage causes ischemia of the gland, cellular damage and edema. In turn, the edema results in swelling of the pituitary gland (which is already enlarged by the lactotroph hyperplasia) further restricting the normal blood flow to the gland. The result is an infarct in the gland that causes loss of its secretions. This is initially manifest by failure of lactation (lack of prolactin) and amenorrhea (loss of gonadotrophins) but may also variably demonstrate hypothyroidism (TSH) and hypoadrenalism (ACTH). This has been termed Sheehan's syndrome and, it is to be emphasized, improvements in routine obstetric care have rendered it very rare.

Three important clinical observations may be made. The first is that destructive lesions of the pituitary gland, whether they be due to a tumor, infarct, radiotherapy or, indeed, basal meningitis (Box 7.9) all have similar effects. They reduce secretions from the anterior pituitary gland leading to hypopituitarism (the severity of which depends on the lesion). The second is that the sequence of the loss of trophic hormones due to progressive lesions tends to be the same. Thus, somatotrophin-secreting cells are lost first, then gonadotrophs, whilst thyrotrophs seem to survive till last. The third is that such lesions rarely cause a deficiency of the posterior pituitary hormone secretions, oxytocin and arginine vasopressin (AVP). Indeed, it is to be emphasized that the polyuria and intense thirst seen in Clinical Case 7.1 resulting from a deficiency of AVP (causing diabetes insipidus, see below) was related to damage to the neural stalk or the hypothalamus and not to the posterior pituitary gland.

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Box 7.9

Causes of pituitary failure. Holoprosencephaly - abnormal development of the embryonic forebrain resulting in hypothalamic abnormalities and facial dysmorphism e.g. cleft palate, hypertelorism (widely spaced eyes), absent nasal septum. Septo-optic dysplasia (more...)

Clinical Cases 7.1 and 7.2 illustrate how lesions of the pituitary gland cause loss of several hormone secretions. There are also diseases in which there is a deficiency of a single anterior pituitary hormone. One of the most common is a relative lack (or insufficiency) or complete deficiency of somatotrophin or growth hormone (GH), affecting approximately 1 in 4000 live births. This may be caused either by a failure in the hypothalamic control mechanisms or by a defect in the pituitary gland.

Growth and somatotrophin deficiency

Clinical Case 7.3

A 2-year-old boy was referred to the general Pediatric clinic because of ‘failure to thrive’. He had been born weighing 2.79 kg after a normal pregnancy and delivery. Developmental milestones (such as the age of speaking and walking) were normal. Both parents were about the 25th centile for height. In the clinic, he was noted to be short (well below the 3rd centile, but also dysmorphic with a short body (sitting height SDS -5, subischeal leg length SDS -2). (Box 7.10). He weighed 10.03 kg (3rd centile). He was noted to be kyphotic with a short neck. X-rays revealed shortening of the cervical spine but MR imaging of the spine was normal. An endocrine cause of his short stature was thought unlikely. Review of his clinical appearance and the radiological findings by clinical geneticists failed to suggest an underlying diagnosis. One year later, he was referred to the Pediatric Endocrine clinic for the very practical reason that he was too short to use the toilets at his nursery school. He was indeed very short (Box 7.12) and the skeletal disproportion still present.

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Box 7.10

Sagittal MR scan of Clinical Case 7.3. Note the short thorax (arrowed), a major factor in his short spine.

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Box 7.12

Growth Chart of Clinical Case 7.3. Age is plotted on the horizontal (X) axis. Two sets of normal data are plotted. Height (the upper set of curves) is plotted on the left-hand vertical (Y) axis and weight (the lower set of curves) on the right-hand Y-axis. (more...)

The young boy in this case was initially referred with ‘failure to thrive’, a term generally used for children under the age of 2 years who are failing to put on weight (i.e. lean for their height). To interpret this case it is necessary to understand the use of growth charts (Boxes 7.11 and 7.12). As can be seen from the charts, at initial presentation he was nearer the 3rd centile for weight than he was the 3rd centile for height. Thus, he was not failing to thrive, he was failing to grow. With parents on the 25th centile, he would have been expected, all other things being equal, also to grow along that line.

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Box 7.11

Growth charts. The growth of a child is multifactorial and complex but, fortunately, predictable. Postnatal growth is rapid in infancy (~15 cm/year rapidly decelerating at age 3 years), a childhood rate of about 6 cm/year (with an adolescent deceleration), (more...)

The fastest relative growth rates occur in embryonic and fetal life when a single fertilized ovum progresses, as in this case, to 2.79 kg of live baby after 40 weeks. This represents an increase in fetal mass of about 44 × 107 fold whilst length increases 3850-fold. Post-natal growth never matches this with only a 20-fold increase in mass and 3–4-fold increase in length. In early childhood, there is a period of rapid growth followed by a period of steady growth with a mid-childhood acceleration, a pubertal growth spurt and a phase of deceleration to final height. In the involutionary years, there is a period of shrinkage, reflecting the changes of spinal shortening.

Intrauterine growth is regulated by endocrine, maternal and genetic factors, though the determinants of prenatal growth are poorly understood. Fetal plasma GH concentrations are very high and yet infants with GH hormone deficiency, and even those with anencephaly, may have normal body length at birth. Loss of human chorionic somatotrophin (hCS) secreted by the placenta (see below) does not appear to affect intrauterine growth. Mothers lacking the hCS gene have given birth to infants of normal birth weight. In contrast, excessive serum insulin may be associated with increased length in infants of diabetic mothers (see clinical case 2.3). The related insulin-like growth factors (IGFs) are also important in fetal growth (see Box 7.19) and, though their precise role is not established, when IGF-1 is lacking (e.g. Laron dwarfs) the reports of birth length show a wide variability, including normality, suggesting that IGF-1 is not a major factor.

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Box 7.19

GH and the IGFs. The IGF family consists of 3 members (insulin, IGF-1 and IGF-2) sharing common structural similarities. There are variant forms of the IGFs (see website). IGF-1 and IGF-2 also have metabolic functions but also play important roles in (more...)

Maternal (intrauterine) influences have been difficult to define but poor maternal nutrition is the most important factor leading to low birth weight and length world-wide (Box 7.13). Maternal alcohol ingestion and smoking are other adverse factors on fetal growth, and maternal infections such as rubella, toxoplasmosis and cytomegalovirus lead to many abnormalities, as well as short stature. Congenital HIV infection also retards fetal growth. Intrauterine growth retardation (IUGR) is usually defined as a birth weight of less that the 10th percentile for gestational age but of these about 10% are not truly abnormal.

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Box 7.13

Causes of poor growth. Genetic short stature - includes normal children born to normal short parents. Intrauterine growth retardation - approximately 2% of infants are small for gestational age. This results from a number of possible factors including (more...)

Growth hormone - secretory patterns and control

Growth hormone or somatotrophin is a single chain polypeptide containing 191 amino acids, two disulfide bridges and four helical structures (Box 7.14). The position of the helices and the three-dimensional structure of this hormone are important for binding to its receptor. It shares structural homologies with prolactin and hCS, the latter being a GH variant synthesized exclusively in the placenta. There is a cluster of five genes from which these polypeptide hormones may be synthesized although normally there is a tissue-specific expression of only one gene. The binding of the tissue-specific transcription factor Pit-1 (Box 7.6) to the promoter region of the GH gene results in only one form of GH being secreted by the anterior pituitary gland.

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Box 7.14

Diagrammatic representation of the structures of human GH and prolactin. GH and prolactin contain disulfide bonds bridging two cysteine residues and they both contain between 190–200 amino acids and have regions of identical amino acid sequences. (more...)

Classically, the synthesis and secretion of GH has been thought to be controlled by two hypothalamic neurohormones; growth hormone-releasing hormone (GHRH) that is stimulatory and somatostatin that is inhibitory of GH secretion (Box 7.15). However, the view that only two hormones are involved in the control of GH secretion has been challenged by the finding of another hormone, ghrelin, that also causes GH release (Box 7.16). In the human hypothalamus, both the 40 and 44 amino acid forms of GHRH are synthesized and secreted by neurosecretory neurons whose cell bodies predominantly reside in the arcuate nucleus of the hypothalamus (Box 7.5). Released from nerve terminals in the median eminence and transported to the anterior pituitary gland via the hypophyseal portal capillaries, GHRH acts on the somatotrophs of the anterior pituitary gland via a G-protein linked receptor to stimulate cAMP synthesis and eventually activates Pit-1 promoter. Thus, mutations in the gene coding for Pit-1 result in hypoplasia of the pituitary gland and deficient secretion of GH as well as that of prolactin and TSH (Box 7.6).

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Box 7.15

Summary of the actions of GH and prolactin and the feedback mechanisms controlling their secretions. The synthesis and secretion of GH and prolactin are controlled by two opposing hypothalamic neurosecretory hormones, although the predominant hypothalamic (more...)

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Box 7.16

Ghrelin - birth of a hormone. The small synthetic hexapeptide hexarelin (GH releasing peptide-6, GHRP-6) was shown in the 1980s to cause the release of GH from somatotroph cells of a number of species. Its mechanism of action was shown to be different (more...)

Somatostatin is a 14 amino acid peptide (the somatostatin variant released by δ cells in the pancreatic islets is a 28 amino acid peptide) synthesized in hypothalamic neurons mainly located in the anterior periventricular nuclei. Somatostatin acts on the somatotrophs to inhibit cAMP generation.

Both GH and prolactin are partly regulated by a ‘short’ feedback loop i.e. each can feedback directly on the hypothalamus to inhibit its own release (Box 7.15). The GH-stimulated release of IGFs from the liver also has important feedback effects on the control of GH.

Pulsatile GH secretion represents the sum activity of GHRH and somatostatin-secreting neurons. These are regulated by an integrated system of neural, metabolic and hormonal signals (Box 7.17) and the metabolic factors include all fuel substrates. The overall metabolic effect of this hormone is to raise blood glucose concentrations. Hypoglycemia stimulates its release, whilst hyperglycemia suppresses it. Oral glucose administration (a glucose tolerance test, see Box 7.24) lowers GH secretion in healthy subjects and this provides a useful test in differentiating a state of GH excess (acromegaly) from normality (see below).

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Box 7.17

Major factors controlling GH secretion.

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Box 7.24

Tests of GH secretion. GH is secreted in a pulsatile fashion and has a diurnal variation. Its secretion is stimulated by exercise and affected by food (being stimulated by amino acids and inhibited by hyperglycemia). Randomly taken GH measurements should (more...)

In the adult human, approximately five pulses of GH are secreted during a 24 h period with a larger peak occurring at the onset of sleep at night (Box 7.18). Between these pulses circulating GH concentrations are too low to be detected even by sensitive two-site immunoradiometric assays (IRMA, Box 3.25), though more sensitive assays are under development. The mean concentration of circulating GH varies throughout life (Box 7.18). It rises after birth reaching concentrations higher than that of adults. A peak period is observed during puberty and there is a marked decline in old age. The reduction in old age has been termed the ‘somatopause’, by analogy with the menopause, and this concept will be discussed further in the context of GH replacement in adults (see website).

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Box 7.18

Growth hormone secretion. Diagrammatic representation of the daily pattern of growth hormone (GH) and prolactin (PRL) secretion in adult humans. There is a sleep-related increase in both GH and prolactin secretion. Life-time pattern of growth hormone (more...)

Actions of growth hormone and insulin-like growth factors

Clinical Case 7.3 illustrates the importance of GH in post-natal growth and development but, apart from growth, this hormone has other important metabolic functions. It is an anabolic hormone with widespread actions, many of which are mediated via the production of insulin-like growth factors, IGF-1 and 2, that are synthesized by the liver and in target tissues (Box 7.19).

Its most profound effect is on linear growth by stimulating proliferation of the cartilage in the epiphyseal plates of long bones before they fuse. In addition to stimulating linear growth, GH also increases total bone mass and mineral content by increasing the activity and probably the number of bone modeling units (see Clinical Case 5.6). GH increases lean body mass, reduces adiposity by its lipolytic effects, and increases organ size and function, the latter effect being mediated by IGFs as in bone (Box 7.20). Normal concentrations of GH are also required to sustain normal pancreatic islet function. Thus, in GH deficiency insulin secretion declines whilst an excess of GH reduces insulin-dependent glucose uptake causing a rise in insulin secretion to compensate for the GH-induced resistance. On balance, GH is a diabetogenic hormone (see Box 7.20).

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Box 7.20

Major actions of growth hormone. GH has direct actions on the liver, adipose tissue and muscle although many of its actions are mediated by increasing the synthesis and release of insulin-like growth factors (IGFs). These stimulate DNA, RNA and protein (more...)

The t1/2 of GH in the circulation is about 20 minutes. It circulates in several forms that vary according to size (molecular weights of 20 000 and 22 000), isoelectric point (acidic forms), oligomers (up to pentamers) and fragments (molecular weights of 12 000 and 16 000). In addition, approximately 50% is bound to the extracellular domain of its receptor (also termed the GH-binding protein GHBP). There are two molecules of the GH receptor, full-length and truncated forms. The full-length form belongs to the Class I cytokine receptor family. These are all proteins with single transmembrane domain in which the intracellular domain is associated with a protein tyrosine kinase known as JAK that, in turn, phosphorylates STAT kinase initiating a cascade of protein phosphorylations (Box 7.21). The GH receptor is cleaved by a metalloproteinase enzyme and the amount of GHBP circulating has been used as a measure of GH receptor in cases where GH insensitivity is suspected. The truncated form of the GH receptor (GHRtr) also produces circulating GHBP and has a dominant negative effect on the activity of the full-length form. Thus, patients with predominantly GHRtr are GH insensitive but have circulating GHBP.

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Box 7.21

Growth hormone and prolactin receptors. The receptors for growth hormone and prolactin, as for most of the cytokines, activate the JAK/ STAT pathway of signal transduction. Such hormone/cytokine receptors have no inherent tyrosine kinase activity, as (more...)

IGFs are also bound in the circulation to IGF- binding proteins (Box 7.22). The binding of IGF-1 to IGFBP3, in particular, forms a very stable complex and this provides a circulating reservoir of these growth factors. Thus, unlike the rapid fluctuations seen in the concentration of circulating GH, IGF-1 concentrations are relatively stable and their circulating t1/2 is much longer. Receptors for IGFs, like those of GH, are single transmembrane proteins but, in this case, their receptors have inherent tyrosine kinase activity (Box 1.18). When phosphorylated by IGF binding, the receptor initiates a series of further kinase phosphorylations and subsequent cytoplasmic or nuclear effects.

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Box 7.22

IGF-binding proteins. The six IGF-BPs share structural homologies of gene structure and have three domains, the conserved amino and carboxyl terminals being cysteine rich. All but IGF-BP6 bind IGF-1 and IGF-2 with equal affinities; BP6 binds IGF-2 with (more...)

From the foregoing, it is obvious that GH deficiency and resistance to GH, caused by a genetic defect in the GH receptor, leads to a deficiency in IGF-1 (Box 7.23). Somatotrophin resistance, known as the clinical syndrome of Laron dwarfism, is characterized by high plasma GH and low IGF-1 concentrations and absence of GHBP in most patients. The clinical picture is associated with dysmorphism particularly affecting the central face (prominent forehead and depressed nasal bridge) and marked short stature, the degree being to some extent related to the severity of the functional defect in the receptor. Other features include obesity and delayed puberty. It is rare and treatment with recombinant human IGF-1 markedly improves growth.

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Box 7.23

Causes of IGF-1 deficiency. Any cause of hypothalamo-pituitary dysfunction (see Box 7.9). GHRH deficiency - to date no mutations have been reported in the GHRH gene itself.

GH replacement therapy

Isolated somatotrophin deficiency affects approximately 1:4000 children and the exact lesion giving rise to the GH deficiency is not usually discovered. Lesser degrees of GH lack are termed insufficiency and these are due to a number of possible causes (Box 7.23). The patient in Clinical Case 7.3 underwent testing of anterior pituitary gland function and was shown to have a very poor somatotrophin response to provocative tests (Box 7.24). The rest of pituitary function was normal as was an MR scan of the brain. It was, therefore, concluded that he had isolated GH deficiency and he was started on replacement GH (Box 7.25). The clinical result was very significant ‘catch-up’ growth (Box 7.12).

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Box 7.25

Treatment of poor growth*.

It is clearly imperative that GH deficient children receive replacement therapy if they are to have any chance of reaching a normal final height. The question as to whether treatment should be continued in lower doses once final height has been attained or whether adults, with an acquired GH deficiency, should also be treated has only recently been raised. Adult GH deficiency certainly can cause marked symptoms and clinical features (Box 7.26) and the beneficial effects of somato-trophin in some deficient adults have been noted for nearly 40 years.

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Box 7.26

Adult GH deficiency and the ‘somatopause’. Adult GH deficiency Decreased energy levels

’Replacement therapy with thyroid, adrenocortical hormone and estrogen in females or androgens in males is usually satisfactory treatment for adult hypopituitarism. One patient, a thirty-five year old teacher, treated in this way for eight years, was treated in addition with human growth hormone, 3 mg three times a week. After two months of GH she noted increased vigor, ambition and sense of well-being. Observations in more cases will be needed to indicate whether the favorable effect was more than coincidental.’

[Raben MS. Growth hormone 2: clinical use of human growth hormone. New England Journal of Medicine 1962, 266: 82-6.]

The lack of adequate supplies of the hormone until 1985 (the onset of industrial supplies of recombinant protein) precluded such therapy. Clinical Case 7.1 had a craniopharyngioma and developed pan-hypopituitarism as a result. Despite his adrenal, thyroid, and gonadal hormone replacement therapy he suffered from fatigue and weight gain (Box 7.26). Although he was just able to hold down a job, he got no social or sporting enjoyment out of life. When he was started on low-dose GH replacement, he noted a spectacular improvement. He lost 15 kg of fat and was able to get back to vigorous training so that he is now competing and coaching again. As will be seen Clinical Case 7.4 was not so fortunate.

GH excess - gigantism and acromegaly

Excessive secretion of somatotrophin before the epiphyses have fused results in excess linear bone growth and gigantism. The tall record holders documented in the Guinness Book of Records are in all likelihood (for the most part undiagnosed) pituitary giants. Such excess is usually the result of somatotrophin-secreting pituitary tumors that are, fortunately, rare. Excessive secretion after epiphyseal fusion results in acromegaly.

Clinical Case 7.4

A 58-year-old carpenter attended an orthopedic surgeon because he had difficulty in holding the tools of his trade. For the previous 12 years, he had seen his primary care physician repeatedly complaining of ‘pins and needles’ and numbness in both hands. The orthopedic surgeon confirmed the clinical diagnosis of bilateral carpal tunnel syndrome and performed bilateral decompression of the median nerve at the wrist. Clinical examination showed the hands to be broad and spatulate (Box 7.27) and the surgeon referred him to the Endocrine outpatient clinic.

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Box 7.27

Clinical Case 7.4 and the clinical features of acromegaly *. Clinical photographs of the hands and face of Clinical Case 7.4

Acromegaly affects approximately 50 people in a million with an annual incidence of about 3 per million. It affects males and females equally and is an insidious disease being present for a number of years before clinical suspicions are aroused. It tends to present in the fifth decade of life. The patient in Clinical Case 7.4 typifies this delay in diagnosis.

Excess somatotrophin results in raised circulating concentrations of IGF. Thus, the growth promoting effects of IGF-1 leads to the characteristic proliferation of bone, cartilage and soft tissues and an increase in the size of other organs to produce the classic signs and symptoms of acromegaly (Box 7.27). Carpal tunnel syndrome, due to pressure on the median nerve in the wrist, is commonly associated with acromegaly and, indeed, this led to the diagnosis in Clinical Case 7.4. The other endocrine condition giving rise to carpal tunnel syndrome is hypothyroidism, though peripheral nerves in patients with diabetes mellitus are more susceptible to compression syndromes.

Glucose intolerance and hyperinsulinemia are common metabolic complications of acromegaly affecting 50–70% patients. Hypogonadism is also frequently associated with excess growth hormone secretion. This may be the result of a GH-secreting tumor impairing gonadotrophin secretion or the excess GH interacting with the prolactin receptor owing to its structural homology with prolactin. Excess prolactin secreted by some tumors impairs pituitary and gonadal function, and also cause galactorrhea (and gynecomastia in men). Another possibility is that excess IGFs stimulated by GH have a negative effect on the gonads where they normally exert paracrine control of gonadal function.

The vast majority of cases of acromegaly (>99%) are due to pituitary tumors although occasional cases due to hypothalamic or ectopic production of GHRH (or, even more rarely, ectopic somatotrophin) have been described. It is noteworthy that most of these rare cases were not diagnosed prospectively. The pituitary tumors are benign (adenomas) and tend to be macroadenomas (i.e. above 10 mm diameter). A number of histological types has been described that may correlate with growth rate and tendency to recur postoperatively. Some tumors are made up of two cell types e.g. one secreting somatotrophin and the other prolactin whilst others contain cells that co-secrete both hormones. It has been suggested that such tumors arise from a presumed precursor cell type.

The diagnosis of acromegaly was confirmed in Clinical Case 7.4 when his serum GH concentrations remained more than 90 mU/l after an oral glucose load (Box 7.24). A pituitary tumor was revealed on a MR scan and the patient underwent treatment (Box 7.28). Transsphenoidal surgery to remove the tumor resulted in a considerable reduction in the somatotrophin response to glucose but the serum concentrations remained elevated. He, therefore, underwent cranial irradiation and 8 years later his somatotrophin responses to insulin-induced hypoglycemia were all less than 2 mU/l (Box 7.24). He subsequently developed hot flushes and was found to be hypogonadal (serum testosterone 2.3 nmol/l, NR 9–25 nmol/l). He also complained of increasing fatigue and weight gain, as was seen in Clinical Case 7.1. By this time, he had no measurable somatotrophin response to insulin-induced hypoglycemia. His hypogonadism was treated with androgens, but, unlike Clinical Case 7.1, somatotrophin replacement was not sanctioned by his Health Authority. The fact he was treated for growth hormone excess and is now clinically affected by its deficiency and yet his Health Authority refused to pay for the treatment, raises number of ethical and political issues (see website).

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Box 7.28

Treatment of pituitary adenomas*.

Pituitary adenomas - incidence and treatment

In post-mortem series about 25% of the population has pathological evidence for a pituitary tumor and about 40% of these stain for prolactin. However, clinical presentations of pituitary tumors are much less common. It is evident from the foregoing cases that pituitary tumors cause clinical problems by any of three mechanisms: unregulated production of a hormone, interference with the normal production of hormones or damage to local structures. It is self-evident that these effects are governed to a large extent by the size of the tumor. As a result, pituitary adenomas are classified by the hormones they produce and by size. Microadenomas are less than 10 mm in diameter and macroadenomas larger than this. Pituitary microadenomas tend to present with symptoms of hormonal excess and usually such tumors can be successfully treated surgically (Box 7.28). More problematic are the large macroadenomas that cause general sellar enlargement, suprasellar damage, visual loss and hypopituitarism (of variable degree) and may extend laterally into the cavernous sinuses. These are much less likely to be curable by surgery alone.

Pituitary tumors may be treated medically, surgically, radiotherapeutically or with any of these in combination (Box 7.28). The use of each of these modalities of therapy varies with the type of tumor and the availability of expertise. Generally speaking microadenomas are treated with transsphenoidal microsurgery with success rates reaching about 90%.

Macroadenomas are treated with surgery and, if appropriate, radiation therapy after incomplete removal of the adenoma. Medical treatment can include dopamine agonists such as cabergoline or bromocriptine for GH and prolactin-secreting tumors or the somatostatin analog octreotide for GH secreting adenomas.

Prolactinomas account for about 30% of primary pituitary tumors whilst GH hypersecretion accounts for approximately 15% and ACTH excess 10%. Those producing no biologically active hormone (null-cell) account for about 30% with gonadotrophinomas about 10% and thyrotrophinomas <1%. Clinical Case 7.5 is a patient with a prolactinoma illustrating some of the problems and treatment associated with pituitary adenomas and serves to introduce the subject of prolactin and its control.


Clinical Case 7.5

A 47-year-old bank clerk woke one morning with severe chest pain radiating to both arms. He was taken to his local hospital and, although his electrocardiogram was normal, he was considered to have suffered an acute myocardial infarction. He was treated intravenously with an infusion of streptokinase and subsequently heparin and oral aspirin. Two hours after finishing the streptokinase, he complained of a sudden severe headache, diplopia (double vision) and blurred vision. On examination, he was fully conscious but with right 3rd and 6th cranial nerve palsies and a left temporal visual field defect. On transfer to Neurosurgery, a CT scan revealed a large pituitary mass with suprasellar extension and evidence of a recent hemorrhage within the mass Box 7.29. This hemorrhage into his existing pituitary tumor was caused by his treatment for a suspected myocardial infarction. As a result there was a sudden swelling of the tumor into the cavernous sinus that caused compression of the 3rd and 6th cranial nerves. His sudden onset of headache caused by the hemorrhage is termed pituitary apoplexy.

Measurement of his serum prolactin (213 000 mU/l, NR <400 mU/l) indicated he had a prolactin- secreting tumor, a prolactinoma. Concerns that he may have suffered a recent myocardial infarction, coupled with the recent therapy with fibrinolytic drugs resulted in medical treatment being preferred to surgical decompression of the optic chiasm and 3rd and 6th cranial nerves. He was treated with the dopamine agonist, cabergoline, to inhibit prolactin secretion. Within hours, clinical improvement was seen and after 3 days the headache disappeared; the cranial nerve palsies recovered after one month. Six months later his serum prolactin concentration was 84 mU/l, fluid within the tumor was no longer visible and the tumor was much reduced in size.

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Box 7.29

CT scan of Clinical Case 7.5. The lower axial scan demonstrates the expansion of the mass into the right cavernous sinus leading to the cranial nerve lesions. The upper, reformatted image demonstrates the extension of the mass above the pituitary fossa. (more...)

Prolactinomas are benign, clonally expanded tumors and clinical presentation is different in males and females; females tend to have smaller tumors that come to light earlier because of their predilection for causing amenorrhea due to the inhibitory effects of excess prolactin on the pituitary gland and ovaries. Males tend to have larger tumors that come to light late, perhaps because males are reluctant to discuss gradually deteriorating gonadal and sexual function.

In the UK, the use of dopamine-agonist drugs (including cabergoline or bromocriptine) is recommended as first line treatment for prolactinomas, even in the presence of visual field defects. This is because they lower serum concentrations of prolactin and shrink the tumors. However, in those who cannot tolerate these drugs, or those in whom the drugs fail to shrink the tumors sufficiently, surgery and/or radiotherapy have been used with results similar to those of other tumor types (Box 7.28). In countries in which other forms of health care funding are used, surgery (that may be curative) may be recommended to minimize ongoing medical costs. In pituitary apoplexy associated with mass effects such as visual loss, surgical intervention may be recommended to decompress the optic chiasm.

Prolactin and its control

Prolactin is a single chain protein made up of 199 amino acids with three disulfide bridges and, as noted above, it shares strong structural homologies with GH. Their cell-surface receptors are also similar, although the intracellular domain of the prolactin receptor is different and shorter than that for GH. The intracellular signal transduction pathway is similar to that of GH involving the JAK-STAT kinase pathway (see Box 7.21) and like the GH receptor, truncated forms of the prolactin receptor are found in a number of tissues.

The main function of prolactin is stimulating breast development and milk production. However, more than 300 functions have been attributed to prolactin (more than for all the other pituitary hormones combined), including salt and water balance, cell growth and proliferation (Box 7.30). Recently prolactin has emerged as a stimulatory modulator of immune function but the clinical relevance of this function has yet to be established.

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Box 7.30

Actions of prolactin. Preparing the female breast for lactation. Other roles poorly understood though widespread tissue expression of prolactin receptors.

It also has effects on the hypothalamo-pituitary-gonadal axis and can inhibit pulsatile GnRH secretion from the hypothalamus and alter the activity of certain steroidogenic enzymes. In women, its actions depend on the phase of the menstrual cycle. Excess prolactin secretion is associated with infertility and menstrual irregularity or even complete amenorrhea. In men, it causes decreased testosterone and sperm production. In addition, excess prolactin can cause galactorrhea (inappropriate milk production) in women and gynecomastia (breast development) in men.

Like GH, prolactin secretion is regulated by a dual hypothalamic inhibitory and stimulatory system and can regulate its own secretion through a short-loop feedback (Box 7.15). In contrast, its hypothalamic control is unique in that the predominant hypothalamic influence is inhibitory whereas for all other hormones the predominant influence is stimulatory. Thus, damage to the hypothalamic control causes increased prolactin secretion rather than decreased secretion, as seen with all other anterior pituitary hormones.

Dopamine, released into the hypophyseal portal veins from the nerve terminals of the intrahypothalamic tuberoinfundibular tract, is the main neurohormone inhibiting prolactin secretion although somatostatin also has an inhibitory effect. Whilst thyrotrophin releasing hormone has a potent stimulatory action on prolactin release, it is clear that other, but as yet undefined, factors are also involved. For example, suckling is a potent stimulus for prolactin secretion but this does not coincide with a rise in TSH secretion. Inhibition of dopamine release or antagonism at the dopamine D2 receptor also increases prolactin secretion. A list of the main factors that stimulate or inhibit prolactin secretion is given in Box 7.31 as well as the causes of hyperprolacinemia. Note that dopamine antagonist drugs and hypothyroidism are the most common causes of hyperprolactinemia.

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Box 7.31

Major factors controlling prolactin secretion and causes of hyperprolactinemia. Inhibitory - Dopamine. Stimulatory - TRH, other releasing factors, pregnancy, lactation (suckling), estrogen, opioids, dopamine D2 receptor antagonists, sleep, stress.

Whilst the secretory patterns of GH and prolactin differ (Box 7.18), both hormones show a sleep-related increase in their secretions. This diurnal rhythm does not occur in the absence of sleep and contrasts with the endogenous circadian rhythm of ACTH/cortisol secretion that normally occurs irrespective of social cues and habits.

Circadian rhythms and the suprachiasmatic nucleus

Many physiological functions such as core temperature, bronchodilation, blood pressure and hormone secretions show daily rhythms. Some of these variables, like ACTH and melatonin secretion (see below), are directly driven by the body's internal ‘clock’. This is thought to reside within the suprachiasmatic nuclei (SCN) of the hypothalamus (Box 7.5) and studies on isolated brain slices from this region have shown that neurons of the SCN show inherent cyclical activity (metabolic and electrical), independent of any input. In animals, lesions of the SCN abolish all circadian rhythms, including those of ACTH/cortisol and melatonin.

In humans, this clock has a natural, free-running periodicity of about 24.5 hours but normally it is entrained to the light-dark cycle (a ‘zeitgeber’) so that its cycle is complete in 24 hours; the body clock is, thus, in time with the environment. The next case illustrates what happens when the endogenous body clock is not entrained.

Clinical Case 7.6

A 7-year-old boy was seen in the long-term follow up clinic. He had initially presented at the age of 5 years with poor vision and on MR scan found to have a large tumor of the optic nerve (an optic nerve glioma, Box 7.32). Following treatment, he had been left blind with no perception of light. His parents were finding day to day life very difficult. In particular, it was evident that his sleep pattern was disrupted and he disturbed the whole family by getting up repeatedly in the middle of the night to play.

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Box 7.32

MR scans of Clinical Case 7.6 at presentation. The axial MR scan shows a large tumor mass and the diagram shows the normal structures that it has replaced.

Brain tumors, together with leukemia, are the most common tumors of childhood and approximately 1 in 2000 20-year-olds are survivors of childhood cancer. The sequelae of these treatments are very important and in this case it was not only the loss of vision (a considerable handicap in itself) but also loss of normal sleep patterns. The disruptions to sleep, meals and school work were major for the family of Clinical Case 7.6 and were caused by the boy's ‘free-running’ clock having lost the synchronizing effects of light. Hormone rhythms such as cortisol also become desynchronized with the environment and whilst societal factors and physical activity can exert some resynchronizing effects the main influence is undoubtedly the light-dark cycle.

This occurs because the SCN receives a direct input from the retina (the retino-hypothalamic tract); it is the only part of the brain, apart from the visual cortex, to receive a direct input from the eye. Neurons from the SCN project to wide areas of the brain including the hypothalamic nuclei, the mid-brain raphe nucleus and the ventral lateral geniculate nucleus. It also projects indirectly to the pineal gland that, nestling between the rostral part of the cerebral hemispheres, secretes melatonin (Box 7.33).

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Box 7.33

Overview of the secretion of melatonin from the pineal gland and its control. The synthesis of hydroxytryptamine from tryptophan is stimulated by light whilst the activity of NAT is stimulated by darkness. Dark bars indicate the dark phase of the light-dark (more...)

The pineal gland and melatonin

In submammalian species, the pineal gland is sensitive to light and has direct neural connections with the brain. In man, these features have been lost. Instead, the SCN projects to the pineal via hypothalamic connections to the brain stem and spinal cord. From thence, the innervation is sympathetic to the superior cervical ganglion and pineal itself. The human pineal weighs approximately 150 mg and, apart from melatonin, contains a large number of chemical agents (including biogenic amines such as norepinephrine and serotonin, peptides such as GnRH and TRH and the neurotransmitter gamma amino butyric acid, GABA). The endothelial cells in the vasculature of the pineal are fenestrated so the organ is outwith the blood-brain barrier.

Pinealocytes are specialized secretory cells controlled by the norepinephrine output from the sympathetic system. In animals, the pineal controls a number of functions primarily to do with the timing of puberty and reproduction and removal of the pineal causes precocious puberty and disrupts the annual breeding patterns of seasonal breeders. Melatonin seems to be the main agent involved in this and it is thought that the duration of the melatonin signal (it is synthesized and secreted primarily during the dark phase of the cycle) is important in such control. The SCN and the pars tuberalis are rich in melatonin receptors.

Melatonin is synthesized from tryptophan (Box 7.33) and is greatest at night in the absence of light. Exposure to natural or bright artificial light rapidly reduces the activity of the enzyme N-acetyltransferase. Melatonin treatment in humans reduces LH and GH secretion, causes sleepiness and alters the electroencephalogram. Tumors of the pineal region in man are rarely (~20%) composed of pinealocytes (forming pinealcytoma or pinealblastoma according to differentiation) and such tumors are very rarely associated with precocious puberty.

Recent studies have shown that melatonin can be used beneficially to improve sleep patterns in patients such as Clinical Case 7.6. Many studies have used very large doses, such as 50 mg, but those using physiological doses of 0.1–1 mg have demonstrated effects on sleep latency and duration and also lower body temperature. Melatonin is now widely available throughout the world as a food additive, though not the UK, where it is treated as a drug (see website). It is used to treat the sleep disturbance that occurs as a result of modern travel across time-zones - giving rise to the phenomenon of ‘jet-lag’ - and it has also been used to help shift-workers adapt their sleeping patterns. Studies in animals and in vitro have suggested that melatonin also has antioxidant effects and that it can influence immune responses and have an effect on malignant cells. Such effects at physiological concentrations or in humans remain unproven.

Autonomic functions of the hypothalamus

The hypothalamus is important in regulating pituitary functions, but it also has a number of other functions generally attributed to autonomic control. These include temperature regulation, food intake, emotion and memory.

An important aspect of hypothalamic autonomic control with regard to the endocrine system is the control of food intake. The effects of obesity on endocrine function can be widespread and endocrine abnormalities can cause obesity. A number of hormones play central roles in the control of food intake.


Obesity is defined as an ‘excess of body fat’ and is one of the least specific definitions in medicine. It can be determined scientifically using a variety of techniques (Box 7.34) with greater or lesser degrees of accuracy. For clinical practice the less sophisticated determination of body mass index (BMI) and waist-hip circumference ratios are undemanding and (given their simplicity) remarkably useful. Using these simple measures obesity may be graded in severity and its epidemiology determined (Box 7.35).

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Box 7.34

Measures of obesity. Three main experimental measures of fat mass in man have been used for many years. They require the determination of body density, water or potassium content and the assumption that the body composition can be divided into fat and (more...)

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Box 7.35

Grades of obesity and its epidemiology.

In general obesity increases with age, and is higher in women and (in Western countries) those from lower socio-economic strata. In many countries, it has reached epidemic proportions and it is more prevalent in certain ethnic groups. The distribution of fat is sexually dimorphic with more subcutaneous fat in women in general and an increase in intra-abdominal fat in men. There is good experi-mental evidence that these two types of adipose tissue behave metabolically differently. The gynecoid distribution leads to low waist-hip circumference ratios whilst android distribution leads to a high ratio. Android obesity is particularly associated with insulin resistance and increased cardiovascular morbidity and mortality (i.e. risk of heart attacks). It is the etiological association with other diseases that makes obesity important (Box 7.36), shortening life-expectancy and reducing its quality.

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Box 7.36

Effects of obesity. Diabetes mellitus Coronary disease

Etiology of obesity

Obesity occurs when caloric intake exceeds caloric expenditure. In a sedentary adult with an average daily intake of 2300 kcals (9700 kilojoules) basal metabolism will account for 60–70% energy expenditure, dietary and obligatory thermogenesis for 5–15% and spontaneous activity for 20–30%. Additional energy may be used for physical work and exercise. Thus:

Total energy expenditure = basal (resting) metabolic rate + thermogenesis + physical activity

For any person to gain weight, food intake (energy) must exceed energy expenditure.

The factors that control food intake are complex and not only involve physiological control mechanisms but also social, cultural and cognitive aspects to eating as well as physical activity. A very powerful billion pound food industry (supported by food technology) has generated highly palatable food and made it ubiquitous and cheap (at least in Western industrialized nations). It is, by and large, rich in fat as this is one of the mechanisms generating palatability (whilst also reducing satiety). Fat is also energy dense at 9 kcal/g compared with carbohydrate or protein at 4 kcal/g. High-fat foods are readily available from fridges, food dispensers or fast-food outlets in a society that is losing the concept of fixed meal-times (resulting in ‘snacking’ and ‘grazing’).

There is no evidence that the obese have a low resting metabolic rate. Indeed, as the total body mass increases, resting metabolic rate increases (Box 7.37). Thus, an obese person has a higher rate than a lean person of the same height. Furthermore, most studies show that the obese do about the same physical activity as lean individuals. Weight gain in some populations (e.g. the Pima Indians of Arizona) is predicted by a lower physical activity but in most instances it seems unlikely that reduced physical activity accounts for more than 40% of the weight gain. However, in a society that becomes progressively more sedentary, it should not be ignored.

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Box 7.37

Calculation of resting metabolic rate*. The formulae of Schofield may be used to calculate resting metabolic rate (kcal/d) in adults.

It is noteworthy that, for most people, body weight remains remarkably constant over many years despite the intake of prodigious numbers of calories. This together with experimental work in both animals and humans has indicated that body fat mass is very tightly regulated around a ‘set-point’. For example, the weight of the cafeteria-fed rat returns to that of its standard-feed litter-mate as soon as the food is returned to normal lab chow and in studies in which American prisoners were deliberately overfed, the weight gain that occurred was lost when they returned to ‘normal’ prison life.

Control of appetite, food intake and satiety

Clinical Case 7.7 is an example of a patient in whom the appetite/feeding ‘set-point’ has been disturbed by neurological damage to his hypothalamus; it will introduce the neural and endocrine control of food intake.

Clinical Case 7.7

A 22-year-old man was referred to the obesity clinic. With a height of 1.79 m he had weighed 73 kg until 2 years previously. Over the succeeding 2 years his weight had progressively increased to 170 kg and over the same period he had become more withdrawn and had lost his job as a handyman. He had been treated by his primary care physician for depression with little success. There was no family history of obesity. On examination, he looked withdrawn and initiated little spontaneous conversation. In the light of his neurological symptoms, an MR scan of the brain was performed that revealed a large hypothalamic mass with an additional lesion in the brain stem (Box 7.38). The list of possible diagnoses for such multiple lesions includes the granulomatous disease sarcoidosis that affects many organs. Chest X-ray was normal and serum biochemistry showed normal calcium concentration but abnormal tests of liver function. A liver biopsy was, therefore, performed and the typical appearances of sarcoid (non-caseating granulomata) were seen on light microscopy. Psychometric testing showed a major problem with short-term memory. He was treated with oral glucocorticoid steroids with considerable improvement in his mental state and memory. His appetite remained unchanged however, and he lost very little weight despite documented shrinkage of the hypothalamic sarcoid tissue (Box 7.38). Additional endocrine replacement treatment for panhy-popituitarism was also required.

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Box 7.38

MR scans of Clinical Case 7.7. At presentation the sagittal section shows the large hypothalamic mass (upper arrows) together with a smaller brain stem mass (lower arrows). The first coronal section shows the extent of the involvement of the hypothalamus (more...)

Regulation of food intake and satiety is a complex process involving the co-ordination of sensory stimuli, circulating hormones (e.g. cortisol, insulin, gut hormones and leptin secreted by adipocytes), and vagal afferents from the gut relayed via the nucleus tractus solitarus (NTS). The hypothalamus co-ordinates this information through a complex network of orexigenic and anorexigenic peptides that have been summarized in Box 7.39.

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Box 7.39

Hypothalamic regulation of satiety and appetite . Image dclcc1.jpg Leptin secreted by adipocytes is transported across the blood-brain barrier. Fasting or loss of body fat mass lowers serum and CSF leptin concentrations. Image dclcc2.jpg The arcuate nucleus (ARC) is rich in leptin (and (more...)

Genetics of obesity

Obesity runs in families. Studies on identical and non-identical twins and also on adults who were adopted have shown a strong genetic component to the development of obesity (accounting for about 80% of the effect). Experimental rodent models of obesity have been extremely useful and recently the human equivalents have been described. These include (with the human equivalent in brackets): the ob/ob mouse (loss of function mutation in leptin gene); the db/db mouse (loss of function mutation in leptin receptor); MC4 receptor knock-out mouse (melanocortin 4 receptor defects); POMC knock-out mouse (POMC cleavage defect leading to loss of MSH). Such patients are rare but they throw considerable light on the biochemical mechanisms underlying appetite, illustrating a general applicability between species. There are a number of other rare disorders associated with obesity such as Prader-Willi or Bardet-Biedl syndromes. For the most part, the exact genes involved in ‘common or garden’ obesity remain to be elucidated. It is clear that a large number of genes is likely to be implicated and current likely contenders in the human include POMC and CART (Box 7.39). It is to be noted that genome-wide linkage studies for polygenic obesity in mouse strains has implicated at least 70 loci, indicating the magnitude of the likely problem in the human.

Not all congenital causes of obesity are genetic. It has been suggested that obesity, together with hypertension and coronary disease result from the intrauterine environment. The ‘thrifty phenotype’ hypothesis is discussed in Box 2.22.

For Clinical Case 7.7, there is no evidence of a genetic cause of obesity and all the clinical information implicates the hypothalamic deposition of sarcoid. It has been recognized for many years that destructive lesions of the midline ventromedial hypothalamus cause this problem whilst more lateral hypothalamic lesions cause anorexia and weight loss. Some of the hypothalamic pathways involved in the regulation of appetite and satiety are shown in Box 7.39. Clinical Case 7.7 showed evidence of the loss of appetite control together with evidence of the loss of satiety. When admitted to the hospital ward, he stole food from other patients at every meal.

Treatment of obesity

Obesity is a disease. It has major effects on morbidity and mortality that are directly related to the severity of the obesity. In general, in the present state of knowledge it is not worth investigating severely obese patients for a cause of their obesity. Exclusion of hypothyroidism or Cushing's often appears in textbooks of endocrinology but they are not causes of severe (also termed morbid) obesity.

The indications for the investigation of hypothalamic disease in Clinical Case 7.7 were the rapid weight gain in adult life, lack of family history and the associated neurological features. The more typical case is of long-standing obesity with a history of repeated partially successful ‘diets’, virtually always ending in a return to the same degree of obesity or worse. Clearly, cases in which there are associated features (e.g. polydactyly and retinitis pigmentosa in Bardet-Biedl syndrome and small hands and feet in Prader-Willi syndrome) suggest an underlying syndrome and, thus, a Mendelian genetic causation will be diagnosed on the associated features. The vast majority of the cases of adult onset obesity will not warrant investigation. Indeed, to do so would be to suggest that treatment lies in any other direction than caloric restriction. The treatment of morbid obesity is extremely difficult and at present the only long-term successful forms of treatment are surgical (Box 7.40).

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Box 7.40

Treatment of obesity.

The neural lobe of the pituitary gland - AVP and oxytocin

Arginine vasopressin (AVP) and oxytocin are small peptides with strong structural homologies. They consist of nine amino acids arranged in a ring structure with a short ‘tail’ (Box 7.41). It is likely that both evolved from a common ancestral gene and the uses ascribed to the gene products have been related to the emergence of land-living amphibia (water retention by AVP) and suckling of young in mammalian species (oxytocin). AVP is mainly synthesized in the supraoptic nuclei and to a lesser extent the paraventricular nuclei while the reverse is true for oxytocin. The hormones synthesized in the large (or magnocellular) neurosecretory cells of these nuclei are transferred to the posterior pituitary gland whilst those in the smaller cells (or parvicellular neurons) control the hormone secretions of the anterior pituitary gland.

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Box 7.41

Synthesis and structures of arginine vasopressin (AVP) and oxytocin (OT). AVP and OT are co-secreted with their associated neurophysins.

Like all other peptide and protein hormones, they are synthesized as a large prohormone and after packaging into secretory granules, the prohormones pass by axonal flow to the nerve terminals (Herring bodies) in the neurohypophysis. During this passage, the prohormones are cleaved into the biologically active AVP or oxytocin and a larger polypeptide fragment. Neurophysin II is the product cleaved from the vasopressin pro-hormone and neurophysin I from the oxytocin pro-hormone. Both neurophysins are co-secreted with the active hormones upon electrical activation of the neuro-secretory cells.

AVP - actions and control

AVP derives its name from the first action ascribed to it nearly 100 years ago, an increase in systemic blood pressure (i.e. a pressor agent). Its actions on water balance in the kidney (where it is effective in very low concentrations) gave rise to the alternative name antidiuretic hormone (ADH) and the terms tend to be used interchangeably. AVP has three known receptors and, whilst this chapter will consider exclusively the actions of AVP on these receptors, this hormone acts in concert with aldosterone and atrial natriuretic peptide to control blood volume and pressure (Box 7.42).

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Box 7.42

Integrated action of arginine vasopressin (AVP) with other hormones regulating blood volume and pressure. Arrows to the left indicate changes in hormone secretion in response to a reduction in blood volume, those on the right the changes in response to (more...)

In the kidney, it acts on the G-protein linked V2 receptors on the capillary (basal) side of the distal convoluted and collecting ducts and stimulates the synthesis of cAMP. The cAMP activates a kinase on the luminal (apical) side of the ducts that initiates a series of events culminating in the insertion of water channels, known as aquaporins, into the luminal membrane (Box 7.43). Water passes into the collecting duct cells and, by osmosis, across the basal membrane, into the interstitial fluid and, hence, back into the circulation. There is also an osmotic gradient (set up by the counter-current activity of the loop of Henle) from the cortex to the medulla of the kidney. Thus, as the collecting ducts pass through the cortex to the medulla increasing amounts of solute-free water (also termed ‘free water’) can be reabsorbed by the osmotic gradient. This is governed by the aquaporins and, hence, AVP.

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Box 7.43

The actions of arginine vasopressin (AVP) secretion and mechanisms of control.

Increased osmolality of the extracellular fluids stimulates AVP release. Changes in osmolality are detected by osmoreceptors. Osmotically sensitive cells were first described in the hypothalamus but it is now known that there are additional osmoreceptors in the circumventricular organs and in systemic viscera. These are not only important in regulating AVP secretion but also in stimulating thirst. As a result, AVP induces increased water retention and a reduction in serum osmolality, the relationship of which is shown in Box 7.44.

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Box 7.44

The relationship between serum arginine vasopressin concentration and blood volume depletion or plasma osmolality.

Another potent stimulus to AVP secretion is a reduction in effective blood volume and AVP secretion is stimulated by a volume reduction of just 5–10% (Box 7.44). This is controlled by so-called stretch receptors that detect changes in blood volume/pressure. These include the baroreceptors and other receptors in the cardiovascular system. Thus, for example, after a hemorrhage AVP secretion is stimulated and water is retained, increasing blood volume. The reverse occurs in response to an increase in blood volume/pressure.

Other stimulants to AVP secretion include emotional stress, pain and a variety of drugs. Nausea and vomiting are also extremely potent stimulators of its release (Box 7.43). The effects of these stimuli may be important in situations such as the post-operative state, affecting water balance. In contrast, alcohol is a potent inhibitor of AVP release (as little as 30–90 ml of whiskey is sufficient) resulting in inappropriate dehydration and some of the symptoms associated with a ‘hang-over’. The preventative measure is to drink a restorative volume of water after excess ethanol consumption.

Apart from its primary role in water conservation, AVP is also important in maintaining blood pressure after hemorrhage as a result of its vasopressive effects on arteriolar smooth muscle. Acting on V1A receptors on smooth muscle cells it induces vasoconstriction via calcium and phospholipase-C generated second messengers. The final established role of vasopressin is the potentiation of CRH action on pituitary corticotrophs via V1B receptors. AVP is released from parvicellular neurosecretory cells into the hypophyseal portal capillaries (see Boxes 4.14 and 7.43).

Vasopressin deficiency - diabetes insipidus

It is evident that AVP is important in controlling the osmolality of body fluids. In AVP deficiency there is loss of solute-free water and (in the absence of a matched intake) a consequent rise in serum osmolality. Patients with AVP deficiency, and subject to constant polyuria are absolutely dependent on the sensation of thirst to guide fluid intake, resulting in polydipsia.

Returning to a consideration of Clinical Case 7.1 (a patient presenting with a visual field defect as the result of a craniopharyngioma), it is now possible to interpret the events and additional symptoms that occurred after the initiation of replacement hormones. This patient noted polyuria and polydipsia soon after starting hydrocortisone and thyroxine replacement therapy. Both thyroxine and cortisol (i.e. hydrocortisone) are required by the kidney to ensure the ability to excrete free water normally. In the absence of these, the patient was protected from the effects of AVP deficiency. Once these were replaced, the increase in free water clearance could not be matched by AVP secretion (because of hypothalamic damage) and as a result the patient developed diabetes insipidus (DI).

Patients such as that of Clinical Case 7.1 are said to have ‘central’ DI due to a lack of AVP that can occur as a result of any of the causes of hypothalamo- pituitary damage (see Box 7.9). However, DI can also occur when the kidneys are insensitive to the action of AVP, termed nephrogenic DI. This may be acquired or congenital and mild or severe (Box 7.45). Cranial DI is usually diagnosed using a water-deprivation test (that includes the response to a long-acting AVP analog) or hypertonic saline infusion. The latter is more expensive but may aid the diagnosis of milder forms of AVP deficiency (Box 7.46). Clinical Case 7.1 underwent a water deprivation test to confirm cranial DI and was treated with desmopressin, a long-acting analog of vasopressin that can be given intranasally, subcutaneously or orally.

Box Icon

Box 7.45

Causes of diabetes insipidus. Any cause of hypothalamo-pituitary damage (see Box 7.9) - Note that these have to cause damage to the pituitary stalk or hypothalamus. Mutation of the AVP-neurophysin gene - none to date affects the coding region for AVP

Box Icon

Box 7.46

Tests to diagnose causes of polyuria and polydipsia: central diabetes insipidus (CDI) versus nephrogenic diabetes insipidus (NDI). Image dclcc1.jpg Water deprivation test Schematic diagram showing typical changes in plasma Image dclccA.jpg and urine Image dclccB.jpg osmolality in subjects during 8 (more...)

Nephrogenic DI does not, by definition, respond to vasopressin or its analog. It has been treated primarily by maintaining fluid intake. Non-steroidal anti-inflammatory drugs have also been used as have mild thiazide diuretics.

Vasopressin excess - syndrome of inappropriate antidiuresis (SIAD)

A variety of disorders are associated with serum AVP concentrations that are inappropriately high for the serum osmolality. This is discussed in relation to Clinical Case 4.5.

Oxytocin - actions and control

The major action of oxytocin is in lactation when, through a neuroendocrine reflex, it initiates the ‘let down’ of milk by inducing contractions of the myoepithelial cells surrounding the alveoli of the mammary gland (Box 7.47). In animals, there is evidence that it plays a major role in parturition but in the human, there is much less evidence to support this role. It does, however, play a contributing role in that it induces powerful contractions of the uterine muscle. Thus, synthetic oxytocin is widely used therapeutically in obstetrics not only to induce labor and maintain progression but also to reduce post-partum bleeding.

Box Icon

Box 7.47

Oxytocin - its actions and control. Abbreviations: MB, mammillary body; OC, optic chiasm; PVN, paraventriular nucleus; SO, supraoptic nucleus

Oxytocin can have stimulatory effects at the AVP V2 receptor in the kidney. There is no naturally occurring disease associated with excess oxytocin secretion but in obstetric situations, when given in high doses as an intravenous infusion in 5% dextrose, it can cause water retention and iatrogenic hyponatremia.

Clinical case questions

Clinical Case Study Q7.1

A 35-year-old patient was seen in the outpatient clinic with amenorrhea of 4 years standing. She had been diagnosed as having paranoid schizophrena 8 years previously and had since received regular intramuscular depot phenothiazine treatment since. Some 2 years previously, she had been seen in the Ob-Gyn clinic and a serum prolactin had been 2457 mU/l (NR <400 mU/l). The serum LH had been 1.2 IU/l and the FSH 1.3 IU/l. The Ob-Gyn made a diagnosis of drug-induced hyperprolactinemia with secondary amenorrhea.

Question 1: Were Ob-Gyn correct? In particular, does the hyperprolactinemia account for the hypogonadotrophic hypogonadism?

Question 2: What other investigations might have been considered by Ob-Gyn?

Question 3: How may these results be interpreted and what further investigations are required?

Question 4: How may these results be interpreted?

Clinical Case Study Q7.2

A 71-year-old woman was referred to the lipid clinic with a serum cholesterol of 8.2 mmol/l (recommended <5.2 mmol/l) and triglycerides of 3.3 mmol/l (NR <2 mmol/l). She had a past medical history of bilateral carpal tunnel decompressions performed some 15 years previously and was being treated for systemic hypertension by her primary care physician. She was 1.65 m tall and weighed 99 kg. Noting her facial features, the physician elicited the fact that her wedding ring had been enlarged twice and that her shoe size had increased 2 sizes. It was noted that her son had diabetes mellitus type 2 at the age of 40 years. She was requested to supply a series of old photographs from the family album (Box Q7.2a see website).

Question 1: What initial tests would you perform?

Question 2: What interpretation do you make of these results?

Question 3: What further tests would you perform?

Question 4: In the light of these results, what is the differential diagnosis and how would you treat her?

Clinical Case Study 7.3

A 28-year-old female secretary developed hyperthyroidism and was treated at another hospital. At initial presentation, the serum sodium concentration was 130 mmol/l (NR 135–145 mmol/l). Hyperthyroidism recurred 2 years later when therapy with carbimazole was discontinued and she was admitted to another hospital for a sub-total thyroidectomy. The preoperative serum sodium concentration was 128 mmol/l (NR 135–145 mmol/l). Two days post-operatively, the serum sodium concentration had fallen to 108 mmol/l (NR 135–145 mmol/l) and she became confused. She was not edematous and there was no evidence of heart failure. Serum biochemical tests of liver and renal function were otherwise normal. Her lying and standing blood pressures were normal with no postural drop.

Question 1: What are the most likely diagnoses and what investigations would you perform?

Question 2: What treatment would you institute and what further investigations should be performed?

Copyright © 2001, BIOS Scientific Publishers Limited.
Bookshelf ID: NBK27