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Download S10 Clinicalbiochem2 DrNansy Hypothalamus And Pituitary
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Endocrinology • Introduction • Dynamic function tests • Hypothalamus and pituitary function tests • Adrenal function • Thyroid function tests • Other glands Hypothalamus and pituitary glands • • • • • • Hypothalamus The pituitary gland Anterior pituitary hormones Posterior pituitary hormones Pituitary tumors Hypopituitarism Case 1 Saleem is a 5 year old boy and is much smaller than his classmates at school. His growth rate has been monitored and has clearly dropped off markedly in the past year. He is a active child, and on examination has normal body proportions. His mother and father are of average height. His bone age is that of 3-year-old child. 1. What is likely cause of his condition? 2. Which biochemical tests would be appropriate in the investigation of this boy? Hypothalamus Integrates activities of nervous and endocrine systems in 3 ways: 1. Secretes regulatory hormones that control endocrine cells in pituitary gland. 2. Acts as an endocrine organ itself. 3. Contains autonomic centers that exert direct neural control over endocrine cells of adrenal medullae (neuroendocrine reflex). Hypothalamic–Pituitary system • Hypothalamus secretes regulatory hormones (releasing hormones). • Causes anterior pituitary to release stimulating hormone (tropic hormones). • Tropic hormones stimulate target cells to respond, either directly or indirect. Regulatory hormone Negative feedback Tropic hormone Resulting hormone Hypothalamus hormones • • • • • • • • TRH: Thyrotropin-releasing hormone PRH: Prolactin-releasing hormone PIH: Prolactin- inhibiting hormone GH-RH: Growth hormone-releasing hormone Gn-RH: Gonadotropin-releasing hormone CRH: Corticotropin-releasing hormone ADH or AVP: antidiuretic hormone or vasopressin Oxytosin Pituitary (Hypophysis) is the Master Endocrine Gland • Pea size gland and secretes 9 major peptide hormones and include two lobes: – Posterior (neurohypophysis): neural – Anterior (adenohypophysis): glandular, synthesis and secretes seven peptide hormones The pituitary gland • Pituitary function is regulated by the hypothalamus, to which it is connected via pituitary stalk, which comprises portal blood capillaries and nerve fibers. • The pituitary gland consists of two parts, the anterior pituitary, or adenohypophysis, which is influenced by a variety of stimulatory and inhibitory hormones through these capillaries. • The posterior pituitary, or neurohypophysis, is a collection of specialized nerve endings that derive from the hypothalamus. • Though very closely related anatomically, they are embryologically and functionally quite distinct. The anterior pituitary comprises primarily glandular tissue, while the posterior pituitary is of neural origin. The pituitary gland is situated at the base of the brain, in close relation to the hypothalamus, which has an essential role in the regulation of pituitary function . Anterior pituitary hormones TSH (thyroid stimulating hormone) • Act specifically act on thyroid gland to elicit secretion of thyroid hormones. • Secretion of TSH is stimulated by the hypothalamic tripeptide TRH and this effect, and probably the release of TRH itself, is inhibited by high circulating concentrations of thyroid hormones. • Thus thyroid hormone synthesis is regulated by a negative feedback system: if plasma concentrations of thyroid hormones decrease, TSH secretion increases, stimulating thyroid hormone synthesis; if they increase, TSH secretion is suppressed. In primary hypothyroidism, TSH secretion is increased; in hyperthyroidism it is decreased. TSH deficiency can cause hypothyroidism. ACTH (adrenocorticotrophic hormone) • Its biological function, which is to stimulate adrenal glucocorticoid (but not mineralocorticoid) secretion. Acts specifically on the adrenal cortex to elicit secretion of cortisol • ACTH secretion is pulsatile and also shows diurnal variation, the plasma concentration being highest at approximately 0800 h and lowest at midnight. Secretion is greatly increased by stress and is inhibited by cortisol. Thus cortisol secretion by the adrenal cortex is controlled by negative feedback, but this and the circadian variation can be overcome by the effects of stress. • Increased secretion of ACTH by the pituitary is seen with pituitary tumors (Cushing's disease) and in primary adrenal failure (Addison's disease). The hormone may also be secreted ectopically by non-pituitary tumors. Excessive ACTH synthesis is associated with increased pigmentation, owing to the melanocytestimulating action of ACTH. • Decreased secretion of ACTH may be an isolated phenomenon but is more commonly associated with generalized pituitary failure. LH (lutenizing hormone) and FSH (follicle stimulating hormone) • Known jointly as the gonadotrophins, act cooperatively on the ovaries in women and the tests in men to stimulate sex hormone secretion and reproductive processes. • The synthesis and release of both hormones are stimulated by the hypothalamic gonadotrophin-releasing hormone (GnRH), these effects being modulated by circulating gonadal steroids. • GnRH is secreted episodically, resulting in pulsatile secretion of gonadotrophins • In males, LH stimulates testosterone secretion by Leydig cells in the testes: both testosterone and oestradiol, derived from the Leydig cells themselves and from the metabolism of testosterone, feedback to block the action of GnRH on LH secretion. • FSH, in concert with high intratesticular testosterone concentrations, stimulates spermatogenesis; its secretion is inhibited by inhibin, a hormone produced during spermatogenesis. • In females, the relationships are more complex. Oestrogen (mainly oestradiol) secretion by the ovaries is stimulated primarily by FSH in the first part of the menstrual cycle; both hormones are necessary for the development of Graafian follicles. • As oestrogen concentrations in the blood rise, FSH secretion declines until oestrogens trigger a positive feedback mechanism, causing an explosive release of LH and, to a lesser extent, FSH. • The increase in LH stimulates ovulation and development of the corpus luteum, but rising concentrations of oestrogens and progesterone then inhibit FSH and LH secretion; inhibin from the ovaries also appears to inhibit FSH secretion. • If conception does not occur, declining concentrations of oestrogens and progesterone from the regressing corpus luteum trigger menstruation, and LH and FSH release, initiating the maturation of further follicles in a new cycle. GH (growth hormone) • Acts directly on many tissues to modulate metabolism. Metabolic fuels (glucose, free fatty acids) in turn modify GH secretion • It is essential for normal growth, although in the main it acts indirectly by stimulating the liver to produce insulin-like growth factor-1 (IGF-1), also known as somatomedin-C (IGF-1 has considerable amino acid sequence homology with insulin and shares some of the actions of this hormone) • GH also has a number of metabolic effects. • The release of GH is controlled by two hypothalamic hormones, growth hormone-releasing hormone (GHRH) and somatostatin. IGF-1 exerts negative feedback at the level of the pituitary, where it modulates the actions of GHRH, and at the level of the hypothalamus where, together with GH itself, it stimulates the release of somatostatin. • The concentration of GH in the blood varies widely through the day and may at times be undetectable (<1 mU/L). GH (growth hormone) • Physiological secretion occurs in sporadic bursts, lasting for 1-2 h, mainly during deep sleep. • The rate of secretion increases from birth to early childhood and then remains stable until puberty, when a massive increase occurs, stimulated by testosterone in males and oestrogens in females; thereafter the rate of secretion declines to a steady level before falling to low levels in old age. • Secretion can be stimulated by stress, exercise, a fall in blood glucose concentration, fasting and ingestion of certain amino acids. • Excessive secretion (usually due to a pituitary tumor) causes gigantism in children and acromegaly in adults; deficiency causes growth retardation in children and can cause fatigue, loss of muscle strength, impaired psychological wellbeing and an adverse cardiovascular risk profile (elevated plasma total and LDL-cholesterol concentrations and hyperfibrinogenaemia) in adults. Growth disorders and acromegaly • Physiological secretion occurs in sporadic bursts, lasting for 1-2 h, mainly during deep sleep. • The rate of secretion increases from birth to early childhood and then remains stable until puberty, when a massive increase occurs, stimulated by testosterone in males and estrogens in females; thereafter the rate of secretion declines to a steady level before falling to low levels in old age. GH is only one of many hormones involved in growth. Insulin-like growth factors, thyroxine, cortisol, the sex steroids and insulin are involved • Growth hormone insufficiency is a rare cause of impaired physical growth. If GH deficiency is diagnosed, and treatment is required, then the earlier it is given the better the chance that the child will eventually reach n normal size. • It is important to differentiate between children whose slow growth or growth failure is due to illness or disease and those whose short stature is a normal variant of the population. Causes of short stature are: • having parents who are both short. • inherited diseases such as achondroplasia, the commonest cause of severe dwarfism. • poor nutrition. • systemic chronic illness, such as renal disease, gastrointestinal disorders or respiratory disease. • psychological factors such as emotional deprivation. • hormonal disorders. Tests of growth hormone insufficiency • Growth hormone deficiency may be present from birth or due to later pituitary failure. A variety of stimulation tests have been used to evaluate GH deficiency. • Serum GH concentrations rise in response to exercise, and this may be used as a preliminary screening test. • They also rise during sleep, and high concentrations in a nocturnal sample may exclude GH deficiency. • The lack of GH response to clonidine, a potent stimulant of GH secretion, is diagnostic. Some centers have now abandoned the use of insulin induced hypoglycaemia as a diagnostic test in children because of its hazards. • The GH response to stimulation may be blunted before puberty, and priming with the appropriate sex steroid is necessary before investigating GH reserve. • Increasingly, urinary growth hormone measurements are being used to assess possible GH lack in children. Random serum IGF I determinations may be of value. Levels within reference limits exclude GH deficiency. Treatment • Genetically engineered GH is available and is used in the treatment of that small group of children with proven GH deficiency. Excessive growth • GH excess in children is characterized by extremely rapid linear growth (gigantism). This condition is uncommon and most often due to a GH secreting pituitary tumor. • Other causes of tall stature in children are rare and include: 1. Hyperthyroidism: an increased growth rate, with advanced bone age, is a feature of hyperthyroidism in children, or hypothyroid children over-replaced with thyroxine. 2. Inherited disorders such as Klinefelter’s syndrome (a 47 XXY karyotype). 3. Congenital adrenal hyperplasia. Acromegaly • Increased GH secretion later in life, after fusion of bony epiphyses (is the rounded end of a long bone). The most likely cause is pituitary adenoma. Clinical features include: 1. Coarse facial features. 2. Soft tissue thickness (e.g. the lips) 3. Characteristic ‘spade like’ hands 4. Protruding jaw 5. Sweating 6. Impaired glucose tolerance or diabetes mellitus Diagnosis • Formal diagnosis of acromegaly requires an OGTT with GH measurements. • Acromegalic patients do not suppress fully in response to hyperglycemia. • IGF 1 produced in response to GH and provides useful additional biochemical information. It is now routinely measured in the diagnosis and especially monitoring of treated acromegaly, with an elevated level suggestive of active disease. Treatment 1. Surgery. Its success depends on the size of the tumor. 2. Radiation. This is usually reserved for patients whose disease remains active despite surgery. It may require years before safe levels of GH are achieved. Medical treatment is required temporarily. 3.Medical. Dopamine agonists like bromocriptine were widely used in the past, but response rates were low. Long-acting synthetic somatostatin, such as octreoids are used today. These are expensive drugs with side effects, and it is sensible to measure GH after administering the drug (octreotide suppression test). Prolactin • Acts directly on the mammary glands to control lactation. Gonadal function is impaired by elevated circulating prolactin concentrations • Prolactin is a polypeptide hormone; its principal physiological action is to initiate and sustain lactation. • It also has a role in breast development in females; at high concentrations, it inhibits the synthesis and release of gonadotrophinreleasing hormone (GnRH) from the hypothalamus, and thus gonadotrophins from the pituitary, inhibiting ovulation in females and spermatogenesis in males. • Prolactin secretion is controlled by the hypothalamus through the release of dopamine, which normally exerts a tonic inhibition. • The principal physiological stimuli to prolactin secretion are pregnancy and suckling. Prolactin • The secretion of prolactin is pulsatile, increases during sleep, after meals, exercise and with stress (both physical and psychological), and, in women, is dependent upon oestrogen status, making it difficult to define a precise upper limit for plasma prolactin concentration in normal men and women, although 500 mU/L is often regarded as the upper reference value in non-pregnant women and 300 mU/L in men. • There is no useful lower reference value for plasma prolactin concentration. • Its secretion increases during pregnancy but concentrations fall to normal within approximately seven days after birth if a woman does not breast feed. With breast-feeding, concentrations start to decline after about three months, even if breast-feeding is continued beyond this time. Hyperprolactinemia • • 1. 2. It is common and can cause infertility in both sexes. Causes of hyperprolactinemia: Stress. Drugs (estrogens). 3. Seizures (acutely) 4. Primary hypothyroidism (prolactin is stimulated by the raised TRH). • If these causes are excluded, the differential diagnosis is between A prolactinoma (a prolactin-secreting pituitary tumor). Idiopathic hypersecretion, which may be due to impaired secretion of dopamine. • Differentiating between these is by detailed pituitary imaging together with DFTs of prolactin secretion. A rise in serum prolactin following administration of TRH or metoclopramide is observed in idiopathic hyperprolactinemia but not in the presence of a pituitary tumor Posterior pituitary hormones • Hypothalamic neurons synthesize arginin vasopressin (AVP, ADH, vasopressin) and oxytocin, which pass along axonal nerve fibers in the pituitary stalk to the posterior pituitary where they are stored in granules in the terminal bulbs of nerves in proximity to the systemic veins. • Secretion of ADH is stimulated by: increased plasma osmolality, severe blood volume depletion, stress and nausea. • Oxytocin is involved in the control of uterine contractility and of milk release from the lactating breast. Disorders of its secretion are probably uncommon and are not clinically important. • A pituitary tumor arising in the anterior gland may cause impaired secretion of this hormone, with consequent diabetes insipidus. • In diabetes insipidus, the lack of vasopressin (or resistance to its actions) results in polyuria (typically >3 L urine/24 h in adults) and thirst Pituitary tumors • Pituitary tumors may be either functional (they secrete hormones) or non-functional. • Local effects include headaches, papilloedema and visual field defects. • There may be specific signs of hormone excess particularly in acromegaly, Cushing’s syndrome and prolactinoma. • The impact of the tumor on pituitary function requires formal assessment by DFTs. • In GH and ACTH secreting cells, an IST may suffice. • Comprehensive assessment of anterior pituitary reserve requires a combined anterior pituitary function test. TRH, GnRH and insulin are administered. All hormones are assessed at 0, 30 and 60 minutes, and GH additionally at 90 and 120 minutes. Treatment 1. Medical. 2. Surgery 3. Radiation: the impact of radiation on pituitary function is cumulative, and irradiated patients require annual DFTs thereafter. Hypopituitarism • There are many causes of hypopituitarism, a relatively uncommon condition in which there is failure of one or more pituitary functions. • The clinical presentation depends on the age of the patient: In infancy, short stature or impaired development may point to this condition. In the reproductive years, women may present with amenorrhea or infertility. Men may present with decreased libido or a lack of male secondary sex characteristics. Elderly patients may complain of symptoms relating to ACTH or TSH deficiency such as hypoglycemia or hypothermia. Hypopituitarism • If insufficient secretion of one (selective form): 1. Cortisol deficiency: because of lack of ACTH. 2. Thyroid hormones deficiency: because of lack of TSH. 3. ADH defficincy: diabetes insipidus. 4. Defficiency of FSH and LH: gonadal failure and loss of secondary sex characteristics. 5. Decrease growth hormone: decrease somatomedin (they affect children growth). 6. Absence of prolactin: postpartum women are unable to lactate. The End