Chapter 3 Endocrine Physiology
|Corticotropin-releasing hormone (CRH)||Stimulates adrenocorticotropic hormone (ACTH) secretion from anterior pituitary||Increase in adrenal insufficiency due to loss of negative feedback|
|Gonadotropin-releasing hormone (GnRH)||Stimulates gonadotropin secretion from anterior pituitary|
|Thyrotropin-releasing hormone (TRH)||Stimulates thyroid-stimulating hormone (TSH) secretion from anterior pituitary||Decrease in primary or secondary hyperthyroidism due to feedback inhibition|
|Growth hormone-releasing hormone (GHRH)||Stimulates growth hormone secretion from anterior pituitary||Decrease in growth hormone (GH)-secreting tumor of anterior pituitary|
|Somatostatin||Inhibits GH secretion from anterior pituitary||Synthetic version (octreotide) used in GH-secreting pituitary adenomas|
|Dopamine||Inhibits prolactin secretion from anterior pituitary|
|Anterior Pituitary Hormones|
|Adrenocorticotropic harmone (ACTH)||Stimulates glucocorticoid and androgen synthesis in adrenal medulla|
|Thyroid stimulating harmone (TSH)||Stimulates thyroid hormone synthesis in the thyroid gland|
|Luteinizing hormone (LH)|
Elevated levels: polycystic ovary syndrome (PCOS), testicular failure, premature menopause, Turner syndrome
|Follicle-stimulating hormone (FSH)|
|Growth hormone (GH)||Anabolic hormone with multiple anabolic and insulin-antagonizing metabolic effects|
|Prolactin||Stimulates breast maturation and milk letdown||Prolactinoma: hypersecreting prolactinoma resulting in galactorrhea and infertility in women|
|Posterior Pituitary Hormones|
|Antidiuretic hormone (ADH)||Stimulates water absorption from the distal nephron|
|Oxytocin||Stimulates uterine contraction during labor|
|Thyroxine (T4)||Prohormone that becomes bioactive on peripheral conversion to T3|
Thyrotoxicosis: any cause for ↑ thyroid hormones (e.g., gland destruction, exogenous intake, ↑ synthesis)
Thyroiditis: destruction of thyroid gland; can transiently cause hyperthyroidism but ultimately causes hypothyroidism
|Triiodothyronine (T3)||Increases basal metabolic rate by up-regulating expression and insertion of Na+,K+-ATPase pump|
|Adrenal Cortex Hormones|
|Aldosterone||Promotes renal Na retention and expands plasma volume||Hypersecreted in primary aldosteronism → hypertension with hypokalemic metabolic alkalosis|
|Cortisol||Helps maintain glucose for glucose-dependent tissues during fasting state by promoting hepatic gluconeogenesis, peripheral resistance to insulin, and lipolysis in adipose tissue|
|Dehydroepiandrosterone (DHEA)||Converted to testosterone in peripheral tissues||Congenital adrenal hyperplasia: oversecretion of androgens results in virilization, precocious puberty, ambiguous genitalia|
|Adrenal Medulla Hormones|
|Dihydrotestosterone (DHT)||Development of the male external genitalia (penis, scrotum) and prostate gland|
|Insulin||Promotes peripheral uptake of glucose in nonfasting (fed) state|
|Glucagon||Promotes hyperglycemia and insulin resistance||Glucagonoma|
|Somatostatin||Used to treat GH-secreting pituitary adenomas|
|Vasoactive-intestinal peptide (VIP)|
Vasoactive intestinal polypeptide-secreting tumor (VIPoma); may be associated with multiple endocrine neoplasia type 1
3-1 Schematic of the hypothalamic-pituitary-endocrine organ axis. ACTH, Adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; FSH, follicle-stimulating hormone; GH, growth hormone; GHRH, growth hormone–releasing hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; LHRH, luteinizing hormone–releasing hormone; TSH, thyroid-stimulating hormone.
(From Kumar P, Clark M: Kumar and Clark’s Clinical Medicine, 5th ed. Philadelphia, Saunders, 2002, Fig. 18-7.)
3-2 After diffusing through the plasma membrane, most steroid hormones bind to a cytoplasmic receptor. This hormone-receptor complex then undergoes a conformational change, which uncovers a nuclear localization site that allows access to the nucleus. The complex then binds to and activates genes that contain the appropriate steroid response element within their sequence. HR, Hormone receptor; NLS, nuclear localization sequence; SRE, steroid response element.
Biochemistry note: The four primary classes of membrane-spanning receptors that peptide hormones bind to are (1) tyrosine and serine kinase receptors, (2) receptor-linked kinases, (3) G protein–coupled receptors, and (4) ligand-gated ion channels. As a gross simplification, the “prototypical” agonists for these receptor types can be considered to be growth factors, growth hormones, peptide hormones, and neurotransmitters, respectively.
3-3 G protein signal transduction cascade. The first step (A) is the binding of hormone (triangle) to a G protein–associated membrane receptor. This hormone binding stimulates the receptor to undergo a conformational change (B), which causes the α-subunit of the G protein to release guanosine diphosphate (GDP) and bind guanosine triphosphate (GTP). This causes the α-subunit to dissociate from the β-γ complex. The α-subunit and the β-γ complex are then free to diffuse laterally within the lipid bilayer and activate or inhibit the activity of various effector molecules, such as adenylate cyclase (C). After several seconds, intrinsic GTPase activity of the α-subunit degrades the GTP to GDP. The GDP-bound α-subunit is inactive and also binds to the β-γ complex (D), restoring the system to its original condition. The intrinsic adenosine triphosphatase (ATPase) activity of the α-GTP complex limits the duration of the response.
|Albumin||Multiple lipophilic hormones|
|Thyroxine-binding globulin||Triiodothyronine (T3), T4|
|Sex hormone–binding globulin||Testosterone, estrogen|
Clinical note: In pregnancy, plasma levels of the hormone-binding protein thyroid-binding globulin and transcortin increase because of the effects of estrogen on the liver, which increases their synthesis. This increases plasma levels of total thyroid hormone and total cortisol hormone but does not affect levels of free thyroid hormone or free cortisol hormone. Therefore, despite elevated levels of total thyroid hormone and cortisol, these women do not manifest symptoms of hyperthyroidism or hypercortisolism. Note, however, that pregnant women can still experience gestational hyperthyroidism and Cushing syndrome, but the pathophysiology of these endocrinopathies is unrelated to altered hormone-binding protein synthesis.
|Hormone||Effect on Anterior Pituitary|
|Growth hormone–releasing hormone (GHRH)||Stimulates growth hormone (GH) secretion|
|Prolactin-inhibitory factor (dopamine)||Inhibits prolactin secretion|
|Somatostatin||Inhibits GH secretion|
|Gonadotropin-releasing hormone (GnRH)||Stimulates luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion|
|Corticotropin-releasing hormone (CRH)||Stimulates adrenocorticotropic hormone (ACTH) secretion|
|Thyrotropin-releasing hormone (TRH)||Stimulates thyroid-stimulating hormone (TSH) secretion|
Pathology note: In certain types of congenital adrenal hyperplasias (CAH), specific enzyme blocks (e.g., 21- and 11-hydroxlase) lead to impaired cortisol synthesis and shunting of proximally located precursors (e.g., 17-hydroxypregnenolone, 17-hydroxyprogesterone) into the androgen biosynthetic pathway. Because androgens do not feedback-inhibit the pituitary, ACTH levels markedly increase. The result is further pathologic androgen production, resulting in precocious puberty in males later in childhood or ambiguous genitalia in female neonates (e.g., clitoris looks like a penis). In severe forms of CAH, salt wasting (hypotension) from insufficient mineralocorticoid production distal to the enzyme block may occur (e.g., 21-hydroxylase deficiency), or salt retention (hypertension) results from increased weak mineralocorticoids like 11-deoxycorticosterone that are proximal to the enzyme block (e.g., 11-hydroxylase deficiency).
Pathology note: A tumor of the adrenal gland that autonomously hypersecretes cortisol exerts negative feedback on the hypothalamus and pituitary and decreases the secretion of ACTH secretion. In this circumstance, the patient will be hypercortisolemic with a low ACTH level, implying the etiology of the hypercortisolism is adrenal in origin.
3-7 Pathways of adrenal steroidogenesis. Note that the primary dehydroepiandrosterone (DHEA) produced by the adrenal is DHEA sulfate, whereas the key DHEA produced by the gonads is DHEA. This is important in working up the cause of hirsutism and virilization. Note also the stimulatory effects of angiotensin II and plasma K+ on aldosterone synthesis.
Clinical note: The CNS is primarily dependent on glucose for a fuel source because it is unable to metabolize fatty acids and proteins to any great extent. Therefore, in patients who experience hypoglycemia (e.g., diabetic patient who takes his pre-meal insulin and then forgets to eat), CNS dysfunction can occur. Symptoms can range from mild confusion and somnolence to coma. Fortunately, unless the hypoglycemia is prolonged, it is rare for brain damage to occur.
Clinical note: Ordinarily, cortisol is degraded by intracellular enzymes in the cells of mineralocorticoid-responsive tissues such as the colon and kidney. However, at higher levels, these enzymes become saturated, at which point cortisol may bind to mineralocorticoid receptors and exert pathologic effects, such as hypertension and electrolyte abnormalities (e.g., hypokalemia).
3-10 Classic physical features of Cushing syndrome. The classic physical presentation of Cushing syndrome is central obesity that spares the extremities (extremity wasting may even occur), a rounded face (“moon facies”), abdominal striae, and a dorsocervical fat pad (“buffalo hump”). Although glucocorticoids are lipolytic, they cause fat deposition on the trunk and face. In addition to hyperglycemia, osteoporosis, hypertension, and muscle wasting, hirsutism may be present in the adrenocorticotropic hormone (ACTH)-dependent forms of Cushing syndrome as a result of stimulation of adrenal androgen production by the excess ACTH. Oligomenorrhea, acne, and deepening of the voice can also occur in females as a result of increased levels of androgens.
Clinical note: The dexamethasone suppression test can be used to differentiate between pituitary Cushing and paraneoplastic secretion ACTH in a patient with hypercortisolism and elevated ACTH. In pituitary Cushing, the pituitary retains some responsiveness to feedback inhibition by cortisol or by synthetic glucocorticoids such as dexamethasone. In contrast, ectopic Cushing or adrenal Cushing is not controlled through feedback inhibition by cortisol or dexamethasone. Therefore, although the administration of a high dose of dexamethasone should decrease cortisol levels in pituitary Cushing, it will have no effect on decreasing cortisol levels in ectopic Cushing or adrenal Cushing.
Clinical note: The exogenous administration of glucocorticoids on a long-term basis normally suppresses the hypothalamic-pituitary-adrenal axis. If steroid therapy is abruptly stopped, patients are susceptible to developing acute adrenal insufficiency. Therefore, whenever steroid therapy is to be stopped, it should be a gradual weaning process, which allows the hypothalamic-pituitary-adrenal axis to recover by the time the steroids are completely stopped.
Chronic adrenal insufficiency also develops when the adrenal cortex is destroyed. Usually, the cause is autoimmune destruction of the adrenals (Addison disease), but sometimes it is tuberculosis or metastatic cancer involving the adrenals. Signs and symptoms of adrenal insufficiency reflect deficiencies in glucocorticoids and mineralocorticoids and include hypotension and salt wasting. Reduced feedback inhibition of the hypothalamic-pituitary axis from deficient cortisol synthesis results in increased ACTH secretion by the pituitary. When ACTH is cleaved from its precursor proopiomelanocortin (POMC), melanocyte-stimulating hormone (MSH) is concurrently released. MSH then stimulates melanin-containing skin cells (melanocytes), causing hyperpigmentation of the skin, which is frequently seen in Addison disease.