Physiology_Levy

Physiology_Levy. Fig. 43.1 ). These give rise to two types of blood vessels that carry blood from the cortex to the medulla (Fig. 43.3 ): (1) relatively few medullary arterioles, which provide high oxygen- and nutrient-laden blood directly to the medullary chromaffin cells, and (2) relatively numerous cortical sinusoids into which cortical cells secrete steroid hormones (including cortisol). Both vessel types fuse to give rise to the medullary plexus of vessels that ultimately drains into a single suprarenal vein. Thus secretions of the adrenal cortex percolate through the chromaffin cells and bathe them in high concentrations of cortisol before leaving the gland and entering the inferior vena cava. Cortisol inhibits neuronal differentiation of the medullary cells, so they fail to form dendrites and axons. Additionally, cortisol induces expression of the enzyme PNMT, which converts norepinephrine to epinephrine (


Physiology_Levy

Physiology_Levy. Fig. 43.4 ). Glucocorticoid receptor–knockout mice have an enlarged cortex, but the size of the medulla is decreased and PNMT activity is undetectable. Epinephrine is then transported back into the granule for storage and to undergo regulated exocytosis. Secretion of epinephrine and norepinephrine from the adrenal medulla is regulated primarily by descending sympathetic signals in response to various forms of stress, including exercise, hypoglycemia, and hemorrhagic hypovolemia •Fig. 43.2 Histologyoftheadrenalgland.A,Lowmagnificationillustratingtheoutercortex(C)andinnermedulla(M;notethecentralvein[V]).B,Highermagnificationclearlyillustratingthezonationofthecortex.Thecorrespondingendocrinefunctionandthedifferentzonesofthecortexandthemedullaarenoted.(FromYoungBetal.Wheater’s Functional Histology. 5thed.Philadelphia:ChurchillLivingstone;2006.)


Physiology_Levy

Physiology_Levy. Fig. 43.5 ). The primary autonomic centers that initiate sympathetic responses reside in the hypothalamus and brainstem, and they receive input from the cerebral cortex, the limbic system, and other regions of the hypothalamus and brainstem. The chemical signal for secretion of catecholamine from the adrenal medulla is acetylcholine (ACh), which is secreted from preganglionic sympathetic neurons and binds to nicotinic receptors on chromaffin cells (see Fig. 43.5 ). ACh increases the activity of the rate-limiting enzyme tyrosine hydroxylase in chromaffin cells (see Fig. 43.4 ). It also increases the activity of dopamine β-hydroxylase and stimulates exocytosis of the chromaffin granules. Synthesis of epinephrine and norepinephrine is closely coupled to secretion so that levels of intracellular catecholamines do not change significantly even in the face of changing sympathetic activity. Mechanism of Action of Catecholamines


Physiology_Levy

Physiology_Levy. Mechanism of Action of Catecholamines Adrenergic receptors are generally classified as α-and β-adrenergic receptors, with the α-adrenergic receptors • Fig. 43.3 Blood flow through the adrenal gland. Capsular arteries give rise to sinusoidal vessels that carry blood centripetally through the cortex to the medulla. (Modified from Young B et al. Wheater’s Functional Histology. 5th ed. Philadelphia: Churchill Livingstone; 2006.) further divided into α1 and α2 receptors and the β-adrenergic receptors divided into β1, β2, and β3 receptors ( Table 43.1 ). These receptors can be characterized according to: 1. Relative potency of endogenous and pharmacological agonists and antagonists. Epinephrine and norepinephrine are potent agonists for α receptors and for β1 and β3 receptors, whereas epinephrine is more potent than norepinephrine for β2 receptors. A large number of synthetic selective and nonselective adrenergic agonists and antagonists now exist. 2. Downstream signaling pathways.


Physiology_Levy

Physiology_Levy. 2. Downstream signaling pathways. Table 43.1 shows the primary pathways that are coupled to the different adrenergic receptors. This is an oversimplification, because differences in signaling pathways for a given receptor have been linked to the duration of agonist exposure and cell type. 3. Location and relative density of receptors. Importantly, different receptor types predominate in different tissues. For example, although both α and β receptors are expressed by pancreatic islet beta cells, the predominant response to a sympathetic discharge is mediated by α2 receptors. Physiological Actions of Adrenomedullary Catecholamines


Physiology_Levy

Physiology_Levy. Physiological Actions of Adrenomedullary Catecholamines Because the adrenal medulla is directly innervated by the autonomic nervous system, adrenomedullary responses are very rapid. Furthermore, because of the involvement of several centers in the central nervous system (CNS), most notably the cerebral cortex, adrenomedullary responses can precede onset of the actual stress (i.e., they can be anticipated) (see Fig. 43.5 ). In many cases the adrenomedullary output, which is primarily epinephrine, is coordinated with sympathetic nervous activity as determined by the release of norepinephrine from postganglionic sympathetic neurons. However, some stimuli (e.g., hypoglycemia) evoke a stronger adrenomedullary than sympathetic nervous response and vice versa. Many organs and tissues are affected by a sympathoadrenal response (


Physiology_Levy

Physiology_Levy. Many organs and tissues are affected by a sympathoadrenal response ( Table 43.2). An informative example of the major physiological roles of catecholamines is the sympathoadrenal response to exercise. Exercise is similar to the “fight-or-flight” response but without the subjective element of fear, and it involves a greater adrenomedullary response (i.e., endocrine role of epinephrine) than a sympathetic nervous response (i.e., neurotransmitter role of norepinephrine). The overall goal of the sympathoadrenal system during exercise is to meet the increased energy demands of skeletal and cardiac muscle while maintaining sufficient oxygen and glucose supply to the brain. The response to exercise includes the following major physiological actions of epinephrine ( Fig. 43.6): 1. Increased blood flow to muscles is achieved by the integrated action of norepinephrine and epinephrine on the heart, veins and lymphatics, and nonmuscular (e.g., splanchnic) and muscular arteriolar beds.


Physiology_Levy

Physiology_Levy. •Fig. 43.4 Stepsinsynthesisandsecretionofcatecholaminesfromadrenalmedullarychromaffincells. 2. Epinephrine promotes glycogenolysis in muscle. Exercising muscle can also utilize free fatty acids (FFAs), and epinephrine and norepinephrine promote lipolysis in adipose tissue. Epinephrine increases blood glucose by increasing hepatic glycogenolysis and gluconeogenesis. The promotion of lipolysis in adipose tissue is also coordinated with an epinephrine-induced increase in hepatic ketogenesis. Finally, the effects of catecholamines on metabolism are reinforced by the fact that they stimulate glucagon secretion (β2 receptors) and inhibit insulin secretion (α2 receptors). Efficient production of adenosine triphosphate (ATP) during normal exercise •Fig. 43.5 Stimulithatenhancecatecholaminesecretion. cAMP,cyclicadenosinemonophosphate;DAG,diacylglycerol. Arteriolardilation:↓ BP↑ Arteriolarvasoconstriction; (β2)(muscle)↑ BP(α1)(splanchnic,renal,cutaneous,genital) BP,bloodpressure.


Physiology_Levy

Physiology_Levy. cAMP,cyclicadenosinemonophosphate;DAG,diacylglycerol. Arteriolardilation:↓ BP↑ Arteriolarvasoconstriction; (β2)(muscle)↑ BP(α1)(splanchnic,renal,cutaneous,genital) BP,bloodpressure. (i.e., a 1-hour workout) also requires efficient exchange of gases with an adequate supply of oxygen to exercising muscle. Catecholamines promote this by relaxation of bronchiolar smooth muscle. 3. Catecholamines decrease energy demand by visceral smooth muscle. In general a sympathoadrenal response decreases overall motility of the smooth muscle in the gastrointestinal (GI) and urinary tracts, thereby conserving energy where it is not immediately needed. Metabolism of Catecholamines


Physiology_Levy

Physiology_Levy. Metabolism of Catecholamines Two primary enzymes are involved in the degradation of catecholamines: monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). The neurotransmitter norepinephrine is degraded by MAO and COMT after uptake into the presynaptic terminal. This mechanism is also involved in the catabolism of circulating adrenal catecholamines. However, the predominant fate of adrenal catecholamines is methylation by COMT in nonneuronal tissues such as the liver and kidney. Urinary vanillylmandelic acid (VMA) and metanephrine are sometimes used clinically to assess the level of catecholamine production in a patient. Much of the urinary VMA and metanephrine is derived from neuronal rather than adrenal catecholamines.


Physiology_Levy


Physiology_Levy

Physiology_Levy. The zona fasciculata produces the glucocorticoid hormone cortisol. This zone is an actively steroidogenic tissue composed of straight cords of large cells. These cells have a “foamy” cytoplasm because they are filled with lipid droplets that represent stored cholesterol esters (CEs). These cells make some cholesterol de novo but import a significant amount of cholesterol from the blood in the form of low-density lipoprotein (LDL). LDL particles bind to their receptor (LDLR) and are endocytosed. Within endolysosomes, free cholesterol (FC) is released from CEs by a lysosomal lipase, and the FC is transported out of the endolysosome by Niemann-Pick C (NPC) proteins. Free cholesterol is stored in lipid droplets in the cytoplasm after esterification by acyl CoA-cholesterol acyltransferase (ACAT) (


Physiology_Levy

Physiology_Levy. Fig. 43.7 ). The stored cholesterol is continually turned back into free cholesterol by hormone-sensitive lipase (HSL), a process that is increased in response to adrenocorticotropic hormone (ACTH; see Regulation of All steroid hormone synthesis begins in the mitochondria, where the first enzyme, CYP11A1, is attached to the inner mitochondrial membrane. Although several proteins appear to be involved in the transfer of FC into the inner mitochondrial matrix, one protein called steroidogenic acute regulatory protein (StAR protein) is indispensable in this process (see


Physiology_Levy

Physiology_Levy. Fig. 43.7). StAR protein is short-lived and rapidly activated posttranslationally (phosphorylation) and transcriptionally by pituitary tropic hormones. In patients with inactivating mutations in StAR protein, cells of the zona fasciculata become excessively laden with lipid (“lipoid”) because cholesterol cannot be accessed by CYP11A1 within the mitochondria and used for cortisol •Fig. 43.6 Someoftheindividualactionsofcatecholaminesthatcontributetotheintegratedsympa-thoadrenalresponsetoexercise.(ModifiedfromWhiteBA,PorterfieldSP.Endocrine and Reproductive Physiology. 4thed.Philadelphia:Mosby;2013.)Bronchiole (˜2) Dilation ° Exchange of O2 and CO2 ° Cardiac output ° Venous return GI and urinary tracts (˜2) ˝ Motility ˝ Energy usage ° Blood glucose ° Blood ketones ° Blood FFAs ° Blood lactate ° Blood glycerol Adipose (˜2, ˜3) ° Lipolysis ˝ Glucose uptake Liver (˜2) ° Glycogenolysis ° Gluconeogenesis ° Ketogenesis Hormonal reinforcement Skeletal muscle (˜2) ° Glycogenolysis ˝ Glucose


Physiology_Levy

Physiology_Levy. ° Blood glycerol Adipose (˜2, ˜3) ° Lipolysis ˝ Glucose uptake Liver (˜2) ° Glycogenolysis ° Gluconeogenesis ° Ketogenesis Hormonal reinforcement Skeletal muscle (˜2) ° Glycogenolysis ˝ Glucose uptake ˜ Cells (˙2) ˝ Insulin secretion ˙ Cells (˜2) ° Glucagon secretion ° Blood glucagon/insulin ratio ° Nutrient supply to muscle and adequate supply of oxygen and glucose to brain ˝ Blood flow to GI tract ° Blood flow to skeletal muscle Splanchnic arterioles (˙) Vasoconstriction Skeletal muscle arterioles (˜2) Vasodilation Veins and lymphatics (˙) Vasoconstriction Heart (˜1) (+)ˆve Inotropic (+)ˆve Chronotropic (+)ˆve Lusitropic •Fig. 43.7 Eventsinvolvedinthefirsttworeactionsinthesteroidogenicpathway:conversionofcholesteroltopregnenolone;conversionofpregnenolone(P5)toprogesterone(P4)inzonafasciculatacells.ACAT,acylCoA:cholesterolacyltransferase;3β HSD,3β hydroxysteroiddehydrogenase;CE,cholesterolesters;CYP11A1alsocalledP450 side-chain cleavage enzyme;


Physiology_Levy

Physiology_Levy. HSD,3β hydroxysteroiddehydrogenase;CE,cholesterolesters;CYP11A1alsocalledP450 side-chain cleavage enzyme; FC,freecholesterol;HSL,hormone-sensitivelipase;LAL,lysosomalacidhydrolase;LDL,low-densitylipoprotein;LDLR,low-densitylipoproteinreceptor;P5,pregnenolone;StAR,steroidogenicacuteregulatoryprotein.(ModifiedfromWhiteBA,PorterfieldSP.Endocrine and Reproductive Physiology. 4thed.Philadelphia:Mosby;2013.) •Fig. 43.8 Summaryofthesteroidogenicpathwaysforeachofthethreezonesoftheadrenalcortex.Theenzymaticreactionsarecolorcodedacrosszones.sER,smoothendoplasmicreticulum.(ModifiedfromWhiteBA,PorterfieldSP.Endocrine and Reproductive Physiology. 4thed.Philadelphia:Mosby;2013.) synthesis. Moreover, these individuals cannot synthesize gonadal steroid hormones. The placenta does not express StAR, so these individuals have normal placental steroid production in utero.


Physiology_Levy

Physiology_Levy. Inthezonafasciculata,cholesterolisconvertedsequentially to pregnenolone, progesterone, 17-hydroxyprogesterone, 11-deoxycortisol, and cortisol (Figs. 43.8 43.9 ). A parallel pathway in the zona fasciculata involves a pathway that bypasses 17-hydroxylation, in which progesterone is converted to 11-deoxycorticosterone (DOC) and then to corticosterone (see Fig. 43.9C ). This pathway is minor in humans, but in the absence of active CYP11B1 (11-hydroxylase activity), the production of DOC is significant. Because DOC acts as a weak mineralocorticoid ( 43.3 ), elevated levels of DOC cause hypertension. Transport and Metabolism of Cortisol


Physiology_Levy

Physiology_Levy. Transport and Metabolism of Cortisol Cortisol is transported in blood predominantly bound to corticosteroid-binding globulin [CBG] (also called transcortin), which binds about 90% of cortisol, and albumin, which binds 5% to 7% of cortisol. The liver is the predominant site of steroid inactivation. It both inactivates cortisol and conjugates active and inactive steroids with glucuronide or sulfate so that they can be excreted more readily by the kidney. The circulating half-life of cortisol is about 70 minutes. Cortisol is reversibly inactivated by conversion to cortisone. This action is catalyzed by the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). Inactivation of cortisol by 11β-HSD2 occurs in cells that also express the mineralocorticoid receptor (MR)and are


Physiology_Levy

Physiology_Levy. •Fig. 43.9, cont’d C,Reactions4and5,involvingCYP21BandCYP11B1,inwhichthelasttwostepsincortisolsynthesisarecarriedout.Alsoshownistheminorpathwayleadingtocorticosteronesynthesisinthezonafasciculata.(ModifiedfromWhiteBA,PorterfieldSP.Endocrine and Reproductive Physiology. 4thed.Philadelphia:Mosby;2013.) target cells of aldosterone (see below). The conversion of cortisol to cortisone prevents the binding of cortisol to the MR and having inappropriate mineralocorticoid actions on these cells. Inactivation of cortisol by 11β-HSD2 is reversible in that another enzyme, 11β-HSD1, converts cortisone back to cortisol. This conversion occurs in tissues expressing the glucocorticoid receptor (GR), including liver, adipose tissue, and the CNS, as well as in skin. Mechanism of Action of Cortisol


Physiology_Levy

Physiology_Levy. Mechanism of Action of Cortisol Cortisol acts primarily through the glucocorticoid receptor, which regulates gene transcription (see ). In the absence of hormone, the GR resides in the cytoplasm in a stable complex with several molecular chaperones, including heat shock proteins and cyclophilins. Cortisol-GR binding promotes dissociation of the chaperone proteins, followed by: aAllvaluesarerelativetotheglucocorticoidandmineralocorticoidpotenciesofcortisol,whichhaveeachbeenarbitrarilysetat1.0.Cortisolactuallyhasonly1/500thepotencyofthenaturalmineralocorticoidaldosterone. 1. rapid translocation of the cortisol-GR complex into the nucleus, 2. dimerization and binding to glucocorticoid response elements (GREs, both “positive” GREs and “negative” GREs) near the basal promoters of cortisol-regulated genes, and 3. recruitment of coactivator proteins and assembly of general transcription factors leading to increased or decreased transcription of the targeted genes.


Physiology_Levy

Physiology_Levy. recruitment of coactivator proteins and assembly of general transcription factors leading to increased or decreased transcription of the targeted genes. In some cases the GR interacts with other transcription factors, such as the proinflammatory nuclear factor (NF)κB transcription factor, and interferes with their ability to activate gene expression. Physiological Actions of Cortisol


Physiology_Levy

Physiology_Levy. Physiological Actions of Cortisol Cortisol has a broad range of actions and is often characterized as a “stress hormone.” In general, cortisol maintains blood glucose levels, CNS function, and cardiovascular function during fasting and increases blood glucose during stress at the expense of muscle protein. Cortisol protects the body against the self-injurious effects of unbridled inflammatory and immune responses. Cortisol also partitions energy to cope with stress by inhibiting reproductive function. As stated later, cortisol has several other effects on bone, skin, connective tissue, the GI tract, and the developing fetus that are independent of its stress-related functions. As the term glucocorticoid implies, cortisol is a steroid hormone from the adrenal cortex that regulates blood glucose. It increases blood glucose by stimulating gluconeogenesis (


Physiology_Levy

Physiology_Levy. As the term glucocorticoid implies, cortisol is a steroid hormone from the adrenal cortex that regulates blood glucose. It increases blood glucose by stimulating gluconeogenesis ( Fig. 43.10 ). Cortisol enhances gene expression of the key hepatic gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK). Cortisol also decreases GLUT4-mediated glucose uptake in skeletal muscle and adipose tissue. During the interdigestive period (low insulin-glucagon ratio), cortisol promotes glucose sparing by potentiating the effects of catecholamines on lipolysis, thereby making FFAs available as energy sources. Cortisol inhibits protein synthesis and increases proteolysis, especially in skeletal muscle, thereby providing a rich source of carbon for hepatic gluconeogenesis.


Physiology_Levy

Physiology_Levy. Fig. 43.10 also contrasts the normal role of cortisol in response to stress and the effects of chronically elevated cortisol as a result of pathological conditions. As discussed later, there are important differences in the overall metabolic effects of cortisol between these two states, particularly with respect to lipid metabolism. During stress, cortisol synergizes with catecholamines and glucagon to promote a lipolytic, gluconeogenic, ketogenic, and glycogenolytic metabolic response while synergizing with catecholamines to promote an appropriate cardiovascular response. During chronically elevated cortisol secondary to pathological overproduction, cortisol synergizes with insulin in the context of elevated levels of glucose (from increased appetite) and hyperinsulinemia (from elevated glucose and glucose intolerance) to promote lipogenesis and truncal (abdominal/ visceral) adiposity.


Physiology_Levy

Physiology_Levy. Cortisol reinforces its effects on blood glucose by its positive effects on the cardiovascular system. Cortisol has permissive actions on catecholamines by increasing adrenergic receptor expression and thereby contributes to cardiac output and blood pressure. Cortisol stimulates erythropoietin synthesis and hence increases red blood cell production. Anemia occurs when cortisol is deficient, and polycythemia occurs when cortisol levels are excessive. Inflammation and immune responses are often part of the response to stress. However, inflammation and immune responses have the potential for significant harm and may cause death if they are not held in homeostatic balance. As a stress hormone, cortisol plays an important role in maintaining immune homeostasis. Cortisol, along with epinephrine and norepinephrine, represses production of proinflammatory cytokines and stimulates production of antiinflammatory cytokines.


Physiology_Levy

Physiology_Levy. Stress during interdigestive period (e.g., elderly person slips on ice and dislocates hip) Liver ˜ Glycogenolysis ˜ Gluconeogenesis Metabolic responses to stress ensure sufficient energy to meet increased demand on body, and will maintain adequate blood glucose levels necessary for conscious, deliberate action by the individual. The metabolic responses are supported by cardiovascular ones, first by those induced by the sympathoadrenal output (see Fig. 43.6) but also by cortisol, which optimizes adrenergic receptor function. Cortisol will also contribute to providing energy for the incipient inflammatory and immune response to this stress, but will also protect the individual from the potential damage of unregulated inflammation.


Physiology_Levy

Physiology_Levy. Metabolic responses to chronically elevated cortisol in patients with Cushing’s disease who are otherwise healthy tend to promote localized obesity (abdominal, neck, and face), with muscle wasting and weakness, especially at the extremities. Note that the elevated cortisol in this case usually occurs in the context of an elevated insulin/glucagon ratio. Elevated cortisol stimulates appetite, which increases the insulin/glucagon ratio. High levels of cortisol antagonize insulin’s effect on GLUT-4mediated glucose uptake into skeletal muscle and adipose tissue, so that glucose intolerance is frequently a symptom in patients with Cushing’s disease. This further contributes to hyperglycemia and hyperinsulinemia. Both cortisol and insulin promote the differentiation of preadipocytes into adipocytes, and lipogenesis.


Physiology_Levy

Physiology_Levy. Chronically elevated levels of cortisol in otherwise well-fed person (e.g., Cushing’s disease) •Fig. 43.10 Metabolicactionsofcortisol(integratedwithcatecholaminesandglucagon)inresponsetostress(upper panel) andcontrastedtotheactionsofchronicallyelevatedcortisol(integratedwithinsulin)inanotherwisehealthyindividual(lower panel). (ModifiedfromWhiteBA,PorterfieldSP.Endocrine and Reproductive Physiology. 4thed.Philadelphia:Mosby;2013.)


Physiology_Levy

Physiology_Levy. The inflammatory response to injury consists of local dilation of capillaries and increased capillary permeability, with resultant local edema and accumulation of white blood cells. These steps are mediated by prostaglandins, thromboxanes, and leukotrienes. Cortisol inhibits phospholipase A2, a key enzyme in prostaglandin, leukotriene, and thromboxane synthesis. Cortisol also stabilizes lysosomal membranes, thereby decreasing release of the proteolytic enzymes that augment local swelling. In response to injury, leukocytes normally leave the vascular system and migrate to the site of injury. This complex process is generally inhibited by cortisol, as is the phagocytic activity of neutrophils, although release of neutrophils from bone marrow is stimulated. Analogues of glucocorticoid are frequently used pharmacologically because of their antiinflammatory properties.


Physiology_Levy

Physiology_Levy. Cortisol inhibits the immune response, and for this reason glucocorticoid analogues have been used as immunosuppressants in organ transplants. High cortisol levels decrease the number of circulating T lymphocytes (particularly helper T lymphocytes) and reduce their ability to migrate to the site of antigenic stimulation. Glucocorticoids promote atrophy of the thymus and other lymphoid tissue. Although corticosteroids inhibit cellular-mediated immunity, antibody production by B lymphocytes is not impaired. Effects of Cortisol on the Reproductive Systems Reproduction exacts a considerable anabolic cost on the organism. In humans, reproductive behavior and function are dampened in response to stress. Cortisol decreases the function of the reproductive axis at the hypothalamic, pituitary, and gonadal levels. Effects of Cortisol on Bone


Physiology_Levy

Physiology_Levy. Effects of Cortisol on Bone Glucocorticoids increase bone resorption. They have multiple actions that alter bone metabolism. Glucocorticoids decrease intestinal Ca++ absorption and renal Ca++ reabsorption. Both mechanisms serve to lower serum [Ca++]. As serum [Ca++] drops, secretion of parathyroid hormone (PTH) increases, and PTH mobilizes Ca++ from bone by stimulating resorption of bone. In addition to this action, glucocorticoids directly inhibit osteoblast bone-forming functions (see ). Although glucocorticoids are useful for treating the inflammation associated with arthritis, excessive use will result in bone loss (osteoporosis). Actions of Cortisol on Connective Tissue Cortisol inhibits fibroblast proliferation and collagen formation. In the presence of excessive amounts of cortisol, the skin thins and is more readily damaged. The connective tissue support of capillaries is impaired, and capillary injury, or bruising, is increased. Actions of Cortisol on the Kidney


Physiology_Levy

Physiology_Levy. Actions of Cortisol on the Kidney Cortisol inhibits the secretion and action of antidiuretic hormone (ADH), and thus it is an ADH antagonist. In the absence of cortisol, the action of ADH is potentiated, which makes it difficult to increase free water clearance in response to a water load and increases the likelihood of water intoxication. Although cortisol binds to the mineralocorticoid receptor with high affinity, this action is normally blocked by inactivation of cortisol to cortisone by the enzyme 11βHSD2. However, the mineralocorticoid activity (i.e., renal Na+ and H2O retention, K+ and H+ excretion) of cortisol depends on the relative amount of cortisol (or synthetic glucocorticoids) and the activity of 11β-HSD2. Certain agents (e.g., compounds in black licorice) inhibit 11βHSD2 and thereby increase the mineralocorticoid activity of cortisol. Cortisol increases the glomerular filtration rate by both increasing cardiac output and acting directly on the kidney.


Physiology_Levy

Physiology_Levy. Actions of Cortisol on Muscle When cortisol levels are excessive, muscle weakness and pain are common symptoms. The weakness has multiple origins. In part it is a result of the excessive proteolysis cortisol produces. High cortisol levels can result in hypokalemia (via mineralocorticoid actions), which can produce muscle weakness because it hyperpolarizes and stabilizes the muscle cell membrane and thus makes stimulation more difficult. Actions of Cortisol on the Gastrointestinal Tract Cortisol exerts a trophic effect on the GI mucosa. In the absence of cortisol, GI motility decreases, GI mucosa degenerates, and GI acid and enzyme production decreases. Because cortisol stimulates appetite, hypercortisolism is frequently associated with weight gain. The cortisol-mediated stimulation of gastric acid and pepsin secretion increases the risk for development of ulcers. Psychological Effects of Cortisol


Physiology_Levy

Physiology_Levy. Psychological Effects of Cortisol Psychiatric disturbances are associated with either excessive or deficient levels of corticosteroids. Excessive corticosteroids can initially produce a feeling of well-being, but continued excessive exposure eventually leads to emotional lability and depression. Frank psychosis can occur with either excessive or deficient hormone. Cortisol increases the tendency for insomnia and decreases rapid eye movement (REM) sleep. People who are deficient in corticosteroids tend to be depressed, apathetic, and irritable. Effects of Cortisol During Fetal Development Cortisol is required for normal development of the CNS, retina, skin, GI tract, and lungs. The best studied system is the lungs, in which cortisol induces differentiation and maturation of type II alveolar cells. During late gestation these cells produce surfactant, which reduces surface tension in the lungs and thus allows the onset of breathing at birth. Regulation of Cortisol Production


Physiology_Levy

Physiology_Levy. Regulation of Cortisol Production Cortisol production by the zona fasciculata is regulated by a standard hypothalamic-pituitary-adrenal axis involving corticotropin-releasing hormone (CRH), ACTH, and cortisol (see ). The hypothalamus and pituitary stimulate cortisol production, and cortisol negatively feeds back on the hypothalamus and pituitary to maintain its set point. Both neurogenic (e.g., fear) and systemic (e.g., hypoglycemia, hemorrhage, cytokines) forms of stress stimulate release of CRH. CRH is also under strong diurnal rhythmic regulation emerging from the suprachiasmatic nucleus, such that cortisol levels surge during the early predawn and morning hours and then continually decline throughout the day and evening. CRH acutely stimulates release of ACTH and chronically increases proopiomelanocortin (POMC) gene expression and corticotrope hypertrophy and proliferation. Some parvicellular neurons coexpress CRH and ADH, which potentiates the actions of CRH.


Physiology_Levy

Physiology_Levy. ACTH binds to the melanocortin 2 receptor (MC2R) located on cells in the zona fasciculata ( Fig. 43.11 ). The effects of ACTH can be subdivided into three phases: 1. The acute effects of ACTH occur within minutes. Cholesterol is rapidly mobilized from lipid droplets by posttranslational activation of cholesterol ester hydrolase and transported to the outer mitochondrial membrane. ACTH both rapidly increases StAR protein gene expression and activates StAR protein through protein kinase A (PKA)-dependent phosphorylation. Collectively, these acute actions of ACTH increase pregnenolone levels. 2. The chronic effects of ACTH occur over a period of several hours. These effects involve increasing transcription of the genes encoding the steroidogenic enzymes and their coenzymes. ACTH also increases expression of the LDL receptor and scavenger receptor BI (SR-BI; the HDL receptor). 3.


Physiology_Levy

Physiology_Levy. 3. The trophic actions of ACTH on the zona fasciculata and zona reticularis occur over a period of weeks and •Fig. 43.11 OverviewoftheactionsofACTHontargetadrenocorticalcells.Notethatthemajorsecondmessenger,cAMP,activatesimmediateproteinmediatorsandalsoinducesproductionoflaterproteinmediators.HDL,high-densitylipoprotein;LDL,low-densitylipoprotein. months. This effect is exemplified by atrophy of the zona fasciculata in patients receiving therapeutic (i.e., supraphysiological) levels of glucocorticoid analogues for at least 3 weeks. Under these conditions the exogenous corticosteroids completely repress CRH and ACTH production, thereby resulting in atrophy of the zona fasciculata and a decline in endogenous cortisol production (


Physiology_Levy

Physiology_Levy. Fig. 43.12 ). At the end of therapy, these patients need to be slowly weaned off exogenous glucocorticoids to allow the hypothalamic-pituitary-adrenal axis to reestablish itself and the zona fasciculata to enlarge and produce adequate amounts of cortisol. Cortisol inhibits both POMC gene expression at the corticotropes and pro-CRH gene expression at the hypothalamus. However, intense stress can override the negative-feedback effects of cortisol at the hypothalamus and reset the “set point” at a higher level. The innermost zone, the zona reticularis, begins to appear after birth at about 5 years of age. Adrenal androgens, especially DHEAS, the main product of the zona reticularis, become detectable in the circulation at about 6 years of age. This onset of adrenal androgen production is called adrenarche, and it contributes to the appearance of axillary and pubic hair at about age 8. DHEAS levels continue to increase, peak during the mid-20s, and then progressively decline with age.


Physiology_Levy

Physiology_Levy. Androgen Synthesis by the Zona Reticularis The zona reticularis differs from the zona fasciculata in several important ways with respect to steroidogenic enzyme activity (see Fig. 43.8 ). First, 3β-HSD is expressed at very low levels in the zona reticularis; thus the Δ5 pathway predominates in the zona reticularis. Second, the zona reticularis expresses cofactors or conditions that enhance the 17,20-lyase function of CYP17, thereby generating the 19-carbon androgen precursor molecule dehydroepiandrosterone (DHEA) from 17-hydroxypregnenolone. Additionally the zona reticularis expresses DHEA sulfotransferase (SULT2A1 gene), which converts DHEA into DHEAS (


Physiology_Levy

Physiology_Levy. Fig. 43.13 ). A limited amount of the Δ4 androgen androstenedione is also made in the zona reticularis. Although small amounts of potent androgens (e.g., testosterone) or 18-carbon estrogens are normally produced by the human adrenal cortex, most active sex steroids are produced primarily from peripheral conversion of DHEAS and androstenedione. Metabolism and Fate of DHEAS and DHEA DHEAS can be converted back to DHEA by peripheral sulfatases, and DHEA and androstenedione can be converted to active androgens (testosterone, dihydrotestosterone) peripherally in both sexes. DHEA binds to albumin and other globulins in blood with low affinity, so it is excreted efficiently by the kidney. The half-life of DHEA is 15 to 30 minutes. In contrast, DHEAS binds to albumin with very high affinity and has a half-life of 7 to 10 hours. Quiescent HPA axis in patient undergoing long-term (>3 wk) Normal HPA axis treatment with glucocorticoid


Physiology_Levy

Physiology_Levy. Quiescent HPA axis in patient undergoing long-term (>3 wk) Normal HPA axis treatment with glucocorticoid Hypothalamus CRH ACTH Pituitary Zona fasciculata Atrophied zona fasciculata Cortisol Exogenous corticosteroid (supraphysiological levels) Biological actions Biological actions and therapeutic actions (e.g., antiinflammatory or immunosuppressive) Pituitary Hypothalamus (–) (–) (–) (–) •Fig. 43.12 Comparisonofanormalhypothalamic-pituitary-adrenal(HPA)axistoaquiescentHPAaxisinindividualreceivingexogenousglucocorticoidtherapy.Thelattercausesthezonafasciculatatoatrophyafter3weeks,thusrequiringacarefulwithdrawalregimentoallowrebuildingoftheadrenaltissuebeforetotalcessationofexogenouscorticosteroidadministration.(ModifiedfromWhiteBA,PorterfieldSP.Endocrine and Reproductive Physiology. 4thed.Philadelphia:Mosby;2013.) Physiological Actions of Adrenal Androgens


Physiology_Levy

Physiology_Levy. Physiological Actions of Adrenal Androgens In men the contribution of adrenal androgens to active androgens is negligible. However, in women the adrenal contributes to about 50% of circulating active androgens, which are required for the growth of axillary and pubic hair and for libido.


Physiology_Levy

Physiology_Levy. Apart from providing androgen precursors, it is not clear what other role or roles if any the zona reticularis plays in adult humans. DHEAS is the most abundant circulating hormone in young adults. It increases steadily until it peaks in the mid-20s and then steadily declines thereafter. Thus there has been considerable interest in the possible role of DHEAS in the aging process. However, the function of this abundant steroid in young adults and the potential impact of its gradual disappearance on aging are still poorly understood. It should be noted that the age-related decline in DHEA and DHEAS has led to the popular use of these steroids as dietary supplements, even though recent studies indicate no beneficial effects.


Physiology_Levy

Physiology_Levy. Duringadrenalandrogenexcess(e.g.,adrenaltumor,Cushing’ssyndrome,congenitaladrenalhyperplasia),masculinization of women canoccur.Thisinvolvesmasculinizationoftheexternalgenitalia(e.g.,enlargedclitoris)inuteroandexcessivefacialandbodyhair(calledhirsutism)andacneinadultwomen.Excessiveadrenalandrogensalsoappeartoplayaroleinovariandysovulation(i.e.,polycysticovariansyndrome). Acrucialclinicalaspectofregulationofthezonareticularisisthatneitheradrenalandrogensnortheirmorepotentmetabolites(e.g.,testosterone,dihydrotestosterone,estradiol-17β)negativelyfeedbackonACTHorCRH( Fig. 43.14 ).Thismeansthatanenzymaticdefectassociatedwiththesynthesisofcortisol(e.g.,CYP21Bdeficiency)isassociatedwithadramaticincreaseinbothACTH(nonegativefeedbackfromcortisol)andadrenalandrogens(becauseoftheelevatedACTH).Itisthis“loophole”inthehypothalamic-pituitary-adrenalaxisthatgivesriseto congenital adrenal hyperplasia (CAH). Regulation of Zona Reticularis Function


Physiology_Levy

Physiology_Levy. Regulation of Zona Reticularis Function ACTH is the primary regulator of the zona reticularis. Both DHEA and androstenedione display the same diurnal rhythm as cortisol (DHEAS does not because of its long circulating half-life). Moreover, the zona reticularis shows the same atrophic changes as the zona fasciculata in conditions typified by little or no ACTH. However, other factors must regulate adrenal androgen function. Adrenarche occurs in the face of constant ACTH and cortisol levels, and the rise and decline of DHEAS is not associated with a similar pattern of ACTH or cortisol production. However, the other factors, whether extraadrenal or intraadrenal, remain unknown.


Physiology_Levy

Physiology_Levy. The thin outermost zone of the adrenal, the zona glomerulosa, produces the mineralocorticoid aldosterone, which regulates salt and volume homeostasis (see ). The zona glomerulosa is minimally influenced by ACTH. Rather it is regulated primarily by the reninangiotensin system, plasma [K+], and atrial natriuretic peptide (ANP).


Physiology_Levy

Physiology_Levy. An important feature in the steroidogenic capacity of the zona glomerulosa is that it does not express CYP17. Therefore zona glomerulosa cells never make cortisol, nor do they make adrenal androgens in any form. Pregnenolone is converted to progesterone and DOC by 3β-HSD and •Fig. 43.13 Steroidogenicpathwaysinthezonareticularis.Thefirstcommonreactioninthepathway,conversionofcholesteroltopregnenolonebyCYP11A1,isnotshown.Expressionof3β-hydroxysteroiddehydrogenase(3β-HSD)isrelativelylowinthezonareticularis,soandrostenedioneisaminorproductincomparisontoDHEAandDHEAS.Thezonareticularisalsomakesasmallamountoftestosteroneandestrogens(notshown).(ModifiedfromWhiteBA,PorterfieldSP.Endocrine and Reproductive Physiology. 4thed.Philadelphia:Mosby;2013.) CYP21, respectively (


Physiology_Levy

Physiology_Levy. CYP21, respectively ( Fig. 43.15 ). A completely unique last three reactions from DOC to aldosterone within the feature of the zona glomerulosa among the steroidogenic zona glomerulosa. These reactions are 11-hydroxylation of glands is its expression of CYP11B2, which is regulated DOC to form corticosterone, 18-hydroxylation to form by different signaling pathways. Furthermore the enzyme 18-hydroxycorticosterone, and 18-oxidation to form aldocoded by CYP11B2, aldosterone synthase, catalyzes the sterone (see Figs. 43.8 43.15). •Fig. 43.14 The“loophole”inthehypothalamic-pituitary-adrenalaxis.ACTHstimulatesproductionofbothcortisolandadrenalandrogens,butonlycortisolnegativelyfeedsbackonACTHandCRH.Thusifcortisolproductionisblocked(i.e.,CYP11B1deficiency),ACTHlevelsincreasealongwithadrenalandrogens.(ModifiedfromWhiteBA,PorterfieldSP.Endocrine and Reproductive Physiology. 4thed.Philadelphia:Mosby;2013.)


Physiology_Levy


Physiology_Levy

Physiology_Levy. Transport and Metabolism of Aldosterone Aldosterone binds to albumin and corticosteroid-binding protein in blood with low affinity and therefore has a biological half-life of about 20 minutes. Almost all aldosterone is inactivated by the liver in one pass, conjugated to a glucuronide group, and excreted by the kidney. Mechanism of Aldosterone Action Aldosterone acts much like cortisol (and other steroid hormones) in that its primary mechanism of action is mediated by binding to a specific intracellular receptor (i.e., mineralocorticoid receptor [MR]). After dissociation of chaperone proteins, nuclear translocation, dimerization, and binding to the mineralocorticoid response element (MRE), the aldosterone-MR complex regulates expression of specific genes (see ). As discussed earlier, cortisol binds to the MR with significant affinity. However, as also discussed, cells that express MR also express 11β-HSD2, which converts cortisol to the inactive steroid cortisone (


Physiology_Levy

Physiology_Levy. Fig. 43.16 ). Cortisone can be converted back to cortisol by 11β-HSD1, which is expressed in several glucocorticoidresponsive tissues, including the liver and skin. Clinicalstudiesinhumanshaverevealedadeleteriouseffectofaldosteroneoncardiovascularfunctionindependentofitseffectsonrenalsodiumandwaterreabsorption.Aldosteronehasaproinflammatory, profibrotic effect onthecardiovascularsystemandcausesleftventricularhypertrophyandremodeling.Thiseffectofaldosteroneisassociatedwithincreasedmorbidityandmortalityinpatientswithessentialhypertension. Physiological Actions of Aldosterone The actions and regulation of aldosterone are discussed in


Physiology_Levy

Physiology_Levy. Physiological Actions of Aldosterone The actions and regulation of aldosterone are discussed in CHAPTER 43 The Adrenal Gland •Fig. 43.15 Steroidogenicpathwaysinthezonaglomerulosa.Thefirstcommonreactioninthepathway,conversionofcholesteroltopregnenolonebyCYP11A1,isnotshown.NotethatthelastthreereactionsarecatalyzedbyCYP11B2.(ModifiedfromWhiteBA,PorterfieldSP.EndocrineandReproductivePhysiol-ogy.4thed.Philadelphia:Mosby;2013.)CH3 CH3 CH3 Pregnenolone C O 3˜-HSD CH3 CH3 CH3 Progesterone C O CYP21B HO CH3 CH3 CH2OH 11-Deoxycorticosterone (DOC) C O CYP11B2 CH3 CH3 CH2OH Corticosterone C O CYP11B2 O HO HO CH3 CH3 CH2OH 18(OH) Corticosterone C O CYP11B2 O HO CH3 CH2OH Aldosterone C O O O CH


Physiology_Levy

Physiology_Levy. Addison’s disease isdefinedbyprimary adrenal insufficiency, withbothmineralocorticoidsandglucocorticoidsusuallybeingdeficient.InNorthAmericaandEurope,themostprevalentcauseofAddison’sdiseaseisautoimmune destruction of the adrenal cortex. Becauseofthecortisoldeficiency,ACTHsecretionincreases.ElevatedlevelsofACTHcancompeteforMC1Rinmelanocytesandcauseanincreaseinskinpigmentation,particularlyinskincreases,scars,andgums(see


Physiology_Levy

Physiology_Levy. •Fig. 43.16 Themineralocorticoidreceptor(MR)isprotectedfromactivationbycortisolbytheenzyme11β-hydroxysteroiddehydrogenasetype2(11β-HSD2),whichconvertscortisoltoinactivecortisone.Cortisonecanbeconvertedbacktocortisolinglucocorticoidtargetcellsbytheenzyme11β-HSDtype1.GRE,glucocorticoidresponseelement;GTF,generaltranscriptionfactors;MRE,mineralocorticoidresponseelement.(ModifiedfromWhiteBA,PorterfieldSP.Endocrine and Reproductive Physiology. 4thed.Philadelphia:Mosby;2013.)Aldosterone Aldosterone 11˜-HSD2 MR-chaperone complex Dissociated chaperones Dissociated chaperonesMR-aldosterone complex Mineralocorticoid-specific biological response Glucocorticoid-specific biological response Mineralocorticoid target cell 11˜-HSD1 Glucocorticoid target cell • Dimerization • Nuclear transport • Binding to MREs • Recruitment of coactivator proteins and GTFs • Altered transcription of aldosterone-regulated genes • Dimerization • Nuclear transport • Binding to GREs • Recruitment of coactivator proteins


Physiology_Levy

Physiology_Levy. MREs • Recruitment of coactivator proteins and GTFs • Altered transcription of aldosterone-regulated genes • Dimerization • Nuclear transport • Binding to GREs • Recruitment of coactivator proteins and GTFs • Altered transcription of cortisol-regulated genes Cortisol Cortisol Cortisol GR-chaperone complex GR-cortisol complex Cortisone Cortisone Cortisone Blood


Physiology_Levy

Physiology_Levy. Adrenocortical hormone excess istermedCushing’s syndrome. Pharmacological useofexogenouscorticosteroidsisnowthemostcommoncauseofCushing’ssyndrome.ThenextmostprevalentcauseisACTH-secreting tumors. TheformofCushing’ssyndromecausedbyafunctionalpituitaryadenomaiscalledCushing’s disease. ThefourthmostcommoncauseofCushing’ssyndromeisprimary hypercortisolism resultingfromafunctionaladrenaltumor.Ifthedisorderisprimaryorifitisaresultofcorticosteroidtreatment,secretionofACTHwillbesuppressedandincreasedskinpigmentationwillnotoccur.However,ifhypersecretionoftheadrenalistheresultofanACTH-secretingnonpituitarytumor,ACTHlevelssometimesbecomehighenoughtoincreaseskinpigmentation. Increasedcortisolsecretioncausesweightgainwithacharacteristiccentripetalfatdistributionanda“buffalohump.”


Physiology_Levy

Physiology_Levy. Figs. 43.8 43.10C ).BecauseofimpairedcortisolproductionandresultantelevatedACTHlevels,steroidogenesisisstimulated,therebyincreasingthesynthesisproducts“upstream”ofthemissingenzyme,aswellasproductsofthezonareticularis.Becausethelatterincludetheadrenalandrogens,afemale 1. The adrenal gland is composed of a cortex that is of mesodermal origin and a medulla that is of neuroectodermal origin. The cortex produces steroid hormones, and the medulla produces catecholamines. 2. The rate-limiting enzymes in medullary catecholamine synthesis are tyrosine hydroxylase and dopamine β-hydroxylase, which are induced by sympathetic stimulation, and phenylethanolamine-Nmethyltransferase, which is induced by cortisol. 3. Catecholamines increase serum glucose and fatty acid levels. They stimulate gluconeogenesis, glycogenolysis, and lipolysis. Catecholamines increase cardiac output but have selective effects on blood flow to different organs. 4.


Physiology_Levy

Physiology_Levy. 4. Pheochromocytoma is a tumor of chromaffin tissue that produces excessive quantities of catecholamines. Symptoms of pheochromocytoma are often sporadic and include hypertension, headaches, sweating, anxiety, palpitations, chest pain, and orthostatic hypotension. 5. The adrenal cortex displays clear structural and functional zonation: the zona glomerulosa produces the mineralocorticoid aldosterone, the zona fasciculata produces the glucocorticoid cortisol, and the zona reticularis produces the weak androgens DHEA and DHEAS. 6.


Physiology_Levy

Physiology_Levy. 6. Cortisol binds to the glucocorticoid receptor. During stress, cortisol increases blood glucose by increasing gluconeogenesis in the liver and breaking muscle protein down to supply gluconeogenic precursors. Cortisol also decreases glucose uptake by muscle and adipose tissue and has permissive actions on glucagon and catecholamines. Cortisol has multiple effects on other tissue. From a pharmacological point of view, the most important is the immunosuppressive/ antiinflammatory effect. 7.


Physiology_Levy

Physiology_Levy. 7. Cortisol is regulated by the CRH-ACTH-cortisol axis. Cortisol negatively feeds back at the hypothalamus on both CRH-producing neurons and pituitary corticotropes. CRH is regulated by several fetuswillbemasculinized.Becausetheyareunabletoproducethemineralocorticoids,aldosterone,DOC,andcorticosterone,patientswiththisdisorderhavedifficultyretainingsaltandmaintainingextracellularvolume.Consequentlytheyarelikelytobehypotensive.Iftheblockageisatthenextstep,11β-hydroxylase (CYP11B1),DOC willbeformedandlevelsofDOCwillaccumulate(see Figs.43.8 43.9C ).BecauseDOChassignificantmineralocorticoid activity anditslevelsbecomehigh,theseindividualstendtoretainsaltandwaterandbecomehypertensive. forms of stress, including proinflammatory cytokines, hypoglycemia, neurogenic stress, and hemorrhage, and by diurnal input. 8.


Physiology_Levy

Physiology_Levy. forms of stress, including proinflammatory cytokines, hypoglycemia, neurogenic stress, and hemorrhage, and by diurnal input. 8. The adrenal androgens DHEA, DHEAS, and androstenedione are androgen precursors. They can be converted to active androgens peripherally and provide about 50% of circulating androgens in women. In men the role of adrenal androgens if any remains obscure. In women, adrenal androgens promote pubic and axillary hair growth and libido. Excessive adrenal androgens in women can lead to various degrees of virilization and ovarian dysfunction. 9.


Physiology_Levy

Physiology_Levy. 9. The zona glomerulosa of the adrenal cortex is the site of aldosterone production. Aldosterone is the strongest naturally occurring mineralocorticoid in humans. It promotes Na+ and water reabsorption by the distal tubule and collecting duct while promoting renal K+ and H+ secretion. Aldosterone promotes Na+ and water absorption in the colon and salivary glands. It also has a proinflammatory, profibrotic effect on the cardiovascular system and causes left ventricular hypertrophy and remodeling. 10. Major actions of angiotensin II on the adrenal cortex are increased growth and vascularity of the zona glomerulosa, increased StAR and CYP11B2 enzyme activity, and increased aldosterone synthesis. 11. Major stimuli for aldosterone production are a rise in angiotensin II and a rise in serum [K+]. The major inhibitory signal is ANP. 12.


Physiology_Levy

Physiology_Levy. 11. Major stimuli for aldosterone production are a rise in angiotensin II and a rise in serum [K+]. The major inhibitory signal is ANP. 12. Addison’s disease is adrenocortical insufficiency. Common symptoms include hypotension, hyperpigmentation, muscle weakness, anorexia, hypoglycemia, and hyperkalemic acidosis. 13. Cushing’s syndrome results from hypercortisolemia. If the basis of the disorder is increased pituitary adrenocorticotropin secretion, the disorder is called Cushing’s disease. Common symptoms of Cushing’s syndrome include centripetal fat distribution, muscle wasting, proximal muscle weakness, thin skin with abdominal striae, capillary fragility, insulin resistance, and polycythemia. 14. Congenital adrenal hyperplasia is caused by a congenital enzyme deficiency that blocks production of cortisol. The enzyme blockage results in elevated


Physiology_Levy

Physiology_Levy. 14. Congenital adrenal hyperplasia is caused by a congenital enzyme deficiency that blocks production of cortisol. The enzyme blockage results in elevated De Bosscher K, et al. Activation of the glucocorticoid receptor in acute inflammation: the SEDIGRAM concept. Trends Pharmacol Sci. 2016;37:4-16. Guerineau NC, et al. Functional chromaffin cell plasticity in response to stress: focus on nicotinic, gap junction, and voltage-gated Ca2+ channels. J Mol Neurosci. 2012;48:368-386. Namsolleck P, Unger T. Aldosterone synthase inhibitors in cardiovascular and renal diseases. Nephrol Dial Transplant. 2014;29(suppl 1): i62-i68. ACTH secretion, which stimulates adrenal cortical growth and secretion of precursors produced before the block. 21-Hydroxylase (CYP21B) deficiency is the most common form. Rafacho A, et al. Glucocorticoid treatment and endocrine pancreas function: implications for glucose homeostasis, insulin resistance and diabetes. J Endocrinol. 2014;223:R49-R62.


Physiology_Levy

Physiology_Levy. Rafacho A, et al. Glucocorticoid treatment and endocrine pancreas function: implications for glucose homeostasis, insulin resistance and diabetes. J Endocrinol. 2014;223:R49-R62. Sundahl N, et al. Selective glucocorticoid receptor modulation: new directions with non-steroidal scaffolds. Pharmacol Ther. 2015;152:28-41. Turcu AF, Auchus RJ. Adrenal steroidogenesis and congenital adrenal hyperplasia. Endocrinol Metab Clin North Am. 2015;44: 275-296. Whittier X, Saag KG. Glucocorticoid-induced osteoporosis. Rheum Dis Clin North Am. 2016;42:177-189. Upon completion of this chapter the student should be able to answer the following questions: 1. Describe the general anatomical components of the male and female reproductive system. 2. Map out the organization of the testis, with the Sertoli cells and developing sperm cells within the intralobular compartment, and the Leydig cells and capillary plexus within the interlobular/interstitial compartment. 3.


Physiology_Levy

Physiology_Levy. 3. Describe the processes of spermatogenesis and spermiogenesis. 4. List the functions of the Sertoli cell. 5. Diagram the process of testosterone synthesis within the Leydig cells, and the peripheral conversion of testosterone to estradiol or dihydrotestosterone. 6. Diagram the male hypothalamus/pituitary/testis axis, including all cell types and hormones involved. 7. Map out the organization of the ovary, and describe the various stages of follicular development, ovulation and corpus luteum formation. 8. List the stages and control of female germ cell progression from oogonia to egg. 9. Map out the steroidogenic pathways in the corresponding cell types that lead to androgen, estrogen and progesterone synthesis. 10. Diagram the female hypothalamus/pituitary/ovarian axis during the menstrual cycle, including all cell types and hormones involved. 11. Explain changes in the female tract, with emphasis on the uterine endometrium, during the menstrual cycle. 12.


Physiology_Levy

Physiology_Levy. 11. Explain changes in the female tract, with emphasis on the uterine endometrium, during the menstrual cycle. 12. List the events involved in fertilization. 13. Describe the development and function of the placenta. 14.


Physiology_Levy

Physiology_Levy. 14. Describe the development and function of the mammary glands he two most basic components of the reproductive system are the gonads and the reproductive tract. The gonads (testes and ovaries) perform an endocrine function that is regulated within a hypothalamic-pituitary-gonadal axis. The gonads are distinct from other endocrine glands in that they also perform gametogenesis. The reproductive tract is involved in several aspects of gamete development, function, and transport and in women allows fertilization, implantation, and gestation. Normal gametogenesis in the gonads and development and physiology of the reproductive tract are absolutely dependent on the endocrine function of the gonads. The clinical ramifications of this hormonal dependence include infertility in the face of low sex hormone production, ambiguous genitalia in dysregulated hormone or receptor expression, and hormone-responsive cancers, especially uterine and breast cancer in women and prostate cancer in men.


Physiology_Levy

Physiology_Levy. The male reproductive system has evolved for continuous lifelong gametogenesis coupled with occasional internal insemination with a high density of sperm (>60 × 106/ mL in 3–5 mL of semen). In adult men the basic roles of gonadal hormones are (1) support of gametogenesis (spermatogenesis), (2) maintenance of the male reproductive tract and production of semen, and (3) maintenance of secondary sex characteristics and libido. There is no overall cyclicity of this activity in men. The Testis Unlike the ovaries, the testes reside outside the abdominal cavity in the scrotum ( Fig. 44.1). This location maintains testicular temperature at about 2°C lower than body temperature, which is crucial for optimal sperm development. The human testis is covered by a connective tissue capsule and divided into about 300 lobules by fibrous septa ( Fig.


Physiology_Levy

Physiology_Levy. Fig. 44.2 ). Within each lobule are two to four loops of seminiferous tubules. Each loop empties into an anastomosing network of tubules called the rete testis. The rete testis is continuous with small ducts, the efferent ductules, that lead the sperm out of the testis into the head of the epididymis on the superior pole of the testis (see Fig. 44.2 ). Once in the epididymis, the sperm pass from the head, to the body, to the tail of the epididymis and then to the vas (ductus) deferens. Viable sperm can be stored in the tail of the epididymis and vas deferens for several months. • Fig. 44.1 Anatomy of the male reproductive system. (Modified from Drake RL et al. Gray’s Anatomy for Students. Philadelphia: Churchill Livingstone; 2005.)


Physiology_Levy

Physiology_Levy. • Fig. 44.1 Anatomy of the male reproductive system. (Modified from Drake RL et al. Gray’s Anatomy for Students. Philadelphia: Churchill Livingstone; 2005.) The presence of the seminiferous tubules creates two compartments within each lobule: an intratubular compartment, which is composed of the avascular seminiferous epithelium of the seminiferous tubule, and a peritubular compartment, which is composed of neurovascular elements, connective tissue cells, immune cells, and the interstitial cells of Leydig, whose main function is to produce testosterone ( Fig. 44.3). The seminiferous tubule is lined by a complex seminiferous epithelium composed of two cell types: sperm cells in various stages of spermatogenesis and the Sertoli cell, which is a “nurse cell” in intimate contact with all sperm cells (Fig. 44.4 Spermatogenesis involves the processes of mitosis and meiosis. Stem cells called spermatogonia reside at the basal level of the seminiferous epithelium (see Fig. 44.4,


Physiology_Levy

Physiology_Levy. Spermatogenesis involves the processes of mitosis and meiosis. Stem cells called spermatogonia reside at the basal level of the seminiferous epithelium (see Fig. 44.4, SA and SB). Spermatogonia divide mitotically to generate daughter spermatogonia (spermatocytogenesis). One or more spermatogonia remain within the stem cell population, firmly adherent to the basal lamina. However, the majority of these daughter spermatogonia enter meiotic division, which results in haploid spermatozoa on completion of meiosis. These divisions are accompanied by incomplete cytokinesis such that all daughter cells remain interconnected by a cytoplasmic bridge. This configuration contributes to the synchrony of development of a clonal population of sperm cells. Spermatogonia migrate apically away from the basal lamina as they enter the first meiotic prophase. At this time they are called primary spermatocytes (see


Physiology_Levy

Physiology_Levy. Fig. 44.4 , S1). During the first meiotic prophase the hallmark processes of sexual reproduction involving chromosomal reduplication, synapsis, crossing over, and homologous recombination take place. Completion of the first meiotic division gives rise to secondary spermatocytes, which quickly (i.e., within 20 minutes) complete the second meiotic division. The initial products of meiosis are haploid spermatids (see Fig. 44.4, S3). Spermatids are small round cells that undergo a remarkable metamorphosis called spermiogenesis ( Fig. 44.5). The products of spermiogenesis are the streamlined spermatozoa see


Physiology_Levy

Physiology_Levy. Fig. 44.4, S3). Spermatids are small round cells that undergo a remarkable metamorphosis called spermiogenesis ( Fig. 44.5). The products of spermiogenesis are the streamlined spermatozoa see Fig. 44.4 , S4). As the spermatid matures into a spermatozoon the size of the nucleus decreases and a prominent tail is formed. The tail contains microtubular structures that propel sperm, similar to a flagellum. The chromatin material in the sperm nucleus condenses, and most of the cytoplasm is lost. The acrosome is a membrane-enclosed structure on the head of the sperm that acts as a lysosome CHAPTER 44 The Male and Female Reproductive Systems 789 Ligamentous remnant Vas deferens of processus vaginalis Fibrous septum Head of epididymis Body of epididymis


Physiology_Levy

Physiology_Levy. CHAPTER 44 The Male and Female Reproductive Systems 789 Ligamentous remnant Vas deferens of processus vaginalis Fibrous septum Head of epididymis Body of epididymis Tail of epididymis • Fig. 44.3 Histology of a testicular lobule. (From Young B etal. Wheater’s Functional Histology. A Text and Colour Atlas. 5th ed. London:ChurchillLivingstone;2006.) and contains hydrolytic enzymes that are important for fertilization. These enzymes remain inactive until the acrosomal reaction occurs (see


Physiology_Levy

Physiology_Levy. Fig. 44.4 , S4) are found at the luminal surface of the seminiferous tubule. Release of sperm, or spermiation, is controlled by Sertoli cells. The process of • Fig. 44.4 Histology of a seminiferous tubule. M, myoid cell just outside the basal lamina; S1, primary spermatocyte; S3, spermatid; S4, mature spermatid or spermatozoon; SB and SA, spermatogonia; St,Sertolicell.(FromYoungBetal.Wheater’s Functional Histology. A Text and Colour Atlas.5thed.London:ChurchillLivingstone;2006.) spermatogenesis takes about 72 days. A cohort of adjacent spermatogonia enter the process every 16 days so that the process is staggered at one point along a seminiferous tubule. In addition the process is staggered along the length of a seminiferous tubule (i.e., not all spermatogonia enter the process of spermatogenesis at the same time along the •Fig. 44.5 Structureofspermcellsduringtheprocessofspermatogenesisandspermiogenesis.


Physiology_Levy

Physiology_Levy. entire length of the tubule or in synchrony with every other tubule; there are about 500 seminiferous tubules per testis; see later). Because the seminiferous tubules within one testis are about 400 m in length, spermatozoa are continually being generated at many sites within the testis at any given time. The Sertoli Cell Sertoli cells are the true epithelial cells of the seminiferous epithelium and extend from the basal lamina to the lumen (see Fig. 44.4 , St). Sertoli cells surround sperm cells and provide structural support within the epithelium, and they form adhering and gap junctions with all stages of sperm cells. Through formation and breakdown of these junctions, Sertoli cells guide sperm cells toward the lumen as they advance to later stages of spermatogenesis. Spermiation requires the final breakdown of Sertoli–sperm cell junctions. Another important structural feature of Sertoli cells is the formation of tight junctions between adjacent Sertoli cells (


Physiology_Levy

Physiology_Levy. Another important structural feature of Sertoli cells is the formation of tight junctions between adjacent Sertoli cells ( Fig. 44.6 ). These Sertoli-Sertoli cell occluding junctions divide the seminiferous epithelium into a basal compartment containing the spermatogonia and early-stage primary spermatocytes and an adluminal compartment containing later-stage primary spermatocytes and all subsequent stages of sperm cells. As early primary spermatocytes move apically from the basal to the adluminal compartment, the tight junctions need to be disassembled and reassembled. These tight junctions form the physical basis for the blood-testis barrier (see


Physiology_Levy

Physiology_Levy. Fig. 44.6 ), which creates a specialized immunologically safe microenvironment for developing sperm. By blocking paracellular diffusion the tight junctions restrict movement of substances between blood and the developing germ cells through a trans–Sertoli cell transport pathway and in this manner allow the Sertoli cell to control the availability of nutrients to germ cells. Healthy Sertoli cell function is essential for sperm cell viability and development. In addition, spermatogenesis is absolutely dependent on testosterone produced by peritubular Leydig cells (see


Physiology_Levy

Physiology_Levy. Healthy Sertoli cell function is essential for sperm cell viability and development. In addition, spermatogenesis is absolutely dependent on testosterone produced by peritubular Leydig cells (see The Leydig Cell ), yet it is the Sertoli cells that express the androgen receptor and respond to testosterone, not the developing sperm cells. Similarly the pituitary hormone follicle-stimulating hormone (FSH) is also required for maximal sperm production, and again it is the Sertoli cell that expresses the FSH receptor, not the developing sperm. Thus these hormones support spermatogenesis indirectly through stimulation of Sertoli cell function.


Physiology_Levy

Physiology_Levy. Sertoli cells have multiple additional functions. They express the enzyme CYP19 (also called aromatase), which converts Leydig cell–derived testosterone to the potent estrogen estradiol-17β (see ). This local production of estrogen may enhance spermatogenesis in humans. Sertoli cells also produce androgen-binding protein (ABP), which maintains a high androgen level within the adluminal compartment, the lumens of the seminiferous tubules, and the proximal part of the male reproductive tract. Sertoli cells also produce a large amount of fluid. This fluid provides an appropriate bathing medium for the sperm and assists in moving the immotile spermatozoa from the seminiferous tubule into the epididymis. Sertoli cells perform an important phagocytic function by engulfing residual bodies, which represent cytoplasm shed by spermatozoa during spermiogenesis.


Physiology_Levy

Physiology_Levy. Finally, the Sertoli cell has an important endocrine role. During development, Sertoli cells produce antimüllerian hormone (AMH; also called müllerian inhibitory substance), which induces regression of the embryonic müllerian duct that is programmed to give rise to the female reproductive tract (discussed later). The Sertoli cells also produce the hormone inhibin. Inhibin is a heterodimer protein hormone related to the transforming growth factor-β family. FSH stimulates inhibin production, which then negatively feeds back on gonadotropes to inhibit FSH production. Thus inhibin keeps FSH levels within a set point. The peritubular compartment contains the primary endocrine cell of the testis, the Leydig cell (


Physiology_Levy

Physiology_Levy. The peritubular compartment contains the primary endocrine cell of the testis, the Leydig cell ( Fig. 44.7 ). This compartment also contains the common cell types of loose connective tissue and an extremely rich peritubular capillary network that provides nutrients to the seminiferous tubules (by way of Sertoli cells) while conveying testosterone away from the testes to the peripheral circulation. The Leydig Cell Leydig cells are steroidogenic stromal cells. These cells synthesize cholesterol de novo, as well as acquire it through low-density lipoprotein (LDL) receptors and high-density lipoprotein (HDL) receptors (also called scavenger receptor BI [SR-BI]), and store cholesterol as cholesterol esters as


Physiology_Levy

Physiology_Levy. CHAPTER 44 The Male and Female Reproductive Systems 791 • Fig. 44.6 Placement of germ cells within seminiferous tubule as they progress through spermatogenesis (From Carlson BM. Human Embryology and Developmental Biology. Philadelphia: Mosby; 2004.) ). Free to progesterone, 17-hydroxyprogesterone, and androstenecholesterol is generated by a cholesterol ester hydrolase and dione by 3β-hydroxysteroid dehydrogenase (3β-HSD) and transferred to the outer mitochondrial membrane and then CYP17 ( Fig. 44.8).


Physiology_Levy

Physiology_Levy. CYP17 to the inner mitochondrial membrane in a steroidogenic is a bifunctional enzyme with 17-hydroxylase activity acute regulatory (StAR) protein–dependent manner. and 17,20-lyase activity. CYP17 displays a robust level As in all steroidogenic cells, cholesterol is converted to of both activities in the Leydig cell. In this respect the pregnenolone by CYP11A1. Pregnenolone is then processed Leydig cell is similar to the zona reticularis cell, except that it expresses a higher level of 3β-HSD, so the Δ4 pathway is ultimately favored. Another major difference is that the Leydig cell expresses a Leydig cell–specific isoform of •Fig. 44.7 Histologyoftheperitubularspace(betweenthreesemi-niferoustubules)containingLeydigcells(L)andrichlyvascularizedbyperitubularcapillaries(cap).(ModifiedfromYoungBetal.Wheater’s Functional Histology. A Text and Colour Atlas.


Physiology_Levy

Physiology_Levy. Functional Histology. A Text and Colour Atlas. 5thed.London:ChurchillLivingstone;2006.)capSeminiferoustubuleSeminiferoustubuleSeminiferoustubuleLcapSeminiferoustubuleSeminiferoustubuleSeminiferoustubuleL 17β-hydroxysteroid dehydrogenase (17β-HSD type 3), which efficiently converts androstenedione to testosterone (see


Physiology_Levy

Physiology_Levy. Fig. 44.8 Fates and Actions of Androgens The testosterone produced by Leydig cells has several fates and multiple actions. Because of the proximity of Leydig cells to the seminiferous tubules, significant amounts of testosterone diffuse into the seminiferous tubules and become concentrated within the adluminal compartment by ABP (see Fig. 44.8 ). Testosterone levels within the seminiferous tubules that are greater than 100 times more concentrated than circulating testosterone levels are absolutely required for normal spermatogenesis. As mentioned earlier, Sertoli cells express the enzyme CYP19 (aromatase), which converts a small amount of testosterone into the highly potent estrogen estradiol-17β. Human sperm cells express at least one isoform of the estrogen receptor, and there is some evidence from aromatase-deficient men that this locally produced estrogen optimizes spermatogenesis in humans. Peripheral Conversion to Estrogen


Physiology_Levy

Physiology_Levy. Peripheral Conversion to Estrogen In several tissues (especially adipose tissue), testosterone is converted to estrogen (see Fig. 44.8 ). Studies involving men with aromatase deficiency have shown that an inability to produce estrogen results in tall stature because of the lack of epiphyseal closure in long bones, as well as osteoporosis. Thus peripheral estrogen plays an important role in bone maturation and biology in men. These studies also implicated estrogen in promoting insulin sensitivity, improving lipoprotein profiles (i.e., increasing HDL, decreasing triglycerides and LDL), and exerting negative feedback on gonadotropins at the pituitary and hypothalamus. Peripheral Conversion to Dihydrotestosterone Testosterone can also be converted into a potent nonaromatizable androgen, 5αα-dihydrotestosterone (DHT), by the enzyme 5α-reductase (see


Physiology_Levy

Physiology_Levy. Peripheral Conversion to Dihydrotestosterone Testosterone can also be converted into a potent nonaromatizable androgen, 5αα-dihydrotestosterone (DHT), by the enzyme 5α-reductase (see Fig. 44.8 ). There are two isoforms of 5α-reductase, type 1 and type 2. Major sites of 5α-reductase 2 expression are the male urogenital tract, genital skin, hair follicles, and liver. 5α-Reductase 2 generates DHT, which is required for masculinization of the external genitalia in utero and for many of the changes associated with puberty, including growth and activity of the prostate gland (see ), growth of the penis, darkening and folding of the scrotum, growth of pubic and axillary hair, growth of facial and body hair, and increased muscle mass (


Physiology_Levy

Physiology_Levy. Fig. 44.9 ). The onset of 5α-reductase 1 expression occurs at puberty. This isozyme is expressed primarily in the skin and contributes to sebaceous gland activity and the acne associated with puberty. Because DHT has strong growth-promoting (i.e., trophic) effects on its target organs, development of selective 5α-reductase 2 inhibitors has benefited the treatment of prostatic hypertrophy and prostatic cancer. Testosterone has a direct action (i.e., without conversion to DHT) in several cell types (see Fig. 44.9).


Physiology_Levy

Physiology_Levy. Testosterone has a direct action (i.e., without conversion to DHT) in several cell types (see Fig. 44.9). As mentioned earlier, testosterone regulates Sertoli cell function. It induces development of the male tract from the mesonephric duct in the absence of 5α-reductase. Testosterone has several metabolic effects, including increasing very low-density lipoprotein (VLDL) and LDL while decreasing HDL, promoting deposition of abdominal adipose tissue, increasing red blood cell production, promoting bone growth and health, and exerting a protein anabolic effect on muscle. Testosterone is sufficient to maintain erectile function and libido. Mechanism of Androgen Action Testosterone and DHT act through the same androgen receptor (AR). The AR resides in the cytoplasm bound to chaperone proteins in the absence of ligand.Testosterone-AR


Physiology_Levy

Physiology_Levy. HO 3˜-HSD CYP17 (17-hydroxylase) CH3 CH3 CH3 C O CH3 OH Pregnenolone OH CH3 CH3 CH3 O C O CH3 CH3 CH3 O H C O Progesterone 17(OH) Progesterone Type III 17˜-HSD Into seminiferous tubule T + ABP T • ABP (predominantly as T) SHBG + T CH3 CH3 O O Androstenedione CH3 CH3 O OH Testosterone (T) CH3 CH3 O OH Dihydrotestosterone (DHT) Into peripheral circulation CYP19 (adipose tissue) 5°-Reductase (genital skin, prostate) Estradiol-17˜Leydig cell HO SHBG • T •Fig. 44.8 SteroidogenicpathwayinLeydigcells(thefirststepofconvertingcholesteroltopregnenoloneisomitted).Testosteroneissequesteredbybindingtoandrogen-bindingprotein(ABP)withintheseminiferoustubulesorcirculateswithintheperipheralcirculationboundtosexhormone–bindingglobulin(SHBG)andcanbeperipherallyconvertedtodihydrotestosterone(DHT)orestradiol-17β (E2).(ModifiedfromWhiteBA,PorterfieldSP.Endocrine Physiology. 4thed.Philadelphia:Mosby;2013.) binding or DHT-AR binding causes dissociation of the vicinity of a specific gene’s promoter. It


Physiology_Levy

Physiology_Levy. (E2).(ModifiedfromWhiteBA,PorterfieldSP.Endocrine Physiology. 4thed.Philadelphia:Mosby;2013.) binding or DHT-AR binding causes dissociation of the vicinity of a specific gene’s promoter. It remains unclear how chaperone proteins, followed by nuclear translocation of testosterone and DHT differ in their ability to activate the the androgen-AR complex, dimerization, binding to an AR in the context of different cell types, although the pres-androgen response element (ARE), and recruitment of ence of different coactivator proteins in different cell types coactivator proteins and general transcription factors to the is probably involved. Such coactivator proteins would have


Physiology_Levy

Physiology_Levy. Feedback suppression of gonadotropin secretion Imprint male pattern of gonadotropins, sex drive, behavior • Fig. 44.9 Spectrum of effects of testosterone (T). Note that some effects result from the action of testosterone itself, whereas others are mediated by dihydrotestosterone (DHT) and estradiol (E2) after they are produced from testosterone. VLDL, LDL, HDL, very-low-density, low-density, and high-density lipoproteins, respectively. different affinities for the testosterone-induced configuration of the AR versus the DHT-induced configuration of the AR. Transport and Metabolism of Androgens


Physiology_Levy

Physiology_Levy. different affinities for the testosterone-induced configuration of the AR versus the DHT-induced configuration of the AR. Transport and Metabolism of Androgens As testosterone enters the peripheral circulation, it binds to and quickly reaches equilibrium with serum proteins. About 60% of circulating testosterone is bound to sex hormone–binding globulin (SHBG), 38% is bound to albumin, and about 2% remains as “free” hormone. Testosterone and its metabolites are primarily excreted in urine. Approximately 50% of excreted androgens are found as urinary 17-ketosteroids, with most of the remainder being conjugated androgens or diol or triol derivatives. Only about 30% of the 17-ketosteroids in urine are from the testis; the rest are produced from adrenal androgens. Androgens are conjugated with glucuronate or sulfate in the liver, and these conjugated steroids are excreted in urine.


Physiology_Levy

Physiology_Levy. The testis is regulated by an endocrine axis (Fig. 44.10 ) involving parvicellular hypothalamic gonadotropin-releasing hormone (GnRH) neurons and pituitary gonadotropes that produce both luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Regulation of Leydig Cell Function The Leydig cell expresses the LH receptor, which acts on Leydig cells much like adrenocorticotropic hormone (ACTH, or corticotropin) does on zona fasciculata cells in the adrenal cortex (see ). Rapid effects include hydrolysis of cholesterol esters and new expression of StAR protein. Less acute effects include an increase in steroidogenic enzyme gene expression and expression of the LDL. Over the long term, LH promotes Leydig cell growth and proliferation.


Physiology_Levy

Physiology_Levy. •Fig. 44.10 Thehypothalamic-pituitary-testicularaxis.Abbreviationsasinotherfigures.Kisspeptin hypothalamic neurons GnRH hypothalamic neurons GnRH Pituitary gonadotropes LH FSH Sertoli cell Sperm cells E2 T DHT Leydig cell T (–) (–) (–)(–) (–) Inhibin B Testosterone, and estradiol produced from peripheral conversion of testosterone, negatively feed back on GnRH hypothalamic neurons indirectly through inhibition of kisspeptin-producing neurons (see Fig. 44.10 ). Testosterone and estradiol also negatively feed back on pituitary gonadotropes. DHT, the other major product of peripheral conversion of testosterone, has little effect on LH or FSH levels. Regulation of Sertoli Cell Function


Physiology_Levy

Physiology_Levy. Regulation of Sertoli Cell Function The Sertoli cell is stimulated by both testosterone and FSH. In addition to stimulating synthesis of proteins involved in the “nurse cell” aspect of Sertoli cell function (e.g., ABP), FSH stimulates synthesis of the dimeric protein inhibin. Inhibin is induced by FSH and negatively feeds back on the gonadotrope to selectively inhibit FSH production (see Fig. 44.10 Once spermatozoa emerge from the efferent ductules, they leave the gonad and enter the male reproductive tract (see


Physiology_Levy

Physiology_Levy. Fig. 44.10 Once spermatozoa emerge from the efferent ductules, they leave the gonad and enter the male reproductive tract (see Fig. 44.1 ). The segments of the tract are the: epididymis (head, body, and tail), vas deferens, ejaculatory duct, prostatic urethra, membranous urethra, and penile urethra. Unlike the female tract, there is a contiguous lumen from the seminiferous tubule to the end of the male tract (i.e., the tip of the penile urethra), and the male reproductive tract connects to the distal urinary tract (i.e., male urethra). In addition to conveying sperm, the primary functions of the male reproductive tract are: 1. Sperm maturation. Sperm spend about a month in the epididymis, where they undergo further maturation.


Physiology_Levy

Physiology_Levy. Thereisanimportant“loophole”inthemalereproductiveaxisthatisbasedonthefactthatintratesticular levels of testosterone needtobegreaterthan100-foldhigherthancirculatinglevelsofthehormonetomaintainnormalratesofspermatogenesis,yetitisthecirculating levels of testosterone (and estradiol) thatprovidethenegativefeedbacktothepituitaryandhypothalamus.ThismeansthatexogenousadministrationoftestosteronecanraisecirculatinglevelsoftestosteroneandestradiolsufficienttoinhibitLHbutnotsufficienttoaccumulateinthetestisattherequiredconcentrationfornormalspermatogenesis.However,thedecreasedLHlevelswilldiminishintratesticularproductionoftestosteronebyLeydigcells,whichresultsinreducedlevels ofspermatogenesis(Fig.44.11 ).This“loophole”iscurrentlybeinginvestigatedasapossiblestrategyfordevelopingamale oral contraceptive. Itisalsothebasisforsterility insomecasesofsteroid abuse inmen.


Physiology_Levy

Physiology_Levy. The epithelium of the epididymis is secretory and adds numerous components to the seminal fluid. Spermatozoa that enter the head of the epididymis are weakly motile but are strongly unidirectionally motile by the time they exit the tail. Spermatozoa also undergo the process of decapacitation, which involves changes in the cell membrane to prevent spermatozoa from undergoing the acrosome reaction before contact with an egg (see later). Sperm become capacitated by the female reproductive tract within the oviduct. The function of the epididymis is dependent on luminal testosterone-ABP complexes that come from the seminiferous tubules and on testosterone from blood.


Physiology_Levy

Physiology_Levy. Normal set point determined by relatively low levels of circulating T, not intratesticular T •Fig. 44.11 Thedifferenceinintratesticulartestosteroneversuscirculatingtestosteroneconcentrationsanditsimportanceinthehypothalamic-pituitary-testisaxis.Upper panel, Feedbackloopinanormaladultman.Lower panel, Administrationoftestosterone(oranandrogenicanalogue)increasescirculatingtestosterone(androgen)levels,whichinturnincreasenegativefeedbackonreleaseofLH.DecreasedLHlevelsdiminishLeydigcellactivityandintratesticularproductionofandrogen.Loweredintratesticulartestosteronelevelsresultinreducedspermproductionandcancauseinfertility.(Theinhibinfeedbackloophasbeenomittedfromthisdiagram.)(ModifiedfromWhiteBA,PorterfieldSP.Endocrine Physiology. 4thed.Philadelphia:Mosby;2013.) 2.


Physiology_Levy

Physiology_Levy. Sperm storage and emission. Sperm are stored in the tail The vas deferens has a very thick muscularis that is richly of the epididymis and vas deferens for several months innervated by sympathetic nerves. Normally in response without loss of viability. The primary function of the vas to repeated tactile stimulation of the penis during coitus, deferens, besides providing a storage site, is to propel the muscularis of the vas deferens receives bursts of symsperm during sexual intercourse into the male urethra. pathetic stimulation that cause peristaltic contractions. Emptying of the contents of the vas deferens into the prostatic urethra is called emission. Emission immediately precedes ejaculation, which is the propulsion of semen out of the male urethra. 3.


Physiology_Levy

Physiology_Levy. Production and mixing of sperm with seminal contents. During emission, contraction of the vas deferens coincides with contraction of the muscular coats of the two accessory sex glands, the seminal vesicles (right and left) and the prostate gland (which surrounds the prostatic urethra). At this point, sperm become mixed with all the components of semen. The seminal vesicles secrete approximately 60% of the volume. These glands are the primary source of fructose, a critical nutrient for sperm. The seminal vesicles also secrete semenogelins, which induce coagulation of semen immediately after ejaculation. The alkaline secretions of the prostate, which make up about 30% of the volume, are high in citrate, zinc, spermine, and acid phosphatase. Prostate-specific antigen (PSA) is a serine protease that liquefies coagulated semen after a few minutes. PSA can be detected in blood under conditions of prostatic infection, benign prostatic hypertrophy, and prostatic carcinoma and is currently


Physiology_Levy

Physiology_Levy. that liquefies coagulated semen after a few minutes. PSA can be detected in blood under conditions of prostatic infection, benign prostatic hypertrophy, and prostatic carcinoma and is currently used as one indicator of prostatic health. The predominant buffers in semen are phosphate and bicarbonate. A third accessory gland, the bulbourethral glands (also called Cowper’s glands), empty into the penile urethra in response to sexual excitement before emission and ejaculation. This secretion is high in mucus, which lubricates, cleanses, and buffers the urethra. Average sperm counts are between 60 and 100 million/mL semen. Men with sperm counts below 20 million/mL, less than 50% motile sperm, or less than 60% normally conformed sperm are usually infertile.


Physiology_Levy

Physiology_Levy. 4.


Physiology_Levy

Physiology_Levy. Erection, penetration, and ejaculation. Emission and ejaculation occur during coitus in response to a reflex arc that involves sensory stimulation from the penis (via the pudendal nerve) followed by sympathetic motor stimulation to the smooth muscle of the male tract and somatic motor stimulation to the musculature associated with the base of the penis. However, for sexual intercourse to occur in the first place, the man has to achieve and maintain an erection of the penis. The penis has evolved as an intromittent organ designed to separate the walls of the vagina, pass through the potential space of the vaginal lumen, and deposit semen at the distal end of the vaginal lumen near the cervix. This process of internal insemination can be performed only if the penis is stiffened from the process of erection. Erection is a neurovascular event. The penis is composed of three erectile bodies: two corpora cavernosa and one corpus spongiosum (Fig. 44.12A ). The penile urethra runs through the


Physiology_Levy

Physiology_Levy. of erection. Erection is a neurovascular event. The penis is composed of three erectile bodies: two corpora cavernosa and one corpus spongiosum (Fig. 44.12A ). The penile urethra runs through the corpus spongiosum. These three bodies are composed of erectile tissue—an anastomosing network of potential cavernous vascular spaces lined with continuous endothelia within a loose connective tissue support. During the flaccid state, blood flow to the cavernous spaces is minimal (see


Physiology_Levy

Physiology_Levy. Fig. 44.12A). This is due CHAPTER 44 The Male and Female Reproductive Systems of the vasculature (called the helicine arteries) and shunting of blood flow away from the cavernous spaces. In response to sexual arousal the parasympathetic cavernous nerves innervating the vascular smooth muscle of the helicine arteries release nitric oxide (NO). NO activates guanylyl cyclase, thereby increasing cyclic guanosine monophosphate (cGMP), which decreases intracellular [Ca++] and causes muscular relaxation (see Fig. 44.12B ). Vasodilation allows blood to flow into the cavernous spaces to induce engorgement and erection. It also presses on veins in the penis and reduces venous drainage (see Fig. 44.12B


Physiology_Levy

Physiology_Levy. Fig. 44.12B ). Vasodilation allows blood to flow into the cavernous spaces to induce engorgement and erection. It also presses on veins in the penis and reduces venous drainage (see Fig. 44.12B Inabilitytoachieveormaintainanerectionistermederectile dysfunction (ED) andisonecauseofinfertilityinmen.MultiplefactorscanleadtoED,includinginsufficientandrogenproduction;neurovasculardamage(e.g.,fromdiabetesmellitus,spinalcordinjury);structuraldamagetothepenis,perineum,orpelvis;psychogenicfactors(e.g.,depression,performanceanxiety);andprescribedmedicationsandrecreationaldrugs,includingalcoholandtobacco.AmajordevelopmentinthetreatmentofsomeformsoferectiledysfunctionisuseofselectivecGMPphosphodiesteraseinhibitorsthatassistinmaintaininganerection(see Fig.44.12B


Physiology_Levy

Physiology_Levy. Fig.44.12B There is no distinct andropause in men. However, as men age, gonadal sensitivity to LH decreases and androgen production drops. As this occurs, serum LH and FSH levels rise. Although sperm production typically begins to decline after age 50, many men can maintain reproductive function and spermatogenesis throughout life. The female reproductive system is composed of the gonads, called ovaries, and the female reproductive tract, which includes the oviducts, uterus, cervix, vagina, and external genitalia. The Ovary The ovary is located within a fold of peritoneum called the broad ligament, usually close to the lateral wall of the pelvic cavity ( Fig. 44.13 ). Because the ovary extends into the peritoneal cavity, ovulated eggs briefly reside within the peritoneal cavity before they are captured by the oviducts. The ovary is divided into an outer cortex and inner medulla (


Physiology_Levy

Physiology_Levy. The ovary is divided into an outer cortex and inner medulla ( Fig. 44.14 ). Neurovascular elements innervate the medulla of the ovary. The cortex of the ovary is composed of a densely cellular stroma. Within this stroma reside the ovarian follicles (see Fig. 44.14, F ), which contain a primary oocyte surrounded by follicle cells. The cortex is covered by a connective tissue capsule, the tunica albuginea, (tactile, visual, auditory, psychic) Collapse of venous return from cavernous spaces Contraction of muscles around base of penis • Fig. 44.12 A, Arrangement of the vasculature and cavernous tissue within the penis. During the flaccid state, blood flow into the cavernous spaces is limited by contraction of the helicine arteries. B, Outline of neurovascular events leading to penile erection. (A, From Bhasun S et al. In: Larsen P et al [eds]. Williams Textbook of Endocrinology. 10th ed. Philadelphia: Saunders; 2003.) CHAPTER 44 The Male and Female Reproductive Systems 799


Physiology_Levy

Physiology_Levy. CHAPTER 44 The Male and Female Reproductive Systems 799 Labia minora Recto-uterine pouch of douglas • Fig. 44.13 Anatomy of the female reproductive system. (Modified from Drake RL et al. Gray’s Anatomy for Students. Philadelphia: Churchill Livingstone; 2005.) • Fig. 44.14 Histology of the ovary. CL, corpus luteum; F, follicle. (Modified from Young B et al. Wheater’s Functional Histology. A Text and Colour Atlas. 5th ed. London: Churchill Livingstone; 2006.) and a layer of simple epithelium consisting of ovarian surface epithelial cells. There are no ducts emerging from the ovary to convey its gametes to the reproductive tract. Thus the process of ovulation involves an inflammatory event that erodes the wall of the ovary. After ovulation the ovarian surface epithelial cells rapidly divide to repair the wall. The majority of ovarian cancer originates from this highly proliferative epithelium. Growth, Development, and Function of the Ovarian Follicle


Physiology_Levy

Physiology_Levy. Growth, Development, and Function of the Ovarian Follicle The ovarian follicle is the functional unit of the ovary, and it performs both gametogenic and endocrine functions. A histological section of the ovary from a premenopausal cycling woman contains follicular structures at many different stages of development. The life history of a follicle can be divided into the following stages: 1. 2. 3. 4. dominant (preovulatory, graafian) follicle 5. dominant follicle within the periovulatory period 6. corpus luteum (of menstruation or of pregnancy) 7.


Physiology_Levy

Physiology_Levy. 2. 3. 4. dominant (preovulatory, graafian) follicle 5. dominant follicle within the periovulatory period 6. corpus luteum (of menstruation or of pregnancy) 7. Fig. 44.15 ) represent the earliest and simplest follicular structure in the ovary. Primordial follicles appear during midgestation through the interaction of gametes and somatic cells. Primordial germ cells that have migrated to the gonad continue to divide mitotically as oogonia until the fifth month of gestation in humans. At this point the approximately 7 million oogonia enter the process of meiosis and become primary oocytes. During this time the primary oocytes become surrounded by a simple epithelium of somatic follicle cells, thereby creating the primordial follicles (see


Physiology_Levy

Physiology_Levy. Fig. 44.15 ). The follicle cells establish gap junctions with each other and the oocyte. The follicle cells themselves represent a true avascular epithelium surrounded by a basal lamina. Similar to Sertoli cell–sperm interactions, a subpopulation of granulosa cells remains intimately attached to the oocytes throughout their development. Granulosa cells provide nutrients such as amino acids, nucleic acids, and pyruvate to support oocyte maturation. •Fig. 44.15 Developmentofaprimordialfollicleuptoasecondarypreantralfollicle.(ModifiedfromWhiteBA,PorterfieldSP.Endocrine Physiology. 4thed.Philadelphia:Mosby;2013.)Primordial follicle Primary oocyte Basal lamina Pregranulosa cells Germinal vesicle with nucleolus Zona pellucida Cuboidal granulosa cells Primary follicle Secondary preantral follicle Theca Stratified granulosa cells The primordial follicles represent the ovarian reserve of follicles (


Physiology_Levy

Physiology_Levy. Fig. 44.16). This reserve is reduced from a starting number of about 7 million to less than 300,000 follicles at reproductive maturity. Of these, a woman will ovulate about 450 between menarche (first menstrual cycle) and menopause (cessation of menstrual cycles). At menopause, less than 1000 primordial follicles are left in the ovary. Primordial follicles are lost primarily from death as a result of follicular atresia. However, a small subset of primordial follicles will enter follicular growth in waves. Because the ovarian follicular reserve represents a fixed finite number, the rate at which resting primordial follicles die or begin to develop (or both) will determine the reproductive life span of a woman. Age at the onset of menopause has a strong genetic component but is also influenced by environmental factors. For example, cigarette smoking significantly depletes the ovarian reserve. An overly rapid rate of atresia or development will deplete the reserve and give rise to


Physiology_Levy

Physiology_Levy. by environmental factors. For example, cigarette smoking significantly depletes the ovarian reserve. An overly rapid rate of atresia or development will deplete the reserve and give rise to premature ovarian insufficiency.


Physiology_Levy

Physiology_Levy. Pituitary gonadotropins maintain a normal ovarian reserve by promoting the general health of the ovary. However, the rate at which resting primordial follicles enter the growth process appears to be independent of pituitary gonadotropins. The decision of a resting follicle to enter the early growth phase is primarily dependent on intraovarian paracrine factors produced by both the follicle cells and oocytes. The Gamete In primordial follicles the gamete is derived from oogonia that have entered the first meiotic division; such oogonia are referred to as primary oocytes. Primary oocytes progress through most of prophase of the first meiotic division


Physiology_Levy

Physiology_Levy. Ovarian reserve ~300,000 primordial follicles at menarche Atresia ~270,000 primordial follicles Growth ~30,000 primordial follicles Atresia About 30,000 primary, secondary, or tertiary follicles Ovulation ~450 dominant follicles •Fig. 44.16 Fateofovarianfollicles.(ModifiedfromWhiteBA,PorterfieldSP.Endocrine Physiology. 4thed.Philadelphia:Mosby;2013.) (termed prophase I) over a 2-week period and then arrest in the diplotene stage. This stage is characterized by the decondensation of chromatin, which supports the transcription needed for oocyte maturation. Meiotic arrest at this stage, which may last for up to 50 years, appears to be due to “maturational incompetence,” or lack of the cell cycle proteins needed to support the completion of meiosis. The nucleus of the oocyte, called the germinal vesicle, remains intact at this stage.


Physiology_Levy

Physiology_Levy. The first stage of follicular growth is preantral, which refers to the development that occurs before the formation of a fluid-filled antral cavity. One of the first visible signs of follicle growth is the appearance of cuboidal granulosa cells. At this point the follicle is referred to as a primary follicle (see Fig. 44.15 ). As granulosa cells proliferate, they form a multilayered (i.e., stratified) epithelium around the oocyte. At this stage the follicle is referred to as a secondary follicle (see Fig. 44.15 Once a secondary follicle acquires three to six layers of granulosa cells, it secretes paracrine factors that induce nearby stromal cells to differentiate into epithelioid thecal cells. Thecal cells form a flattened layer of cells around the follicle. Once a thecal layer forms, the follicle is referred to as a mature preantral follicle (see Fig. 44.15 ). In humans it takes several months for a primary follicle to reach the mature preantral stage.


Physiology_Levy

Physiology_Levy. Fig. 44.15 ). In humans it takes several months for a primary follicle to reach the mature preantral stage. Follicular development is associated with an inward movement of the follicle from the outer cortex to the inner cortex, closer to the vasculature of the ovarian medulla. Follicles release angiogenic factors that induce development of one to two arterioles that form a vascular wreath around the follicle. The Gamete During the preantral stage, the oocyte begins to grow and produce cellular and secreted proteins. The oocyte initiates secretion of extracellular matrix glycoproteins called ZP1, ZP2, and ZP3 that form the zona pellucida (see


Physiology_Levy

Physiology_Levy. Fig. 44.15 ). The zona pellucida increases in thickness and provides a species-specific binding site for sperm during fertilization (see ). Importantly, granulosa cells and the oocyte maintain gap junctional contact via cellular projections through the zona pellucida. The oocyte also continues to secrete paracrine factors that regulate follicle cell growth and differentiation.


Physiology_Levy

Physiology_Levy. Granulosa cells express the FSH receptor during this period, but they are primarily dependent on factors from the oocyte to grow. They do not produce ovarian hormones at this early stage of follicular development. The newly acquired thecal cells are analogous to testicular Leydig cells in that they reside outside the epithelial “nurse” cells, express the LH receptor, and produce androgens. The main difference •Fig. 44.17 Developmentofanearlyantralfollicletoamaturepreovulatoryfollicle.(ModifiedfromWhiteBA,PorterfieldSP.Endocrine Physiology. 4thed.Philadelphia:Mosby;2013.) between Leydig cells and thecal cells is that thecal cells do not express high levels of 17β-HSD. Thus the major product of theca cells is androstenedione as opposed to testosterone. Androstenedione production at this stage is minimal.


Physiology_Levy

Physiology_Levy. Fig. 44.17 ) over a period of about 25 days, during which they grow from a diameter of about 0.1 mm to a diameter of 0.2 mm. Once the granulosa epithelium increases to six to seven layers, fluid-filled spaces appear between cells and coalesce into the antrum. Over a period of about 45 days, this wave of small antral follicles will continue to grow to large recruitable antral follicles that are 2 to 5mm in diameter. This period of growth is characterized by about a 100-fold increase in granulosa cells (from about 10,000 to 1,000,000 cells). It is also characterized by swelling of the antral cavity, which increasingly divides the granulosa cells into two discrete populations: mural granulosa cells and cumulus cells (see Fig. 44.17


Physiology_Levy

Physiology_Levy. Fig. 44.17 Mural granulosa cells (also called the stratum granulosum) form the outer wall of the follicle. The basal layer is adherent to the basal lamina and in close proximity to 802 SECTION8Berne & Levy Physiology Oogonium Primary oocyte arrested at prophase I Meiosis begins, but levels of proteins required for completion of meiosis are too low – oocyte arrests at prophase I. As oocyte grows, it synthesizes enough proteins (e.g., CDK1, cyclin B) to complete meiosis (i.e., meiotic competence), but high cAMP levels generated by GPR3 actively maintain arrest. A few hours before ovulation, the oocyte completes meiosis I and extrudes the first polar body. It has synthesized enough MAPK pathway proteins to arrest at metaphase II.


Physiology_Levy

Physiology_Levy. A few hours before ovulation, the oocyte completes meiosis I and extrudes the first polar body. It has synthesized enough MAPK pathway proteins to arrest at metaphase II. The secondary oocyte completes meiosis at fertilization and extrudes second polar body. Haploid ovum •Fig. 44.18 Eventsinvolvedinmeioticarrestandmaturationoftheoocyte.MAPK,mitogen-activatedproteinkinase.(ModifiedfromWhiteBA,PorterfieldSP.Endocrine Physiology. 4thed.Philadelphia:Mosby;2013.) the outer-lying thecal layers. Mural granulosa cells become highly steroidogenic and remain in the ovary after ovulation to differentiate into the corpus luteum.