Lecture 41: Male Reproductive System - Hormones, Anatomy and Function

REPRODUCTIVE ORGANS The gonads are primary reproductive organs. Gonads are made up of a pair of testes in males and a pair of ovaries in females. The mature gonads have two main functions: 1. Producing gametes (gametogenesis) i) In males, spermatogenesis gives rise to spermatozoa or sperms whil...

REPRODUCTIVE ORGANS The gonads are primary reproductive organs. Gonads are made up of a pair of testes in males and a pair of ovaries in females. The mature gonads have two main functions: 1. Producing gametes (gametogenesis) i) In males, spermatogenesis gives rise to spermatozoa or sperms while ii) In females, oogeneseis gives rise to the ova or egg 2. Production of sex hormones i) In males, testosterone, and ii) In females, estrogen & progesterone The male internal genitalia and accessory sex organs Panel A: The two major elements of the male sexual anatomy are the gonads (i.e., testes) and the sex accessories (i.e., epididymis, vas deferens, seminal vesicles, ejaculatory duct, prostate, bulbourethral or Cowper glands, urethra, and penis). Note that the urethra can be subdivided into the prostatic urethra, the bulbous urethra, and the penile urethra. Panel B: The structure of focus here is the prostate gland. The prostate gland secretes a slightly acidic milky fluid that make up 50-75% of the volume of semen. Although the prostate secretion is slightly acidic, however, the overall nature of semen is alkaline due fluid from the seminal vesicle. Semen alkalinity neutralizes vaginal acidity to prolong the life of the spermatozoa. Panel C: The spermatozoa form in the seminiferous tubules and then flow into the rete testis and from there into the efferent ductules, the epididymis, and the vas deferens. Panel D: The seminiferous tubule is an epithelium formed by Sertoli cells, with interspersed germ cells. The most immature germ cells (the spermatogonia) are near the periphery of the tubule, whereas the mature germ cells (the spermatozoa) are near the lumen of the tubule. The Leydig cells are interstitial cells that lie between the tubules. Leydig cells produce testosterone. Sertoli cells support spermatogenesis During early embryogenesis, primordial germ cells (with embryonic stem cells characteristics) migrate to the gonads, where they become spermatogonia. At the onset of puberty, the spermatogonia undergo repeated mitotic division. Some of these spermatogonia (2N DNA) undergo the first meiotic division, at which point they are referred to as (forming) the primary spermatocytes. During prophase, each primary spermatocyte has a full complement of duplicated chromosomes (4N DNA). Each primary spermatocyte divides into two secondary spermatocytes, each with a haploid number of duplicated chromosomes (2N DNA). The secondary spermatocyte enters the second meiotic division, producing two spermatids, each of which has a haploid number of unduplicated chromosomes (1N DNA). Further maturation of the spermatids yields the spermatozoa (mature sperm). One primary spermatocyte yields four spermatozoa. Sperm maturation occurs in the epididymis  The hypothalamic-pituitary axis The hypothalamus produces neurohormones which are generally called hypothalamic releasing hormones. These hormones stimulate or inhibit the release of pituitary hormones. In addition the hypothalamus have many other functions including regulation of circadian cycle, sleep, fatigue, body temperature, hunger and thirst. Median eminence Pituitary stalk (Adenohypophysis) (Neurohypophysis)  Hypothalamic and Pituitary Hormones ANTERIOR PITUITARY  Glandular tissue in the anterior lobe of the Hormone pituitary synthesizes and secretes six peptide Releasing (Inhibitory) Target Cell in Released by hormones: GH, TSH, ACTH, LH, FSH, and Factor Made by Anterior Anterior Target of Anterior Pituitary PRL. Hypothalamus Pituitary Pituitary Hormone The secretion of these hormones is under GHRH (inhibited by Somatotroph GH Stimulates IGF-1 production by the control of hypothalamic releasing somatostatin) multiple somatic tissues, hormones. The sources of these releasing especially liver hormones are small-diameter neurons located TRH Thyrotroph TSH Thyroid follicular cells, stimulated mainly in the periventricular portion of the to make thyroid hormone hypothalamus that surrounds the third CRH Corticotroph ACTH Fasciculata and reticularis cells of ventricle. the adrenal cortex, to make corticosteroids The anterior pituitary regulates reproduction, growth, energy metabolism, and stress GnRH Gonadotroph FSH Ovarian follicular cells, to make response. estrogens and progestins Sertoli cells, to initiate spermatogenesis GnRH Gonadotroph LH Leydig cells, to make testosterone (inhibited by dopamine) Lactotroph PRL Mammary glands, to initiate and maintain milk production POSTERIOR PITUITARY Hormone Synthesized Hormone Released into Target of Posterior Pituitary The paraventricular nucleus of the in Hypothalamus Posterior Pituitary hypothalamus synthesizes arginine vasopressin (AVP) and oxytocin (OT), and AVP AVP Collecting duct, to increase water these hormones are transported via the permeability median eminence and pituitary stalk to the OT OT Uterus and breast posterior pituitary for release. The posterior pituitary regulates water OT, oxytocin. balance and uterine contraction IGF-1, Insulin-like growth factor 1  The pituitary hormones and their targets The hypothalamus controls the pituitary glands, pituitary hormones produced and the responses of the different target tissues. The release of the anterior pituitary hormones is stimulated by releasing hormones and suppressed by inhibiting hormones. A hormone that stimulates the release of another hormone with growth effect is known as a trophic hormone.  The male hypothalamic-pituitary-axis The male hypothalamic-pituitary-gonadal axis controls two primary functions:  Production of male gametes (spermatogenesis) in the seminiferous tubules and  Androgen biosynthesis in the Leydig cells of the testes. The hypothalamus produces: Gonadotropin-releasing hormone (GnRH), which stimulates the gonadotrophs in the anterior pituitary to secrete the two gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Hypothalamic-pituitary-gonadal axis and control of male sexual functions  The male hypothalamic-pituitary-gonadal axis controls two main functions: – 1) production of male gametes (spermatogenesis) in the seminiferous tubules and – (2) androgen biosynthesis in the Leydig cells in the testes.  Gonadotropin-releasing hormone (GnRH) is synthesized by small-bodied peptidergic neurons in the hypothalamus, stimulates the synthesis, storage, and secretion of gonadotropins by gonadotroph cells of the anterior pituitary.  The neurons that synthesize, store, and release GnRH are dispersed throughout the hypothalamus but are principally located in the arcuate nucleus and preoptic area.  GnRH is a decapeptide that is synthesized as a prohormone with 69 amino acids, from which the mature GnRH is generated by enzymatic cleavage. The neurons release GnRH into the extracellular space, to be carried to the anterior pituitary via the long portal vessels.  GnRH stimulates the release of both follicle stimulating hormone (FSH) and the luteinizing hormone (LH) from the gonadotroph cells of the anterior pituitary. FSH and LH are the primary gonadotropins and stimulate testicular function in males. The cell surface of the pituitary gonadotrophs is the site of high- affinity membrane receptors for GnRH. These receptors are coupled to the G protein (Gαq), which activates phospholipase C (PLC). PLC acts on membrane phosphoinositides to liberate inositol 1,4,5- triphosphate (IP3) which triggers Ca2+ release from internal stores, and diacylglycerol (DAG) which stimulates protein kinase C. Correspondingly, synthesis and release of LH and FSH from the gonadotrophs occurs. Because secretion of GnRH into the portal system is pulsatile, secretion of both LH and FSH by the gonadotrophs is also episodic.  Hypothalamic and anterior pituitary peptides Hypothalamus Anterior Pituitary Target organs Thyroid gland Ovary and testis Adrenal gland Bone, muscles etc Mammary glands The male hypothalamic-pituitary-axis Small-bodied neurons in the arcuate nucleus and preoptic area of the hypothalamus secrete gonadotropin-releasing hormone (GnRH), a decapeptide that reaches the gonadotrophs in the anterior pituitary via the long portal veins. Stimulation by GnRH causes the gonadotrophs to synthesize and release follicle stimulating hormone (FSH) and luteinizing hormone (LH). The LH binds to receptors on Leydig cells, stimulating the transcription of proteins involved in the biosynthesis of testosterone. FSH binds to receptors on the basolateral membrane of Sertoli cells, stimulating gene transcription and protein synthesis. These proteins include androgen-binding protein, aromatase, growth factors and inhibin. Negative feedback on the hypothalamic-pituitary- (Testosterone) testicular axis occurs by two routes. First, testosterone inhibits the pulsatile release of GnRH by the hypothalamic neurons and the release of LH by the gonadotrophs in the anterior pituitary. Second, inhibin inhibits the release of FSH by the gonadotrophs in the anterior pituitary.  Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH) The GnRH control the secretion of LH and FSH by the gonadotrophs in the anterior pituitary  LH and FSH are the primary regulators of testicular function. LH, FSH, human chorionic gonadotropin (hCG) and thyroid-stimulating hormone (TSH) belong to the family of glycoprotein hormone.  All these glycoprotein hormones are composed of two polypeptide chains designated α and β. Both subunits, α and β, are required for full biologic activity. The α subunits of LH, FSH, hCG and TSH are identical. It is the β subunits that differ among these four hormones and thus confer specific functional and immunologic characteristics to the intact molecules.  The β subunits of LH and hCG are identical, except that the β subunit of hCG has an additional 24 amino acids and additional glycosylation sites at the C terminus. hCG is secreted mainly by the placenta but small amounts are made in the testes, pituitary gland, and other non-placental tissue. The biologic activities of LH and hCG are very similar. Indeed, in most clinical uses (e.g., in an attempt to initiate spermatogenesis in oligospermic males), hCG is substituted for LH because hCG is much more readily available.  FSH production is greater than that of LH during the prepubertal period, a pattern that is reversed after puberty. GnRH preferentially triggers LH release in an adult human male. This preferential release of LH may reflect maturation of the testes, which secrete inhibin, a specific inhibitor of FSH secretion at the level of the anterior pituitary gland. Increased sensitivity of the pituitary to increasing gonadal steroid production may also be responsible for the diminished secretion of FSH.  Plasma levels of FSH, LH, and testosterone from puberty to adulthood During early puberty in boys, both FSH and LH levels increase while, simultaneously, the Leydig cells proliferate and plasma levels of testosterone increase. Plasma levels of biologically active LH,FSH and of testosterone increase during puberty, expressed in terms of both the stages of puberty and bone age. FSH production is greater than that of LH during the prepubertal period, a pattern that is reversed after puberty. GnRH preferentially triggers LH release in an adult human male. This preferential release of LH may reflect maturation of the testes, which secrete inhibin, a specific inhibitor of FSH secretion at the level of the anterior pituitary gland. Increased sensitivity of the pituitary to increasing gonadal steroid production may also be responsible for the diminished secretion of FSH. Luteinizing Hormone (LH) In both sexes, LH stimulates secretion of sex steroids from the gonads. In the testes, LH binds to receptors on Leydig cells, stimulating synthesis and secretion of testosterone. Theca cells in the ovary respond to LH stimulation by secretion of testosterone, which is converted into estrogen by adjacent granulosa cells. The interstitial cells of the testis and the Leydig cells are the primary source of testosterone production in the male. Leydig cells synthesize androgens from cholesterol by using a series of enzymes that are part of the steroid bio-synthetic pathways. The LH derives its name from effects observed in the female, that is, from the ability to stimulate luteal function. The comparable substance in the male was originally referred to as interstitial cell-stimulating hormone (ICSH). Subsequently, it was realized that LH and ICSH are the same, so the common name became LH. Luteinizing Hormone (LH) LH also stimulates the synthesis of other proteins, including sterol-carrier protein (SCP) and sterol-activating protein (SAP). Sterol-carrier protein (SCP-2), contributes to the transport of cholesterol from the outer mitochondrial membrane to the inner mitochondrial membrane, where the side-chain-cleavage enzyme is located. This process is thus necessary for the first step of steroidogenesis, the synthesis of pregnenolone. The sterol-activating protein (SAP) also activates steroidogenesis. LH binds to specific high-affinity cell-surface receptors on the plasma membrane of Leydig cells. Binding to G-protein- coupled receptor stimulates membrane-bound adenylyl cyclase to form cAMP and thus activates protein kinase A (PKA). The activated PKA modulates gene transcription for the biosynthesis of testosterone. Thus, the action of LH on steroidogenesis in Leydig cells requires the synthesis of new protein. New mRNA is necessary for the synthesis of these proteins in as much as their synthesis is inhibited by the transcription inhibitor actinomycin D. The net effect of LH on Leydig cells is to stimulate the synthesis of testosterone  Follicle-Stimulating Hormone The Sertoli cells are the primary testicular site of FSH action. FSH also regulates Leydig-cell physiology via effects on Sertoli cells. Like LH, FSH binds to G-protein-coupled receptor initiates a series of reactions involving stimulation of adenylyl cyclase, increase in [cAMP]i, stimulation of PKA, transcription of specific genes, and increased protein synthesis.  Follicle-Stimulating Hormone Several proteins are synthesized in response to FSH. These include synthesis of the following: Androgen-binding protein (ABP), which is secreted into the luminal space of the seminiferous tubule, near the developing sperm cells. ABP helps keep local testosterone levels high. P-450 aromatase (P-450arom). In the Sertoli cells, this enzyme converts testosterone, which diffuses from the Leydig cells to the Sertoli cells, into estradiol (estrogen). Growth factors and other products by Sertoli cells that support sperm cells and spermatogenesis. These substances greatly increase the number of spermatogonia, spermatocytes, and spermatids in the testis. Thus, the stimulatory effect of FSH on spermatogenesis occurs via the action of FSH on Sertoli cells. FSH may also stimulate sperm motility and thus increase the fertility potential. Inhibins are produced by Sertoli. The inhibins are members of the “transforming growth factor β” (TGF-β) gene family, which also includes the antimüllerian hormone necessary for the male pattern of sexual differentiation. Inhibins are glycoprotein heterodimers consisting of one α and one β subunit that are covalently linked. The granulosa cells in the ovary and the Sertoli cells in the testis are the primary sources of inhibin in humans. Inhibins have both paracrine and endocrine actions and in the male play an important feedback role in the hypothalamic-pituitary-testicular axis. The male hypothalamic-pituitary-axis Small-bodied neurons in the arcuate nucleus and preoptic area of the hypothalamus secrete gonadotropin-releasing hormone (GnRH), a decapeptide that reaches the gonadotrophs in the anterior pituitary via the long portal veins. Stimulation by GnRH causes the gonadotrophs to synthesize and release follicle stimulating hormone (FSH) and luteinizing hormone (LH). The LH binds to receptors on Leydig cells, stimulating the transcription of proteins involved in the biosynthesis of testosterone. FSH binds to receptors on the basolateral membrane of Sertoli cells, stimulating gene transcription and protein synthesis. These proteins include androgen-binding protein, aromatase, growth factors and inhibin. Negative feedback on the hypothalamic-pituitary- (Testosterone) testicular axis occurs by two routes. First, testosterone inhibits the pulsatile release of GnRH by the hypothalamic neurons and the release of LH by the gonadotrophs in the anterior pituitary. Second, inhibin inhibits the release of FSH by the gonadotrophs in the anterior pituitary.  Cross talk between Leydig cells and Sertoli cells Sertoli cells convert testosterone-synthesized by Leydig cells to estradiol (estrogen), which then acts on the Leydig cells. Also, FSH acts on Sertoli cells to produces growth factors that may increase the number of LH receptors on Leydig cells during development and thus result in an increase in steroidogenesis (i.e., an increase in testosterone production).  Cross talk between Leydig cells and Sertoli cells Leydig- and Sertoli-cell physiology Leydig Cell Sertoli Cell The Leydig cell has receptors for LH. The binding of LH increases testosterone production by synthesizing sterol-carrier protein (SCP) and sterol- activating protein (SAP2). The Sertoli cell has receptors for FSH. The FSH promotes the synthesis of androgen-binding protein (ABP), aromatase, growth factors and inhibin. There is crosstalk between Leydig cells and Sertoli cells. The Leydig cells make testosterone, which acts on Sertoli cells. Conversely, the Sertoli cells convert some of this testosterone to estradiol (because of the presence of aromatase), which can act on the Leydig cells. Sertoli cells also generate growth factors that act on the Leydig cells. In summary: Leydig Cell Sertoli Cell  Conditions for optimal spermatogenesis For optimal spermatogenesis Leydig cells and Sertoli cells as well as two gonadotropins (LH and FSH) and one androgen (testosterone) are required. LH and Leydig cells are required to produce testosterone. LH, or rather its substitute hCG, is used therapeutically to initiate spermatogenesis in oligospermic men. FSH and Sertoli cells are important for the nursing of developing sperm cells and for the production of inhibin and growth factors, which affect the Leydig cells. Thus, FSH regulates the development of the appropriate number of Leydig cells such that adequate testosterone levels are available for spermatogenesis.  Plasma levels of FSH, LH, and testosterone from puberty to adulthood During early puberty in boys, both FSH and LH levels increase while, simultaneously, the Leydig cells proliferate and plasma levels of testosterone increase. Plasma levels of biologically active LH,FSH and of testosterone increase during puberty, expressed in terms of both the stages of puberty and bone age. FSH production is greater than that of LH during the prepubertal period, a pattern that is reversed after puberty. GnRH preferentially triggers LH release in an adult human male. This preferential release of LH may reflect maturation of the testes, which secrete inhibin, a specific inhibitor of FSH secretion at the level of the anterior pituitary gland. Increased sensitivity of the pituitary to increasing gonadal steroid production may also be responsible for the diminished secretion of FSH.  TESTOSTERONE PRODUCTION  The main sex steroid produced by both the fetal and the postnatal testis is testosterone.  Leydig cells are the source of sex-steroid production in the testes.  The testes also produce smaller quantities of dihydrotestosterone (DHT) and estradiol.  Leydig cells differentiate from mesenchymal tissue that surround the testicular cords. The early increase in the number of Leydig cells and secretion of testosterone in humans could depend on either maternal chorionic gonadotropin (hCG) or fetal luteinizing hormone (LH).  SYNTHESIS OF TESTOSTERONE  The Leydig cell uses a series of five enzymes to convert cholesterol to testosterone. Three of these enzymes are P-450 enzymes. Because 3β-hydroxysteroid dehydrogenase (3β-HSD) oxidizes the “A” ring or (cyclopentanophenanthrene ring) of four intermediates, testosterone synthesis from cholesterol can take four pathways. The "preferred" pathway is indicated below:  Testosterone synthesis begins in the mitochondria, where the cytochrome P-450 side-chain-cleavage (SCC) enzyme (also called 20,22-desmolase or P-450SCC) removes the long side chain (carbons 22 to 27) from the carbon at position 20 of the cholesterol molecule (27 carbon atoms). The rate-limiting step in the biosynthesis of testosterone, as for other steroid hormones, is the conversion of cholesterol to pregnenolone. The LH stimulates this reaction and is the primary regulator of the overall rate of testosterone synthesis by the Leydig cell. LH promotes pregnenolone synthesis by increasing the affinity of the enzyme for cholesterol and LH has long-term action in which it increases steroidogenesis in the testis by stimulating synthesis of the SCC enzyme.  In the smooth endoplasmic reticulum (SER), 17α-hydroxylase (P-450c17) then adds a hydroxyl group to pregnenolone to forming 17α-hydroxy-pregnenolone.  In the SER, the 17,20-desmolase (a different activity of the same P-450c17 whose 17α-hydroxylase activity catalyzes the previous step) removes the side chain from carbon 17 of 17α-hydroxypregnenolone. That side chain begins with carbon 20. The result is a 19-carbon steroid called dehydroepiandrosterone (DHEA).  In addition, the testis can also use 5α-reductase, which is located in the SER, to convert testosterone to dihydrotestosterone (DHT). However, it is extratesticular tissue that is responsible for most of the production of DHT. The conversion of testosterone to DHT is especially important in certain testosterone target cells.  Other organs-such as adipose tissue, skin, and the adrenal cortex also produce testosterone and other androgens. However, the Leydig cells of the testes make about 95% of the circulating testosterone. Although testosterone is the main product, the testis also secretes pregnenolone, progesterone, 17-hydroxyprogesterone, androstenedione, androsterone, and DHT. Androstenedione is a precursor for extraglandular estrogen formation. Biosynthesis of adrenal steroids and androgens Testosterone is a steroid. Below is a schematic summary of the synthesis of the adrenal steroids from cholesterol. The enzymes involved are shown in the horizontal and vertical boxes; they are located in either the smooth endoplasmic reticulum (SER), or the mitochondria. The side-chain cleavage enzyme that produces pregnenolone is also known as 20,22 desmolase. The chemical groups modified by each enzyme are highlighted in the reaction product. If the synthesis of cortisol is prevented by any one of several dysfunctional enzymes, other steroid products might be produced in excess. For example, a block in the 21α- hydroxylase will diminish production of both cortisol and aldosterone and increase production of the sex steroids. Certain of these Source: Boron & Boulpaep, Medical Physiology, 2nd Edition pathways are shared in the biosynthesis of the  Steroid and thyroid hormone receptors Receptor Full name Dimeric arrangement GR Glucocorticoid receptor GR/GR MR Mineralocorticoid MR/MR receptor Steroids PR Progesterone receptor PR/PR ER Estrogen receptor ER/ER AR Androgen receptor AR/AR VDR Vitamin D receptor VDR/RXR THR Thyroid hormone THR/RXR receptor RAR Retinoic acid receptor RAR/RXR The androgen receptor functions as a homodimer (AR/AR) and is a member of the family of nuclear receptors In contrast, the other "steroid" receptors (VDR, THR, RAR) preferentially bind to DNA as heterodimers formed with RXR, the receptor for 9-cis-retinoic acid. Thus the dimers are VDR/RXR, THR/RXR, and RAR/RXR. Interestingly, these heterodimers work even in the absence of the ligand of RXR (i.e., 9-cis-retinoic acid).  The androgen receptor Androgens diffuse into target cells and act by binding to androgen receptors, which are present in genital tissues. The androgen receptor functions as a homodimer (AR/AR) and is a member of the family of nuclear receptors The AR/AR receptor complex is a transcription factor that binds to hormone-response elements on DNA located 5' from the genes that the androgens control. Interaction between the receptor-steroid complex and nuclear chromatin causes increased transcription of structural genes, and subsequent translation and production of new proteins. Congenital absence of the androgen receptor, or the production of abnormal androgen receptor, leads to a syndrome known as testicular feminization.  Mechanism of action of testosterone and other steroid hormones Steroids hormones are synthesized from cholesterol. Only two tissues in the body possess the enzymatic apparatus to convert cholesterol to active hormones. The adrenal cortex makes cortisol (the main glucocorticoid hormone), aldosterone (the principal mineralocorticoid in humans), and androgens. The gonads make either estrogen and progesterone (ovary) or testosterone (testes). In each case, production of steroid hormones is regulated by trophic hormones released from the pituitary Steroid hormones bind to intracellular receptors that regulate gene transcription The activated steroid hormone receptor binds to specific stretches of DNA called hormone response elements or steroid response elements (SREs), thus stimulating the transcription of appropriate genes, for example heat shock protein (hsp)  Testosterone acts on target organs by binding to a nuclear receptor  Most testosterone in the circulation is bound to specific binding proteins. About 45% of plasma is bound to sex hormone-binding globulin (SHBG)-also called testosterone-binding globulin (TeBG), whereas about 55% is bound to serum albumin and corticosteroid-binding globulin (CBG).  A small fraction (2%) of the total circulating testosterone circulates free, or unbound, in plasma. It is the free form of testosterone that enters the cell by passive diffusion and subsequently exerts biologic actions or undergoes metabolism by other organs such as the prostrate, liver, and intestines. Thus, the quantity of testosterone entering a cell is determined by the plasma concentration and by the intracellular milieu of enzymes and binding proteins.  Once testosterone diffuses into the cell, it either binds to a high affinity-androgen receptor in the nucleus or is converted to DHT, which also binds to the androgen receptor. The androgen receptor functions as a homodimer (AR/AR) and is a member of the family of nuclear receptors that includes receptors for glucocorticoids, mineralocorticoids, progestins, estrogens, vitamin D, thyroid hormone, and retinoic acid.  The gene coding for the androgen receptor is located on the X chromosome. The androgen-AR complex is a transcription factor that binds to hormone response elements on DNA located 5' from the genes that the androgens control. Interaction between the androgen-AR complex and nuclear chromatin causes marked increases in transcription, ultimately leading to the synthesis of specific proteins implicated in specific cell functions like growth and development. The presence of the androgen receptor in a cell or tissue determines whether that tissue can respond to androgens.  Dihydrotestosterone In certain target tissues, cytoplasmic 5α-reductase converts testosterone to dihydrotestosterone (DHT) which binds to the same androgen receptor as testosterone. DHT binds to the androgen receptor with an affinity that is about 100-fold greater than the binding of testosterone to the androgen receptor. DHT-receptor complex binds to chromatin more tightly than does the testosterone-receptor complex.  Testosterone and the aging male  Previously, hormonal alterations in female menopause were believed to have no correlate in males. Men do experience a gradual decline in serum testosterone levels. This is closely related with many of the changes that accompany aging like decreased bone formation, muscle mass, growth of facial hair, appetite, and libido. Testosterone therapy can restore muscle and bone mass and correcting anemia.  Although testosterone decline with aging, the levels of luteinizing hormone (LH) are frequently not elevated. This finding indicates that some degree of hypothalamic-pituitary dysfunction accompanies aging. (Testosterone)  Testosterone and the aging male  Previously, hormonal alterations in female menopause were believed to have no correlate in males. Men do experience a gradual decline in serum testosterone levels. This is closely related with many of the changes that accompany aging like decreased bone formation, muscle mass, growth of facial hair, appetite, and libido. Testosterone therapy can restore muscle and bone mass and correcting anemia.  Although testosterone decline with aging, the levels of luteinizing hormone (LH) are frequently not elevated. This finding indicates that some degree of hypothalamic-pituitary dysfunction accompanies aging. Plasma testosterone versus age in human males.  Metabolism of testosterone  Testosterone is metabolized mainly in the liver and prostate. Only small amounts gets into urine without metabolism; this urinary testosterone represents less than 2% of the daily production.  The large remaining balance of testosterone and other androgens are converted in the liver to 17-ketosteroids, and in the prostate to DHT.  The degradation products of testosterone are primarily excreted in the urine as water-soluble conjugates of either sulfuric acid or glucuronic acid. These conjugated testosterone metabolites are also excreted in the feces.  Functions of androgens The male sex steroids, also known as androgens affect nearly every tissue in the body, including the brain. Testosterone is the most important androgen produced by the testes.  Androgens play two major roles in male phenotypic differentiation: 1) They trigger conversion of the wolffian ducts to the male ejaculatory system and 2) They direct the differentiation of the urogenital sinus and external genitalia.  Functions of androgens continues…  Androgens determine male secondary sexual characteristics 1) The development of both the external and the internal genitalia depends on male sex hormones. 2) Androgens stimulate adult maturation of the external genitalia and accessory sexual organs, including the penis, the scrotum, the prostate, and the seminal vesicles. 3) Androgens also determine the male secondary sexual characteristics, which include deepening of the voice, as well as evolving male patterns of hair growth. 4) The effects on the voice are a result of androgen-dependent actions on the size of the larynx, as well as the length and thickness of the vocal cords. In boys, the length of the vocal cords increases by about 50% during puberty, whereas girls have little increase in vocal cord length.  Functions of androgens continues…  Muscle development and growth are androgen-dependent processes. The biologic effects of testosterone and its metabolites are classified according to their tissue sites of action. Effects related to the growth of the male reproductive tract or development of secondary sexual characteristics are referred to as androgenic, whereas the growth-promoting effects on somatic tissue are called anabolic. These androgenic and anabolic effects are two independent biologic actions of the same class of steroids. However, these responses are organ specific and the same molecular mechanisms initiate androgenic responses and anabolic activity.  Disorders related to androgen deficiency  Feminization syndrome: Testicular descent is an androgen-dependent process, and development of the structures involved in testicular descent is dependent on testosterone. In testosterone-deficient states caused by inadequate secretion or disordered androgen action, the testes of genetic males often fail to descend. This abnormality can be seen in individuals with both 5α-reductase deficiency and complete androgen resistance (i.e., testicular feminization syndrome).  Disorders related to androgen deficiency continues… Testicular descend During the final month of fetal life, the testes descend into an integumentary pouch called the scrotum. Because the internal temperature of the testicle must be closely regulated for optimum function, localization of the testes within the scrotum is a necessary adaptation for optimal testicular function. An abnormal retention of the testes in the abdominal cavity (cryptorchidism) causes severe damage to the seminiferous tubules and diminished testicular function.  Disorders related to androgen deficiency continues… Testicular descent occurs in three phases during the last two thirds of gestation. Phase-3 In the third stage, the gubernaculum acquires a similar Phase-2 diameter as the testis. As its Phase-1 During the second stage there is proximal portion degenerates, the During the first stage, the herniation of the abdominal wall gubernaculum draws the testis testes move down to the to the gubernaculum. into the scrotum through the inguinal region. (Herination = protrude through an abnormal processus vaginalis. opening). Gubernaculum = Ligament attaching the lower part of the testes to the labioscrotal fold. Source: Boron & Boulpaep, Medical Physiology, 2nd Edition In testosterone-deficient states caused by inadequate secretion or disordered androgen action, the testes of genetic males often fail to descend.  Functions of androgens continues…  Male pseudohermaphroditism: Any defect in the mechanisms by which androgens act on target tissues in genotypic males may lead to a syndrome of male pseudohermaphroditism. Affected individuals have a normal male karyotype (46, XY) and unambiguous and clearly distinct male gonads, but ambiguous external genitalia or may phenotypically appear as females.  Functions of androgens continues… 5α-reductase deficiency: The activity of 5α-reductase is necessary for the conversion of testosterone to dihydrotestosterone (DHT). DHT-dependent development may not occur (e.g., male-pattern development of the urogenital sinus and external genitalia). This disorder is transmitted as an autosomal recessive gene that is phenotypically manifested only in genetic males. At birth, these children have ambiguous genitalia, with a blind vaginal pouch and a small phallus that is bound ventrally and covered by a hood; they also have hypospadias (i.e., the urethral orifice is located too low on the undersurface of the penis). Hypospadias: Developmental anomaly in which the urethra opens inferior to its usual location; usually seen in males with the opening on the underside of the penis Influence of autonomic nerves on the male genital system  Neuronal control of the male genital system The sympathetic and parasympathetic divisions of the autonomic nervous system control the male genital system. The testes, epididymis, male accessory glands, and erectile tissue of the penis receive dual innervation from the sympathetic and parasympathetic branches of the autonomic nervous system (ANS). The penis also receives both somatic efferent (i.e., motor) and afferent (i.e., sensory) innervation through the pudendal nerve.  Neuronal control of the male genital system……..  The major efferent (i.e., motor) pathways for the regulation of penile erection are: i) parasympathetic (pelvic nerve), ii) sympathetic (right and left hypogastric nerves), and iii) somatic (pudendal nerve). Source: Boron & Boulpaep, Medical Physiology, 2nd Edition  Erection is controlled mainly by the parasympathetic system The corpora cavernosa and the corpus spongiosum coordinate erection (i.e., tumescence) and detumescence. During erection, relaxation of the smooth muscles of the corpora allows increased inflow of blood to fill the corporal space, resulting in an increase in volume and rigidity. In erectile tissue, parasympathetic postganglionic terminals release acetylcholine (ACh) and nitric oxide. ACh binds to M3-muscarinic receptors on endothelial cells. Through Gαq, these receptors would stimulate PLC, increased [Ca2+]i, activation of nitric oxide synthase (NOS), and local release of nitric oxide (NO). Source: Boron & Boulpaep, Medical Physiology, 2nd Edition  Erection is controlled mainly by the parasympathetic system The corpora cavernosa and the corpus spongiosum coordinate erection (i.e., tumescence) and detumescence. During erection, relaxation of the smooth muscles of the corpora allows increased inflow of blood to fill the corporal space, resulting in an increase in volume and rigidity. In erectile tissue, parasympathetic postganglionic terminals release acetylcholine (ACh) and nitric oxide. ACh binds to M3 muscarinic receptors on endothelial cells. Through Gαq, these receptors would stimulate PLC, increased [Ca2+]i, activation of nitric oxide synthase, and local release of nitric oxide (NO). Source: Boron & Boulpaep, Medical Physiology, 2nd Edition The nerve terminals may also directly release NO. Regardless of the source, NO diffuses to the vascular smooth muscle cell, where it stimulates soluble guanylyl cyclase (sGC) to generate cyclic guanosine monophosphate (cGMP), which, in turn, causes vasodilation.  Sympathetic control of erection Tonic sympathetic activity contributes to penile flaccidity. During erection, a decrease in this sympathetic tone allows relaxation of the corpora and thus contributes to tumescence. Source: Boron & Boulpaep, Medical Physiology, 2nd Edition  Somatic control of erection Somatic (i.e., not autonomic) fibers, also innervates the striated penile muscles. Contraction of the striated ischiocavernosus muscle during the final phase of erection increases pressure inside the corpora cavernosa to values that are even higher than systemic arterial pressure. Contraction of the striated bulbospongiosus muscle increases engorgement of the corpus spongiosum, and thus the glans penis, by pumping blood up from the penile bulb underlying this muscle. Humans are less dependent on striated penile muscle for achieving and maintaining erection. Source: Boron & Boulpaep, Medical Physiology, 2nd Edition However, these muscles are active during ejaculation and contribute to the force of seminal expulsion.  Erectile dysfunction  It is the inability to develop or maintain an erection during sexual act.  Sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis) are oral medications used to treat erectile dysfunction. Men with erectile dysfunction experience significant improvement in rigidity and duration of erections after treatment with these medications.  These drugs potentiate the relaxation of penile smooth muscles (corpus cavernosum) by preventing the degradation of cGMP. The smooth muscle tone of corpus cavernosum is regulated by nitric oxide, which increases the concentration of cGMP, thereby relaxing and dilating the smooth muscle, leading to erection. Breakdown of cGMP by cGMP-specific phosphodiesterase type-5 limits the degree of vasodilation and, in the case of the penis, limits erection. Sildenafil, vardenafil, and tadalafil are highly selective, high-affinity inhibitors of cGMP-specific phosphodiesterase type-5 and thereby raise [cGMP]i in smooth muscle and improve erection in men with erectile dysfunction.  One of the side effects of sildenafil is "blue vision," a consequence of the effect of inhibiting cGMP-specific phosphodiesterase in the retina.  In women, sildenafil may improve sexual function by increasing blood flow to the accessory secretory glands. Seminal emission is primarily under sympathetic control Seminal emission refers to movement of the ejaculate into the prostatic or proximal part of the urethra. Under some conditions, seminal fluid escapes episodically or continuously from the penile urethra; this action is also referred to as emission. Emission is the result of peristaltic contractions of the ampullary portion of the vas deferens, the seminal vesicles, and the prostatic smooth muscles. These actions are accompanied by constriction of the internal sphincter of the bladder, which is under sympathetic control, thus preventing retrograde ejaculation of sperm into the urinary bladder.  Ejaculatory Dysfunction Seminal emission refers to movement of the ejaculate into the prostatic or proximal part of the urethra. Emission is normally accompanied by constriction of the internal urethral sphincter. Retrograde ejaculation occurs when this sphincter fails to constrict, causing semen to enter the urinary bladder rather than passing down the urethra. Retrograde ejaculation should be suspected in patients who report absent or small-volume ejaculation after orgasm. The presence of more than 15 sperm per high-power field in urine specimens obtained after ejaculation confirms the presence of retrograde ejaculation.  Ejaculatory Dysfunction… Lack of emission or retrograde ejaculation may result from any process that interferes with the innervation of the vas deferens and bladder neck. Several medical illnesses, such as diabetes mellitus (which can cause peripheral neuropathy) and multiple sclerosis, or the use of medications that interfere with sympathetic tone can lead to retrograde ejaculation. Retrograde ejaculation may also occur as a result of nerve damage associated with certain surgical procedures, including bladder neck surgery, trans-urethral resection of the prostate, colorectal surgery, and retroperitoneal lymph node dissection.  Ejaculatory Dysfunction….. Treatment Strategies: Retrograde ejaculation from causes other than surgery involving the bladder neck may be treated with pharmacological therapy. Sympathomimetic drugs such as phentolamine (an α-adrenergic antagonist), ephedrine (which enhances norepinephrine release), and imipramine (which inhibits norepinephrine re-uptake by presynaptic terminals) may promote normal (i.e., anterograde) ejaculation by increasing the tone of the vas deferens (propelling the seminal fluid) and the internal sphincter (preventing retrograde movement).