# Lecture 1: Male Reproductive Anatomy and Physiology ## Unit 2.4: Reproductive System --- ## Learning Objectives By the end of this lecture, students will be able to: 1. Describe the gross and microscopic anatomy of the male reproductive system 2. Explain the hypothalamic-pituitary-gonadal axis in males 3. Describe spermatogenesis and sperm maturation 4. Explain testosterone synthesis, transport, and actions 5. Describe the physiology of erection and ejaculation 6. Explain the hormonal regulation of male reproduction --- ## Lecture Outline ### I. Male Reproductive Anatomy - Overview The male reproductive system comprises the testes, a system of ducts, accessory glands, and the external genitalia. Understanding this anatomy provides the foundation for comprehending both normal reproductive physiology and the pathophysiology of common disorders including infertility, hypogonadism, and erectile dysfunction. The principal components of the male reproductive system serve distinct but integrated functions. The testes are the primary reproductive organs, responsible for both spermatogenesis (exocrine function) and testosterone production (endocrine function). The epididymis, a highly coiled tube adjacent to each testis, provides the environment for sperm maturation and storage. The vas deferens (ductus deferens) transports mature sperm from the epididymis to the ejaculatory duct during emission. The seminal vesicles contribute the majority of seminal fluid volume, providing fructose as an energy source for sperm and prostaglandins that may facilitate transport in the female tract. The prostate gland surrounds the prostatic urethra and contributes alkaline fluid containing zinc, citric acid, and prostate-specific antigen (PSA), which liquefies the semen after ejaculation. The bulbourethral (Cowper's) glands produce pre-ejaculate that lubricates and neutralizes urethral acidity before ejaculation. The penis serves as the organ of copulation and urination. Testicular anatomy reflects the organ's dual functions. The testes are located in the scrotum, which maintains them at a temperature 2-4°C below core body temperature—essential for normal spermatogenesis. Each testis measures approximately 4 × 3 × 2.5 cm with a volume of approximately 20 mL; volumes below 15 mL suggest testicular atrophy or hypoplasia. The tunica albuginea, a dense fibrous capsule, covers each testis and sends septa inward to divide the parenchyma into approximately 250 lobules, each containing 1-4 seminiferous tubules. Testicular descent from the abdomen to the scrotum normally occurs by 32-36 weeks of gestation; failure of descent (cryptorchidism) impairs spermatogenesis and increases the risk of testicular cancer. The blood supply to the testes has important clinical implications. The testicular arteries arise directly from the abdominal aorta, reflecting the testes' embryologic origin as intra-abdominal organs. Venous drainage forms the pampiniform plexus, a network of veins surrounding the testicular artery that functions as a countercurrent heat exchanger to cool arterial blood before it enters the testis. The right testicular vein drains directly into the inferior vena cava, while the left testicular vein drains into the left renal vein at a right angle. This anatomic difference explains why varicoceles (dilated veins of the pampiniform plexus) are far more common on the left side, where the venous drainage is less direct. Panel A: Sagittal view of the male reproductive system showing testes in scrotum, epididymis, vas deferens ascending through inguinal canal, seminal vesicles and prostate posterior to bladder, and penis with corpora cavernosa and corpus spongiosum. Panel B: Testicular cross-section displaying tunica albuginea, septa, lobules containing seminiferous tubules, and rete testis. Panel C: Blood supply illustration with testicular arteries from aorta and pampiniform plexus surrounding arteries. Panel D: Venous drainage comparison showing asymmetric pattern with right testicular vein to IVC and left testicular vein to renal vein at 90-degree angle. --- ### II. Testicular Histology The microscopic anatomy of the testis reveals two distinct functional compartments: the seminiferous tubules where spermatogenesis occurs, and the interstitial tissue containing the testosterone-producing Leydig cells. Understanding this histology is essential for interpreting semen analysis abnormalities and hormonal patterns in male hypogonadism. The seminiferous tubules comprise approximately 90% of testicular volume and represent the site of spermatogenesis. Each testis contains approximately 250 meters of seminiferous tubules when uncoiled. The tubular epithelium contains two cell types: Sertoli cells and germ cells at various stages of development. The tubules converge into the rete testis, a network of channels at the testicular mediastinum, which drains into the efferent ductules leading to the epididymis. The tubular lumen contains mature spermatozoa and the fluid secreted by Sertoli cells. Sertoli cells are the essential supporting cells of spermatogenesis. These tall columnar cells extend from the basement membrane to the tubular lumen, creating a scaffold within which germ cells develop. Sertoli cells form tight junctions with each other near their bases, creating the blood-testis barrier that divides the tubular epithelium into basal and adluminal compartments. This barrier protects developing germ cells, which express unique antigens after meiosis, from immune attack. Sertoli cells provide structural support and nutritional factors for developing germ cells, phagocytose excess cytoplasm discarded during spermiogenesis, secrete fluid that transports sperm to the rete testis, and produce several important proteins. Inhibin B provides negative feedback specifically to FSH at the pituitary. Androgen-binding protein (ABP) concentrates testosterone within the tubule. Anti-Müllerian hormone (AMH), while primarily important in fetal development, remains a marker of Sertoli cell function. FSH is the primary regulator of Sertoli cell activity. The blood-testis barrier has both immunological and physiological importance. The tight junctions between adjacent Sertoli cells create one of the tightest barriers in the body. The basal compartment, below the barrier, contains spermatogonia (which share antigens with somatic cells and are not immunogenic). The adluminal compartment, above the barrier, contains meiotic and post-meiotic germ cells that express novel antigens. This segregation explains why autoimmune orchitis can develop after testicular trauma or infection when the barrier is breached, and why testicular tumors can evade immune surveillance. Leydig cells (interstitial cells) occupy the spaces between seminiferous tubules and produce testosterone. These cells are characterized histologically by abundant smooth endoplasmic reticulum and lipid droplets, consistent with their role in steroid hormone synthesis. Leydig cells may also contain distinctive Reinke crystals, eosinophilic cytoplasmic inclusions of uncertain function. LH from the anterior pituitary is the primary stimulator of Leydig cell steroidogenesis. Each pulse of LH triggers a corresponding pulse of testosterone secretion. Panel A: Cross-section of seminiferous tubule showing Sertoli cells extending from basement membrane to lumen with columnar shape and pale nuclei. Panel B: Germ cells at various developmental stages arranged from base to lumen including spermatogonia, primary spermatocytes, secondary spermatocytes, spermatids, and spermatozoa. Panel C: Tight junctions between Sertoli cells demonstrating blood-testis barrier dividing basal and adluminal compartments. Panel D: Interstitial space with Leydig cell clusters showing eosinophilic cytoplasm and lipid droplets, plus inset of Sertoli cell secretions including inhibin B, ABP, and fluid. --- ### III. Hypothalamic-Pituitary-Gonadal Axis The hypothalamic-pituitary-gonadal (HPG) axis regulates male reproductive function through a hierarchical system of hormonal signals and feedback loops. Understanding this axis is essential for interpreting hormonal laboratory findings and for understanding the mechanism of hormonal therapies used in treating hypogonadism, infertility, and prostate cancer. The hierarchy of the HPG axis proceeds from hypothalamus to pituitary to testes. The hypothalamus secretes gonadotropin-releasing hormone (GnRH), which stimulates the anterior pituitary gonadotrophs to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH acts on Leydig cells to stimulate testosterone production, while FSH acts on Sertoli cells to support spermatogenesis. Testosterone and inhibin B complete the circuit by providing negative feedback to the hypothalamus and pituitary. GnRH secretion has critical characteristics that determine its physiological effects. GnRH is a decapeptide secreted by hypothalamic neurons whose cell bodies reside in the arcuate nucleus and whose axons terminate in the median eminence. The crucial feature of GnRH secretion is its pulsatility: GnRH is released in discrete pulses every 60-120 minutes. This pulsatile pattern is essential for maintaining gonadotroph responsiveness; continuous GnRH exposure causes receptor downregulation and paradoxically suppresses LH and FSH release. This phenomenon is exploited therapeutically: GnRH agonists (such as leuprolide) initially stimulate but then suppress the axis when given continuously, providing medical castration for prostate cancer treatment. LH (luteinizing hormone) specifically targets Leydig cells to stimulate testosterone synthesis. LH binds to G protein-coupled receptors on Leydig cells, activating adenylyl cyclase and increasing intracellular cAMP. This signaling cascade increases the expression of steroidogenic enzymes and enhances cholesterol transport into mitochondria via the steroidogenic acute regulatory protein (StAR). LH secretion occurs in pulses that mirror GnRH pulsatility. Testosterone provides negative feedback by suppressing both hypothalamic GnRH release and pituitary LH secretion. FSH (follicle-stimulating hormone) specifically targets Sertoli cells to support spermatogenesis. FSH is essential for the initiation of spermatogenesis at puberty, and while spermatogenesis can continue with testosterone alone in adults, FSH significantly increases sperm production. FSH stimulates Sertoli cell production of androgen-binding protein, which maintains high intratubular testosterone concentrations essential for spermatogenesis. Inhibin B, produced by Sertoli cells in proportion to spermatogenic activity, specifically suppresses FSH secretion without affecting LH. This selective feedback allows FSH to respond to spermatogenic function independently of testosterone levels. Negative feedback in the HPG axis operates through multiple pathways. Testosterone acts at both the hypothalamus (suppressing GnRH pulse frequency) and the pituitary (reducing gonadotroph sensitivity to GnRH). Interestingly, testosterone's hypothalamic effects are largely mediated by its conversion to estradiol by aromatase in the brain; estradiol is a more potent suppressor of GnRH than testosterone itself. Inhibin B selectively suppresses FSH at the pituitary level. This dual feedback allows the axis to independently regulate testosterone production (via LH) and spermatogenesis (via FSH). Panel A: Three-tier HPG axis hierarchy showing hypothalamus with GnRH neurons in arcuate nucleus, median eminence, and graph of pulsatile GnRH secretion. Panel B: Anterior pituitary with gonadotroph cells releasing LH and FSH, and testes showing Leydig cells producing testosterone and Sertoli cells producing inhibin B. Panel C: Negative feedback loops with testosterone feeding back to hypothalamus and pituitary, including aromatization to estradiol, and inhibin B specifically targeting FSH. Panel D: Comparison of pulsatile versus continuous GnRH administration effects on LH release demonstrating importance of pulsatility. --- ### IV. Testosterone Synthesis and Metabolism Testosterone is the principal androgen produced by the testes, responsible for masculinization during fetal development, pubertal maturation, and maintenance of male secondary sex characteristics and reproductive function throughout life. Understanding its synthesis pathway, transport, and peripheral metabolism is essential for interpreting hormonal assays and understanding disorders of androgen production and action. The synthesis pathway for testosterone proceeds from cholesterol through a series of enzymatic steps in Leydig cells. The rate-limiting step is the transport of cholesterol from the outer to inner mitochondrial membrane, mediated by StAR (steroidogenic acute regulatory protein), which is upregulated by LH signaling. Once inside the mitochondrion, CYP11A1 (cholesterol side-chain cleavage enzyme) converts cholesterol to pregnenolone. Pregnenolone exits the mitochondrion and is converted to progesterone by 3β-hydroxysteroid dehydrogenase (3β-HSD) in the smooth endoplasmic reticulum. CYP17 (17α-hydroxylase/17,20-lyase) then converts progesterone to androstenedione, and 17β-hydroxysteroid dehydrogenase (17β-HSD) catalyzes the final step to testosterone. Alternative pathways through dehydroepiandrosterone (DHEA) exist but are less prominent in the testis. Testosterone circulates in blood predominantly bound to carrier proteins. Only approximately 2% of circulating testosterone is free and immediately bioavailable to tissues. Approximately 45% is bound with high affinity to sex hormone-binding globulin (SHBG), and this tightly bound fraction is generally considered unavailable for tissue uptake. Approximately 53% is bound more loosely to albumin, and this fraction can dissociate and become available to tissues. The concept of "bioavailable testosterone" encompasses both free and albumin-bound fractions. SHBG levels are increased by estrogens, hyperthyroidism, liver disease, and aging, and decreased by androgens, obesity, insulin resistance, and hypothyroidism. Changes in SHBG can significantly affect free testosterone levels even when total testosterone remains stable. Peripheral metabolism of testosterone produces two important derivatives with distinct biological activities. 5α-reductase converts testosterone to dihydrotestosterone (DHT), which is 2-3 times more potent than testosterone at the androgen receptor. 5α-reductase exists in two isoforms: type 1 is present in skin and liver, while type 2 predominates in prostate, seminal vesicles, and hair follicles. DHT is responsible for development of the external genitalia during fetal life, prostate growth, sebum production, and androgen-dependent hair patterns. Aromatase (CYP19) converts testosterone to estradiol in various tissues including adipose tissue, brain, and bone. Estradiol is essential for epiphyseal fusion (which is why men with aromatase deficiency continue growing and develop eunuchoid proportions), bone mineral density maintenance, and negative feedback on GnRH secretion. The liver inactivates testosterone through glucuronidation and sulfation, producing metabolites excreted in urine. DHT has particularly important clinical implications. Because DHT is more potent than testosterone and is the primary androgen in prostate tissue, DHT-mediated signaling drives benign prostatic hyperplasia (BPH). 5α-reductase inhibitors (finasteride, dutasteride) reduce DHT levels and are effective treatments for BPH. Similarly, androgenetic alopecia (male pattern baldness) is driven by DHT action on hair follicles, and finasteride is also used to treat this condition. 5α-reductase type 2 deficiency causes a disorder of sexual development in which affected 46,XY individuals have female-appearing external genitalia at birth (since DHT is required for male external genital development) but virilize at puberty when rising testosterone levels partially compensate. Panel A: Testosterone synthesis pathway in Leydig cells showing cholesterol transport by StAR into mitochondria with sequential enzyme actions of CYP11A1, 3beta-HSD, CYP17, and 17beta-HSD. Panel B: Testosterone transport pie chart displaying circulating forms as 2% free, 45% SHBG-bound, and 53% albumin-bound with factors affecting SHBG levels. Panel C: Peripheral metabolism via 5alpha-reductase converting testosterone to DHT in prostate, hair follicles, and skin with type 1 and 2 isoform distributions. Panel D: Aromatase conversion of testosterone to estradiol in adipose, brain, and bone with clinical applications of 5alpha-reductase inhibitors and aromatase inhibitors noted. --- ### V. Testosterone Actions Testosterone exerts its effects through the androgen receptor, a nuclear receptor transcription factor. Understanding the mechanism of androgen action and the tissue-specific effects of testosterone explains both normal male physiology and the clinical manifestations of androgen deficiency and excess. The mechanism of action of testosterone follows the classical nuclear receptor pathway. Testosterone, being lipophilic, crosses the plasma membrane and enters target cells. In tissues expressing 5α-reductase, testosterone is converted to DHT, which has higher affinity for the androgen receptor. Either testosterone or DHT binds to the androgen receptor (AR), a member of the nuclear receptor superfamily. Upon ligand binding, the receptor undergoes conformational changes, dissociates from heat shock proteins, and translocates to the nucleus. In the nucleus, the activated receptor dimerizes and binds to androgen response elements (AREs) in the promoter regions of target genes, recruiting coactivators and the transcriptional machinery to activate or repress gene expression. The effects of androgen action therefore require time for transcription and translation, explaining the relatively slow onset of testosterone's effects. Developmental effects of androgens are essential for male sexual differentiation. During fetal development, testosterone produced by the fetal Leydig cells drives differentiation of the Wolffian ducts into the epididymis, vas deferens, and seminal vesicles. Testosterone conversion to DHT by 5α-reductase type 2 is required for development of the prostate and male external genitalia (penis, scrotum). Anti-Müllerian hormone (AMH) from fetal Sertoli cells causes regression of the Müllerian ducts, preventing female internal reproductive tract development. At puberty, rising testosterone levels trigger the development of secondary sex characteristics. Tissue-specific effects of testosterone reflect both direct androgen receptor activation and peripheral metabolism. In skeletal muscle, testosterone increases protein synthesis and muscle mass, which is why anabolic steroids are misused by athletes and bodybuilders. In bone, androgens (primarily through aromatization to estradiol) increase bone mineral density; estradiol is also responsible for epiphyseal fusion, determining final adult height. In skin, androgens stimulate sebaceous gland activity and influence hair growth patterns: stimulating terminal hair development on the face, chest, and pubic area while potentially causing hair follicle miniaturization on the scalp (androgenetic alopecia) through DHT action. In the larynx, androgens cause thickening of the vocal cords, resulting in voice deepening. Sexual function depends on adequate testosterone for libido and often for normal erections. In the bone marrow, testosterone stimulates erythropoietin production and directly enhances erythropoiesis, explaining the higher hemoglobin levels in men compared to women. Effects on the brain include mood regulation, cognitive function, and spatial ability. Metabolic effects of testosterone include anabolic effects on protein metabolism, favorable effects on body composition (decreasing fat mass and increasing lean mass), and complex effects on lipid profiles. At physiological levels, testosterone may have neutral or slightly beneficial effects on cardiovascular risk. However, supraphysiological doses (anabolic steroid abuse) decrease HDL cholesterol and may increase cardiovascular risk. Testosterone improves insulin sensitivity and glucose metabolism, which is why hypogonadal men have increased risk of metabolic syndrome and type 2 diabetes. Panel A: Molecular mechanism showing testosterone or DHT binding to cytoplasmic androgen receptor, conformational change, nuclear translocation, dimerization, and binding to ARE for gene transcription. Panel B: Body diagram of tissue-specific effects including muscle hypertrophy, bone density via estradiol, skin sebum and hair patterns, larynx vocal cord thickening, brain libido and mood, and bone marrow erythropoiesis. Panel C: Developmental timeline showing fetal Wolffian duct differentiation and external genitalia via DHT, and pubertal secondary sex characteristics with growth spurt. Panel D: Adult maintenance of male phenotype with indicators for testosterone-mediated, DHT-mediated, and estradiol-mediated effects. --- ### VI. Spermatogenesis Spermatogenesis is the process by which male germ cells undergo mitotic and meiotic divisions to produce haploid spermatozoa. This highly organized process occurs within the seminiferous tubules over approximately 64 days and produces approximately 200 million sperm daily. Understanding spermatogenesis is essential for evaluating male infertility and for understanding the mechanism of hormonal male contraception. The overview of spermatogenesis establishes its spatial and temporal organization. Spermatogenesis occurs exclusively within the seminiferous tubules, supported by Sertoli cells. The process requires temperatures 2-4°C below core body temperature, explaining why cryptorchid testes fail to produce mature sperm. A complete cycle of spermatogenesis—from spermatogonial stem cell division to release of mature spermatozoa—takes approximately 64 days in humans. Because multiple stages of development occur simultaneously at any given location in the tubule, the cycle of the seminiferous epithelium (one complete set of cellular associations at a single site) takes approximately 16 days, and about four cycles are required for complete spermatogenesis. Spermatogenesis proceeds through distinct stages. Spermatogonia are the diploid stem cells at the base of the seminiferous epithelium, adjacent to the basement membrane. Type A dark (Ad) spermatogonia are reserve stem cells that divide rarely, maintaining the stem cell pool. Type A pale (Ap) spermatogonia are actively dividing cells that either self-renew or differentiate into type B spermatogonia. Type B spermatogonia are committed to differentiation and give rise to primary spermatocytes. Primary spermatocytes are the largest germ cells and undergo meiosis I. During prophase I, homologous chromosomes pair and undergo crossing over (genetic recombination), generating genetic diversity. Meiosis I produces secondary spermatocytes, which are haploid for chromosomes but still contain sister chromatids. Secondary spermatocytes rapidly undergo meiosis II, separating sister chromatids to produce spermatids. Each primary spermatocyte thus produces four haploid spermatids. Meiosis in spermatogenesis has crucial features distinguishing it from oogenesis. Meiosis I reduces the chromosome number from diploid (46 chromosomes, 2n) to haploid (23 chromosomes, n), though each chromosome still consists of two sister chromatids joined at the centromere. Crossing over during prophase I of meiosis I exchanges genetic material between homologous chromosomes, ensuring that each sperm is genetically unique. Meiosis II separates sister chromatids, producing cells with 23 single chromosomes. Unlike oogenesis, where three products (polar bodies) degenerate, all four products of male meiosis develop into functional spermatozoa. Also unlike oogenesis, which arrests twice during development, spermatogenesis proceeds continuously from puberty onward. Spermiogenesis is the dramatic morphological transformation of round spermatids into mature spermatozoa, occurring without any further cell division. The acrosome, a specialized lysosome-like organelle, forms from the Golgi apparatus and caps the anterior nucleus; it contains enzymes (hyaluronidase, acrosin) essential for penetrating the egg investments during fertilization. The flagellum (tail) develops from the centriole, growing into the characteristic 9+2 microtubule arrangement of the axoneme. Mitochondria arrange helically around the proximal flagellum to form the midpiece, providing ATP for motility. The nucleus condenses dramatically, with histones replaced by protamines to create a compact, hydrodynamic shape. Excess cytoplasm is shed as the residual body and phagocytosed by Sertoli cells. Spermiation is the release of mature spermatozoa from Sertoli cells into the tubular lumen. Panel A: Cross-section of seminiferous epithelium showing spermatogonia types Ad, Ap, and B at basement membrane, primary spermatocytes in prophase with crossing over, secondary spermatocytes, round spermatids, and elongating spermatids with 64-day timeline. Panel B: Meiosis diagram showing 2n primary spermatocyte dividing to two n secondary spermatocytes then to four n spermatids. Panel C: Spermiogenesis transformation from round spermatid to mature sperm with acrosome formation from Golgi and flagellum development from centriole. Panel D: Final sperm maturation showing mitochondrial arrangement, nuclear condensation, cytoplasm shedding, and mature spermatozoa release at tubular lumen. --- ### VII. Sperm Structure and Maturation The mature spermatozoon is a highly specialized cell designed for a single purpose: delivering the male genome to the oocyte. Understanding sperm structure explains the results of semen analysis parameters, while understanding the maturation process explains why epididymal dysfunction can cause infertility. Sperm structure reflects extreme specialization for motility and fertilization. The head, approximately 5 μm long and 3 μm wide, contains the highly condensed haploid nucleus with the male genetic contribution. The acrosome, covering the anterior two-thirds of the head, is bounded by inner and outer acrosomal membranes and contains digestive enzymes including hyaluronidase (which disperses cells of the corona radiata) and acrosin (a protease that creates a path through the zona pellucida). The midpiece, approximately 5 μm long, contains the mitochondria arranged in a tight helix around the axoneme; these mitochondria provide ATP for flagellar beating. The tail (principal piece and end piece) comprises approximately 45 μm of the total 55 μm sperm length. The axoneme running through the tail has the classic 9+2 microtubule arrangement: nine peripheral doublet microtubules surrounding two central singlet microtubules, with dynein arms providing the force for flagellar bending. The acrosome reaction is essential for successful fertilization. When sperm reach the egg, they first bind to the zona pellucida through receptors on the sperm head. This binding triggers the acrosome reaction: fusion of the outer acrosomal membrane with the sperm plasma membrane and exocytosis of acrosomal contents. The enzymes released digest a path through the zona pellucida, and the inner acrosomal membrane becomes the leading surface as the sperm penetrates toward the oocyte. Sperm that have prematurely undergone the acrosome reaction cannot fertilize, explaining why prolonged exposure to capacitating conditions eventually renders sperm infertile. Epididymal maturation is required for sperm to acquire fertilizing ability. Sperm leaving the testis are immotile and incapable of fertilization. During the approximately 12 days of transit through the 6-meter length of the epididymis, sperm undergo significant changes. Surface proteins are modified, including the addition of proteins secreted by the epididymal epithelium. The plasma membrane lipid composition changes, including increased cholesterol content, which stabilizes the membrane against premature acrosome reaction. Motility capacity develops, though sperm remain quiescent in the epididymis. The cauda (tail) of the epididymis serves as the storage site for mature sperm, which can remain viable there for several weeks. Capacitation is the final functional maturation step, occurring in the female reproductive tract. Ejaculated sperm cannot fertilize immediately; they require several hours (approximately 7 hours in humans) of exposure to the female tract environment. Capacitation involves removal of cholesterol from the sperm membrane (increasing fluidity and preparing for the acrosome reaction), loss of decapacitation factors present in seminal plasma, increased intracellular calcium, and hyperactivation of motility characterized by vigorous, whip-like flagellar beating. Only capacitated sperm can undergo the acrosome reaction in response to zona pellucida binding. This timing mechanism helps ensure that sperm are optimally prepared when they encounter the egg. Panel A: Detailed sperm anatomy showing head with condensed nucleus and acrosome membranes, midpiece with mitochondrial helix surrounding axoneme, and tail with 9+2 microtubule cross-section, total length approximately 55 micrometers. Panel B: Acrosome reaction sequence depicting zona binding, membrane fusion, enzyme release, zona penetration, and inner acrosomal membrane contact with oocyte. Panel C: Maturation pathway showing testicular sperm as immotile and not fertilizable, then epididymal transit over 12 days with protein modification and cholesterol addition. Panel D: Capacitation in female tract over approximately 7 hours showing cholesterol removal, hyperactivation, and acrosome reaction priming. --- ### VIII. Accessory Glands and Semen The accessory glands of the male reproductive system—seminal vesicles, prostate, and bulbourethral glands—contribute the fluid component of semen. Understanding their secretions and the composition of normal semen is essential for interpreting semen analysis in the evaluation of male infertility. The seminal vesicles are paired glands located posterior to the bladder that contribute 60-70% of semen volume. Despite their name, they do not store sperm. Their secretion is alkaline and contains fructose (the primary energy source for ejaculated sperm), prostaglandins (which may facilitate sperm transport and modulate the female immune response), and fibrinogen-like proteins (semenogelin and fibronectin) that cause semen to coagulate immediately after ejaculation. The seminal vesicles are androgen-dependent, and their secretions are reduced in hypogonadism. Fructose measurement in semen is used to assess seminal vesicle function; absence of fructose with azoospermia and low semen volume suggests congenital bilateral absence of the vas deferens (often associated with CFTR mutations). The prostate gland surrounds the prostatic urethra immediately below the bladder and contributes 20-30% of semen volume. The prostate is divided into zones: the peripheral zone (70% of glandular tissue, site of most prostate cancers), central zone (25%, surrounding the ejaculatory ducts), and transitional zone (5%, surrounding the prostatic urethra, site of benign prostatic hyperplasia). Prostatic secretions include citric acid (a buffer), zinc (antibacterial, stabilizes sperm DNA), acid phosphatase (function unclear), and prostate-specific antigen (PSA). PSA is a serine protease that liquefies the semen clot by degrading the seminal vesicle proteins, allowing sperm to become motile; liquefaction normally occurs within 20-30 minutes of ejaculation. The bulbourethral (Cowper's) glands are pea-sized glands at the base of the penis that produce pre-ejaculate. This clear, mucoid secretion lubricates the urethra and neutralizes any residual urinary acidity before ejaculation. Pre-ejaculate may contain sperm (particularly if ejaculation has recently occurred), which is relevant to discussions of withdrawal as a contraceptive method. Semen composition and normal parameters are assessed by semen analysis. Normal ejaculate volume is 2-5 mL; low volume suggests incomplete collection, retrograde ejaculation, ejaculatory duct obstruction, or seminal vesicle dysfunction. Normal sperm concentration is greater than 15 million per mL (oligozoospermia if lower, azoospermia if absent). Total sperm count should exceed 39 million per ejaculate. Progressive motility (sperm moving forward) should be at least 32%, with total motility above 40% (asthenozoospermia if reduced). Normal morphology is defined as at least 4% morphologically normal sperm by strict criteria (teratozoospermia if reduced). Semen pH is normally 7.2-8.0, and the sample should liquefy within 60 minutes. White blood cells should be fewer than 1 million per mL (leukocytospermia suggests infection or inflammation). Panel A: Anatomical location of accessory glands showing seminal vesicles paired posterior to bladder, prostate surrounding prostatic urethra with peripheral, central, and transitional zones, and bulbourethral glands at penile base. Panel B: Gland secretion table with seminal vesicles contributing fructose, prostaglandins, and clotting proteins, and prostate contributing PSA, citric acid, zinc, and acid phosphatase. Panel C: Bulbourethral gland secretions of mucus and alkaline fluid, with volume contributions from each gland indicated. Panel D: Normal semen analysis parameters including volume, concentration, total count, motility, morphology, pH, and liquefaction time with abnormality terms oligozoospermia and asthenozoospermia. --- ### IX. Erection and Ejaculation Penile erection and ejaculation are neurovascular events requiring coordinated parasympathetic, sympathetic, and somatic nervous system activity. Understanding the physiology of erection, particularly the nitric oxide-cGMP pathway, explains both erectile dysfunction and the mechanism of its pharmacological treatment. Penile anatomy provides the structural basis for erection. The penis contains three cylindrical bodies of erectile tissue: two corpora cavernosa (dorsal, side by side) and one corpus spongiosum (ventral, surrounding the urethra). The corpora cavernosa are the main erectile bodies, consisting of smooth muscle trabeculae surrounding blood-filled sinusoids, all encased in the tunica albuginea, a thick fibrous sheath. The corpus spongiosum expands distally to form the glans penis; it is more distensible than the corpora cavernosa, which prevents urethral compression during erection. Blood enters through the helicine arteries (branches of the deep arteries of the penis) and drains through emissary veins that penetrate the tunica albuginea. The erection mechanism involves hemodynamic changes driven by smooth muscle relaxation. Sexual stimulation—either psychogenic (from visual, auditory, or cognitive stimuli via the brain) or reflexogenic (from tactile stimulation via sacral spinal cord)—activates parasympathetic outflow from S2-S4 via the pelvic nerves. Parasympathetic neurons release nitric oxide (NO) directly, as do endothelial cells of the helicine arteries and sinusoidal spaces. NO diffuses into vascular smooth muscle cells, where it activates soluble guanylyl cyclase, increasing intracellular cyclic GMP (cGMP). cGMP activates protein kinase G, which decreases intracellular calcium and causes smooth muscle relaxation. Relaxation of smooth muscle in the helicine arteries increases blood inflow. Relaxation of trabecular smooth muscle expands the sinusoids, which fill with blood. As the sinusoids expand against the tunica albuginea, the emissary veins are compressed, restricting outflow. This combination of increased inflow and decreased outflow produces erection. The nitric oxide-cGMP pathway is the target of phosphodiesterase-5 (PDE5) inhibitors. cGMP is degraded by phosphodiesterase type 5 (PDE5), which terminates the erectile signal. PDE5 inhibitors (sildenafil, tadalafil, vardenafil) block this degradation, prolonging and enhancing the effect of NO released during sexual stimulation. These drugs require sexual stimulation to work (they enhance but do not initiate erection) and are contraindicated with nitrate medications (the combination can cause severe hypotension). Ejaculation proceeds through emission and expulsion phases. Emission is the movement of sperm and secretions from the epididymis, vas deferens, seminal vesicles, and prostate into the prostatic urethra. This is controlled by sympathetic outflow from T10-L2, releasing norepinephrine that contracts smooth muscle in the reproductive ducts. Simultaneously, sympathetic activation closes the internal urethral sphincter, preventing retrograde ejaculation into the bladder. Expulsion (ejaculation proper) is the rhythmic propulsion of semen out of the urethra by contractions of the bulbospongiosus and ischiocavernosus muscles. This phase is controlled by the somatic pudendal nerve (S2-S4). Retrograde ejaculation occurs when the internal sphincter fails to close, often due to autonomic neuropathy (diabetes) or surgical damage; affected men report dry orgasm and have sperm in post-ejaculation urine. Panel A: Penile cross-sectional anatomy showing paired corpora cavernosa with trabecular smooth muscle and sinusoids, corpus spongiosum surrounding urethra, tunica albuginea, and neurovascular structures. Panel B: Veno-occlusive mechanism with expanded sinusoids compressing emissary veins against tunica, and NO-cGMP pathway from parasympathetic activation through guanylyl cyclase to smooth muscle relaxation. Panel C: PDE5 degradation of cGMP and PDE5 inhibitor blockade of this degradation pathway. Panel D: Ejaculation phases showing emission with sympathetic T10-L2 control, duct contraction, sphincter closure, and expulsion phase with somatic S2-S4 rhythmic contractions plus retrograde ejaculation mechanism. --- ### X. Male Puberty Puberty is the developmental period during which the hypothalamic-pituitary-gonadal axis matures, leading to reproductive capacity and the development of secondary sex characteristics. Understanding normal puberty allows recognition of delayed or precocious puberty and appropriate clinical evaluation. Hormonal changes initiate puberty. The trigger for puberty remains incompletely understood but involves decreased sensitivity to gonadal steroid negative feedback and increased activity of hypothalamic GnRH neurons, possibly influenced by metabolic signals (leptin) and developmental genes (KISS1/kisspeptin). GnRH pulsatility first increases during sleep, producing nocturnal elevations in LH and testosterone that can be detected before physical pubertal changes appear. As puberty progresses, GnRH pulsatility extends throughout the 24-hour period. Rising LH stimulates Leydig cell testosterone production, while rising FSH initiates spermatogenesis by supporting Sertoli cell function. Tanner staging provides a standardized assessment of pubertal development. Stage I is prepubertal, with childlike genitalia and no pubic hair. Stage II marks the first evidence of puberty: testicular enlargement to greater than 4 mL (the first objective sign, typically at age 9-14 years), beginning of scrotal skin thinning and pigmentation, and sparse pubic hair at the base of the penis. Stage III shows continued testicular growth, penile lengthening primarily, and darker, curlier pubic hair. Stage IV features further testicular growth, penile widening and glans development, and adult-type pubic hair not yet extending to the thighs. Stage V represents full adult maturity, with adult-sized testes (15-25 mL), adult penis and scrotum, and pubic hair extending to the thighs. Physical changes of puberty follow a characteristic sequence. Testicular enlargement is the first sign; an orchidometer is used to measure testicular volume. Penile growth follows testicular development and is typically complete by Tanner stage V. Pubic and axillary hair development is driven by adrenal and gonadal androgens; the adrenal contribution (adrenarche) often precedes gonadarche slightly. Voice deepening results from testosterone-induced laryngeal growth and vocal cord thickening. Facial hair typically appears later in puberty, beginning with mustache and progressing to beard. Acne develops from androgen stimulation of sebaceous glands. Muscle mass and strength increase. The growth spurt in males occurs later than in females (approximately age 14, during Tanner stage IV) and is more pronounced; males typically gain approximately 28 cm during puberty. Growth and skeletal maturation are importantly influenced by sex steroids. Testosterone contributes directly to muscle mass and bone growth, but estradiol (produced by aromatization of testosterone) is essential for epiphyseal fusion, which terminates linear growth. Males with aromatase deficiency continue growing into adulthood due to failure of epiphyseal fusion. The normal pubertal growth spurt and epiphyseal fusion occur later in males than females, contributing to greater adult height. Bone mineral density increases substantially during puberty, laying the foundation for peak bone mass. Panel A: Hormonal changes timeline showing sleep-related GnRH pulses expanding to 24-hour pulsatility with corresponding LH and testosterone increases, onset typically 9-14 years. Panel B: Tanner stages I-V with visual representations showing testicular volume in mL, penile development, and pubic hair distribution at each stage. Panel C: Physical development timeline showing sequence of testicular enlargement first, then penile growth, pubic hair, voice change, growth spurt at age 14, and facial hair. Panel D: Skeletal maturation inset explaining role of testosterone and estradiol from aromatization in growth and epiphyseal fusion leading to adult proportions. --- ## Summary The male reproductive system comprises the testes, duct system (epididymis, vas deferens), accessory glands (seminal vesicles, prostate, bulbourethral glands), and external genitalia. The testes contain seminiferous tubules with Sertoli cells that support spermatogenesis and form the blood-testis barrier, and interstitial Leydig cells that produce testosterone. The HPG axis regulates male reproduction: pulsatile GnRH stimulates LH and FSH release from the pituitary; LH stimulates testosterone synthesis in Leydig cells; FSH supports Sertoli cell function and spermatogenesis. Testosterone and inhibin B provide negative feedback to maintain homeostasis. Testosterone is synthesized from cholesterol in Leydig cells, circulates bound to SHBG and albumin, and is metabolized peripherally to DHT (5α-reductase) and estradiol (aromatase). Testosterone and DHT act via the androgen receptor to produce developmental, metabolic, and anabolic effects. Spermatogenesis is the 64-day process of germ cell development from spermatogonia through meiosis to spermatids, followed by spermiogenesis (morphological transformation into spermatozoa). Sperm mature during epididymal transit and undergo capacitation in the female tract before fertilization. Erection is a vascular event driven by parasympathetic-mediated nitric oxide release, which increases cGMP and causes smooth muscle relaxation. Ejaculation involves sympathetic-mediated emission followed by somatic-mediated expulsion. --- ## Key Terms | Term | Definition | |------|------------| | Sertoli cells | Support cells in seminiferous tubules that form the blood-testis barrier and support spermatogenesis | | Leydig cells | Interstitial cells that produce testosterone in response to LH | | Spermatogenesis | The process of germ cell development from spermatogonia to spermatozoa | | Blood-testis barrier | Tight junctions between Sertoli cells that protect developing germ cells from immune attack | | DHT | Dihydrotestosterone; potent androgen produced from testosterone by 5α-reductase | | Capacitation | Final functional maturation of sperm in the female reproductive tract | | Acrosome reaction | Exocytosis of acrosomal enzymes that allows sperm penetration through the zona pellucida | | Inhibin B | Sertoli cell hormone that provides selective negative feedback to FSH | --- *This content is subject to the [MIT License](https://opensource.org/licenses/MIT). © 2024–2026 Hibbert School of Medicine.*