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Male Reproductive Physiology

Male Reproductive Physiology. Jeremy Johnson D.O. November 26, 2008. Male Reproductive Physiology. Male Reproductive Axis Testis Epididymis Spermatozoa Vas Deferens. Male Reproductive Axis. 3 tiers of organization: Hypothalamus, Pituitary gland, Testis

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Male Reproductive Physiology

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  1. Male Reproductive Physiology Jeremy Johnson D.O. November 26, 2008

  2. Male Reproductive Physiology • Male Reproductive Axis • Testis • Epididymis • Spermatozoa • Vas Deferens

  3. Male Reproductive Axis • 3 tiers of organization: Hypothalamus, Pituitary gland, Testis • Hypothalamus: GnRH (gonadotropin-releasing hormone) • Pituitary gland: LH (luteinizing hormone), FSH (follicle-stimulating hormone) • LH: stimulates Testosterone production by Leydig cells in interstitium • FSH: supports spermatogenesis by stimulating Sertoli cells in the seminiferous epithelium • Inhibin: secreted by Sertoli cells, suppresses FSH secretion by gonadotropes; ? Use of Inhibin B as marker for impaired testicular function • Activin: secreted by Sertoli cells, stimulate transcription of FSH B subunit

  4. Male Reproductive Axis • Hypothalamus: • GnRH - 3 types of rhythmicity • Seasonal (in months) – peaks in Spring • Circadian (in hours) – highest Testosterone levels in AM • Pulsatile (in minutes) – peaks occur every 90 - 120 minutes Melatonin: modifies seasonal & circadian rhythms from inputs from pineal gland (seasonal) & neural connections (circadian) from suprachiasmatic nucleus (mammalian 24-hr clock) Precursors of GnRH neurons migrate to hypothalamus from olfactory placode during development Kallman’s Syndrome: congenital hypogonadotropic hypogonadism, failure of normal migration of GnRH neurons -> hypothalamus unable to secrete GnRH; anosmia/other midline defects + hypogonadism is diagnostic

  5. Pituitary gland Anterior Pituitary (Adenohypophysis) – regulated by bloodborne factors Gonadotropes (secrete LH & FSH)* Corticotropes (secrete ACTH)? Lactotropes (secrete PRL)* Somatotropes (secrete GH)* Thyrotropes (secrete TSH) *significant effects on male reproductive function ?unknown effects on male reproductive function Posterior Pituitary (Neurohypophysis) – regulated by neural stimuli Oxytocin Vasopressin (ADH) Male Reproductive Axis

  6. Male Reproductive Axis • Steroid Feedback • Testosterone exerts negative feedback suppression on the release of GnRH at the level of hypothalamic neurons & pituitary; T is not the only active steroid in the target cells • Testosterone –(aromatase) Estradiol • Testosterone –(5 alpha reductase)  DHT • Testosterone acts primarily to feedback at the hypothalamus; Estrogens primarily feedback to the pituitary gland • In males: • LH secretion is regulated primarily by Testosterone • FSH secretion is regulated primarily by Estradiol

  7. Development of male reproductive axis 7 weeks gestation: 1st identifiable step differentiating ovarian from testicular pathways is movement of primordial germ cells into medullary cords SRY (Sex-Determining Region on Y c’some) controls early testis differentiation SRY gene product (a TF) acts w/ other TFs (WT-1, SOX-9, DAX-1) to initiate male sexual differentiation 10% of 46 XX males have no identifiable SRY gene Sertoli Cells: secrete MIS (Mullerian Inhibiting Substanceaka: Anti-Mullerian Hormone); causes female reproductive structures to regress Leydig Cells: secrete Testosterone which induces differentiation of the Wolffian duct system (epididymis, vas deferens, sex accessory glands) Male Reproductive Axis

  8. Endocrinology of Testis Leydig cell differentiation 1st wave - 7 weeks gestation: stimulated by hCG from placenta; androgens appear in circulation 2nd wave - 2-3 months after birth: stimulated by gonadotropin production from neonate’s pituitary; briefly elevates Testosterone Androgens produced during first 2-6 months of life are thought to hormonally imprint hypothalamus, liver, prostate, phallus & scrotum Leydig cells of infants then regress & testes are dormant until puberty Puberty Hypothalamus generates pulses of GnRH around 12th year of life Onset of GnRH pulses typically occurs at night, due in part to gradual decrease in nocturnal melatonin secretion from pineal gland Also influenced by nutritional status of body and growth rate GH & IGF-1 stimulate reproductive function Leptin determines size of fat stores in body - ? Role in puberty Male Reproductive Axis

  9. Aging of Hypothalamic/Pituitary Axis Testosterone: levels decline at > 50 years of age LH: basal levels increase in older men; LH pulsatility is blunted Leydig cells: steroidogenic capacity decreases Spermatogenesis: lower fecundity at > 40 years, 50% lower probability of achieving pregnancy w/in 1 yr compared to men < 25 years of age Male Reproductive Axis

  10. Testis • Gross structure & vascularization • Volume: 15 - 25 ml • Longitudinal length: 4.5 - 5.1 cm • 3 layers of capsule: outer visceral layer of tunica vaginalis, tunica albuginea, innermost layer of tunica vasculosa • Tunica albuginea contains smooth muscle; smooth mm. provides contractile capability to testis as well as affects blood flow into testis • Testicular arteries penetrate tunica albuginea & travel inferiorly on post. surface w/ branches passing anteriorly; also major branches present on inferior pole (potential for injury during orchiopexy/biopsy); medial and lateral midsection of testis have fewer vessels • Capsule separated by septa; between septa are seminiferous tubules & interstitial tissue • Seminiferous tubules: developing germinal elements & supporting cells (Sertoli cells) • Interstitial tissue: Leydig cells, mast cells, macrophages, nerves, blood/lymph vessels (20 – 30 % of total testicular volume

  11. Innervation: No somatic innervation Autonomic innervation from intermesenteric nn. & renal plexus; travel along testicular artery Arterial supply: Internal spermatic testicular Deferential vasal External spermatic (cremasteric) Countercurrent exchange of heat between pampiniform plexus & arteries Intratesticular temps 3 – 4 degrees C lower than rectal temps Variability in # of arteries entering testis exists 1 artery: 56%; 2 arteries: 31%; 3 or more arteries: 31% Testis

  12. Testis • Cryoarchitecture & Function • Interstitium: blood/lymph vessels, fibroblastic supporting cells, macrophages, mast cells & Leydig cells • Leydig cells: responsible for steroid production; Testosterone is synthesized from cholesterol & is principle steroid produced in human testis • 3 sources for cholesterol: external (bloodborne), de novo (acetate), stored cholesterol esters • LH: regulates Testosterone production; generates cAMP & initiates transport of cholesterol into mitochondria • Testosterone peaks: • 12-18 wks gestation • 2 months of age • 3rd decade of life (max concentration)

  13. Testis • Seminiferous tubules – germinal elements & supporting cells • Germinal elements: spermatozoa • Supporting cells: sustentacular cells (basement membrane) & Sertoli cells • Sertoli cell functions: • Creates specialized microenvironment of adluminal compartment of seminiferous epithelium • Supports germ cells through gap junctions between Sertoli & germ cells • Facilitates migration of differentiating germ cells into seminiferous tubule

  14. Testis • Blood-Testes Barrier • 3 levels: • 1.) Tight junctions between Sertoli cells & spermatogonia from other germ cells • 2.) Endothelial cells in capillaries • 3.) Peritubular myoid cells • Spermatogonia & young spermatocytes are outside blood-testes barrier in basal compartment; mature spermatocytes & spermatids are above barrier in adluminal compartment • Blood-Testes Barrier functionally develops at onset of spermatogenesis

  15. Testis • Germinal Epithelium – 123 x 106 spermatozoa/day (21 – 374 x 106) • Phases of spermatogenesis • Proliferative: spermatogonia divide to replace their numbers; or produce daughter cells committed to becoming spermatocytes • Type A spermatogonia; Ad (dark) – stem cell renewal; Ap (pale) – produce daughter cells • Meiotic: reduction division resulting in haploid spermatids • Type B spermatogonia • Spermiogenic: spermatids undergo changes to form mature spermatozoa • Round Sa spermatid • Entire process requires 64 days (Ap spermatogonium  spermatozoon)

  16. Hormonal Regulation of Spermatogenesis Intratesticular Testosterone levels are 100 x greater than serum levels Testosterone will initiate & qualitatively maintain spermatogenesis in humans Genetic Basis of Spermatogenesis AZF (azoospermia factor) region on long arm of Y c’some implicated in deletions resulting in azoospermia Paternal centromere: appears to organize embryonic mitotic activity; viable embryo cannot be produced w/out this contribution Testis

  17. Epididymis • Gross structures: • Tubule: 3-4 meters in length • 3 regions: Caput, Corpus, Cauda • Contractile tissue (myofilaments) • Innervation: intermediate spermatic nerves (hypogastric plexus); inferior spermatic nerves (pelvic plexus); sympathetic fibers increase in # proximally • Vascularization: Testicular artery (Caput & Corpus), Deferential artery (Cauda); collateral circulation exists from Deferential & Cremasteric aa • Histology: • Ciliated cells • Principal cells: absorptive/secretive processes • Basal cells

  18. Epididymis • Function • Sperm transport: 2 -12 days; transport time influenced by daily testicular sperm production; 2 days in men w/ high sperm counts vs 6 days in men w/ low sperm counts; recent emission reduces transit time thru Cauda by 68%; principal mechanism for moving spermatozoa thru epididymis is probably due to spontaneous rhythmic contractions of cells surrounding epididymal tract • Sperm storage: 50% of total # of epididymal spermatozoa are stored in Cauda (capable of undergoing motility & have capacity to fertilize); fate of unejaculated spermatozoa is unknown

  19. Epididymis • Function • Sperm motility maturation: increase motility observed during transit • Efferent ducts: 0% • Caput: 3% • Proximal Corpus: 12% • Distal Corpus: 30% • Cauda: 60%

  20. Epididymis • Function • Sperm fertility maturation: • Testicular spermatozoa are incapable of fertilizing eggs (unless injected) • Maturation is achieved at level of distal Corpus or proximal Cauda • Biochemical changes: • Increased capacity for glycolysis • Changes in intracellular pH & calcium content • Modification of adenylate cyclase activity • Alterations in cellular phospholipid & phospholipid-like fatty acid content

  21. Spermatozoa • Mature spermatozoa stored in Cauda epididymis & Ductus deferens • 60 micrometers in length • Head: measures 4.5 micrometers in length & 3 micrometers in width • Oval sperm head: consists mostly of a nucleus which contains highly compacted chromatin material & an acrosome which contains enzymes necessary for penetration of outer membrane of female egg • Middle piece: helically arranged mitochondria surrounding a set of fibers & characteristic 9 + 2 microtubular structure of axoneme • Mitochondria contains enzymes required for oxidative metabolism & production of ATP (primary energy source for cell) • Axoneme contains enzymes & structural proteins necessary for transduction of ATP into mechanical movement resulting in motility • Outer dense fibers are rich in disulfide bonds & thought to provide sperm tail; fibers surround middle & principal piece, terminate at end piece • Plasma membrane envelops spermatozoan (except at end piece); regulates transmembrane movement of ions & other moleculs; at head, specialized proteins in membrane participate in sperm-egg interactions during early stages of fertilization

  22. Spermatozoa • Effects of Sex Accessory Gland Secretions on Spermatozoal Function • Human ejaculate maintains an ability to coagulate initially & is liquefied by proteases from prostate (specifically PSA) • Unknown as to whether or not coagulum provides to maintain spermatozoa w/in vagina • Spermatozoa must traverse cervical mucus into uterus & finally into oviduct where fertilization occurs • Uterine transport in woman takes 5 – 68 minutes • Spermatozoa must undergo capacitation prior to oocyte fertilization ; capacitation occurs at different rates for each spermatozoan • Many changes occur during capacitation; most notably, the acrosome reaction & development of hyperactivatedmotility occurs • Unknown as to whether or not prostatic or seminal vesical secretions contribute to capacitation • Ejaculate: • Fructose – produced in seminal vesicle, provides energy for spermatozoa • Albumin – supports & stimulates spermatozoa • Antioxidants – enzymes (Glutathione peroxidase, Superoxide dismutase, Catalase), molecules (Taurine, Hypotaurine, Tyrosine) all provide anti-oxidant protection for sperm; oxidative effects on sperm include lower sperm motility & increased damage to sperm DNA

  23. Derived from Mesonephric (Wolffian) duct 30 – 35 cm in length Begins at Cauda epididymis & terminates at ejaculatory duct near prostate gland Outer diameter: 2 -3 mm; Lumen diameter: 300 – 500 micrometers 5 portions Sheathless epididymal portion w/in tunica vaginalis Scrotal portion Inguinal division Retroperitoneal (pelvic) portion ampulla Outer adventitia (blood vessels, small nerves) Muscular coat (middle circular, inner/outer longitudinal) Mucosal inner layer (epithelial lining) Ductus Vas Deferens

  24. Ductus Vas Deferens • Vascularization & Innervation • Blood supply: Deferential artery via Inferior vesicle artery • Nervous supply: sympathetic & parasympathetic inputs • Parasympathetic (cholinergic) is of minor importance in motor activity of vas deferens • Sympathetic (adrenergic) nerves provide rich supply to vas deferens; sympathetics derived from Hypogastric nerves via Presacral nerve; vas deferens also receive a special type of short adrenergic nerve which are present in all 3 layers of the muscle layers of vas deferens (greatest concentration of these nerves are present in outer longitudinal layer)

  25. Ductus Vas Deferens • Cryoarchitecture of Ductus Deferens • Lined by pseudostratified epithelium • Height of epithelium decreases along the length of ductus • Longitudinal folds of epithelium are simple in proximal region & more complex at distal segments • Muscle thickness gradually decreases along the length of the ductus • Pseudostratified epithelium is composed of basal cells & 3 types of columnar cells (Principal cells, Pencil cells & Mitochondrian-rich cells) • Columnar cells all show steriocilia & irregular convoluted nuclei • Principal cells more prominent in proximal portion of ductus • Pencil & Mitochondrian-rich cells more prominent in distal portion of ductus

  26. Ductus Vas Deferens • Spermatozoal transport • Ductus exhibits spontaneous motility, has capacity to respond when stretched & contents of ductus can be propelled into urethra by strong peristaltic contractions elicited by stimulation of hypogastric nerve or adrenergic neurotransmitters • Immediately before emission, rapid & effective transport of spermatozoa from distal epididymis & proximal vas deferens occurs (apparently related to sympathetic stimulation) • This efficient transport of spermatozoa has revealed that the ductus deferens has the greatest muscle-lumen ratio (10:1) of any hollow viscus in the human body • Epididymal spermatozoal reserves: 182 million (26% caput, 23% corpus, 52% cauda); transit times in days (0.7 caput, 0.7 corpus, 1.8 cauda) • Ductus spermatozoal reserves: 130 million; storage site for spermatozoa

  27. Ductus Vas Deferens • Spermatozoal transport • “During the sexual rest, epididymal contents were transported distally through the vas deferens into the urethra in small amounts and at irregular intervals” • Urethral disposal is a mechanism for ridding the epididymis of excess spermatozoa • After sexual stimulation and/or ejaculation: contents of ductus can be propelled towards proximal ductus & cauda epididymis because distal portion had increased contractility compared to proximal portion of ductus • Refluxing was noted to reverse w/ sexual rest

  28. Ductus Vas Deferens • Absorption & Secretion • Suggested that ductus deferens may have absorptive & secretory functions • Principal cells have characteristics typical of cells that are capable of synthesizing & secreting glycoproteins • Stereocilia, apical blebbing, primary & secondary lysosomes of Principal cells are characteristic of cells involved in absorptive functions • Rat models have shown that terminal region of ductus possesses the ability to phagocytose & absorb spermatozoa; unknown if significant portion of human ductus deferens possesses sufficient spermiophagy • Structure & function of ductus deferens probably depends on androgen stimulation • Human ductus deferens converts Testosterone to DHT • Castration causes atrophy of ductus deferens; Testosterone treatment causes restoration of ductus deferens • Castration and/or Testosterone treatment alters adrenergic contractions of ductus

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