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

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
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
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
Male Reproductive Axis

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

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
Male Reproductive Axis

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 Substance aka: 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

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

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
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
Testis

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

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)
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
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
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


Meiotic: reduction division resulting in haploid spermatids


Type A spermatogonia; Ad (dark) – stem cell renewal; Ap (pale) – produce daughter cells
Type B spermatogonia
Spermiogenic: spermatids undergo changes to form mature spermatozoa

Round Sa spermatid

Entire process requires 64 days (Ap spermatogonium  spermatozoon)
Testis

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
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
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
Epididymis

Function

Sperm motility maturation: increase motility observed during transit





Efferent ducts: 0%
Caput: 3%
Proximal Corpus: 12%
Distal Corpus: 30%
Cauda: 60%
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



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
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 hyperactivated motility 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
Ductus Vas Deferens





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

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)
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







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




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
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