October 29, 2001.

the male internal genitalia 
Anatomy:  

Testes:	-  seminiferous tubules:  spermatozoa formation
      wall lined by primitive germ cells and Sertoli cells

-  interstitial cells of Leydig (testosterone secretion)

Duct system:
-	Epididymis (network of ducts)
-	Vas deferens 
-	Ejaculatory duct

Accessory glands:  nourishment of sperm
-	Seminal vesicles (fructose)
-	Prostate

Blood-testis barrier:  tight junctions between Sertoli cells
interstitium  lumen
steroids pass the barrier
the lumen is rich in :  	androgens
estrogens
potassium
inositol
glutamic acid
aspartic acid
poor in:  protein
glucose

the function of the testes

I.  Spermatogenesis

1.  The gametogenic function of Sertoli cells in the seminiferous tubule:

spermatogonia (outside the blood-testis barrier)

primary spermatocytes (from adolescence; push through between Sertoli cells))

secondary spermatocytes (enveloped by Sertoli cells – nutritional support)

spermatids (released into the lumen)

spermatozoa (sperms):  not fully mobile

further maturation in the epididymis (10-14 days)

1 spermatogonium  512 spermatids (74 days)

2.  The endocrine function of Sertoli cells:

-	androgen-binding protein
-	inhibin:  suppresses the effects of FSH locally in the testes as well as suppresses FSH secretion by the pituitary
-	activin:  locally opposes the effects of inhibin
-	AMH:  up to 8-10 years of age, suppressed by local testosterone
-	aromatase (androgens  estrogens; function?)

3.  The endocrine control of spermatogenesis:

FSH and testosterone maintain the gametogenic function.

FSH:  stimulates the proliferation and secretory activities of Sertoli cells

spermatogonia  spermatids: 	androgen-independent
spermatids 	 spermatozoa: androgen dependent

II.  Steroidogenesis:  testosterone

Chemical structure:  C19 steroid
-OH @ 17

Source of testosterone:  

1.  Circulating testosterone:  from Leydig cells (sER, mitochondria, intracellular lipid droplets)
11-hydroxylase and 21-hydroxylase are absent
17-hydroxylase is present

2.  Source of testosterone in target tissues:
a.  Circulating testosterone pool
b.  “Intracrine” formation of testosterone from DHEA:  expression of tissue-specific genes that encode steroidogenic enzymes responsible for the transformation of DHEA into androgens, e.g., 50% of testosterone in prostate is from DHEA.

Synthesis:

DHEA

Androstenedione
    17-hydroxysteroid dehydrogenase (activator):  key to normal testicular testosterone secretion
	lack of enzyme:  male pseudohermaphroditism
Testosterone
			aromatase

Estradiol (minute amounts, but:  if testes are over stimulated by LH  estradiol   e.g., gynecomastia)

    5-reductase

Dihydrotestosterone

Secretion:  - fetal  ( development of male genitalia)
- neonatal  (function?)
- very low quantities secreted before until puberty (function:  negative feed back on hypothalamic GnRH)
-  from puberty: 

Regulation:  

GnRH:  intrinsic rhythmic activity
low frequency pulses:  FSH
high frequency pulses: LH

G protein-coupled receptors in pituitary  Ca influx  hormone release 
LH both release (90 – 140 min period time) and synthesis

Leydig cells:  LH receptors (G protein-coupled)

cAMP

PKA

StAR:  -  cholesteryl ester  cholesterol
-  cholesterol  pregnenolone  (rate limiting step)

Plasma transport and metabolism:

The amounts of sex hormones and SHBG determines the transport characteristics of testosterone

98% protein bound:  	55% sex hormone-binding globulin (SHBG)
 	40% albumin
			5% cortisol-binding globulin

SHBG may promote estrogen-like effects in males:
-	SHBG affinity for testosterone > for estradiol  increase in SHBG secretion causes shifts of free-T/free-E2 towards increased free E2

Estrogens may promote androgen-like effects:
-	Free SHBG binds to SHBG receptors  G protein  cAMP  PKA  intracellular androgen receptor phosphorylation;
Once SHBG is bound to the receptor, estradiol can bind to SHBG and stimulate the intrinsic activity of SHBG on the receptor (= androgen-independent activation of androgen receptors)

Metabolism:  
in target tissues:  17-hydroxysteroid dehydrogenase isoenzymee (inactivator), e.g., endometrium, placenta, liver, prostate

in liver:  17-ketosteroids  urine

The effects of testosterone

I.  The effects during prenatal development 
-	differentiation of wolffian duct-related structures
-	development of prostate
-	masculinization of external genitalia
-	descent of testes

II.  Stimulatory effect on the growth and development of male genital tract during adolescence

1.  External genitalia:  penis enlarges
2.  Internal genitalia:  seminal vesicles enlarge, secretion
prostate enlarge, secretion 

III.   Stimulatory effects on gametogenesis

IV.  Development and maintenance of male secondary sex characteristics

1.  Male physique
-  shoulders broaden
-  muscles enlarge

2.  Laryngeal growth  voice deeper

3.  Mental effects:  more aggressive and active attitude
libido

V.  Anabolic effects

1.  Muscles 	
-  protein synthesis  and protein breakdown, 
-  increased muscle cell size (not number), 
-  increased lean body mass

2.  Bones
-  accelerated linear growth  eventually elicits the closure of epiphyseal plates 
-  increased bone density (bone mass)

VI.  Hematologic and immunologic effects
	
1.  Erythropoetin  by kidneys  red blood cell count increases

2.  Decreases the incidence of autoimmune diseases?

VII.  Water-electrolyte balance:  retention of Na+, water, K+, calcium, phosphate, sulfate

VIII.  Skin and hair

1.  Stimulates the growth of body hair
-  axillary hair and hair in the lower pubic area respond to low concentrations of androgens
-  hair on chest, face and higher pubic area requires higher androgen concentrations (beard, male-pattern pubic hair and hair on chest)

2.  Male-pattern balding (hairline recedes anterolaterally)

3.  Increased sebum production by sebaceous glands (acne)

IX.  Suppression of GnRH secretion
-	local aromatization of testosterone in the hypothalamus  estrogen receptor activation  GnRH surge amplitude 
-	activation of endogenous opioids in the hypothalamus  GnRH frequency 

mechanism of testosterone action

1.  Direct binding to IC receptors:

sex drive
muscle
differentiation of wolffian duct  male internal genitalia

2.   Conversion to dihydrotestosterone (DHT) in target cells (sweat glands, sebaceous glands, hair follicles, dermal fibroblasts, prostate)

-	10% of circulating testosterone is DHT
-	intracrine action
-	enzyme:  5-reductase

DHT binds to the same receptor as T, but higher affinity   effect 2,5x

a.  Absolute DHT requirement for:
-	development of male external genitalia
-	development of prostate

b.  Relative DHT requirements for:
-	enlargement of external genitalia
-	male pattern body hair
-	descent of testes

c.  DHT is not required for:
-	development of wolffian duct-related structures
-	laryngeal enlargement
-	anabolic effects on muscle
-	stimulation of spermatogenesis
-	libido

5-reductase deficiency:
-	male internal genitalia
-	female external genitalia  raised as girls
-	at puberty:  LH surge  testosterone   male body contours and male libido  change in gender identities

control of testicular function

LH:  tropic to Leydig cells  testosterone
FSH:  tropic to Sertoli cells  ABP
inhibin

Negative feedback mechanisms:

inhibin  FSH
testosterone  GnRH
LH

pathology of the testicular functions

1.  Hyperandrogenism:  androgen abuse

Over 12 years of age:  0.9% of males and 0.1% of females had taken anabolic steroids
More than 1 million current or former steroid users in the US  

Androgens are taken in high doses, up to 100 times the dose used in replacement therapy

Complications and side effects:
-  spermatogenesis
-  testicular atrophy
-  various forms of degenerative liver diseases and hepatic tumors
-  women:  hirsutism, amenorrhea, frank virilization
-  behavioral effects:  increased aggression, variety of psychotic symptoms, increased or decreased libido

2.  Hypogonadism

Causes:
a.	Primary (hypergonadotropic) hypogonadism:  primary testicular disease
-  gonadal defects (genetic, viral, radiation, etc.)
-  hormone resistance:  androgen insensitivity or LH insensitivity

b.  Secondary (hypogonadotropic) hypogonadism:  pituitary dysfunction
Symptoms:
a.  Onset before puberty:
-  delayed development of secondary sex characteristics
-  linear growth continues beyond 16-18 years
-  “eunuchoid” body shape:  long arms and legs, female phenotype fat deposits, 

b.  Onset after puberty:
-  muscular atrophy
-  body hair 
-  sexual libido and potency 
-  voice does not change significantly
-  occurrence of atherosclerosis and prostate tumors

3.  Male infertility:  10% of couples infertile, 1/3 due to male infertility

a.  Endocrine causes
-  Klinefelter’s sy.
-  hypopituitarism
-  primary testicular failure (autoimmune)
-  hyperprolactinemia
-  hypothyroidism

b.  Non-endocrine causes