Gonad Hormones : Gonad Hormones : MaleMale

Prof.Dr.Gülden BurçakProf.Dr.Gülden Burçak

2011-20122011-2012

TestisTestis male sex hormones male sex hormones male germ cellsmale germ cells

Testis : two functional units

Semineferous tubules lined with Sertoli cells and germ cells (spermatogonia) for production and transport of sperm .

Sertoli cells provide the environment necessary for germ cell differentiation and maturation

Interstitial cells ( Leydig cells) for production of testosterone.

Hypothalamic-Pituitary-Testis Axis

Constant pulsatile release of GnRH from the hypothalamus

Synthesis, storage and secretion of gonadotropins (FSH and LH) from the anterior pituitary

(-)feedback relationship between the androgens and GnRH, FSH, LH secretions

Prolonged exposure to LH results in desensitization

In childhood testosterone and plasma gonadotropin levels are

low HPA is highly sensitive to (-) feedback effects of

gonadal steroids Onset of puberty Bursts of GnRH release Sleep associated surges in LH secretion and to a

lesser extent in FSH secretion Later in puberty pulsatile gonadotropin secretion

throughout the day and night and more sustained plasma gonadotropin, testosterone and dihydrotestosterone

For normal testicular function, GnRH pulses occur at a frequency of 3.8 pulses every 6 hours.

At a lower pulse rate FSH release ; at a higher pulse rate LH is more prominent

Circulating half-life : FSH,4 hours ; LH, 30 minutes

Testosterone : diurnal rythmic pattern, highest in the early morning

LH binds Leydig cells testosterone synthesis and secretion secretion is inhibited by both testosterone and

estradiol conversion of testosterone to estradiol in brain,

pituitary and testes FSH binds Sertoli cells synthesis of androgen binding protein, aromatase

enzyme complex, inhibin secretion is primarily inhibited by inhibin B but

also by testosterone

Testosterone biosynthesis

Cholesterol de novo synthesis or from LDL cholesterol esters storage in cytoplasm LH (cAMP) (acute) : esterase activation

and cholesterol transport to the inner mitochondrial membrane (steroidogenic (steroidogenic acute regulatory protein (StAR)acute regulatory protein (StAR)

LH (cAMP) (chronic) : steroidogenic LH (cAMP) (chronic) : steroidogenic enzyme synthesisenzyme synthesis

Side chain cleavage and removal of the six-carbon fragment

Cytochrome P450 side chain cleavage

Two hydroxylations first at C22 then at C20 (O2 and NADPH)

Cholesterol 20,22- desmolase

5α-reductase,type I : liver

Type II : reproductive tissues and peripheral targets

Daily testicular production 5mg testosteron, 50-100μg DHT ; %25 of DHT in circulation %25 of estradiol (E2) in circulation Testosterone : a circulating precursor of

DHT and E2

DHT (5α-reductase) in liver, kidney, muscle, prostate, external genitalia and genital skin

E2 (aromatase enzyme complex) in muscle, liver, kidney, brain, adipose tissue.

50% loosely bound to albumin (> 400 mg /L)

45% bound with high affinity to SHBG 1-2% to CBG < % 4 is free The normal level of SHBG is about 30-50%

lower in men than in women SHBG levels may be elevated in

testosterone deficient men. A change in the level of SHBG causes a

greater change in the free testosterone level than in the free estradiol level.

Effects of androgens

Sexual differentiation Spermatogenesis Development of secondary sexual

organs Anabolic metabolism and gene

regulation Male pattern behaviourEstradiol : sexual behavior and control

of LH secretion

Targets for testosterone Embryonic Wolffian structures,

spermatogonia, muscles,bone, kidney and brain

Targets for dihydrotestosterone Prostate, external genitalia and the genital

skin The kidney is a major target tissue of the

androgens : general enlargement of the kidney

Excretory metabolites : inactive or less active

Oxidation at the 17-position in many tissues, including the liver

17 ketosteroids : androsterone and etiocholanolone

conjugated with glucuronide and sulfate

Androstanediol

Pathological States Primary hypogonadism Genetic disorders : Klinefelter’s syndrome Androgen receptor defects : Testicular

feminization syndrome Inherited enzyme defects : 20,22-

desmolase, 3ß-hydroxydehydrogenase,17α-hydroxylase

17,20 desmolase , 17-ketosteroid reductase

Failure of the pituitary/hypothalamus to respond to low testosterone levels

In hypogonadismIn hypogonadism

Hypothalamus : Low GnRH ; low Hypothalamus : Low GnRH ; low FSH,LH; low E2 /testosteroneFSH,LH; low E2 /testosterone

Pituitary : High GnRH ; low FSH,LH ; Pituitary : High GnRH ; low FSH,LH ; low E2 /testosterone low E2 /testosterone

Gonad : High GnRH ; high FSH,LH ; Gonad : High GnRH ; high FSH,LH ;

low E2 /testosteronelow E2 /testosterone Hyperprolactinemia is associated Hyperprolactinemia is associated

with diminished libido and impotencewith diminished libido and impotence

Hypergonadism Testicular hyperfunction : Testicular

tumors (often produce hCG and α-fetoprotein)

Hypothalamic/pituitary hyperactivity usually from a tumor

Benign prostatic hypertrophy : extensive and uncontrolled division of prostate cells

Testosterone / dihydrotestosterone + estradiol

Erectile dysfunction may occur secondarily to vascular problems associated with diabetes, atherosclerosis

Infertility