HORMONES OF THE GONADS

The gonads are bifunctional organs that produce germ cells and the sex hormones. The ovaries produce ova and the steroid hormones estrogen and progesterone while the testes produce spermatozoa and testosterone. The productions of these hormones are tightly regulated through a feed- back loop that involves the pituitary and hypothalamus. The testes have two functions Testosterone production. Spermatozoa.

Three specialized cell types carry out these functions: -Spermatogonia more differentiated germ cells are located in the seminiferous tubules. - The leyding cells (also called interstitial cells) which are scattered in the connective tissue between the coiled seminiferous tubules and which produce testosterone in response to LH. -The Sertoli cells which form the basement membrane of the seminiferous tubules and provide the environment necessary for germ cell differentiation and maturation, through the production of the androgen binding protein (ABP) under the effect of FSH and this ABP has a very high affinity for Testosterone (TT) and so TT will enter to inside leading to a very high concentration of TT (*100) and this very high concentration will ensure differentiation and maturation of sperms therefore spermatogenesis require TT which is form under the control of LH which will ensure the differentiation and maturation of sperms.

BIOSYNTHESIS OF TESTOSTERONE: Testicular androgens are synthesized in the interstitial tissue by the Leyding cells . The immediate precursor of the gonadal steroids as for the adrenal steroid is delivery of cholesterol to the inner membrane of the mitochondria by the transport protein steroidogenic acute regulatory protein (STARP) . Once in the proper location, the side chain cleavage enzyme P450SCC acts it upon. The conversion of cholesterol to pregnenolone is identical in adrenal, ovary, and testis, except that in the later tissues the reaction is promoted by LH rather than by ACTH. This occurs in the mitochondria and following the formation of pregnenolone it will leave the mitochondria to the endoplasmic reticulum where all the subsequent steps will occur.

The conversion of pregnenolone to testosterone requires the a action of five active enzyme activities these are: 3b-hydroxysteroid dehydrogenase (3bOHD) and D5,4isomerase. 17a-hydroxylase and C17, 20 lyase. 17b-hydroxysteroid dehydrogenase (17bOHSD). This sequence referred to as the progesterone (or D4)which is on the right side of the figure.

Pregnenolone can also be converted to testosterone by the dehydroepiandrosterone (or D5pathway) which is on left side of the figure. The route D5pathway appears to be preferred in human testes. Therefore formation follows 2- pathways: -The upper pathway (D5pathway). -The lower pathway (D4pathway). The TT can be converted in to another hormone in the testes as in peripheral target tissue or even in the liver and therefore TT is considered to be a hormone and pre-hormone. The reduction of ring A at position 5 through the action of the enzyme (5-a-reductase) lead to the production of 5adihydroxytestosterone. 2types of (5areductase) are present: Type I which is present in the liver and Type II which present in the peripheral target tissue.

During the day about 5mg of TT is synthesized and on the other hand the testes produce about 0.1mg of DHT however about 0.3-0.4 mg of DHT is being produced in the extratesticular tissues making the day production of DHT to about 1\10 the day production of TT (0.5mg\day for DHT to 5mg\day for TT). Target tissues in the body which are sensitive to TT such as : spermatogonia,embryonic walfain structure,muscle ,liver and brain as well as kidney. On the other hand there are certain organ which are sensitive to DHT such as: prostate, seminal vesicle, external genitalia and genital skin. The testes as well as extratesticular tissue can also lead to the production of small amount of estrogen specially estradiol (E2). Through aromatization of ring A and this occur as part of the source for estrogen in male and this small amount of E2 play a role in feed back control of spermatogenesis through feed back inhibition on FSH together with inhibin, DHT, TT but the inhibin is the most potent inhibitor. E2 has also an additional effect on modifying the behavior of the testes.

PLASMA TRANSPORT OF TT: TT binds to plasma b-globulin that binds TT with specificity, relatively high affinity and limited capacity. This called (SHBG) sex hormone binding globulin or testosterone-estrogen binding globulin (TEBG) is produced in the liver its production is increased by * estrogen (women have twice the serum conc. Of SHBG as men), * certain type of liver disease and, *hyperthyroidism.

It is decreased by androgens,. advancing age, and by. hypothyroidism It is decreased by androgens, *advancing age, and by *hypothyroidism. TT bind to SHBG and albumin 97-99% so 3%-1% only present in free (active) form .The primary function of SHBG may be to restrict the free concentration of TT in the serum, so a change in the level of SHBG causes a greater change in the free TT level than in free estradiol because it has less affinity to bind with SHBG. An increase in SHBG leads to increase free E2: TT ratio noted aging, cirrhosis, and hyperthyroidism.

METABOLIC FUNCTION OF TT: 1-Sexual differentiation. 2-Spermatogenesis METABOLIC FUNCTION OF TT: 1-Sexual differentiation. 2-Spermatogenesis. 3-Development of secondary sexual features. 4-Developments of anabolic features which are of systemic wide stress effect on somatic growth, include bone, Ms. Cartilage. -Anabolic effect (promoting synthesis effect).

Male Femal Total TT 11-33nmol\l 0. 5-2 Male Femal Total TT 11-33nmol\l 0.5-2.5nmol\l SHBG 58% 97% Albumin 40% 2% Free 2% 1%

Metabolism of TT: TT is metabolized by 2 pathways: -Involves oxidation at the 17-position. -Involves reduction of the A ring double bond and the 3-ketone. Metabolism of 1st pathway occur at many tissues include liver ,and produce 17-ketosteroids that are generally inactive or less active than the parent compound while metabolism via the 2nd pathway which is less efficient occurs primarily in the target tissues and produces the potent metabolite DHT. TESTOSTERONE a-5reductase DHT NADPH

The most important metabolic product of TT metabolism is the DHT The most important metabolic product of TT metabolism is the DHT. Since in many tissues include prostate, external genitalia, and some area of skins it’s the active form of hormone. Plasma content in adult male is 1\10 of TT and about 400mg of DHT is produced daily while TT 5mg. Two form of 5a-reductase are present (type II and I). Type I predominantly expressed in the liver, while type II is predominant in reproductive tissues and peripheral targets. Mutation of this type II associated with male pseudohermaphroditism. The major 17-ketosteroid metabolites, androsterone and etiocholanolone are conjugated with glucuronide and sulfate in the liver to make them water soluble and excretable compounds.

REGULATION OF TT LH stimulates steroidogenesis and testosterone production by binding to the receptors on the plasma membrane of leyding cells (an analogous LH receptor is found in the ovary on cells of corpus luteum) and activating adenyl cyclase, thus increase intracellular cAMP. This action enhances the rate of cholesterol transport by STARP and side chain cleavage by P450SCC. TT provides for feed back control at the hypothalamus through inhibition of GnRH release, GnRH production or both.