Anabolic agents and male impotence

Author: Luca Gargano
Date: 24/03/2013



Androgens are hormons secreted by testicles, ovary and adrenal gland, having anabolizing and virilizing action. Male's hormon, testosterone, also has an important action on anabolic metabolism: epifisis ossification, development of muscle mass, sexual dimorfism.
Testosterone origins from the perypheral conversion of DHEA and androstenedione by a dehydrogenase (produced in the adrenal cortex) and it's also produced in the testes in much bigger amount.

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Hypothalamic and pituitary control

Corticotrophin-releasing hormone (CRH), secreted by the hypothalamus, is transported to hypophisis and acts on a G-protein linked receptor to stimulate a cAMP increase. This causes synthesis and release of adrenocorticotrophin (ACTH). ACTH derives from a precursor molecule called pro-opiomelanocortin (from wich derive opioid peptides and melanocyte stimulating hormone too), and stimulates the release of glucocorticoids and androgens. It also increases pregnelone production from cholesterol and, as subsequent action, the induction of steroidogenic enzymes.

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Gonadotrophin synthesis and secretion

GnRH is a peptide synthesized mainly in the arcuate nucleus of the hypotalamus, and plays a role in sexual behavior. It's secreted in a pulsatile manner, hourly, and released with gonadotrophin associated peptide (GAP), acting on the gonadotoph via a G-protein linked receptors that activate phospholipase C with hydrolisis of PIP2 to IP3 and diacylglycerol and activation of protein kinase C.

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GnRH secretory pulses regulate the releasing of LH and FSH; in the absence of regular pulses, pituitary gonadotrophin loses GnRH receptors and become less and less sensitive (causing hypothalamic hypo-gonadism).

Gonadotrophins and testicular function

FSH and LH are important regulators of spermatogenesis and steroidogenesis, acting respectively on the Sertoli cells and Leydig cells. They increase intracellular concentrations of free cholesterol and its transport through the mitochondrial membrane by the StAR protein (the regulation of StAR is the rate-limiting step in gonadotrophin-induced steroid synthesis). Here cholesterol is converted into pregnenolone, then in androstenedione, DHEA and testosterone: these androgens bind to an androgen-binding protein (ABP), which carries them in the testicular fluid. Some testosterone is converted to estradiol by Sertoli cell-derived aromatase enzyme.

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Leydig cell steroidogenesis is controlled primarily by LH with negative feedback of testosterone on the hypothalamic-pituitary axis. Testosterone and FSH act synergically on the Sertoli cells, that produces inhibin (which has a selective negative feedback action on FSH secretion) and androgen receptors. The small amount of estrogen formed from peripheral aromatization of testosterone can inhibit both FSH and LH secretion.
If testicular androgen production is inhibited by the administration of exogenous androgens then spermatogenesis ceases.

Transport, metabolism and actions of androgens

The 98% of circulating testosterone is bound to albumin or to sex-hormone-binding globulin (SHBG). SHBG is synthesized in the liver and its circulating concentration is increased by estrogen or excess thyroid hormones and decreased by exogenous androgens, glucocorticoids or growth hormone and by hypothyroidism, acromegaly and obesity. In the liver, testosterone is converted to androsterone and etiocholanolone.
In target tissues, testosterone or its reduced form DHT induces release of a heat shock protein, dimerization of two receptors and translocation to the nucleus where the dimer binds to an estrogen-like hormone response element on DNA.

Anabolic agents

Anabolic steroids are testosterone-derivated, used to treat retarded puberty (mostly hypogonadism), osteoporosys and particular forms of anemia. They bind to receptors on the cell surface, inducing the production of proteic synthesis enymes such as RNA polymerase, which increase body mass and N balance.
Athletes abuse (10-100 times the therapeutic dose) of these agents to increase their performance: in facts, anabolic agents compete with glucocorticoids during episodes of stress, inhibiting catabolism and promoting employ of Nitrogen for the proteic construction. There have been many attempts to create androgen-effect-laking anabolic agents, by modification of the testosterone molecule in 3 different positions (A, B and C). Efficacy has been implemented, but it hasn't been possible to reduce androgenic action. B and C-class per os steroids (Danazolo, Fluoximesterone, Metiltestosterone, Oxandrolone) are more toxic than the class A ones, but also more effective. A-class injectable steroids are less toxic but they've a minor activity.

Adverse reactions

Anabolic agents have been associated to trombotic events (heart attack, stroke), epatic cancer, tendon rupture, psychological damages and dramatic effects on the reproductive system. Sexual behavior is initially characterised by an encreasing of libido and virility. Successively, exogen anabolic steroids replace testosterone in the negative-feedback to the pituitary and hypothalamic system, causing a gonadotrophins decrease. As a result, testes production of testosterone is heavily lowered and testicles atrophy (sometimes irreversibly). Spermatogenesis decreases by 90%, leading to infertility. Androgens in excess are aromatized and converted in estradiol, which reaches levels up to 7 times the level of a woman in ovulation, causing ginecomasty and impotence.
Erection and eiaculation are affected by this deficiency of androgens, which causes a gradual loss of sex interest and an increasing incidence of erectile disfunction.

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2014-06-28T13:25:36 - Luca Gargano
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