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Sex hormones- Androgens

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أستاذ المادة انتصار جواد حمد المختار       21/06/2018 13:38:46
Sex hormones- Androgens
Dr. Entisar Al-Mukhtar

Androgens
• Have anabolic and/or masculinizing effects in both sexes.
• Testosterone, the most important androgen synthesized by Leydig cells in the testes & in smaller amounts, by thecal cells in the ovary & by the adrenal gland in both sexes.
• Testes secreted other androgens including 5?-dihydrotestosterone (DHT), androstenedione & dehydroepiandrosterone (DHEA) in small amounts. In males, testosterone secretion is controlled by GnRH, which stimulate FSH & LH secretion from anterior pituitary. [Note: LH stimulates steroidogenesis in the Leydig cells, whereas FSH is necessary for spermatogenesis.]
Testosterone or its active metabolite DHT inhibits FSH & LH production through a negative feedback loop and thus, regulates testosterone production.
The androgens are necessary for:
1. Normal maturation in the male
2. Sperm production.
3. Increased synthesis of muscle proteins & Hb.
4. Decreased bone resorption.
Synthetic modifications of the androgen are designed to (1) modify solubility and susceptibility to enzymatic breakdown (thus prolonging the half-life of the hormone), and (2) separate anabolic and androgenic effects.
MOA:
Testosterone itself is the active ligand in muscle and liver, but in other tissues it must be metabolized to derivatives such as DHT. For example, after diffusing into the cells of the prostate, seminal vesicles, epididymis and skin, testosterone is converted by 5?-reductase to DHT.

Therapeutic uses
1. Androgenic steroid: indicated for primary hypogonadism (due to Leydig cell dysfunction) or, secondary hypogonadism (due to hypothalamic or pituitary failure) .

2. Anabolic steroids: used to treat chronic wasting associated with HIV or cancer.
Note: Unapproved use of anabolic steroids is to increase lean body mass, muscle strength and endurance in athletes & body builder. In some popular publications, DHEA (testosterone & estrogen precursor) has been touted as the antiaging hormone as well as a "performance enhancer". With its ready availability in health food stores, the drug has been abused. There is no definitive evidence that it slows aging, or that it improves performance at normal therapeutic doses.

3. Danazol: is a weak androgen used for the treatment of endometriosis (ectopic growth of endometrium) & fibrocystic breast disease. [Note: Danazol also possesses antiestrogenic activity.]

Pharmacokinetics
1. Testosterone:
• Ineffective orally (first-pass metabolism).
• C17-esters of testosterone (eg. testosterone cypionate or enanthate) are administered I.M.
Note: addition of esters increase hormone lipid solubility & duration of action.
• Transdermal patches, topical gels & buccal tablets of testosterone are available.
• Testosterone & its esters exhibit a 1:1 relative ratio of androgenic to anabolic activity.
2. Testosterone derivatives:
Alkylation of testosterone allows its oral administration (e.g., fluoxymesterone)
• Fluoxymesterone: orally effective agent with long half-life & it has a 1:2 androgenic to anabolic ratio.
• Oxandrolone: orally active testosterone derivative with anabolic activity 3 to 13 times that of testosterone.
• Hepatic adverse effects are associated with the alkylated androgens.

Adverse effects
1. In females:
• Masculinization, acne, facial hair growth, deep voice, male pattern baldness & menstrual irregularities may also occur.
• Testosterone can cause virilization of female fetus (should not be used during pregnancy).
2. In males:
• Priapism, impotence, decreased spermatogenesis & gynecomastia.
• Cosmetic changes like those described for females may occur.
• Prostate growth stimulation.

3. In children:
• Abnormal sexual maturation & growth disturbances due to premature epiphysis plates closure.
4. General effects:
• ? LDL & ? HDL levels thus, ? LDL:HDL & risk of premature coronary heart disease.
• Fluid retention & edema.
5. In athletes:
• Anabolic steroids, (eg, DHEA) used by athletes can cause premature closing of the long bones epiphysis, which stunts growth & interrupts development.
• High doses taken by young athletes may result in (1) reduction of testicular size, (2) hepatic abnormalities, (3) increased aggression (“roid rage”), (4) mood disorders & (5) other adverse effects described above.

Antiandrogens
They either inhibit androgens synthesis or blocking their receptors.
1. Finasteride and dutasteride inhibit 5?-reductase decreasing DHT formation in the prostate & reducing its size, they are used for the treatment of BPH.

2. Flutamide, bicalutamide, enzalutamide and nilutamide act as competitive inhibitors of androgens & are effective orally for the treatment of prostatic cancer.

3. Cyproterone is a progesterone derivative, it competes on testosterone receptors in peripheral organs reducing spermatogenesis that may even cause azoospermia (reversible), it also compete on testosterone receptors in the CNS reducing sexual drive & thoughts resulting in impotence.
• Due to its progesterone activity, cyproterone inhibits gonadotrophin secretion decreasing testicular androgen production.
Cyproterone uses:
(1) Reduce male hypersexuality.
(2) Prostatic CA.
(3) Cyproterone-ethinylestradiol combination is used to treat severe
hirsutism & acne in female. This combination is also used as an OC (but should
not be used primarily for this purpose).

4. Spironolactone is a DHT receptor antagonist, used to treat hirsutism in female.


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