• Overview

  •  Testes -- gametogenic/endocrine functions

    • Gametogenic: FSH-dependent (pituitary secretion)

      • Androgens (high concentrations): required for sperm production in seminiferous tubules

      • Sertoli cells in seminiferous tubules: source for testicular estradiol

      • With LH stimulation:

        •  androgens synthesized in interstitial/Leydigcells between seminiferous tubules

      • Sertoli cell synthetic products and secretions:

        •  mullerian duct inhibitory factor

        •  inhibin-- feedback inhibition (with dihydrotestosterone) of pituitary FSH secretion

        •  activin--stimulates pituitary FSH release

• Introduction:androgens/anabolic steroids

  • Most important androgen: testosterone

  • Leydig cells account for 95% of synthesis

  • Adrenal: 5%

  • Also secreted by the testes:

    •  dihydrotestosterone (potent androgen)

    •  androstenedione

    •  dehydroepiandrosterone

    • pregnenolone -- small amounts; along with 17-hydroxylation derivatives

    • progesterone -- small amounts; along with 17-hydroxylation derivatives

  • 65% of circulating testosterone: bound to sex hormone-binding globulin (SHBG)

  • 33% of circulating testosterone: bound to albumin

  • 2% -- free; they enter cells; bind to intracellular receptors

  • Factors that increase SHBG:

    • thyroid hormone

    • estrogen

    • increased in patients with liver cirrhosis

  • Factors that decreases SHBG:

    • androgen

    • growth hormone

    • obesity

• Metabolism:androgens & anabolic steroids:

  • In many peripheral tissues:testosterone converted to dihydrotestosterone by 5-a reductase

    • in these peripheral tissues: major androgen = dihydrotestosterone

  • In some tissues: testosterone is converted  to estradiol by P450 aromatase, e.g.:

    •  fat

    •  liver

    •  hypothalamus (possible role in a gonadal function regulation)

  • Testosterone Degradation:

    • production of inactive agents (androsterone & etiocholanolone)

    • subsequent conjugation

    • urinary excretion

  • Adrenal Products:

    •  androstenedione

    •  dehydroepiandrosterone (DHEA)

    •  dehydroepiandrosterone sulfate (DHEAS)

•  Physiological Effects:androgens & anabolic steroids

  •  Testosterone:

    • General changes associated with puberty including:

      •  penile/scrotal growth

      •  appearance of pubic, axillary, beard hair

      •  skin changes: oilier/thicker; more active sebaceous glands; darkening; increased circulation

      •  larynx: grows; thicker vocal cords (decrease voice pitch)

      •  increased skeletal growth; acceleration -- epiphysial closure

      •  prostate/seminal vesicles growth

      •  stimulation/maintaining male sexual function

      •  promote lean body mass/stimulate body hair growth

    • Metabolic effects:testosterone

      •  reduced hormone binding; reduced carrier protein

      •  increased (liver) clotting factor synthesis

      •  increased (liver) triglyceride lipase

      •  increased (liver) a₁-antitrypsin

      •  increased (liver) haptoglobin

      •  increased (liver) sialic acid

      •  stimulation of renal erythropoietin secretion

      •  reduction: HDL levels

  • Synthetic Steroids possessing Androgenic & Metabolic Activity

    • Testosterone:

      • Oral administration

        • rapidly absorbed

        • converted to inactive metabolites

        • bioavailability: 17%

        • alkyl-testosterone derivatives (17 position) are orally active:

          • methyltestosterone

          • fluoxymesterone

      • Parenteral Administration:

        • improved absorption time/greater activity when testosterone is esterified to these derivatives:

          • propionate

          • cypionate

          • undecanoate

          • enanthate

    • Testosterone & Testosterone-Derivatives--Uses:

      • anabolic effects

      • replacement treatment in testosterone deficiency

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Pharmacological Effects:testosterone & derivatives

• Mechanisms of Action: testosterone & derivatives

  • Testosterone: Intracellular target sites

  • Converted to 5a dihydrotestosterone (primary androgen) by 5-a reductase in certain tissues:

    • skin

    • seminal vesicles

    • epididymis

    • prostate

  • Testosterone/dihydrotestosterone:

    1. bind to cytosolic androgen receptor

    2. subsequent process is similar to that determined for estradiol/progesterone

• Effects: androgens

  • Puberty: male --

    • secondary sex characteristics

  • androgen + inhibin result in gonadotropic secretion suppression

  • Women: androgens produce physiological changes similar to those observed in the male: (e.g., facial/body hair growth; clitoris enlargement; frontal baldness; more prominent musculature)

• Androgen replacement treatment -- Men:

  • hypogonadal men: androgen replacement/augmentation

  • pituitary deficiency: androgen is used --usually not gonadotropin

    •  androgen added at puberty to promote growth spurt/secondary sex characteristic development

    •  long-acting agent is used:

      • testosterone enanthate

      • testosterone cypionate

    • Other agents/routes of administration:

      • testosterone propionate -- duration of action is too short

      • transdermal:

        • testosterone -- scrotal application (and others areas)

•  Gynecological Disorders:androgens

  •  Used with caution due to undesirable side effects

  • Androgens:

    • reduce breast engorgement during postpartum (usually with estrogens)

    • treat endometriosis (danazol -- weak androgen)

    • In combination with estrogens: postmenopausal replacement therapy to reduce endometrial bleeding {associated with estrogen monotherapy}

    •  chemotherapy: premenopausal women with breast tumors

•  Protein Anabolic Agents:androgens

  • Androgen/Anabolic steroids + diet + exercise reverse  protein loss after:

    • trauma

    • prolonged immobilization

    • individuals with debilitating illness

    • trauma

• Anemia:androgens --

  • Recombinant erythropoietin: has now replaced androgens for treatment of:

    • aplastic anemia

    • Fanconi's anemia

    • sickle cell anemia

    • hemolytic anemias

    • myelofibrosis

•  Osteoporosis:androgens

  • Androgen/anabolic agents:

    • used to treat osteoporosis +/- estrogens

•  Growth Stimulation:androgens

  • Effective in stimulating growth in boys, with delayed puberty

  • Proper use promotes normal height attainment

  • radiological evaluation of epiphyses may help control therapy (note: hormonal action at epiphysial regions persist after therapy is stopped)

•  Anabolic steroid/Androgen abuse in sports:

  • inadvisable due to adverse effects

  • probably increases strength/performance in women; possibly similar effects in men

•  Masculinizing actions

  • women/prepubertal children

  • Effects of women -- testosterone:

    • hirsuitism, acne, depression of menses, clitoral enlargement, voice deepening, endometrial bleeding (progestational effects), serum lipid alterations.

•  Androgens should not be used in children:

  • may cause detrimental changes in maturation of CNS centers involved in sexual development; also peripheral effects on external genitalia.

•  Synthetic Androgens/Anabolic Substances -- 17-alkyl-substituted steroids

  •  Hepatic dysfunction --

    • increased sulfobromophthalein retention

    • increased AST levels (aspartate aminotransferase)

    • clinical jaundice may appear (cholestatic jaundice reversible)

  •  older males:prostatic hyperplasia

  •  Replacement therapy in men:

    • acne, sleep apnea, phases permit, gynecomastia, erythrocytosis.

    • supraphysiologic doses: azoospermia, acting, reduced testicular size --long recovery time

    •  high-dose alkylated androgens:

      • peliosis hepatica

      • cholestasis

      • hepatic failure

      • reduce plasma HDL₂ and increase LDL

•  pregnant women or women who may become pregnant during therapy

•  children

•  Men with breast/prostatic carcinoma

•  patients with renal/cardiac disease in which edema development could worsen the underlying disease state

•  possible relationship between treatment of aplastic anemia with androgen anabolic agents and development of hepatocellular carcinoma.

• Androgen Suppression:

  • Management of advanced prostatic carcinoma:

    • Orchiectomy-- undesirable option

    • large dose estrogen (to reduce androgen availability)-- undesirable option

    • Gonadotropin-releasing hormone analogs also work, e.g.:

      • Leuprolide acetate: gonadotropin releasing hormone analog

        • produce gonadal suppression with constant blood level (not pulses)

        • subcutaneous-- daily or depot injection

        • effective in management of prostatic carcinoma

      • Goserelin:once per month -- subcutaneous slow-release formulation

    • Testosterone levels fall to 10% of the initial values (after a significant initial increase, during which time tumor activity/symptoms may also increase)

    • This initial stimulation may be suppressed by combining the GnRH agonist with flutamide

• Antiandrogens:

  • Steroid synthesis inhibition:

    • Ketoconazole -- inhibits adrenal & gonadal steroid synthesis

    • High dosage required to inhibit P450 enzymes.

    • Other ketoconazole effects:

      • reduces placental aromatase activity

      • men: reversible gynecomastia

  • Conversion Inhibitors:

    • Finasteride: 5-a reductase inhibitor decreases dihydrotestosterone levels in the prostate (dihydrotestosterone: the essential prostatic androgen)

    • May be moderately effective in reducing prostate size in men with benign prostatic hyperplasia

  • Receptor Inhibitors:

    • Cyproterone & cyproterone acetate: effective antiandrogens

      • notable progestational effect -- suppresses feedback enhancement of LH/FSH, further improving antiandrogen effect

      •  clinical use:

        • hirsuitism in women

        • reduction of sexual drive in men

        • orphan drug status in U.S.

    • Flutamide:potent antiestrogen

      •  Clinical use: management of prostatic carcinoma

      • rapidly metabolized

      • often causes mild gynecomastia

      • may be useful in managing excessive androgen synthesis in women

    • Bicalutamide: potent antiandrogen

      •  Clinical use: management of prostatic carcinoma

    • Spironolactone: aldosterone competitive inhibitor

      • also competes with dihydrotestosterone for androgen receptors

      • reduces 17 a hydroxylase activity, decreasing plasma testosterone and androstenedione levels