Medical Pharmacology Chapter 31:  Endocrine: Gonadal Hormones

• 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

Androgen/Anabolic Steroids

• Introduction:  androgens/anabolic steroids

  • Most important androgen: testosterone

  • Leydig cells account for 95% of synthesis

  • Adrenal: 5%

  • Also secreted by the testes:

    • Dhydrotestosterone (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 and 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 and etiocholanolone)

    • Subsequent conjugation

    • Urinary excretion

  • Adrenal Products:

    •  Androstenedione

    •  Dehydroepiandrosterone (DHEA)

    •  Dehydroepiandrosterone sulfate (DHEAS)

•  Physiological Effects:  androgens and 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 and 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 and Testosterone-Derivatives and their Uses:

      • Anabolic effects

      • Replacement treatment in testosterone deficiency

 

Pharmacological Effects:  testosterone and derivatives

• Mechanisms of Action: testosterone and 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)

 Clinical Uses

• Androgen replacement treatment in 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)

    • Rreat 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

  Adverse Effects: androgens

•  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.

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

    • High-dose alkylated androgens:

      • Peliosis hepatica

      • Cholestasis

      • Hepatic failure

      • Reduce plasma HDL₂ and increase LDL

Contraindications: Androgenic Steroids

• 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 and Antiandrogens

• 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 and gonadal steroid synthesis

    • High dosage required to inhibit P450 enzymes.

    • Other ketoconazole effects:

      • Reduces placental aromatase activity

      • Men:  reversible gynecomastia

  • Conversion Inhibitors:

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

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

  • Receptor Inhibitors:

    • Cyproterone and 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

 

Primary Reference: Goldfien, A., The Gonadal Hormones and Inhibitors, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 653-680.

Carr, B. R. and Bradshaw, K.D, Disorders of the Ovary and Female Reproductive Tract , In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 2097-2115.

Mitchell-Leef, D.E. Endometriosis in Medicine for the Practicing Physician, Fourth edition, (Hurst, J. Willis, editor in chief) Appleton and Lange, 1996, pp 751-755.

 

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