Follicle-Stimulating Hormone (FSH)

• Overview:  FSH

  • Glycoprotein hormone

  • Synthesis site: anterior pituitary

• Function:  FSH

  • FSH + LH (luteinizing hormone): gonadal function regulation which is mediated by increasing cAMP levels in gonadal tissue.

  • FSH:  principal function:

    • Gametogenesis and follicular development stimulation in women

    • Spermatogenesis in men

  • FSH site of action: immature ovarian follicular cells:  promoting development of the mature follicle and oocyte

    • FSH + LH required for correct ovarian steroidogenesis

      • (LH stimulates and production; FSH stimulates androgen conversion into estrogens (granulosa cells))

  • Testes are the site of action for FSH at Sertoli cells resulting in  enhancement of androgen-binding protein production

• Modified FSH molecules

  • Obtained from postmenopausal women's urine

  • One agent exhibits FSH-like characteristics; 4% potency

  • Another agent shows LH-like characteristics

  • FSH-LH combination: menotropins

  • Another preparation: also from postmenopausal women's urine but with no LH is urofollitropin

 

 Leutinizing Hormone (LH)

• Glycoprotein hormone (two chains)

• Site of synthesis: anterior pituitary

• Major physiological role:

  • Regulation of gonadal steroid hormone production

  • Site of action:  male:

    • Testicular Leydig cells:   stimulation of testosterone production

  • Site of action in the female:

    • Mature follicle:  induce ovulation;

    • Stimulation of corpus luteum (in menstrual cycle luteal phase):  to produce progesterone and androgens

  • Note: no LH preparation available for clinical use. Human chorionic gonadotropin (very similar structure) may be used as a leutinizing hormone substitute

 

Gonadotropins (hMG, Menotropins and FSH, Urofollitropin)

• Overview:  gonadotropins

  • Human menopausal gonadotropins (hMG): Composition

    • Mixture, partially catabolized human FSH and LH (extraction -- postmenopausal women's urine)

    • Standardized for FSH and LH content

    • Used for treating infertility --

      •  In women: stimulation of ovarian follicle development

      •  In man: spermatogenesis

      •  Both sexes: hMG must be used with luteinizing hormone (human chorionic gonadotropin, hCG) to ensure:

        • Ovulation implantation women

        • Testosterone production and full masculinization in men

• Pharmacokinetics:  gonadotropins

  • 7-12 day course daily hMG or urofollitropin (simulating ovarian cycle follicular phase in women with hypothalamic amenorrhea): 

    •  FSH levels increase to 2X baseline;

    •  LH levels increase to 1.5X baseline (hMG only; not with urofollitropin)

• Pharmacodynamics:  gonadotropins

  • Women: hMG or FSH treatment of gonadotropin-deficient women:   ovarian follicular growth/maturation

    • Ovulation: chorionic gonadotropin requirement following follicular maturation

  • Men with gonadotropin deficiency: chorionic gonadotropin pre-treatment:  external sexual maturation

    • Subsequent hMG treatment:  permatogenesis, fertility

• Clinical Use:  gonadotropins

  • Indication: pituitary or hypothalamic hypergonadism with infertility

  • Population of anovulatory women would these conditions may benefit from human menopausal gonadotropin:

• hMG and FSH: used in in vitro fertilization programs for ovarian hyperstimulation

• Men with hypogonadotropic hypogonadism become fertile following hMG administration: success frequency = 50%.

•  Toxicity:  gonadotropins

  • Ovarian overstimulation with hMG: ovarian enlargement (uncomplicated) exhibits a frequency 20% of patients

  • "Hyperstimulation syndrome": more serious: frequency = 0.5-4%

    • hMG-induced ovarian enlargement

    • Ascites

    • Hydrothorax

    • Hypovolemia (shock may occur)

    • Hemoperitoneum (secondary to ruptured ovarian cyst)

    • Fever

    • Arterial thromboembolism

  • Possible abnormal development/premature corpus luteum degeneration in some patients

  • In men: gynecomastia -- occasionally

• Other Effects:  gonadotropins

  • Frequency multiple births following hMG treatment: 25%

•  Contraindications:  gonadotropins

  • Human menopausal gonadotropin and urofollitropin should not be used in the presence of uterine, tubal, or ovarian diseases or pregnancy

Hypothalamic/ Pituitary Agents

Primary Reference: Fitzgerald, P.A. and Klonoff, D.C. Hypothalamic and Pituitary Hormones, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 603-618.

Primary Reference: Biller, Beverly M. K. and Daniels, Gilbert, H. Neuroendocrine Regulation and Diseases of the Anterior Pituitary and Hypothalamus, 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 1972-1998