Medical Pharmacology: Pituitary Pharmacology and Physiology

Overview: FSH
- Glycoprotein hormone
- Synthesis site: anterior pituitary
Function: FSH
- FSH + LH (luteinizing hormone): gonadal function regulation-- 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-- Site of action for FSH: Sertoli cells, enhance androgen-binding protein production
Modified FSH molecules
- Obtained from postmenopausal women's urine
- One agent --FSH-like characteristics; 4% potency
- Another agent --LH-like characteristics
- FSH-LH combination: menotropins
- Another preparation: also from postmenopausal women's urine but with no LH is urofollitropin

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 -- 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:

Primary amenorrhea	Secondary amenorrhea
Polycystic ovary syndrome	Anovulatory cycle

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) -- 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**
Generic	Trade name
Bromocriptine	Parlodel
Chorionic gonadotropin (hCG)	generic, Profasi
Corticotropin	generic, ACTH
Cosyntropin	Cortrosyn
Desmopressin	DDAVP, Stimate
Gonadorelin acetate (GnRH)	Lutrepulse
Gonadorelin hydrochloride (GnRH)	Factrel
Goserelin acetate	Zoladex
Histrelin	Supprelin
Leuprolide	Lupron
Menotropins (hMG)	Pergonal, Humegon
Nafarelin	Synarel
Octreotide	Sandostatin
Oxytocin	generic, Pitocinit, Syntocinon
Pergolide	Permax
Protirelin	Thypinone, Relefact TRH
Sermorelin (GHRH)	Geref
Somatrem	Protropin
Somatropin	Humatrope, Nutropin
Thyrotropin (TSH)	Thytropar

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