Progestins

Progesterone & derivatives estrogenic androgenic anti-estrogenicccc antiandrogenic anabolic

progesterone

-

-

+

-

-

Hydroxyprogesterone capoate

-/+

-/+

-

-

-

Medroxyprogesterone acetate

-

+

+

-

-

Megestrol acetate

 - + - + -
17 ethinyl -testosterone derivatives & testosterone drivatives          

Dimethisterone

 - - -/+ - -
19-Nor-testosterone derivatives          
Desogestrel - - - -  
Norethynodrel + - - - -
Norethindrone -/+ + + - +
Ethynodiol acetate -/+ + + -  
L-Norgestrel - + + - +

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  •  Synthetic Progestins I:
    • Variable Properties within the group:
    • Most closely related: 21-carbon agents, e.g.
      • hydroxyprogesterone
      • hydroxyprogesterone
      • megestrol
      • dimethisterone
    • Newer, "third-generation" synthetic progesterones
      • components of oral contraceptives
      • includes newer "19-nor, 13-ethyl" steroids, e.g.
        • gestodene
        • norgestimate
        • desogestrel

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  • Pharmacokinetics:progesterone
    • Progesterone
      •  rapidly absorbed
      •  half-life = approximately five minutes
      •  extensive first pass metabolism (oral administration -- ineffective)
      •  Hepatic Metabolism:progesterone
        • metabolized to pregnanediol
        • urinary excretion product: pregnanediol glucuronide
          • pregnanediol glucuronide levels: useful to assess progesterone secretion
          • other metabolites formed in small quantities

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  • Physiological mechanisms:progesterone
    • Mechanism:progesterone
      1. progestins enter the cell
      2. binds to progesterone receptors (distributed between nucleus & cytoplasm)
      3. ligand-receptor complex: binds to nuclear response elements, activating gene transcription
        • response elements: similar to corticoid response elements
        • response specificity dependencies:
          •  receptor type present
          •  cell-specific transcription factors
      4. progesterone-receptor complex dimerizes then binds to DNA

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 Progesterone effects: Metabolic
stimulates lipoprotein lipase promotes fat deposition limited effect on protein metabolism significant effect on carbohydrate metabolism
increases basal insulin levels increases insulin response to glucose promotes glycogen storage (liver) promotes ketogenesis

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  • competes with aldosterone and renal tubule: decreasing sodium reabsorption
  • reduce other reabsorption promotes increased adrenocortical aldosterone secretion
  • increases body temperature
  • increases developed for response to CO2
    • reduces arterial/alveolar PCO2 during pregnancy
    • reduces PCO2 during menstrual cycle luteal phase
  • depressant/hypnotic CNS effects
  • causes alveolobular development of the breast secretory apparatus
  • following ovulation
  • decreases amino acid plasma levels which increases urinary nitrogen excretion

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  • Synthetic Progestins II:
    • 21-carbon progesterone analogues
      • antagonism: aldosterone-induced sodium retention
      • slight androgenic/estrogenic effects
    • "19-nortestosterone", third-generation drugs:
      • induce decidual endometrial stromal change
      • more effective gonadotropin inhibitors
      • minimal androgenic/estrogenic/anabolic activity

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Progestins without androgenic activity include:
desogestrel gestodene norgestimate

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  • Clinical Uses: Progestins
    •  Therapeutic Uses:
      • Major uses:
        • hormone replacement treatment
        • hormone contraception

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    • Other Uses:
      • Induction of long-term ovarian suppression {large, parenteral does -- e.g.,medroxyprogesterone acetate} ® prolonged anovulation; amenorrhea
        • may be used to treat:
          •  dysmenorrhea
          •  endometriosis
          •  hirsuitism
          •  bleeding disorders (where estrogens -- contraindicated)
          •  contraception
        • significant problem: substantial delay before normal ovulatory function is regained
      • Medroxyprogesterone acetate: stop maturation in children with precocious puberty
        • Precocious puberty:
          • Definition:
            • breast budding before age 8
            • menarche before age 9
            • developing sexual characteristics: appropriate for genetic/gonadal sex: isosexual percocity
            • developing such characteristics: appropriate for opposite genetic/gonadal sex: heterosexual percocity
          • Cause:
            • early, otherwise normal sequence of pubertal development; with increase gonadotropin secretion and ovulatory menstrual cycles
            •  Idiopathic (constitutional) precocious puberty: frequency -- 90%
            •  10% of cases: due to organic brain disease including:
              • brain tumors
              • encephalitis
              • meningitis
              • head injury
              • neurofibromatosis
              • tuberous sclerosis
      • Progestins: no role in treatment of threatened/habitual abortions

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  • Diagnostic Uses:Progestins
    • Estrogen secretion testing
      • administration of progesterone or medoxyprogesteronethat are withdraw bleeding in amenorrheic patients (only in estrogen-stimulated endometrium)

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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.