Gonadal Page 6

Hormonal Contraception

Overview:
- Oral contraceptive preparations contain:
  - estrogens
  - progestins
  - estrogens and progestins
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- Two types of preparations for oral administration:
  - estrogen/progestin combinations
  - continuous progestin treatment (no concurrent estrogen administration)
  - preparations for oral use: all well-absorbed
  - for estrogen/progestin combinations: neither drug alters pharmacokinetics of the other.
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- Implant Preparation:
  - Norgestrel -- effective ovulation suppressant; released from subcutaneous implants (norgestrel may also be utilized as progestin component of oral contraceptives preparation reprint
  - Medroxyprogesterone -- large dose, intramuscular injection ® long duration contraception
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Pharmacological Effects:
- Mechanism of Action:contraception
  - estrogen/progestins: contraception by selective pituitary function inhibition leading to ovulation-inhibition
  - Combination agents (estrogen + progestins) cause change in cervical mucus
  - Combination agents (estrogen + progestins) produce motility and uterine tube secretion changes
  - *note: continuous use of progestins alone (effective contraceptive): does not always inhibit ovulation, i.e. other factors (above) are significant.
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- Ovarian Effects:
  - Combination agent/chronic use:
    - ovarian function depression
    - minimal follicular development
    - absence of:
      - corpus lutea
      - larger follicles
      - stromal edema
  - Following drug discontinuation: most patients (75%) on the late in first post-treatment cycle; 97% by the third post-treatment cycle
  - About 2% of patients remain amenorrheic for long periods (up to several years following contraceptive treatment)
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- Uterine Effects:
  - Following long contraceptive use:
    - possible cervical hypertrophy; polyp formation
    - cervical mucus changes (resembles postovulation mucus {thick/less copious}
  - Combination (estrogen/progestin) agents cause:
    - stromal deciduation at cycle end
  - Combination agents containing (19-nor) progestins:
    - increased glandular atrophy
    - less bleeding
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- Effects on the Breast:estrogen-containing agents
  - stimulation; some enlargement
  - estrogen + estrogen/progestins combination ® lactation suppression
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- CNS Effects:estrogen-containing agents
  - estrogen: increase in CNS excitation
  - progestin: decrease in CNS excitation
  - thermogenic effect (progesterone + synthetic progestins ® (possibly mediated in the CNS
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- Endocrine Function:estrogen/oral contraceptives
  - change adrenal structure and function
  - estrogens: increase corticosteroid-binding globulin concentration in the plasma
  - changes in angiotensin-aldosterone system; increased plasma renin activity; increased aldosterone secretion
  - increase in thyroxine-binding globulin;
    - increased plasma thyroxine (T₄) levels
    - increase SHBG levels (sex hormone-binding globulin)® decrease free androgen plasma levels
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- Effects on Blood:estrogens/oral contraceptives
  - inconsistent alteration in blood coagulation times
  - increase in factors VII, VIII, IX and X
  - decrease in antithrombin III
  - increase in coumarin derivatives amounts required to increase prothrombin time in patients on oral contraceptives.
  - increase in serum iron/total iron-binding capacity
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- Hepatic Effects:estrogen/contraceptives
  - changes in hepatic drug excretion/metabolism
  - delayed clearance of sulfobromophthalein
  - reduced bile flow
  - increased cholic acid component in bile acids; proportion of chenodeoxycholic acid increased ® incidence of cholelithiasis
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- Lipid Metabolism Effects:estrogen/contraceptives
  - estrogens: increase serum triglycerides, free and esterified cholesterol
  - estrogens: increase phospholipids
  - estrogens: increase high-density lipoproteins (HDL)
  - estrogens: decrease low-density lipoproteins (LDL)
  - estrogen effects seen at somewhat higher doses (i.e. 100 ug of mestranol or ethinyl estradiol; minimal effects at doses < 50 ug).
  - Progestins-- antagonizes these estrogen effects
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- Carbohydrate Metabolism Effects: estrogen/contraceptives
  - Effects similar to those observed in pregnancy
  - Decreased GI tract carbohydrate absorption
  - Progesterone: increases basal insulin; increases insulin rise induced by carbohydrates
  - Reduced carbohydrate tolerance associate with long-term potent progestin use, e.g. norgestrel -- (effect reversible)
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- Cardiovascular System Effects:estrogen/contraceptives
  - higher systolic/diastolic blood pressure (usually slight)
  - increased heart rate
  - important to monitor blood pressure
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- Skin Effects:estrogen/contraceptives
  - increase pigmentation (chloasma)
    - enhanced by exposure to UV light
    - enhanced in women with darker complexions
  - androgen-like progestins: increased sebum; acne
  - typical ovarian androgens suppression often leads to decreased sebum production and acne
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Clinical Uses

Primary clinical use of combined estrogen/progestins: oral contraception
- Small risk of conception (when these agents are used as directed)
- Pregnancy rate (combination agents): 0.5-1 per 100 women years at risk
- Factors contributing to contraceptive failure:
  - phenytoin administration
  - antibiotic administration
  - missing doses

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Other Clinical Uses:
- Endometriosis Treatment
- Severe dysmenorrhea -- major symptom
  - estrogen therapy may induce painless periods; however this approach is often inadequate
  - Alternatively: long-term progestin dose or long-term progestin/estrogen doses prevents endometrial tissue periodic breakdown

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