Pilot trial of a gonadotropin hormone agonist with replacement hormones as a prototype contraceptive to prevent breast cancer

Contraception. 1993 May;47(5):427-44. doi: 10.1016/0010-7824(93)90095-o.


Combination oral contraceptive (COC) users have reduced risks of ovarian and endometrial cancer, but COCs have not reduced breast cancer risk. We have previously argued that a hormonal contraceptive with substantially lower doses of sex-steroids should reduce breast cancer risk by decreasing the breast epithelial cell proliferation below usual premenopausal levels. We report here the preliminary results of a pilot trial with such a prototype contraceptive consisting of an agonist of gonadotropin releasing hormone (GnRHA) administered with low doses of an oral estrogen (0.625 mg of conjugated estrogen, CE, for 6 days every week) and intermittent oral progestogen (10 mg of medroxyprogesterone acetate, MPA, for 13 days every 4 months). Eighteen subjects at five-fold or greater increased breast cancer risk were entered and randomized -12 to the contraceptive arm and 6 to a control arm. The principal endpoints included tolerance of the regimen, vaginal bleeding patterns, and the regimen's effect on the endometrium, bone metabolism, and lipids. A symptom questionnaire was used to assess tolerance; the contraceptive subjects had fewer symptoms following initiation of the regimen. This results from the elimination of symptoms associated with the luteal phase of the menstrual cycle, commonly referred to collectively as premenstrual syndrome, PMS. The few occurrences of hot flushes or vaginal dryness that did occur were eliminated by small increases in estrogen dose (0.9 mg CE). Scheduled vaginal bleeding occurred associated with most periods of progestogen administration. Unscheduled bleeding or spotting was infrequent and decreased with time on the regimen. A beneficial rise in high-density lipoprotein cholesterol was evident in the contraceptive subjects. Despite the use of an estrogen dose which is known to prevent loss of bone mineral density in normal postmenopausal women, an annualized loss of 1.9% was seen in contraceptive subjects. It is hypothesized that this is secondary to inhibition of ovarian androgen production by the GnRHA, which may additionally account for changes in libido occasionally reported with GnRHA. The study continues with the addition of a small dose of androgen to replace that lost by the action of the GnRHA.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Bone Density / drug effects
  • Breast / drug effects
  • Breast / pathology
  • Breast Neoplasms / prevention & control*
  • Contraceptives, Oral, Combined / adverse effects
  • Contraceptives, Oral, Combined / pharmacology*
  • Delayed-Action Preparations
  • Drug Tolerance
  • Endometrium / drug effects
  • Endometrium / pathology
  • Estrogens, Conjugated (USP) / adverse effects
  • Estrogens, Conjugated (USP) / pharmacology
  • Female
  • Humans
  • Leuprolide / adverse effects
  • Leuprolide / pharmacology
  • Lipids / blood
  • Medroxyprogesterone Acetate / adverse effects
  • Medroxyprogesterone Acetate / pharmacology
  • Menstruation / drug effects
  • Pilot Projects


  • Contraceptives, Oral, Combined
  • Delayed-Action Preparations
  • Estrogens, Conjugated (USP)
  • Lipids
  • Medroxyprogesterone Acetate
  • Leuprolide