PILOT TRIAL OF A GONADOTROPIN HORMONE AGONIST WITH REPLACEMENT HORMONES AS A PROTOTYPE CONTRACEPTIVE TO PREVENT BREAST-CANCER

Combination oral contraceptive (COC) users have reduced risks of ovari an and endometrial cancer, but COCs have not reduced breast cancer ris k. We have previously argued that a hormonal contraceptive with substa ntially lower doses of sex-steroids should reduce breast cancer risk b y decreasing the breast epithelial cell proliferation below usual prem enopausal levels. We report here the preliminary results of a pilot tr ial with such a prototype contraceptive consisting of an agonist of go nadotropin 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-f old or greater increased breast cancer risk were entered and randomize d - 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 li pids. A symptom questionnaire was used to assess tolerance; the contra ceptive subjects had fewer symptoms following initiation of the regime n. This results from the elimination of symptoms associated with the l uteal phase of the menstrual cycle, commonly referred to collectively as premenstrual syndrome, PMS. The few occurrences of hot flushes or v aginal dryness that did occur were eliminated by small increases in es trogen dose (0.9 mg CE). Scheduled vaginal bleeding occurred associate d with most periods of progestogen administration. Unscheduled bleedin g or spotting was infrequent and decreased with time on the regimen. A beneficial rise in high-density lipoprotein cholesterol was evident i n the contraceptive subjects. Despite the use of an estrogen dose whic h is known to prevent loss of bone mineral density in normal postmenop ausal women, an annualized loss of 1.9% was seen in contraceptive subj ects. It is hypothesized that this is secondary to inhibition of ovari an androgen production by the GnRHA, which may additionally account fo r changes in libido occasionally reported with GnRHA. The study contin ues with the addition of a small dose of androgen to replace that lost by the action of the GnRHA.