Secondary amenorrhea commonly affects women who participate in competitive and recreational sports, particularly running and dance. Women of reproductive age with this condition require estrogen replacement and, often, additional cyclic progestin to prevent excessive growth of the endometrium. Some of the most commonly used synthetic oral and transdermal progestins produce undesirable side effects related to the liver, making natural progesterone a better alternative. In addition, orally administered progesterone can cause dizziness and drowsiness; therefore, a transvaginal delivery method may be the only practical route. Warren and associates evaluated the safety and effectiveness of cyclic vaginal natural progesterone gel in women with secondary amenorrhea.

Women of reproductive age with confirmed secondary amenorrhea were eligible for the study. The study period consisted of three consecutive 28-day treatment cycles during which all patients received either 0.625 mg daily of conjugated estrogen or approximately 0.05 mg of transdermal estradiol daily. Patients were then randomized to receive 1.125 g of either 4 percent (45 mg) or 8 percent (90 mg) transvaginal progesterone gel every other day starting on day 15 of cycles two and three, for a total of six applications per cycle. Ultrasound examinations and laboratory studies were obtained before progesterone gel therapy was started to document that the endometrium had been adequately estrogenized. Efficacy was based on endometrial biopsy findings and the presence of withdrawal bleeding.

Of the 127 women enrolled in the study, 62 received 4 percent gel and 65 received 8 percent gel. Demographic data were similar between groups. Biopsy results showed that all patients in the higher dosage group had progestational changes in their endometrium, compared with 92 percent of patients in the lower dosage group. None of the patients had endometrial hyperplasia. Withdrawal bleeding occurred with equal frequency (about 82 percent) in the active drug treatment groups. Sixty-three percent of patients (17 of 27) who received the estradiol transdermal system experienced withdrawal bleeding compared with 69 percent (69 of 100) who received oral conjugated estrogen. Most patients experienced withdrawal bleeding 10 to 12 days after the initial placement of the progesterone gel.

The incidence of side effects, particularly psychologic effects, bloating and nausea, decreased significantly after patients began taking the progesterone gel, compared with estrogen alone. Headaches decreased significantly in the higher dosage group. Vaginal discharge increased significantly in frequency in the lower dosage group but decreased significantly in the higher dosage group. Cramping increased in both groups after initiation of gel therapy.

The authors conclude that progesterone vaginal gel is safe and effective in providing hormone replacement therapy in women with secondary amenorrhea. Transvaginal progesterone gel resulted in withdrawal bleeding in 81 percent of estrogenized women with hypothalamic amenorrhea or premature ovarian failure. Results also indicated that some women might require the higher dosage to maximize progestogenic effects on the endometrium. Psychologic side effects diminished with the combination of estrogen and progesterone, compared with estrogen alone. In fact, unexpected improvement in the feeling of well-being was observed when estradiol and natural progesterone were combined.