Bleeding pattern in postmenopausal women using constant combined association of the vaginal progesterone crinone 4% and transdermal estradiol (E2) twice weekly.

Abstract

Objective: Uterine bleeding is one of the primary reasons invoked by women who interrupt postmenopausal hormone replacement therapy (HRT). To palliate this problem, constant combined HRT regimens have been designed with the objective that the uninterrupted progestin administration induces endometrial atrophy and amenorrhea. Unfortunately however, local effects of progestins fragilize the perivascular tissue and trigger dysfunctional uterine spotting and/or bleeding. This occurring in a relatively large fraction of constant combined HRT users, often leads to interrupting HRT. We conceived the present trial to determine whether constant uterine exposure to progesterone rather than progestins in conjunction with estrogen replacement therapy could improve the bleeding pattern and increase the incidence of complete amenorrhea at 6 months of treatment. Design: Single center, 1 year prospective open trial. Materials/Methods: 35 healthy postmenopausal women 53 (2.1), mean (SD), years of age and at least 3 years into menopause elected to participate. An endometrial biopsy and pelvic transvaginal ultrasound was performed before and at study completion. Bleeding pattern was self recorded by patient in a diary card. Cycles without or with spotting and/or frank bleeding were computed. Treatment consisted of transdermal E2 systems (0.05 mg/day) and the vaginal progesterone gel Crinone 4% administered twice weekly. Results: 28/35 (80%) patients completed the 12–14 month study while 3 dropped out because of excessive bleeding and 4, for personal reasons. This amounted to 340 cycles studied. Of these, 67 (20%) were associated with spotting or bleeding. 14 patients (50%) did not bleed at all during the entire study and 12 presented with some bleeding and/or spotting for less than 6 months. After 6 months of therapy amenorrhea was achieved in 26/28 (93%) patients. In 2 cases, bleeding continued until month 7 and 8, respectively and later subsided. At study completion, endometrial thickness on ultrasound was <5 mm in all patients and endometrial biopsies showed no hyperplasia. Conclusions: Twice weekly administration of the progesterone gel Crinone 4% in conjunction with transdermal E2 resulted in amenorrhea in 273/340 (80%) cycles. 28/35 (80%) patients completed the one year study and after 6 months of therapy, >90% of them reached complete amenorrhea. Compared to published data on constant combined regimens using oral synthetic progestins, our findings obtained with twice weekly administration of the vaginal progesterone gel showed an improvement of in the incidence of complete amenorrhea. Furthermore, the high incidence of study completion (80%) speaks strongly for the good acceptance of this HRT regimen. It also indicates that menopausal women accept long term vaginal therapy with Crinone 4% because of the limited side effects (Warren et al., Int. J. Fertil. 1999;44:96–103) and because, in most it results in a true “no bleed” HRT regimen. Supported by: Serono Italy.