We investigated the presence of mutations/polymorphisms in the FSH receptor (FSHR) gene and their association with phenotype in women with premature ovarian failure (POF) in southern Brazil. Clinical and hormonal variables were determined in 36 46,XX women with primary or secondary amenorrhea before the age of 40 yr, FSH >40 IU/l and ovarian failure. DNA was isolated from peripheral leukocytes. Exons 6, 7, 9, and 10 of the FSHR gene were analyzed by PCR, restriction enzyme analysis, denaturing gradient gel electrophoresis, and direct sequencing. No inactivating mutations were found. Exon 10 had two polymorphisms, Ala307Thr and Ser680Asn (allelic frequency: 52.9 and 35.7%, respectively), which were not related to FSH, LH or estradiol serum levels. Ovarian size and small ovarian follicles on transvaginal sonography were not associated with FSHR genetic variants. In contrast, the last menstruation occurred significantly earlier in patients with the Ala307Thr polymorphism (A: age=33.3+/-7.1 yr vs T: 28.6+/-11.4 yr, p=0.04). In conclusion, we did not identify inactivating mutations in exons 6, 7, 9, and 10 of the FSHR gene. A high frequency of two polymorphisms that are in linkage disequilibrium was found in exon 10 of the FSHR gene. The presence of the Ala307Thr polymorphism may be associated with a more precocious onset of clinical disease.

Endometrial response to natural estradiol and low-dose vaginal progesterone replacement therapy was evaluated in 20 postmenopausal women with chronic, mild-to-moderate hypertension. A cyclic hormone replacement therapy (HRT) regimen was used (21/28 days) with percutaneous estradiol (1.5 mg/day) and vaginal micronized progesterone (100 mg/day). Menopausal symptoms decreased and estradiol concentrations increased substantially and remained in the physiological range throughout treatment. Serum gonadotropin concentrations decreased significantly (p < 0.001, Friedman's ANOVA). Bone mineral density increased by 2.1% (p = 0.029) only at the lumbar spine. Endometrial thickness remained unchanged. Breakthrough bleeding or spotting occurred in 18% of cycles in the first 3 months of HRT, 30% in months 4-9 and 22% in months 10-12. Withdrawal bleeding occurred in 40% of cycles in the first 3 months and decreased to 25% in months 10-12. At month 12, there were 11 women with amenorrhea due to endometrial atrophy. Nine women had active endometria (proliferative or secretory) and thus reported vaginal bleeding. No severe bleeding, hyperplasia, or carcinoma was found. Vaginal bleeding was tolerated, and no subject withdrew from the study. Results suggest that this regimen confers endometrial protection and is well tolerated, and can therefore safely be used for at least 1 year by postmenopausal women with hypertension and menopausal symptoms.

These results suggest that the proposed HRT regimen with percutaneous estradiol associated with low-dose vaginal micronized progesterone could be a safe alternative for postmenopausal women with hypertension at least during the period required to treat menopausal symptoms.