Bone loss in young women with karyotypically normal spontaneous premature ovarian failure.

OBJECTIVE: To evaluate the effects of karotypically normal spontaneous premature ovarian failure on femoral neck bone mineral density. METHODS: Eighty-nine women with karyotypically normal spontaneous premature ovarian failure who desired fertility were evaluated at a tertiary care academic center and underwent hip and spinal bone density measurements by conventional dual-photon absorptiometry. Seventy-seven of the women (87%) had sought medical advice previously and had taken a variety of estrogen and progestin replacement regimens at least intermittently. The median (range) age was 32 (20-39) years, and the median (range) time since diagnosis was 1.5 (0.5-11) years. Findings were compared with a reference group of 218 regularly menstruating women of similar age. RESULTS: Sixty of the 89 women with premature ovarian failure (67%, 95% confidence interval 57, 77) had a femoral neck bone mineral density more than 1 standard deviation (SD) below the mean of the reference group (P < .001, chi2 with Yates correction). Even in women in whom the bone mineral density measurement was made within just 1.5 years of the diagnosis, nearly one-half (47%) had a femoral neck bone mineral density more than 1 SD below the mean of the reference group (P < .01). CONCLUSION: Two-thirds of young women with karyotypically normal spontaneous premature ovarian failure have a femoral neck bone mineral density more than 1 SD below the mean of a reference group. These young women need early education regarding strategies to maintain their bone mass and ongoing medical evaluation to maintain compliance with these strategies.

Routine endocrine screening for patients with karyotypically normal spontaneous premature ovarian failure.

OBJECTIVE: To evaluate the usefulness of routine screening for other associated autoimmune endocrine disorders in patients with karyotypically normal spontaneous premature ovarian failure. METHODS: One hundred nineteen women with karyotypically normal spontaneous premature ovarian failure (FSH exceeding 40 mIU/mL) who desired fertility were evaluated at a tertiary care academic center by physical examination, measurement of serum free thyroxine and TSH, ACTH stimulation test, fasting serum glucose, 3-hour glucose tolerance test, measurement of serum electrolytes including total calcium, and measurement of serum vitamin B12. RESULTS: Twenty-two of 119 patients (18.5%) were known to have hypothyroidism and three were known to have Addison disease. Ten new cases of hypothyroidism and three new cases of diabetes mellitus were discovered. However, no new cases of adrenal insufficiency, hypoparathyroidism, or pernicious anemia were found. CONCLUSION: Screening for hypothyroidism and diabetes appears justified in those patients with karyotypically normal spontaneous premature ovarian failure who desire fertility. However, our findings suggest that in these patients, testing for other associated autoimmune endocrine disorders may be reserved for those with clinical indications.

Development of luteinized graafian follicles in patients with karyotypically normal spontaneous premature ovarian failure.

Despite having amenorrhea and markedly elevated serum gonadotropin levels, some women with karyotypically normal spontaneous premature ovarian failure, nevertheless, have ovarian follicles that function intermittently. Graafian follicles capable of responding to these high FSH levels are faced with high serum LH levels as well, which might induce inappropriate luteinization and prevent normal follicle function. We examined this possibility using weekly blood sampling and sonography in 65 patients. Nearly 50% of our patients demonstrated ovarian follicle function [serum estradiol, > 183 pmol/L (50 pg/mL)] during a median of 4 months of observation (range, 2-6 months). However, during this observation, only 16% achieved an ovulatory serum progesterone level [> 9.5 nmol/L (3.0 ng/mL)]. We imaged an antral follicle by sonography in over 40% of patients (27 of 65), and serum estradiol was significantly greater when an antral follicle was present. The follicles in these patients were not functioning normally, however. In contrast to normal women, patients with ovarian failure had poor correlation between follicle diameter and serum estradiol. We biopsied these antral follicles in 6 patients and found luteinized Graafian follicles in all cases. Therefore, luteinized Graafian follicles account for at least 60% of the antral structures imaged (95% confidence limit). Thus, inappropriate luteinization of Graafian follicles appears to be a major pathophysiological mechanism in patients with karyotypically normal spontaneous premature ovarian failure.

A controlled study of danazol for the treatment of karyotypically normal spontaneous premature ovarian failure.

OBJECTIVE: To determine if the immunomodulatory and gonadotropin-suppressing properties of danazol would improve follicle function or ovulation rates in patients with karyotypically normal spontaneous premature ovarian failure. DESIGN: Prospective, double-blind, crossover trial. SETTING: Tertiary care research institution. INTERVENTIONS: Two intervention phases lasting 4 months each: one phase during which patients received a standardized estrogen and progestin replacement regimen and one phase during which each patient received a twice daily 400 mg oral dose of danazol. PATIENTS: Fifty-two patients with karyotypically normal spontaneous premature ovarian failure ranging in age from 21 to 39 years. MAIN OUTCOME MEASURES: We measured serum E2 and P levels weekly during the 2 months after each intervention. We defined a serum E2 > 50 pg/mL (184 pmol/L) as evidence of ovarian follicle function and a P > 3.0 ng/mL (9.5 nmol/L) as evidence for ovulation. RESULTS: Of the 46 patients who completed the study, danazol did not significantly enhance ovarian follicle function or the chance of ovulation. Eight patients ovulated after danazol and four patients ovulated after estrogen and progestin. The power to detect a 30% and a 5% ovulation success rate with therapy was 0.80 and 0.90, respectively. Overall, 30 of 46 women (65%) demonstrated ovarian follicle function and 10 women (21%) ovulated. CONCLUSION: We were unable to demonstrate a statistically significant benefit from the immunomodulatory and gonadotropin-suppressing effects of danazol in patients with karyotypically normal spontaneous premature ovarian failure. These patients often have spontaneous remission. Thus, controlled studies are required to determine the effectiveness of treatments for this condition.

Karyotypically normal spontaneous premature ovarian failure: evaluation of association with the class II major histocompatibility complex.

Patients with premature ovarian failure (POF) have been reported to have an increased frequency of the major histocompatibility class (MHC) class II antigen HLA-DR3. Here we attempt to confirm this association. We performed MHC class II immunophenotyping of HLA-DR antigens 1-10 on 102 North American caucasians with confirmed POF and 102 control caucasian women. All patients had experienced amenorrhea before the age of 40 yr and had elevated serum gonadotropins on repeated study. We found no significant increase in HLA-DR3 frequency in patients with POF when compared to our control group (P = 0.52) or even when compared to a large reference population (n = 1927) that did not differ significantly from our control group (P = 0.47). Our patients did have an increased frequency of HLA DR4 compared to this large reference population (41% vs. 23%; P < 0.001), but we were unable to demonstrate increased HLA DR4 frequency using our control group (31%; P = 0.14). In conclusion, despite a power of 99%, we were unable to confirm a significant increase in MHC class II HLA-DR3 frequency in patients with POF.