A randomized, controlled trial of estradiol replacement therapy in women with hypergonadotropic amenorrhea.

Premature ovarian failure is classically defined as menopause occurring before age 40 and is associated with elevated serum FSH levels. If elevated FSH levels indicate lack of ovarian feedback and depletion of primordial follicles, women with prematurely elevated FSH levels should have infertility. However, there are many reports of pregnancies in affected women occurring during estrogen therapy leading to the hypothesis that estrogen may have a salutary effect on folliculogenesis and conception. This randomized, controlled trial was designed to investigate whether estrogen replacement therapy offered a significant therapeutic benefit in hypergonadotropic amenorrhea and to evaluate the potential pathophysiologic mechanisms that would explain the reported pregnancies. Thirty seven women, aged 16 to 40, with menstrual dysfunction and documented FSH levels elevated above the 95% confidence limits of the mid-cycle gonadotropin peak of the normal menstrual cycle (> 40 IU/L 2nd IRP hMG in our RIA) on at least two occasions, entered the study. The average duration of their amenorrhea was 15.9 months (range 2-96 months). Subjects were randomized to begin estradiol replacement (micronized estradiol [Estrace TM], 2 mg orally each day) or no therapy for 6 weeks in a 12-week, cross-over design with weekly monitoring by both pelvic ultrasonography and serum hormone levels. Thirty-one women completed the entire randomized study. As expected, estradiol therapy increased mean serum estradiol levels by 98 pg/mL and was associated with a significant decrease in mean LH and FSH levels (LH: 45.4 IU/L 2nd IRP hMG vs. 37.1 IU/L, FSH: 63.4 IU/L vs. 40.6 IU/L, geometric means). However, there was no effect of estradiol replacement on mean ovarian volume, the number or size of new follicles, or the ovulation rate in all subjects or in the subset with no identified cause for their hypergonadotropic hypogonadism (n = 20). Two pregnancies occurred during the randomized trial, one on and one off estradiol. In both arms of the study, the majority of subjects developed cystic ovarian structures by ultrasound that were temporally associated with increasing serum estradiol levels, indicating functional ovarian follicles. Seventy-eight percent of all subjects grew at least one new follicle over 10 mm in diameter and 46% ovulated at least once, as determined by a serum progesterone level more than 4 ng/mL. Although ovulations were significantly more common in the 10 women subjects who had less than 3 months of amenorrhea (all of whom ovulated) than in the 27 with greater than 3 months of amenorrhea (only 7 of whom ovulated (26%), P < 0.001), there was no significant difference in eventual pregnancies (2 of the 10 women with less than 3 months of amenorrhea vs. 3 of the 27 with greater than 3 months of amenorrhea, P = 0.47). We conclude that in hypergonadotropic women with amenorrhea: 1) folliculogenesis occurs often but is less frequently followed by ovulation and rarely by pregnancy, suggesting that elevated FSH is a marker of oocyte dysfunction occurring distinct from and earlier than granulosa cell or follicular dysfunction; and 2) estrogen therapy does not improve the rate of folliculogenesis or ovulation.

Thyroid disease in women.

Thyroid diseases occur more commonly in women than men, in part because of the autoimmune nature of many thyroid disorders. Hypothyroidism, and thyroid nodules occur frequently in both pre- and postmenopausal women. Pregnancy is also associated with changes in thyroid function. The goal of this article is to review the current information on the pathophysiology and treatment of thyroid disorders which are common in women.

Comparison of bone mineral density of the phalanges, lumbar spine, hip, and forearm for the assessment of osteoporosis in postmenopausal women.

The objective of this study was to compare peripheral bone mineral density (BMD) of the phalanges with BMD of the lumbar spine, total hip, femoral neck, and forearm and to determine the clinical value of measuring a single peripheral site (phalanges) in identifying postmenopausal women with osteoporosis. BMD was measured by dual energy X-ray absorptiometry using the accuDEXA((R)) (ADXA-finger) (Schick, New York, NY) and the QDR-4500 (DXA-lumbar spine, hip, forearm) (Hologic, Waltham, MA). Correlation coefficients between ADXA and DXA of the lumbar spine, total hip, femoral neck and one third radial site ranged from 0.53 to 0.73. The sensitivity of an ADXA T-score of -2.5 in identifying patients with a DXA T-score of < or = -2.5 at the femoral neck was 35%. An ADXA T-score cut point of -1.0 improved the sensitivity of ADXA in identifying patients with a femoral neck T-score of < or = -2.5 (85%), but the specificity declined from 88 to 49%. There was substantial discordance in the diagnosis of osteoporosis when a single site was measured, regardless of technique. Within the limitations of single-site measurements, BMD measured by ADXA has adequate sensitivity to identify women with low BMD at the femoral neck, if an appropriate T-score criterion is used.

Clenbuterol-induced muscle growth: investigation of possible mediation by insulin.

The role of insulin as a possible mediator of the beta-adrenergic agonist stimulation of muscle growth was investigated. To exclude possible action of the beta-agonist on the pancreatic release of insulin, diabetes was induced in rats by a streptozotocin injection (100 mg/kg). Insulin levels were almost not detectable in these rats. Feeding either normal diet or diet containing the beta-adrenergic agonist clenbuterol (10 parts/million) did not alter plasma insulin concentrations. The effects of clenbuterol on muscle and weight gain were determined in diabetic rats given daily insulin replacement (D + I) and fed either a normal diet or clenbuterol-treated diet. Clenbuterol, fed for 1 wk, increased the wet weight of the gastrocnemius, soleus, and extensor digitorum longus muscles (15-23%) in both normal and D + I rats. Although clenbuterol increased body weight gain, it did not alter feed consumption and, therefore, feed efficiency (g gain/g food) was improved. Activities of cathepsin B and N-acetyl-beta-glucosaminidase, but not cathepsin D, were elevated in the soleus muscles of clenbuterol-treated rats. The clenbuterol-induced increase in muscle growth in the insulin-replaced diabetic rats indicated that this beta-adrenergic agonist effect was not mediated by an alteration of circulating levels of insulin, secondary to beta-agonist action on pancreatic insulin release.

Lipid-rich follicular carcinoma of the thyroid in a patient with McCune-Albright syndrome.

A 41-year-old woman with McCune-Albright syndrome and a 2-cm thyroid nodule of ten years' duration presented for fine-needle aspiration, which yielded vacuolated clear cells with granular chromatin in pseudopapillary arrangement. The resected tumor showed 90% clear cells and 10% nonclear cells with capsular and vascular invasion. The cytoplasmic vacuoles in the clear cells were 3+ for oil red O stain in touch imprint cytology. Immunohistochemistry demonstrated thyroglobulin positivity in the nonclear neoplastic cells, whereas most of the clear cells were negative. Ultrastructural study demonstrated the gradual transition from protein synthesis to lipid synthesis as the neoplastic cells progressed from nonclear to clear. The study suggested that the lipid accumulation resulted from the uncontrolled fatty acid synthesis in the neoplastic cells rather than metaplasia. The karyotype of the tumor cells was normal, 46XX. Literature of lipid-rich thyroid neoplasms were reviewed.