The benefits of adding metformin to tamoxifen to protect the endometrium-A randomized placebo-controlled trial.

BACKGROUND: We investigated whether metformin prevents tamoxifen-induced endometrial changes and insulin resistance (IR) after a diagnosis of breast cancer. METHODS: This was a single-centre, randomized, double-blind, placebo-controlled, parallel group trial. Postmenopausal women with hormone receptor-positive breast cancer taking tamoxifen were randomly allocated to metformin 850 mg or identical placebo, twice daily, for 52 weeks. Outcome measures included double endometrial thickness (ET) measured by transvaginal ultrasound, fasting insulin, glucose and IR estimated by the homeostasis model of assessment (HOMA-IR). RESULTS: A total of 112 women were screened and 102 randomized. Results are presented as median (range). The 101 women who took at least one dose of medication were aged 56 (43-72) years, with 5(0.5-28) years postmenopause, and had taken tamoxifen for 28.9 (0-367.4) weeks. The baseline ET was 2.9 mm (1.4-21.9) for the placebo group (n = 52) and 2.5 mm (1.3-14.8) for the metformin group (n = 50). At 52 weeks, the median ET was statistically significantly lower for the metformin (n = 36) than for the placebo group (n = 45) (2.3 mm (1.4-7.8) vs 3.0 (1.2-11.3); P = 0.05). 13.3% allocated to placebo had an ET greater than 4 mm vs 5.7% for metformin (P = 0.26). There was no endometrial atypia or cancer. Compared with placebo, metformin resulted in significantly greater baseline-adjusted reductions in weight (P < 0.001), waist circumference (0.03) and HOMA-IR (P < 0.001). CONCLUSIONS: Metformin appears to inhibit tamoxifen-induced endometrial changes and has favourable metabolic effects. Further research into the adjuvant use of metformin after breast cancer and to prevent EH and cancer is warranted.

Seladin-1/DHCR24 expression in normal ovary, ovarian epithelial and granulosa tumours.

OBJECTIVE: The human DIMINUTO/DWARF1 homolog seladin-1/DHCR24 has been recently reported to be up-regulated in adrenocortical adenomas. Seladin-1 expression has been reported in the normal ovary. Granulosa cell tumours of the ovary (GCT) as with adrenocortical adenomas arise from a steroidogenic tissue, respond to pituitary hormone stimulation and synthesize steroid hormones. DESIGN: To test the hypothesis that seladin-1 may also have a role in the pathogenesis of GCT, we determined the expression of seladin-1 in a cohort of GCT and in mucinous and serous cystadenocarcinomas and in normal ovary. MEASUREMENTS: Expression was determined by RT-PCR using gene specific primers and probes combined with Southern blot analysis of the PCR products. RESULTS: Seladin-1 expression was identified in the normal ovary, mucinous cystadenocarcinomas and serous cystadenocarcinomas of the ovary whereas no expression was observed in the GCT. CONCLUSIONS: Based on our results, seladin-1 is not expressed in the granulosa cells or at least not in those that give rise to GCT.

Inhibins and ovarian cancer.

The inhibins are produced and secreted by several ovarian cancers. Monitoring serum levels by immunoassay may be a useful diagnostic aid in the initial assessment of this disease and in monitoring its potential recurrence following surgery. The assays are applicable to women after menopause when the majority of ovarian cancers are detected, and when the normal ovarian production of inhibin is low to negligible. A new inhibin immunoassay (total inhibin ELISA) has been developed with the intention of widespread clinical application. The assay readily detects granulosa cell and mucinous tumours. CA125, a widely used ovarian cancer marker, detects the other main ovarian cancer types (serous, endometrioid, undifferentiated) with high sensitivity. The combination of the two tests detects the majority of ovarian cancers with high specificity (95%) and sensitivity (95%). Studies have been undertaken to assess its application to women in the perimenopausal stage and to younger women during normal reproductive life. These studies are providing a platform for the introduction of the test into clinical practice.

Inhibins as biomarkers for reproductive cancers.

Inhibin is a dimeric (alpha and either betaA or betaB subunit) protein involved in the regulation of fertility. Inhibin A and B or its free alpha subunit monomer are elevated in various gonadal and prostate cancers and thus serve as useful diagnostic tools for certain ovarian tumors either as a serum marker or as an immunocytochemical marker for tissue sections. Serum inhibin levels are of value in the initial diagnosis and subsequent follow-up of sex cord stromal tumors, in particular granulosa cell tumors, and mucinous epithelial adenocarcinomas primarily after menopause. Immunocytochemistry using inhibin alpha subunit antisera can aid in the classification of sex cord stromal tumors and their differentiation from other cancers. Although serum inhibins are elevated in prostatic and testicular cancers, this is of little diagnostic value at the present time.