A novel approach to breast cancer prevention: reducing excessive ovarian androgen production in elderly women.

Minimizing endogenous estrogen production and activity in women at high risk for breast cancer is a prominent approach to prevention of the disease. A number of clinical trials have shown that the administration of selective-estrogen receptor modulators or aromatase inhibitors significantly reduces the incidence of breast cancer in healthy women. Unfortunately, these drugs often produce adverse effects on the quality of life and are, therefore, poorly accepted by many women, even those who are at high risk for breast cancer. We propose a novel alternative approach to decreasing estrogen production: suppression of ovarian synthesis of the androgen precursors of estrogens by administration of long-acting gonadotropin-releasing hormone analogs to women with ovarian stromal hyperplasia. The specific target population would be elderly postmenopausal women, at increased risk of breast cancer, and with high blood levels of testosterone, marker of ovarian hyperandrogenemia, and recognized factor of risk for breast cancer. Testosterone levels are measured at baseline to identify women at risk and during the follow-up to evaluate the effectiveness of therapy. The postmenopausal ovary is an important source of excessive androgen production which originates from the ovarian interstitial cell hyperplasia frequently present in breast cancer patients. We propose to counter the source of androgen excess in women with ovarian stromal hyperplasia, thus reducing the substrate for estrogen formation without completely inhibiting estrogen synthesis. Available evidence indicates that gonadotropin-releasing hormone analogs can be safely used for breast cancer prevention in postmenopausal women.

Role of androgen excess in the development of estrogen receptor-positive and estrogen receptor-negative breast cancer.

The androgen-excess theory posits a central role of androgens in promoting breast cancer development. At first glance, this appears to contradict the currently accepted central role of estrogens in this process, but as we will show, the apparent contradiction is not a real one. In the present article, we review the mechanisms by which androgen excess may stimulate cancer growth in different subsets of estrogen receptor-positive and estrogen receptor-negative tumors. We also propose an endocrine classification of postmenopausal breast cancer based on the simultaneous evaluation of a patient's serum testosterone levels and the estrogen receptor status of the tumor. This classification identifies several different subsets of tumors and may have important clinical implications.

Reversal of the hypogonadotropic hypogonadism of obese men by administration of the aromatase inhibitor testolactone.

Studies from this laboratory have shown that obese men have elevated serum estrogen levels and diminished levels of follicle-stimulating hormone (FSH) and free and total testosterone, all in proportion to their degree of obesity. The decreases in testosterone and FSH constitute a state of hypogonadotropic hypogonadism (HHG), and we have hypothesized that it results from feedback suppression of the pituitary by the elevated estrogen levels. We tested this hypothesis by lowering the serum estrogens of 6 health obese men (body mass index [BMI], 38 to 73) by administering the aromatase inhibitor testolactone (1 g daily for 6 weeks). Twenty-four-hour mean serum testosterone rose in every subject, from a mean of 290 +/- 165 ng/dL to a mean of 403 +/- 170 (P <.0003); 24-hour mean serum estradiol decreased in every subject, from a mean of 40 +/- 10.8 pg/mL to a mean of 29 +/- 6.7 (P <.004); and 24-hour mean serum luteinizing hormone (LH) increased in every subject, from a mean of 14.3 +/- 4.1 mIU/mL to a mean of 19.3 +/- 5.1 (P <.004). The rise in mean LH was due to an increase in the amplitude of the individual secretory pulses, especially at night. Twenty-four-hour mean serum estrone decreased nonsignificantly, from 48 +/- 14 pg/mL to 39 +/- 6.4, and 24-hour mean serum FSH increased nonsignificantly, from 13.5 +/- 5.3 mIU/mL to 15.0 +/- 5.4. The results are in accordance with the hypothesis, in that inhibition of estrogen biosynthesis (through administration of the aromatase inhibitor testolactone) results in alleviation of the HHG of our obese male subjects.

Relationship of endogenous levels of sex hormones to cognition and depression in frail, elderly women.

Neuropsychological evaluations and sex hormone assays for 188 elderly, female nursing home residents (mean age: 87.8 years; standard deviation: 7.0 years) revealed inverse relationships for dehydroepiandrosterone (DHEA) blood levels and cognition scores based on the Mini-Mental State Exam and the Test for Severe Impairment, as well as for scores of the Immediate Recall, Copy, and Recognition tests of the Visual Reproduction subtest of the Wechsler Memory Scale-Revised (WMS-R; VR). A positive correlation between estrone and depression approached significance, as did the inverse relationships between the Recognition scores of the WMS-R; VR with androstenedione. These results and findings of others suggest that sex hormone actions in elderly women may differ from those in younger populations. A possible stress-related mechanism is also posited.