Renzo Grattarola

Androgens in breast cancer

Abstract Urinary interstitial cell stimulating hormone (ICSH), testosterone, and estrogens (estrone and estradiol-17β) levels were determined in eight endometrial cancer patients and in 17 breast cancer patients. In the endometrial cancer patients the ICSH concentration was significantly increased as was the urinary testosterone compared to normal control value. Histologic examination of the ovaries in these patients revealed interstitial cell hyperplasia. In the breast cancer patients the urinary ICSH was not significantly different from the normal control value; in nine of the 17 patients examined the endometrial pattern was hyperplastic and the testosterone excretion level was very significantly elevated; in the remaining eight patients whose endometrium was hypotrophic the urinary testosterone did not differ significantly from that of normal controls.

Androgens in breast cancer: III. Breast cancer recurrences years after mastectomy and increased androgenic activity

To test the hypothesis that increased androgenic activity is involved in breast cancer, the urinary testosterone was assayed in 19 clinically cured breast cancer patients and in 22 patients developing metastases from breast cancer during the same period of observation (5 to 15 years after mastectomy). The levels in the clinically cured patients were near normal whereas those in patients with metastases were significantly above normal.

Increase in the androgenic activity of the ovary as an etiological factor in the appearance of cancer of the breast

In our previous study (4) we showed that anovulatory menstrual cycles combined with a hyperplastic endometrium are very common in premenopausal breast cancer patients. We showed (5) that endometrial hyperplasia is accompanied by increased androgenic activity as shown by the 11-deoxy-17-ketosteroid (etiocholanolone, androsterone) excretion values; it has been shown in other studies (7, 8) that when a hyperplastic endometrial pattern is present in premenopausal breast cancer patients the excretion level of 11-deoxy-17-ketosteroids is even higher than in women without breast cancer but with a hyperplastic endometrium. In the present study we determined the urinary excretion level of testosterone in breast cancer premenopausal and postmenopausal patients and found it significantly higher than the normal control value, which is further proof that an abnormal androgenic activity must play an etiologic role in the development of breast cancer. Such increased androgenic activity observed in women with breast cancer has an ovarian origin; some of these patients were given human chorionic gonadotropin and, when an increase of urinary testosterone followed, the ovaries were resected. Histological examination of the resected ovaries disclosed interstitial cell hyperplasia. The same gonadotropic treatment did not induce an increase of androgenic activity in ovariectomized women (5).

[Urinary 11-deoxy-17-ketosteroids in breast cancer patients considered in relation to the menstrual cycle: ovulatory and non ovulatory].

The urinary levels of 11-deoxy-17-ketosteroids (dehydroepiandrosterone, etiocholanolone and androsterone) of 32 patients with breast cancer, at premenopausal age (between 30 and 47 years of age) were determined in the premenstrual period (72–48 hours before menstrual bleeding) and an endometrial specimen, obtained 48–24 hours before the menstrual period was examined histologically. The urinary levels of 11-deoxy-17-ketosteroids together with the premenstrual specimen of 22 women at premenopausal age without breast cancer, who were in the same age range (between 31 and 49 years) as the women with breast cancer, were examined and considered as control values. The average value (3.77 ± 0.44 mg/24 hrs.) of the sum of urinary 11-deoxy-17-ketosteroids in control subjects without ovulatory cycle (proliferative premenstrual endometrium) was found to be higher than the average value (2.23 ±0.14 mg/24 hrs.) of the sum of 11-deoxy-17-ketosteroids of control subjects with ovulatory cycle (progestational premenstrual endometrium) and this difference was found to be highly significant (P < 0.01). The average value (4.76 ± 0.29 mg/24 hrs.) of the sum of urinary 11-deoxy-17-ketosteroids in breast cancer patients without ovulatory cycle (proliferative premenstrual endometrium) was found to be higher than the average value of the sum of urinary 11-deoxy-17-ketosteroids (3.05 ± 0.27 mg/24 hrs.) in patients with breast cancer having ovulatory cycle (progestational premenstrual endometrium) and this difference was found highly significant (P < 0.001). The levels of 11-deoxy-17-ketosteroids in the group of breast cancer patients without ovulation were the highest of all groups considered in the present study and the difference between this average value and that found in the control subjects without ovulatory cycle was also significant (P < 0.05).

Breast Cancer Years after Hysterectomy and Bilateral Ovariectomy and Increased Androgenic Activity

26 patients, in whom hysterectomy and bilateral ovariectomy had been performed for a gynecological indication several years before, were tested for urinary testosterone (by a gas chromatographic method) and interstitial cell-stimulating hormone (ICSH) (by a hemagglutination-inhibition method). 12 patients did not develop any pathology of the breast 8.1 +/- 2.2 years after ovariectomy (control group), and 14 patients developed breast cancer 13.0 +/- 3.0 years after ovariectomy (breast cancer group). The average number of years following ovariectomy did not differ significantly between the two groups. There was no significant difference in the mean values of testosterone and of ICSH excretion between the patients of the control group and those of the breast cancer group, but a significant proportion (6 out of 14) of the breast cancer group patients had a much higher testosterone excretion than the highest level (8.4 microgram/24 h) in patients of the control group. This incidence (42.8%) tested by the chi-square method was found to be significant (p less than 0.02).

[Clomiphene-test for evaluation of residual pituitary activity after Y 90 implantation in patients with advanced breast carcinoma].

It has been suggested that tumor regression following hypophyseal implantation of Yttrium sources is not always related to the endocrine effect of this procedure. It has been observed that although relief of pain was obtained in the majority of patients with bone metastases from breast cancer with hypophyseal implantation of radioactive Yttrium, only a small proportion showed endocrinological evidence of complete hypophyseal destruction. Nevertheless, it has been shown that patients with tumor regression after hypophyseal irradiation included a higher proportion with a marked fall in gonadotropin excretion than did the non-responding patients. In order to obtain more information on the residual pituitary ability to synthesize gonadotropins, after hypophyseal implantation of Yttrium, oral Clomiphene was administered to 3 women with advanced breast cancer treated by implantation of radioactive Yttrium twenty days before. One of these patients (12R-50) was subjected to bilateral ovariectomy 4 years before Yttrium implantation. In another patient (11R-61) the Clomiphene-test was done seven months after hypophyseal irradiation with Yttrium. The dose of Clomiphene used was 100 mg daily for five days. Urinary interstitial cell stimulating hormone (ICSH), determined by using competitive hemoagglutination based upon the cross-reaction between the antiserum to HCG and ICSH, estrogens (estrone and estradiol-17beta) and testosterone were determined before hand, after 5 days of treatment with Clomiphene (500 mg) and 4 days after clomiphene therapy. In all patients before clomiphene therapy, ICSH was present in the urine and its value was very elevated in the patient treated with Yttrium implantation 7 months before. After Clomiphene therapy, at 5th day of treatment, in three patients instead of observing, as expected, a rise in ICSH output, a rise in urinary estrogens was shown, together with a decrease in the urinary ICSH level. In these patients 4 days after Clomiphene therapy the urinary level of ICSH increased to high levels, whereas the estrogen level decreased. We suggest that Clomiphene acted upon the ovaries of these patients and the adrenals giving up an increase in urinary estrogens which inhibited the progressive rise of ICSH. In the absence of ovarian or adrenal activity, as in case (12R-59), shown by the absence of estrogens before and during Clomiphene therapy, Clomiphene can induce an early rise in urinary ICSH. There is still uncertainty as to the site of action of Clomiphene and two basic hormone changes have been put forward, one an initial rise in estrogens, the other a primary increase in gonadotropins. From our data we presume that either the hypothalamic-pituitary axis or ovary and adrenals may be the target organ for clomiphene. In this way the Clomiphene-test would give not only better information on the residual pituitary activity after radiological (or surgical) ablation but also on the relationship between the pituitary and peripheral endocrine organs in breast cancer patients.