J.P. Deslypere

Aromatase, 17β-hydroxysteroid dehydrogenase and intratissular sex hormone concentrations in cancerous and normal glandular breast tissue in postmenopausal women

In a study of the origin of estrogens in patients with breast cancer, the concentrations of estrogens and their androgen precursors, and aromatase and 17 beta-hydroxysteroid dehydrogenase (E2DH) activities were determined in normal glandular and cancerous breast tissue. The correlation between tissue estrogens, precursor concentrations, enzyme activities and plasma levels and/or receptor status were calculated. In both normal glandular and carcinomatous breast tissue, the concentrations of androstenedione (A), dehydroepiandrosterone (DHEA), 5 androstene-3 beta, 17 beta-diol (5-Adiol), estrone (E1), estradiol (E2) and progesterone (P) were significantly higher than plasma concentrations. While testosterone (T) concentrations were similar, dehydroepiandrosterone (DHCA) and estrone sulphate (E1S) concentrations were lower in tissue than in plasma. In carcinomatous tissue androgen concentrations were lower, but estrogen concentrations were higher than in glandular breast tissue. Estradiol (E2) concentration was positively correlated with the receptor concentration with the mean E2 concentration corresponding to an estimated receptor occupancy of about 25%, probably sufficient for a submaximal biological response. Aromatase and E2DH (E2----E1) activities were observed in all breast cancer and glandular breast tissues, activities being higher in carcinoma than in glandular breast tissues; nevertheless, aromatase activity accounts probably only for a small fraction of tissue estrogen concentration. E2DH, but not aromatase activity, was significantly higher in estrogen receptor positive than in estrogen receptor negative tissues and was negatively correlated with tissue dehydroepiandrosterone (DHEA) and its sulphate (DHEAS) concentration; the latter two steroids are non competitive inhibitors of E2DH which inactivates E2 to E1. This effect of DHEA(S) may constitute a mechanism by which these androgens stimulate cancer growth and a rationale (besides suppression of estrogen precursors) for medical or surgical adrenalectomy in hormone sensitive metastatic mammary cancer. E2DH activity might constitute an additional marker of hormone dependency of mammary cancer.

A new look to the andropause: Altered function of the gonadotrophs

After being controversial for a long time, the age associated decline in plasma T levels and secretion in normal men is now generally accepted. Although most data point towards a primary testicular origin for the decline in Leydig cell function, other data point towards alterations at the hypothalamo-pituitary levels: T levels in elderly men are decreased notwithstanding an important secretory reserve of both LC and gonadotrophs. Nycthemeral variations in plasma T levels are significantly decreased in elderly men. The increase in immunoreactive LH levels is dysproportionate to the increase of bioactive LH levels. Study of the activity of the LHRH pulse generator in 27 young and 21 elderly men revealed a significant decrease in frequency of high amplitude pulses for both LH and T. Moreover the sensitivity of the gonadostat to sex hormone feed back was significantly greater in the elderly men. Acute administration of an antiopoid (Naloxone), 2 mg i.v. both in young and elderly men at rest showed that in young and elderly men, Naloxone induced a comparable increase of LH levels. Naltrexone on the other hand increased LH pulse frequency in elderly but not in young men. The data show that opioids maintain their inhibitory effect on LHRH secretion in elderly men and suggest either that the opioid tone in the elderly men is decreased or that the response of the gonadotrophs to LHRH is decreased.

Androgen and precursor levels in serum and testes of adult rats under basal conditions and after hCG stimulation

In adult male Wistar rats, serum and testicular concentration of testosterone (T), estradiol (E2), dihydrotestosterone (DHT), 5 alpha-androstane 3 alpha, 17 beta-diol (Adiol), and their precursors were measured under basal conditions as well as 4 and 8 h respectively after i.m. injection of 100 I.U. of hCG. Under basal conditions T (203 +/- 30 (SE) ng/dl) was quantitatively by far the most important serum steroid, followed by progesterone (P) (76.5 +/- 12 ng/dl), 17-hydroxyprogesterone (170HP) (37.3 +/- 4.1 ng/dl), androstenedione (A) (24.6 +/- 2.5 ng/dl) and pregnenolone (P5) (22.9 +/- 4 ng/dl). Estradiol (E2) was present in a low concentration (1.06 +/- 0.26 ng/dl). In the testes, T was quantitatively the most important steroid (89 +/- 7.2 ng/g), followed by 5 alpha-androstane-3 alpha-17 beta-diol (Adiol) (26.5 +/- 2.8 ng/g) whereas 170HP (11.8 +/- 1.0 ng/g), P (11.5 +/- 1.0 ng/g) and P5 (16.6 +/- 1.8 ng/g) were present in roughly the same concentration, concentrations of A, DHT, dehydroepiandrosterone (DHEA), 17 hydroxy-pregnenolone (170HP5) and androst-5-ene-3 beta-17 beta-diol (D5diol) being much lower; E2 (0.06 +/- 0.01 ng/g) was hardly detectable. Within 4-8 h after hCG stimulation, serum androgen concentrations increased by a factor of 4-12, except for DHEA and D5diol (X2), and E2 (X 1.5). Intratesticular androgens and delta 4 steroid precursors increased by a factor of 5-10, delta 5 precursors by a factor of 2-4 and E2 by a factor of 2, the data tending to confirm that the delta 4 pathway is preferred over the delta 5 pathway. After hCG the relative increase of T precursors was the most important for P, suggesting that 17 hydroxylation might be the rate limiting step in T biosynthesis.

Steroid dynamics in the normal and carcinomatous mammary gland

UNLABELLED As an approach to the study of the origin of estrogens in breast cancer tissue, the concentration of estrogens and their androgen precursors, as well as aromatase and 17 beta-dehydrogenase activities in normal glandular (GL) and cancerous (CA) breast tissue were determined and correlations with plasma levels and/or receptor status were studied. In both normal GL and CA breast tissue, steroid concentrations were significantly higher than plasma conc., except for dehydroepiandrosterone sulphate (DHEAS), estrone sulphate (E1S) and testosterone (T). Androgen conc. were lower, but estrogen conc. were higher in CA than in GL breast tissue. Estradiol (E2) conc. was positively correlated with the E2R conc., mean E2 conc. corresponding to an estimated E2R occupancy of about 25%. Aromatase and 17 beta-hydroxysteroid dehydrogenase (E2DH) (E2----E1) activities were observed in all breast CA and GL tissues, aromatase accounting probably only for a small fraction of tissue estrogens. E2DH, but not aromatase activity, was significantly higher in E2R+ than in E2R- tissues and was negatively correlated with tissue dehydroepiandrosterone (DHEA) and DHEAS conc.; the latter two steroids are non competitive inhibitors of E2DH which inactivates E2 to E1. CONCLUSION in both normal and carcinomatous breast tissue, conc. of E1 and E2 are significantly higher than in plasma, suggesting either uptake or local synthesis. As to the latter, aromatase activity accounts probably only for a minor fraction of the tissue estrogens. Breast CA tissue has higher aromatase and E2DH activity than normal glandular tissue, E2 conc. and E2DH activity being higher in E2R+ hormone sensitive, tumors than in E2R-tumors. Tissue conc. of DHEA(S) which inhibits oxidative inactivation of E2, is negatively correlated with E2DH activity and may have an important modulating role in intratissular estrogen metabolism.

Androgen concentrations in sexual and non-sexual skin as well as in striated muscle in man

Abstract Androgen concentrations, e.g. testosterone, 17β-hydroxy-5α-androstane-3-one and 5α-androstane-3α-17β-diol, have been determined in scrotal, pubic and non-sexual skin, as well as in striated muscle of males who had died suddenly.These concentrations have been compared to concentrations in benign prostatic hyperplasia. It is concluded that differences in androgen concentration in tissues are compatible with the assumption that high androgen responsiveness is characterized by high receptor concentration, a high 5α reductase and a low 3α reductase activity.

Inhibitory action of androstenedione on the proliferation and cell cycle kinetics of aromatase-free MXT and MCF-7 mammary tumour cell lines.

The effects of androstenedione (AD) on cell proliferation and kinetics have been measured in MXT mouse and MCF-7 human mammary cancer cell lines using SAMBA 200 cell image analysis of Feulgen-stained nuclei. At a concentration of 0.01 microM AD inhibited the proliferation of both cell lines whereas a higher dose (1 microM) was inhibitory on MCF-7 cell proliferation but stimulatory in MXT cells. It is unlikely that these effects are due to aromization of AD into oestrogen since (a) both cell lines were devoid of aromatase and (b) both cell lines were similarly affected by oestradiol (E2), being stimulated at low concentrations and inhibited at high doses. Furthermore, inhibition by AD seems to occur, at least in part, by blockade of the cell cycle whereas that by E2 appears to be cell cycle independent.