A. Vermeulen

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.

Hormonal effects of an antiestrogen, tamoxifen, in normal and oligospermic men.

The administration of tamoxifen, 20 mg/day for 10 days, to normal males produced a moderate increase in luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and estradiol levels, comparable to the effect of 150 mg of clomiphene citrate (Clomid). However, whereas Clomid produced a decrease in the LH response to LH-releasing hormone (LHRH), no such effect was seen after the administration of tamoxifen. In fact, prolonged treatment (6 weeks) with tamoxifen significantly increased the LH response to LHRL. Treatment of patients with idiopathic oligospermia for 6 to 9 months resulted in a significant increase in gonadotropin, testosterone, and estradiol levels. A significant increase in sperm density was observed only in subjects with oligospermia below 20 X 10(6)/ml and normal basal FSH levels. When basal FSH levels were increased or oligospermia was moderate (greater than 20 X 10(6)/ml); no effect on sperm density was seen. As sperm density increased, FSH levels decreased, suggesting an inhibin effect. Sperm motility was not improved by tamoxifen treatment. In five boys with delayed puberty, tamoxifen treatment appeared to activate the pituitary-gonadal axis and pubertal development.

Improved fertility after varicocele correction: fact or fiction? *

Fertility after varicocele correction by embolization of the vena spermatica in 62 subjects was compared with fertility in an untreated group (n = 20) of subjects with varicocele. One year after varicocele correction of infertile males with oligozoospermia, asthenozoospermia, or teratozoospermia but normal follicle-stimulating hormone levels, 15 of 62 had achieved a pregnancy; in the untreated group, 8 had achieved a pregnancy. Comparison of results by cumulative pregnancy rate analysis reveals that the pregnancy rate was only marginally higher in the treated group. Varicocele correction induced only a modest improvement of sperm quality; the severity of varicocele had no influence either on sperm characteristics or on the outcome of treatment. It is concluded that the effects of varicocele correction on the pregnancy rate can be seriously doubted and that large-scale prospective studies are urgently required to determine whether or not varicocele correction improves the pregnancy rate and which subjects could eventually benefit from the treatment.

Metabolic effects of the triphasic oral contraceptive TrigynonR

Effects of Trigynon, a triphase low-dose oral contraceptive, containing ethinylestradiol and l-norgestrel in various proportions, on testosterone binding globulin, transcortin, thyroxine, free testosterone, free cortisol and free thyroxine as well as on plasma lipids and glucose tolerance were studied in 12 normal women treated for 3-6 months. Trigynon appears to have dominant estrogenic effects as evidenced from the increase in transport proteins and the decrease in free testosterone concentration. Plasma lipids were not significantly influenced; glucose tolerance was slightly, but not significantly decreased.

EFFECT OF LONG-TERM HORMONAL CONTRACEPTION ON PLASMA LIPIDS

Serum lipid and apoprotein levels were determined in fasting women after long-term use (5-12 years) of Depo Provera, Orgametril, Ortho Novum SQ, Binordiol, Microgynon-50, and Ministat. Compared with matched controls, pure progestogens (Depo Provera and Orgametril) caused a moderate decrease of TG, HDL chol, and Apo A1, whereas estrogen-dominant oral contraceptives (Ortho Novum SQ) increased the same parameters. The effects of long-term use of hormonal contraception on lipids did not differ from those predicted from short-term (6 months) studies.

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.

The medroxyprogfstepone acetate intravaginal silasttc ring as a contraceptive device

Abstract Both the 100 mg and the 200 mg MPA-Silastic rings inserted vaginally on day 5 and worn for 3 weeks suppressed, ovulation in all of the 14 women investigated. A secondary mechanism of action involves interference with the spinnbarkeit of the cervical mucus. Under the experimental conditions, the method was acceptable and the device well tolerated.

Steroid dynamics in the normal and carcinomatous mammary gland

UNLABELLEDnAs 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.nnnCONCLUSIONnin 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.

Plasma levels of ethinylestradiol (EE) during cyclic treatment with combined oral contraceptives

The purpose of the present study was to extend the still limited data concerning ethinylestradiol (EE) plasma levels after repeated daily ingestion of a combination pill during the course of classical cyclic treatment. Plasma EE levels were followed in 13 volunteers throughout, in total, 19 treatment cycles with either a 50 ug EE (+ 125ug d-norgestrel) or a 30 ug (+ 150ug d-norgestrel) containing oral contraceptive. In addition, single plasma EE determinations were performed in 110 chronic oral contraceptive users. Whereas different patterns in plasma EE levels (sampling 24 hours following last pill ingestion) were observed among the different volunteers, the mean levels increased progressively during treatment and reflected closely the differences in dosage. The values obtained in the volunteers at the end of the treatment cycle showed important interindividual variations. The findings during a first treatment cycle or during the following ones were similar and for different treatment cycles in the same patient, the patterns in plasma EE levels were consistent. The results for single plasma determinations in chronic contraceptive users (sampling between 8th and 21st day of treatment cycle, 9 to 24 hours since last pill ingestion) showed more pronounced interindividual variations, the individual EE levels being not correlated to parameters such as body weight, body surface, months of oral contraception prior to the study, sex hormone binding capacity or day of the cycle. However, significant differences in mean plasma EE levels were noticed for patients treated with different commercial preparations with identical EE content, suggesting the existence of differences in bioavailability. The relevancy of plasma EE determinations is discussed and from the results of the present study, it is concluded that a strictly standardized time of sampling is an absolute condition for obtaining interpretable results.

Effects of Weight Loss on the Fatty Acid Composition of Serum Lipids in Obese Women

The effect of a weight reduction regimen, consisting of a protein-sparing modified fast and an exercise program, on the fatty acid composition of serum phospholipids and cholesterol esters of obese women, is described. In phospholipids, this treatment did not induce any significant change of the different fatty acid families (total saturated, monounsaturated, omega 9, omega 7, omega 6 and trans-fatty acids), except for total omega 3 fatty acids which increased. Within families, individual fatty acids change however. The changes are compatible with increased delta 5 and delta 6 desaturase activity. In cholesteryl esters, significant changes occurred which are suggestive of an increase in serum of the fraction of cholesteryl esters of intracellular origin. The changes in fatty acid compositions may not be beneficial with respect to atherosclerosis.