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Intratumoral activity of the enzyme 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) was measured in 55 patients with breast cancer (17 pre- and 38 post-menopausal) before and/or after 8 days of a progestin treatment (lynestrenol 10 mg/day). In 12 patients the 17 beta-HSD ability to be stimulated was compared to estradiol and progesterone receptor (ER and PR) levels. In premenopausal patients 17 beta-HSD was higher when tumorectomy was performed in the luteal phase than in the follicular phase. In post-menopausal patients, 17 beta-HSD is higher after progestin treatment. However 17 beta-HSD stimulation by lynestrenol depends on receptor levels. It is most after markedly stimulated in ER+ PR+ tumors. It remains low in ER- PR- tumors. In conclusion, intratumoral measurement of the progesterone dependent enzyme (17 beta-HSD) in breast cancer after progestin treatment provides a fine and reliable index of the presence and functional character of PR and hormone dependence of the tumor.

In contrast to cancer cell lines, normal human breast epithelial cells are infrequently studied. Such cells, now routinely cultured in our laboratory from tissue obtained at the time of reduction mammoplasty, were used to study the actions of estradiol (E2), the progestin promegestone (R5020), and the antiprogesterone RU486 on cell growth and progesterone-dependent 17 beta-hydroxysteroid dehydrogenase (E2DH) activity, which is considered good marker of epithelial differentiation as well as progesterone dependency. The studies were carried out using secondary cultures to assure equal initial cell distribution. Cell growth was estimated daily by a histometric method providing a growth index and DNA assay. E2 stimulation of cell growth was not found when the cells were grown in our usual culture medium, but E2 dose-dependent growth stimulation occurred in medium minimally supplemented with serum (1%), insulin; and epidermal growth factor. R5020 inhibited cell growth and stimulated E2DH activity in a dose-dependent manner. RU486 behaved as a pure but low potent progestin agonist concerning E2DH stimulation, but as an agonist with partial antagonist properties concerning cell growth inhibition. In conclusion, E2 stimulated proliferation of human breast epithelial cells in culture, whereas the progestin R5020 inhibited cell multiplication and favored differentiation. The antiprogesterone RU486 had a biphasic effect acting both as progestin agonist and partial antagonist.

Steroidal (progestins) and non steroidal antiestrogens (tamoxifen and derivatives) are strong antiproliferative molecules when added to normal human breast cells in culture. The antiproliferative action of tamoxifen and 4-hydroxytamoxifen isomers is comparable to that observed in cultured breast cell lines. The progestin promegestone (R 5020) is a strong antiproliferative agent in the presence as well as in the absence of estradiol. Identically, at higher concentration the antiprogestin RU 486 slows down cell proliferation probably due to its progesterone agonist activity. Both progestins and antiprogestins stimulate 17 beta-hydroxysteroid dehydrogenase activity, a marker of progesterone receptor but only in estradiol primed cells.

Plasma 21-deoxycortisol (21-DOF) and 17-hydroxyprogesterone (17-OHP) concentrations were assayed before (basal) and 1 h after ACTH stimulation in 4 groups of normal subjects (35 follicular phase women, 22 luteal phase women, 33 adult men, and 15 prepubertal children) and in a group of 31 patients with the late-onset form of congenital adrenal hyperplasia (LOCAH) due to 21-hydroxylase deficiency as well as in 31 LOCAH) heterozygotes. The mean basal plasma 21-DOF concentrations in each of the 4 groups of normal subjects were between 8 ng/dL (0.23 nmol/L) and 11 ng/dL (0.31 nmol/L), and they increased significantly after ACTH stimulation to between 36 ng/dL (1.04 nmol/L) and 44 ng/dL (1.27 nmol/L). There were no differences in basal or ACTH-stimulated plasma 21-DOF levels in these 4 groups, whereas their basal and post-ACTH plasma 17-OHP levels did vary. Among the LOCAH patients, 83.8% had basal plasma 21-DOF levels and 61.2% had basal plasma 17-OHP levels higher than the highest basal 21-DOF [30 ng/dL (0.86 nmol/L)] and 17-OHP [450 ng/dL (13.61 nmol/L)] concentrations in the normal subjects, and all individual 21-DOF and 17-OHP levels after ACTH stimulation [greater than or equal to 404 ng/dL (11.67 nmol/L) and greater than or equal to 1040 ng/dL (31.47 nmol/L), respectively] were markedly higher than the highest 21-DOF [76 ng/dL (2.19 nmol/L)] and 17-OHP [580 ng/dL (17.55 nmol/L)] levels in the normal subjects. The mean post-ACTH/basal plasma level ratios among the LOCAH patients were 19.75 for 21-DOF and 8.03 for 17-OHP. In LOCAH heterozygotes, basal 21-DOF values were higher than normal in 48.3%, and post-ACTH values were higher than normal in 93.5% of the cases. In contrast, basal plasma 17-OHP levels were similar in LOCAH heterozygotes and normal subjects, and only 16.1% of the LOCAH heterozygotes had post-ACTH plasma 17-OHP levels higher than the highest normal value. If sex and phase of the menstrual cycle are taken into account, along with the incremental responses (post-ACTH minus baseline value) of plasma 21-DOF and 17-OHP, to compare LOCAH heterozygotes and normal subjects, the discriminating power for detection of heterozygocity was somewhat increased for 21-DOF (to 100%) and appreciably increased for 17-OHP (to 30%).(ABSTRACT TRUNCATED AT 400 WORDS)

In most target tissues of the female genital tract, an adequate cell differentiation can be obtained with the successive and synergistic action of estradiol (E2) and progesterone (P), essentially because the progesterone receptor (PR) synthesis implicates the previous action of E2 via its E2 receptor (ER). In normal breast, E2 stimulates the growth of the ductal system whereas the development of acini depends on P secretion. In other words, when E2 plus P are secreted by the ovaries in balanced proportions, the two hormones permit a complete and harmonious development of the mammary gland. The antiestrogenic activity of P is carried out through the decrease of ER resynthesis and stimulation of 17 beta-hydroxysteroid dehydrogenase enzyme activity, which transforms E2 into its less active metabolite estrone (E1) in the target cells. These biochemical events are well documented concerning the endometrium. They have also been observed in normal mammary cells in primary cultures as well as in breast fibroadenomas with high epithelial cellularity. Moreover, data from literature indicate that E2 could be both a direct and indirect factor of cell multiplication in cancerous cell lines. P as well as progestins have the opposite effect. Recent results from this laboratory indicate that E2 and P also have antagonistic effects on the cell multiplication of normal human mammary cells in primary culture. Therefore, the hypothesis that a lack of P during a long period of the female genital like could be a factor in the promotion of breast cancer must be considered.

21-deoxycortisol is a steroid produced mainly by the adrenal gland. Its normal plasma baseline concentrations (0.03 to 0.30 n/ml) and its concentrations after tetracosactide injection (0.15 to 0.76 ng/ml) do not significantly vary with age, sex and phases of the menstrual cycle. 21-deoxycortisol was assayed in plasma by a specific radioimmunological method and its values were compared with those of 17-OH progesterone in heterozygous subjects with the classical and non-classical forms of 21-hydroxylase deficiency, and in the amniotic fluid of foetuses with this deficiency. Baseline concentrations of 21-deoxycortisol in the classical forms of 21-hydroxylase deficiency (n = 12; 55.36 to 186.6 ng/ml) and post-tetracosactide concentrations in non-classical late onset forms (n = 31; 4.04 to 47 ng/ml) were much higher than in normal subjects, thus making this steroid as sensitive as, or even more sensitive than 17-OH progesterone in diagnosing 21-hydroxylase deficiency. Post-tetracosactide assays of 21-deoxycortisol in 84 heterozygous subjects with 21-hydroxylase deficiency (0.70 to 5.40 ng/ml) enabled these subjects to be detected with a more than 90 percent sensitivity, which cannot be obtained with 17-OH progesterone assays. 21-deoxycortisol concentrations in the amniotic fluid of foetuses with 21-hydroxylase deficiency (n = 11; 0.391 to 0.930 ng/ml) were constantly superior to those observed in normal foetuses (n = 38; 0.034 to 0.221 ng/ml), so that the deficiency can be diagnosed with the steroid as easily as with 17-OH progesterone.

We studied the incidence of late-onset adrenal hyperplasia as a cause of hirsutism, its association with the major histocompatibility complex, and its clinical expression. Twenty-four of 400 women seen because of hirsutism were found to have late-onset adrenal hyperplasia, diagnosed on the basis of a high plasma level of 17-hydroxyprogesterone, and its marked increase after ACTH stimulation. The degree of hirsutism varied widely. Plasma antigen levels were high, especially the level of androstenedione, whereas 5 alpha-reductase activity, considered to be a good index of peripheral androgen utilization, showed frequent normal or low values. The 24 patients were genotyped, along with 84 family members, and plasma hormones were measured in the family members. We found a high correlation between late-onset adrenal hyperplasia and HLA antigens B14 and Aw33. Similar biologic profiles were observed in the patients and those of their siblings who were HLA identical (n = 9), confirming that late-onset adrenal hyperplasia is linked to the histocompatibility complex. These nine siblings had no hirsutism. We therefore conclude that the role of skin sensitivity to androgens is important in determining the clinical expression of this disorder.

Plasma 21-deoxycorticosterone (21-DB) concentrations were measured before (basal) and 1 h after ACTH stimulation in a population of 34 normal subjects, 18 patients with the late-onset form of congenital adrenal hyperplasia (LO-CAH) due to 21-hydroxylase deficiency, and 19 LOCAH heterozygotes. For comparison, plasma 21-deoxycortisol (21-DOF) and 17-hydroxyprogesterone (17-OHP) were determined simultaneously in the same subjects. Plasma 21-DB concentrations as well as those of 21-DOF did not vary significantly as a function of age, sex, or phase of the menstrual cycle, in contrast to plasma 17-OHP. The mean plasma 21-DB concentrations in normal subjects (adult men, follicular and luteal phase women, and children) were 19.0 +/- 9.5 (+/- SD) pmol/L before and 73.2 +/- 31.0 after ACTH stimulation. In the LOCAH patient group, the mean post-ACTH plasma 21-DB concentration was 1736.0 +/- 1243.0 pmol/L, and all values were above the highest post-ACTH value (148.2 pmol/L) in the normal subjects. Similarly, in the LOCAH patients the post-ACTH plasma 21-DOF concentration was 33.7 +/- 20.3 nmol/L, and the post-ACTH plasma 17-OHP value was 134.0 +/- 70.6 nmol/L; all LOCAH patients had supranormal responses to ACTH. However, 38.9%, 11.2% and 16.7% of the basal plasma 21-DB, 21-DOF, and 17-OHP values in the LOCAH patients overlapped those in the normal subjects. There was a rather large overlap (63.2%) in post-ACTH plasma 21-DB levels between the LOCAH heterozygotes and the normal subjects; it was less than the overlap in plasma 17-OHP (74%) and more than the overlap in plasma 21-DOF values (5.2%) in these same 2 groups. There was moderate overlap (21%) in the post-ACTH plasma 21-DB levels between the LOCAH heterozygotes and LOCAH patients, but no overlap between these 2 groups for either 21-DOF or 17-OHP. The abnormally elevated post-ACTH plasma 21-DB levels found in all the LOCAH patients as well as in some LOCAH heterozygotes suggest the existence of minor 21-hydroxylase deficiency in the mineralocorticoid synthetic pathway in these patients in addition to the well known impairment in the glucocorticoid pathway demonstrated by the elevated post-ACTH 21-DOF and 17-OHP levels.

Human skin, an accessible tissue, is an androgen target organ. We have measured the androgen-binding capacity of human skin cytosol using either 5 alpha[3H]dihydrotestosterone ([3H]DHT) or [3H]methyltrienolone ([3H]R-1881) as ligand. Samples were incubated for 20 h at 0 C, and dextran-coated charcoal was used to separate bound from free steroids. The androgen receptor has a high affinity for both ligands (0.23 +/- 0.04 nM for [3H]DHT; 0.32 +/- 0.16 nM for [3H]R-1881). Testosterone, cyproterone acetate, and, to a lesser extent, estradiol also bind this protein. Progesterone displaces R-1881 from its binding sites, whereas its 5 alpha-reduced metabolite somewhat inhibits DHT binding. The highest binding capacity is measured in cytosol of skin from external genitalia (129.14 +/- 58.0 fmol/g skin; n = 34); it is lower in pubic skin (21.8 +/- 13 fmol/g skin; n = 6). There is no variation as a function of age or sex in genital skin; the higher concentrations observed in the cytosol of pubic skin of women compared to that of men are probably related to lower levels of endogenous steroids. Whereas most patients with the complete form of the testicular feminization syndrome do not have detectable concentrations of androgen receptor, one patient with apparent complete clinical androgen insensitivity had a normal androgen-binding capacity. The parity of values in genital skin from men and women, the absence of variation with age, and the presence of a cytosolic androgen receptor in some androgen-insensitive patients suggest that the androgen receptor in human skin cytosol is not regulated by androgens.

One-hundred and fifty hirsute women (68 with type I or II polycystic ovary syndrome and 82 with idiopathic hirsutism) were treated for periods of 6 to 48 months with oral cyproterone (CPA), a drug with peripheral antiandrogenic, antigonadotrophic and progestative properties, and 17 beta-estradiol given percutaneously to ensure estrogenic impregnation. CPA was administered in daily doses of 50 mg from day 5 to day 25 of the menstrual cycle, and E 2 (3 mg/day) from day 16 to day 25. The dramatic regression of hirsutism observed after 3 to 6 months of treatment was paralleled by a marked decrease of plasma testosterone and delta 4-androstenedione levels and a decrease of the androgen-dependent skin testosterone 5 alpha-reductase. The CPA-percutaneous E 2 combination also has contraceptive properties. Beside its remarkable therapeutic effectiveness, it has the advantages of avoiding the adverse reactions reported with higher doses of CPA and the metabolic and vascular effects of synthetic estrogen administered orally.

In an open prospective study, we have tested clinical efficacy and tolerance of two antigonadotropic drugs, that is danazol (D) and cyproterone-acetate (CA). This study was performed in 11 female patients ranging in age from 19 to 47 years, who suffered from midly-active SLE, during 12 therapeutic periods on the whole (that is 6 for each drug), the minimum period of which was one year. Because of side-effects, D had to be early withdrawn in 2 patients, whereas (the) AC appeared to be well-tolerated in all of them. On the whole, 16 clinical exacerbations of DLE were observed during the 12 months pre-treatment period, versus 9 exacerbations during the 12 months treatment period (p less than 0.05, Wilcoxon test), whereas the average dose of prednisone was reduced from 9.6 to 3.5 mg/day. A dramatic improvement was then observed in 3 patients suffering from mucous ulcerations. Increased plasma testosterone level without any change in estradiol level was observed in patients treated with D. Conversely, plasma estradiol decreased without any change in testosterone level in patients treated with CA. Both drugs induced reduction in plasma sex-hormone binding protein. These preliminary results suggest that D and CA may both reduce lupus disease activity, in parallel with an hormonal environment modification, towards a lower estrogen-androgen balance, along with a better tolerance as for CA.

Hirsutism may arise from two different causes: an increased production of active androgens by the adrenals and/or an increased utilization of circulating androgens by the target cells of the skin i.e. idiopathic hirsutism. Plasma testosterone and androstenedione levels are the best indexes of androgen production. Testosterone 5 alpha-reductase capacity in the skin and urinary 3 alpha-androstanediol reflect androgen utilization. In most hirsutisms, the only plasma testosterone level give sufficient information: it is normal with normal ovulatory cycles in idiopathic hirsutism, it is slightly elevated in ovarian dystrophy, the most frequent causes of hirsutism. More sophisticated investigations are only needed when testosterone levels appear to be over 1.50 ng/ml. In these cases, one could expect an uncommon etiology such as virilizing tumor on a delayed onset of congenital adrenal hyperplasia.

This review analyzes recent data from international literature concerning the antiestrogen action of progesterone, progestins and the antiprogesterone RU 486 at the level of mammary cells in culture from either breast cancer lines or normal breast obtained from reduction mammoplasties. Most data indicate that progesterone, progestins and even RU 486 have a strong antiestrogen effect on breast cell appreciated by the decrease of estradiol receptor content, the decrease of cell multiplication and the stimulation of 17 beta-hydroxysteroid activity which may be considered as a marker of breast cell differentiation dependent of progesterone receptor.

Since harmful effects of estrogens in murine lupus are well established, we studied the influence of oral contraceptive therapy on systemic lupus erythematosus activity in 26 female patients with lupus nephropathy. Combined preparations containing either 50 micrograms (14 patients) or 30 micrograms (7 patients) of ethinyl-estradiol were used in 21 courses in 20 patients. Initial manifestations or exacerbations of systemic lupus activity appeared within 3 months of beginning hormonal therapy in 9 patients, an overall incidence of lupus flare-up of 43%; there was major renal involvement in 4 patients. Conversely, evidence of lupus exacerbation did not develop in any of 11 patients who received pure progestogen oral contraceptive therapy with either continuous low-dose norsteroids (6 patients) or discontinuous progestogens at normal dosage (5 patients). These patients were followed for 5--30 months. Our data indicated that oral contraceptive therapy that used estrogens, even at low doses, often induced exacerbation of systemic lupus erythematosus activity. Pure progestogens, which were effective and devoid of such unfavorable effects, may be preferred in these patients.

Influence of oral contraceptive therapy on SLE activity was evaluated in 33 female patients with lupus nephropathy. Estroprogestative preparations containing either 50 micrograms (18 cases) or 30 micrograms (11 cases) of ethinylestradiol were used in 29 courses in 28 patients. Onset or exacerbation of clinical SLE activity occurred within 3 months after starting hormonal therapy in 13 cases, an overall incidence of lupus flare-up of 44 percent, involving major renal histological lesions in 5 cases. In contrast, of 16 patients receiving pure progestogen contraceptive therapy with either discontinuous normal dosage progestogens (9 cases) or continuous low-dose norsteroids (7 cases), only one developed clinical or immunological evidence of lupus exacerbation within 3 months of hormonal therapy. We conclude that oral contraceptive therapy using estrogens, even at low dosage, is associated with a high risk of SLE exacerbation. Pure progestogens, which have proven effective and devoid of such unfavorable effects, should be preferred in these patients when hormonal contraception is needed.

Summary In human beings, androgen metabolism plays an important role in mediating the action of male hormones upon target structures of the skin. First, human skin is capable of transforming inactive steroids supplied through the blood, such as androstenedione and dehydroisoandrosterone, into the active androgen testosterone. Second, human skin is able to reduce testosterone to 5alpha-DHT, an essential prerequisite, during embryogenesis, for the male differentiation of target structures derived from urogenital sinus. At puberty, hair growth in sexual areas of skin also requires the transformation of testosterone to DHT. Regulation of 5alpha-reductase activity varies according to the anatomical site of the enzyme. In foetuses, 5alpha-reductase activity present in tissues derived from the urogenital tract does not seem to be androgen-dependent, since it is acquired before the onset of testosterone secretion by foetal testis. By contrast, the enzyme that mediates development of certain secondary sex characteristics, such as pilosebaceous gland activity in sexual areas, is clearly androgen-dependent, since it is absent before puberty and in persons with hypogonadism. These differences in the control of the 5alpha-reductase activity mediating the appearance of either primary or secondary sex characteristics are important and may explain the differences in 5a-reductase activity observed in adult skin of both sexes derived from different sexual areas. In addition, the knowledge of androgen relation to the skin is necessary in order to understand the action of the anti-androgens, particularly the compounds which may be used by topical administration.

Twelve patients with clinic and anatomic features of polycystic ovary syndrome type 1 were investigated for gonadotropic and androgenic functions. Basal LH level was 3 times higher than in normal women in the beginning of follicular phase (16,2 +/- 3,0 mUI/ml). After LH-RH stimulation (100 microgram), peak LH level was excessively high (70 +/- 10 mUI/ml) whereas FSH was normal. Clomiphen citrate (100 mg X 5 days) was followed in all cases by temperature ascension and biologic evidence of luteinisation. Four pregnancies were obtained. Plasma androstenedione was elevated in most cases (320 +/- 30 ng/ml) with elevated urinary androstanediol (80 +/- 20 microgram/24 h.) These elevated levels were strikingly reduced in all cases after ethinyl-estradiol, 50 microgram X 20 days. Physiopathologic hypothesis consistent with these results are discussed.

Percutaneous administration of estradiol (E2) is a new substitutive treatment for postmenopausal women. In order to compare hepatic action of percutaneous E2 with that of conjugated estrogens, 18 postmenopausal women were allocated at random to receive one of these two types of natural estrogens for 21 days. Eight patients (group I) received conjugated estrogens orally, 1.25 mg daily. Ten patients (group II) were told to apply percutaneous E2 ointment, 5 gm (i.e., 3 mg of E2), each evening on the abdominal skin. E2, estrone (E1), follicle-stimulating hormone (FSH), and luteinizing hormone (LH), and several markers of estrogen action were evaluated before and after treatment. Both types of treatment were biologically effective, as indicated by the decrease in plasma gonadotropins and the increase in estrogen levels. However, conjugated estrogens produced a greater increase in E1 than in E2; hence, the E2/E1 ratio was 0.57 in group I, whereas it was approximately 1 in group II. Plasma renin substrate increased significantly (by 180%) in group I but not in group II. In the same way, conjugated estrogens produced a modest (12%) but significant decrease in antithrombin III, whereas there was no variation with percutaneous E2. Sex steroid-binding protein was the most sensitive parameter for the hepatic action of estrogen, and increased by 18.66% with percutaneous E2 and by 150% with conjugated estrogens. Plasma triglycerides tended to increase in group I and to decrease in group II, but not significantly. Therefore, percutaneous administration of of E2, in contrast to conjugated estrogens, can produce plasma levels of estrogens closer to those observed in the follicular phase and less alterations in protein synthesis. This lesser toxicity may be explained partially by the route of administration, since with percutaneous administration of E2, the steroid bypasses the liver.

We have measured the total (cytosolic plus nuclear) androgen binding capacity of pubic skin fibroblasts from nine patients with hirsutism of various origin. Confluent intact cell monolayers were incubated with increasing concentrations (0.05-2 nM) of [3H]dihydrotestosterone ([3H]DHT) with or without a 200-fold excess of unlabeled DHT. The androgen binding capacities (mean +/- SD) were similar in normal men (411 +/- 171 fmol/mg DNA), women (310 +/- 103 fmol/mg DNA), and hirsute patients (313 +/- 141 fmol/mg DNA) regardless of the plasma androgen levels. In contrast, the 5 alpha-reductase level in pubic skin fibroblasts (mean +/- SD) was, as previously described, higher in hirsute women (3.3 +/- 2.6 fmol/micrograms DNA . h) than in normal women (1.1 +/- 0.6 fmol/microgram DNA . h; P less than 0.05). We conclude from these data that: 1) increased androgen binding capacity cannot be held responsible for hypersensitivity to androgens in hirsutism; 2) the androgen receptor is not regulated by androgens in human skin, as similar levels are observed in men, women, and hirsute patients; 3) this contrasts with 5 alpha-reductase activity and emphasizes the importance of this enzyme as an amplifier of androgen action in areas where it is stimulated by androgens, such as pubic skin.

The presence of a virilizing ovarian hilum cell tumours was suspected on account of a rise of plasma testosterone level above 3.5 ng/ml in one patient and a rise of plasma androstenedione level above 3.0 ng/ml in another. The diagnosis was made by selective catheterization of the ovarian and adrenal veins, which showed a high androgen concentration gradient in the vein of the ovary affected as compared with that observed in the adrenal and peripheral veins, and was confirmed by histological examination after ovariectomy. These two cases are contrasted with two other cases with high testosterone plasma levels but without gradient on selective catheterization. One of the patients had abnormal hepatic metabolism (porto-caval shunt) and the other had taken high doses of androgens.

The embryonic testicular regression syndrome associated with severe mental retardation is reported in three 46,XY sibs each of whom has a 46,XY chromosome complement. A fourth sib, a sister, also is severely retarded mentally; her chromosome complement is 46,XX. The 46,XY individuals, who were raised as females, presented varying degrees of genital ambiguity, indicating that their gonadal activities had been arrested at different times during embryogenesis. No trace of gonadal tissue could be found in either patient. The coincidence of the embryonic testicular regression syndrome and severe mental retardation in the same sibship is discussed.

Testosterone-estradiol binding globulin (TeBG) was studied in 50 hirsute women, before and after 6-month treatment with cyproterone acetate (CPA). 50 mg CPA was administered orally from the 5th to the 25th day of the menstrual cycle and combined with 3 mg 17 beta-estradiol (E2) administered percutaneously from days 16-25 of the cycle. TeBG was evaluated by a filter assay measuring [3H]-DHT binding capacity. Before treatment, the mean plasma TeBG level was 40 +/- 12 nM in hirsute patients, which is significantly lower than TeBG value in normal women (60 +/- 9 nM, n = 20, P less than 0.01) and intermediate between normal women and normal men (30 +/- 8 nM, n = 20). After a 6-month treatment, TeBG strikingly decreased to 22 +/- 8 nM, which is significantly lower than pretreatment values (P less than 0.01) and even less than TeBG level in normal men. Parallel TeBG assay by immunoelectrodiffusion in 8 of these hirsute patients provided similar results. With this treatment, plasma testosterone and delta 4-androstenedione, measured between the 20th and 25th days of the cycle, decreased from 68 +/- 21 to 25 +/- 8 ng/dl, and 210 +/- 95 to 98 +/- 31 ng/dl respectively. Plasma estradiol decreased from 150 +/- 62 pg/ml to 75 +/- 25 pg/ml. In contrast, urinary 3 alpha-androstanediol glucuronide remained high: 112 +/- 51 and 123 +/- 55 micrograms/24 h respectively before and with CPA treatment. Three mechanisms have been proposed to explain TeBG decrease under CPA + E2perc. treatment (1) relative competition of CPA with labelled DHT in the TeBG-binding capacity assay, (2) relative hypoestrogenism with this treatment, (3) a progestagen or even a partial agonistic androgen effect of CPA on TeBG synthesis in the liver. The third mechanism appears to be predominant. In any case. TeBG decrease combined with the partial enzymatic induction effect of CPA on the liver contributes to the increase in the metabolic clearance rate of T and the high urinary Adiol levels previously reported with CPA treatment.

Cultures of skin fibroblasts from different anatomical sites have been established and testosterone 5 alpha-reductase assayed after the 2nd, 6th and 12th subcultures. After the 2nd passage, 5 alpha-reduction of testosterone to both dihydrotestosterone and androstanediols correlated well with that measured in direct assays performed in total skin homogenates; this is an additional evidence that different types of skin have specific levels of testosterone 5 alpha-reductase activity. However, there was a marked increase in 5 alpha-reductase activity with successive subcultures (X4--5 between 2nd and 12th subcultures) in all the cell strains studied. This finding could explain why data concerning 5 alpha-reductase in cultured skin fibroblasts are often conflicting with those in skin homogenates. It emphasizes the necessity of performing enzyme assays after the same number of passages to allow comparison from strain to strain. Different hypotheses are discussed in order to explain such variations of 5 alpha-reductase in cultured human skin fibroblasts.

Intratumoral activity of the progesterone-dependent enzyme 17 beta-hydroxysteroid dehydrogenase (E2DH) was measured in 114 patients with breast cancer (33 pre- and 81 postmenopausal) before and/or after 8 days of a progestin treatment (lynestrenol, 10 mg/day). In 12 postmenopausal patients, the ability of E2DH to be stimulated by lynestrenol was compared to estradiol receptor (ER) and progesterone receptor (PR) levels. In premenopausal patients, E2DH was higher when tumors were excised in the luteal phase than when excised in the follicular phase. In postmenopausal patients, E2DH was higher after progestin treatment. However, E2DH stimulation by lynestrenol depended on receptor levels. It was most often markedly stimulated in ER-positive, PR-positive tumors. It remained low in ER-negative, PR-negative tumors. Intratumoral measurement of the progesterone-dependent enzyme E2DH in breast cancer after progestin treatment could therefore provide a fine and reliable index of the presence and functional character of PR and hormone dependency of the tumor.

Twenty hirsute women were treated with 50 mg cyproterone acetate orally, administered from the 5th to the 25th day of the menstrual cycle, along with 3 mg 17 beta-estradiol administered percutaneously from days 16-25. Percutaneously administered 17 beta-estradiol was used rather than ethinylestradiol in order to avoid the side effects of oral administration of synthetic estrogens. From a clinical point of view there was a dramatic improvement of hirsutism after 3-6 months of treatment. Biologically, plasma testosterone decreased markedly (P < 0.01) from 64.6 +/- 24.2 ng/dl (n = 20) to 25.2 +/- 11.8 (n = 20), 26.1 +/- 16.6 (n = 16), and 13.3 +/- 10.8 ng/dl (n = 14) after 3, 6, and 9 months of treatment. There was also a significant decrease in delta 4-androstenedione from 251.0 +/- 110.2 ng/dl to 129.9 +/- 66.5, 114.2 +/- 45.8, and 62.0 +/- 21.5 ng/dl after the same periods. From these results it may be assumed that this therapeutic combination has an antigonadotropic effect, as confirmed by the decrease in plasma estradiol, FSH, and LH and the absence of a significant progesterone level in all cases. Plasma and urinary cortisol, lipids, and hepatic tests remained normal. The good clinical and biological tolerance of this treatment makes it interesting to consider for use in the management of hirsutism.

We prospectively studied the effects of hormonal modulation using the antigonadotropic drug, cyproterone acetate (CA), in 7 female patients who had moderately active systemic lupus erythematosus. CA was taken orally at a mean daily dose of 50 mg for 21-33 months by 6 patients (9 months by the seventh patient) without any side effects. The number of clinical lupus exacerbations during CA treatment was lower than that during the corresponding pretreatment period (15 of 170 patient-months versus 27 of 156 patient-months; P less than 0.05), despite a reduction in the daily maintenance dose of corticosteroids or antimalarial drugs. Mean plasma testosterone levels were low initially and remained unchanged (0.66 +/- 0.31 to 0.59 +/- 0.23 nmoles/liter), whereas plasma estradiol decreased markedly (from 0.6 +/- 0 38 to 0.11 +/- 0.03 nmoles/liter), resulting in a significant reduction in the estradiol:testosterone ratio (from 1.19 +/- 0.68 to 0.23 +/- 0.12) and in the plasma concentration of the sex hormone-binding protein. Thus, cyproterone acetate induced improvement in clinical lupus activity in parallel with the expected lower estradiol:testosterone balance.

This study reports the changes in the principal biological parameters seen during the human menstrual cycle (plasma FSH and LH gonadotrophins, oestradiol and progesterone) and provoked by the discontinuous administration of a progestational agent. Fourteen women aged from 25 to 40 years, volunteers, received this treatment. In 9 women, 10 mg of lynoestrenol were administered from the 10th to the 25th day of the cycle. In 5 others, the progestational agent was given at the same dose from the 5th to the 25th day of the cycle. In all cases, there was a rapid and durable fall in gonadotrophins and ovarian steroids in the plasma. These results suggest a marked antigondadotrophic effect of the progestational agent used, which would provide effective contraception. The possibilities offered in the area of human contraception by the dicontinuous administration of progestational agents are discussed in relation with the indications of these substances, in particular during the premenopausal phase and in cases of luteal progesterone insufficiency.

Recent developments have occurred in the understanding of the physiopathology of polycystic ovary (Stein-Leventhal) syndrome. The authors describe in particular the present bio-chemical definition of so-called type I polycystic ovary syndrome: very high and anarchical secretion of LH by the pituitary, explosive response of LH during the LH-RH test, contrasting with normal levels of FSH under basal conditions and after stimulation with LH-RH. In the polycystic ovary, positive and negative feedback exerted by oestrogens at the level of the hypothalamus are intact. In particular, the administration of clomiphene results, in the majority of cases, in ovulation in patients with this disorder. The mechanisms (ovarian hyperproduction of androstenedione, increased transformation of androstenedione into testosterone then dihydrotestosterone and into androstanediol) responsible for the development of hyperandrogenism during polycystic ovary syndrome are also analysed.

The influence of lupus nephropathy on pregnancy and reciprocally was retrospectively studied in a series of 131 pregnancies observed from 1962 to 1981 in 45 systemic lupus erythematosis (SLE) women with renal involvement. Renal biopsy showed proliferative lupus glomerulonephritis in 27. The incidence of live births, corrected for induced abortions, was 87% in 89 pregnancies started before, and 89% in 32 started after the clinical onset of SLE; it was only 63% in 10 cases where lupus nephritis developed during gestation. Relapse or exacerbation of disease activity occurred in 15 (47%) of 32 pregnancies antedated by the onset of SLE, with irreversible renal failure in two cases. Clinical exacerbation of SLE was observed in 13 (76%) of 17 cases where SLE was clinically active at the time of conception, and in only 2 of 15 cases where lupus nephritis was in stable clinical remission for at least 5 months prior to conception. Our data suggest that a successful outcome of pregnancy, without SLE exacerbation, may be expected, even in the more severe forms of lupus nephritis, when gestation begins after a sustained, complete clinical remission.

Human pubic skin was obtained from normal subjects and patients with abnormal sex differentiation. Skin samples (200 mg) supplemented with NADPH, were incubated for 1 h with labelled testosterone. The conversion of testosterone to dihydrotestosterone, 3alpha- and 3beta-androstanediol was calculated. This conversion averaged 14.9 plus or minus 3.4% (SE) in 11 normal men and 3.6 plus or minus 1.4% (SE) in 8 normal women. In 4 children as in 4 young hypogonadotrophic hypogonadal men, the conversion rate of testosterone to 5alpha-reduced metabolites was low (0.8 to 3.5%) and increased at puberty (13.5 to 19.2%). After administration of HCG for 3 months to 1 of the hypogonadal men, it reached 30.2%. Inversely, the formation of dihydrotestosterone and androstanediols from testosterone was suppressed in 2 men treated with large doses of oestrogen. In 3 subjects with an incomplete form of testicular feminization syndrome, the conversion rate of testosterone to 5alpha-reduced metabolites was in the normal male range (6.4 to 18.3%), whereas it was low in one case of the complete form of the syndrome (1.5%). In 9 women with idiopathic hirsutism the rate of 5alpha-reduced metabolites recovered from testosterone was close to that of normal men (13.5 plus or minus 5.5% (SE). From these results, it is postulated that in human subjects, there is a good correlation between hair growth in skin from a sexual area and the extent of testosterone 5alpha-reduction in this tissue. Such an enzymatic activity might be induced by active androgens; this latter hypothesis is in good agreement with the increase of 5alpha-reduction activity observed at puberty or after treatment of young hypogonadal males. In addition, it is pointed out that a positive correlation is observed between the 5alpha-reductase activity present in each skin sample studied and the urinary 3alpha-androstanediol found for the same individual. This confirms our previous findings suggesting that the determination of urinary 3alpha-androstanediol might prove of clinical interest in the evaluation of the androgenic status in human subjects.