The effects of o,p'-DDD on human adrenal steroid synthesis

In the present study, the effects of o,p'-DDD on plasma levels of pregnenolone, 17 alpha-hydroxypregnenolone, progesterone, 17 alpha-hydroxyprogesterone, 11-deoxycorticosterone, deoxycortisol, corticosterone, cortisol, androstenedione and testosterone were studied in 6 patients with adrenal carcinoma (3 with Cushing's syndrome, 2 with adrenogenital syndrome, one without clinical manifestation) and 6 with Cushing's disease. Plasma levels of these steroids were decreased in all of the patients with adrenal carcinoma. The decrement of progesterone and 17 alpha-hydroxyprogesterone was greater than that of pregnenolone and 17 alpha-hydroxypregnenolone. These results indicate that o,p'-DDD inhibits both cholesterol cleavage enzyme and 3 beta-hydroxysteroid dehydrogenase coupled with delta 5 to 4 isomerase system. Plasma levels of pregnenolone and 17 alpha-hydroxypregnenolone showed a twofold increase on the 7th day after consecutive administrations of o,p'-DDD in patients with Cushing's disease. Plasma levels of cortisol were decreased to normal one month after continuous o,p'-DDD treatment. Urinary 17-OHCS and 17-KS have been decreased out of proportion to the decrease in plasma cortisol in the first week of o,p'-DDD treatment. Such a disparity suggests that o,p'-DDD might affect the extra-adrenal metabolism of cortisol. However, no evidence was found for the inhibition of hepatic C17-20lyase and glucuronyl transferase. Regression of pulmonary metastases was observed in one case with Cushing's syndrome due to adrenal carcinoma, suggesting that o,p'-DDD causes necrosis of the metastatic adrenal carcinoma. A remission of the disease was obtained in one patient with Cushing's disease after 6 months of continuous o,p'-DDD treatment. The usefulness of o,p'-DDD for the treatment of adrenal carcinoma with metastases and Cushing's disease was confirmed.     

Plasma levels of gonadotropins, prolactin, thyroxine, and adrenal and gonadal steroids in obese prepubertal girls.

Plasma levels of gonadotropins, PRL, T4, and adrenal and gonadal steroids were measured in two groups of 7- to 9-yr-old and 10- to 11-yr-old obese prepubertal girls, and were compared to those found in groups of nonobese girls of the same age. The data found in normal weight subjects confirm the data reported in the literature, showing a significant rise between the 7- to 9- and 10- to 11-yr groups, of FSH, pregnenolone, dehydroepiandrosterone, testosterone, and estradiol plasma levels, while LH, PRL, T4, cortisol, progesterone, 17-hydroxyprogesterone (17P), and androstenedione remained constant. In the obese subjects, pregnenolone and dehydroepiandrosterone levels are notably higher than in the normal girls, in the same range as those found in adult women; furthermore, they show no rise between the two age groups. The obese prepubertal groups had significantly higher progesterone, androstenedione, and PRL levels in comparison with those observed in girls of normal weight, but 17-hydroxyprogesterone, cortisol, testosterone, LH, and T4 were similar in both groups. Estradiol levels were markedly depressed in the obese girls; FSH levels were higher in the younger girls than in normal subjects. These data indicate that in prepubertal obesity, maturation of adrenal gland function (chiefly the delta 5 pathway), is notably enhanced, whereas gonadal secretion of estradiol is impaired in the presence of high levels of FSH and PRL.     

Partial 17, 20-desmolase and 17 alpha-hydroxylase deficiencies in a 16-year-old boy

Thirteen plasma steroids as well as ACTH, LH and FSH were measured by specific RIAs under basal and dynamic conditions in a 16-year-old boy (normal external genitalia, 46, XY karyotype) who presented slowness and unachievement of pubertal development. On the delta 4-pathway: basal levels of testosterone and dihydrotestosterone were low- with a normal ratio-, delta 4-androstenedione and 11 beta-hydroxyandrostenedione were in the low normal range. Meanwhile, 17 alpha-hydroxyprogesterone and progesterone levels were markedly elevated. On the delta 5-pathway: dehydroepiandrosterone was extremely low while 17 alpha-hydroxypregnenolone and pregnenolone were almost normal; dehydroepiandrosterone sulfate was subnormal while pregnenolone sulfate was normal. Cortisol, aldosterone were normal while ACTH was moderately increased. Basal and responsive levels of LH and FSH were markedly increased. ACTH stimulation induced a subnormal rise of cortisol and 11 beta-hydroxyandrostenedione, a low or absent rise of dehydroepiandrosterone, 17 alpha-hydroxypregnenolone, androstenedione and 17 alpha-hydroxyprogesterone contrasting with a marked rise of pregnenolone and progesterone. After hCG stimulation, responses were low for testosterone, extremely high for 17 alpha-hydroxyprogesterone with a normalisation of the 17 alpha-hydroxyprogesterone/progesterone ratio. Fluoxymesterone dramatically reduced the pathologically high basal levels of progesterone and 17 alpha hydroxyprogesterone. Dexamethasone induced only a minute decrease in the delta 4-progestagens, a marked decrease in pregnenolone, with a more than 80% reduction of 17 alpha- hydroxypregnenolone, dehydroepiandrosterone, dehydroepiandrosterone sulfate and androstenedione. These data suggest a defect involving the cytochrome P450 common to both 17 alpha-hydroxylase and 17, 20-desmolase activities.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hormonal pattern of adolescent menstrual cycles.

Serum FSH, LH, PRL, estradiol, pregnenolone, progesterone, 17-hydroxyprogesterone, androstenedione, testosterone, 5 alpha-dihydrotestosterone, and androsterone were measured radioimmunologically in 20 normal girls aged 13-17 yr. Samples were taken every day or every second day during one menstrual cycle. The cycles recorded could be divided into three groups. The first and oldest group consisted of 10 girls with a mean gynecological age (years since menarche) of 2.9 yr. The luteal phase was at least 11 days and the progesterone concentration was at least 5 ng/ml. The testosterone rise (mean, 55%) on the day of LH surge correlated well with the simultaneous progesterone rise (mean, 270%) and the following luteal progesterone secretion. A negative correlation was seen between the FSH concentration on days 3-4 of the cycle and the length of the follicular phase. The second group consisted of 4 girls who had a mean gynecological age of 1.5 yr. The luteal phase was of 4- to 8-day duration and the progesterone secretion was lower than in group I. The follicular phase testosterone concentration was lower in group II as compared to group I. No "periovulatory" testosterone increases were seen, although every cycle displayed an LH and FSH peak. The third group consisted of 6 girls with a mean gynecological age of 1.1 yr. These cycles were anovulatory, as the serum progesterone concentration never exceeded 1.0 ng/ml. In two cycles, signs of follicular maturation were seen. In the four others, the androgen levels tended to be elevated. In two cases, the testosterone and androstenedione concentrations were 2-4 times elevated from the beginning of these two cycles. Thus, the hormonal pattern of adolescent menstrual cycles is far from uniform. It is very likely that in addition to gonadotropins, estradiol and progesterone, androgens may also have a role in the development and maintenance of normal menstrual function in the female.     

A testosterone-producing adrenal cortical adenoma in an elderly woman.

A 76-year-old woman with virilization had menopausal levels of circulating LH and FSH, and a markedly elevated concentration of plasma testosterone (9130 pg/ml) into the range for adult men. Plasma cortisol and androstenedione levels andurinary 17-ketosteroid secretion were normal. Ethinyl estradiol suppressed plasma testosterone, LH, and FSH levels into the normal range for premenopausal women, but the testosterone concentration was unaffected by the administration of dexamethasone or ACTH. Retrograde venous sampling and angiography localized a right adrenal adenoma preoperatively. Following adrenalectomy, there was a prompt fall in testosterone, but there was no change in the LH concentration. Thus, this patient had an adrenal adenoma which secreted only testosterone and appeared to be gonadotropin-responsive. Testosterone levels in the adult male range failed to suppress gonadotropins. The significance of these findings is discussed.     

Cortisol and androgen secretion in a case of Nelson's syndrome with paratesticular tumors: response to cyproheptadine therapy.

Bilateral paratesticular tumors were observed in a 32-yr-old man 14 yr after he developed a pituitary tumor after adrenalectomy for Cushing's disease (Nelson's syndrome). Plasma ACTH concentrations were markedly elevated (mean, 6350 pg/ml), but urinary free cortisol concentrations were low (27-31 micrograms/24 h). Catheterization revealed a spermatic to peripheral venous gradient for cortisol consistent with secretion of this steroid by the tumor. This was confirmed by decreased cortisol excretion after tumor excision. Serum androgen (testosterone, androstenedione, dihydrotestosterone, and dehydroepiandrosterone-sulfate) and progestin (progesterone and 17-hydroxyprogesterone) concentrations were decreased and did not decline further after tumor removal. These latter observations suggested that the paratesticular tumors did not secrete appreciable testosterone or any of its immediate precursors. Serum gonadotropin levels were also low. Cyproheptadine treatment resulted in a marked lowering of plasma ACTH concentrations (221-320 pg/ml). This was associated with an increase in both plasma LH and testosterone concentrations. These observations are consistent with the hypothesis that ACTH may directly affect LH and testosterone secretion.     

SERUM STEROIDS AND PITUITARY HORMONES IN FEMALE PUBERTY: A PARTLY LONGITUDINAL STUDY

Pubertal development of 200 normal girls, 7--17 years of age, was investigated in a partly longitudinal manner with two examinations 1.5 years apart. Samples from postmenarchal girls were taken on days 6--9 and 20--23 of the menstrual cycle. Serum pregnenolone, progesterone, 17-hydroxyprogesterone, dehydroepiandrosterone, androstenedione, testosterone, 5 alpha-dihydrotestosterone, androsterone, oestradiol and cortisol as well as ACTH, FSH, LH and prolactin were measured radioimmunologically and were related to bone age, breast and pubic hair developmental stages, and gynaecological age. In the samples of premenarchal girls as well as the follicular phase of postmenarchal girls the concentration of all the steroids increased with age. Of all the steroids measured, serum dehydroepiandrosterone and pregnenolone displayed the earlier increase, from the youngest age group of 7.5 years onwards. Serum oestradiol testosterone and androstenedione in creased rapidly from the bone age group of 9.5 years (subjects 9.0--9.9 years of age) onwards, in close association with the appearance of the first physical signs of puberty. A marked increase in these three steroids continued until 13.5 years, the age at which menarche took place. Menarche was followed by a plateau of 1--2 years duration and then a second increase took place up to the two oldest age groups (17.5 and 18.5 years bone age), a trend seen in the follicular phase levels of all the steroids measured. The 5 alpha-dihydrotesterone/testosterone ratio decreased with increasing testosterone concentration. Serum oestradiol, testosterone, androstenedione, dehydroepiandrosterone and FSH showed no overlapping in the 2.5--97.5% range of concentrations and androsterone and LH in the 16--84% range between prepubertal and postmenarchal subjects. Pregnenolone, progesterone, 17-hydroxyprogesterone, 5 alpha-dihydrotesterone, cortisol, ACTH and prolactin overlapped even in the 16--84% range between these two groups of subjects. In postmenarchal girls, about 80% of the cycles were anovulatory in the first year after menarche, 50% in the third and 10% in the sixth year. The background of the majority of the anovulatory cycles seems to be a physiological variant of the pattern seen in the polycystic ovary syndrome: the levels of testosterone, and androstenedione and LH were increased in anovulatory cycles compared to ovulatory ones.     

Endocrine status in stage II vs. advanced premenopausal and postmenopausal breast cancer patients.

Circulating preoperative levels of DHEA-S, androstenedione and SHBG were measured in 40 premenopausal and 49 postmenopausal breast cancer patients, and in 30 and 15 age-matched healthy controls, respectively. Moreover, the levels of LH, FSH, prolactin, estradiol, progesterone, testosterone, DHEA-S, androstenedione and SHBG of Stage II breast cancer patients were compared with advanced patients and also with controls. In premenopausal patients the levels of steroid hormones were significantly low whereas those of peptide hormones were significantly high. On the contrary, in postmenopausal patients, except DHEA-S, all other hormones were significantly elevated in comparison with controls. In premenopausal patients, DHEA-S, androstenedione, estradiol, progesterone, and testosterone decreased as stage advanced with concomitant increase of SHBG, LH, FSH and prolactin when compared with hormone levels of Stage II patients. In postmenopausal advanced breast cancer patients, when compared with Stage II patients, the levels of SHBG, LH, FSH, and prolactin increased significantly, while DHEA-S, androstenedione, estradiol, and progesterone decreased as stage advanced.     

Endocrine effects of masturbation in men.

The levels of pregnenolone, dehydroepiandrosterone (DHA), androstenedione, testosterone, dihydrotestosterone (DHT), oestrone, oestradiol, cortisol and luteinizing hormone (LH) were measured in the peripheral plasma of a group of young, apparently healthy males before and after masturbation. The same steroids were also determined in a control study, in which the psychological antipation of masturbation was encouraged, but the physical act was not carried out. The plasma levels of all steroids were significantly increased after masturbation, whereas steroid levels remained unchanged in the control study. The most marked changes after masturbation were observed in pregnenolone and DHA levels. No alterations were observed in the plasma levels of LH. Both before and after masturbation plasma levels of testosterone were significantly correlated to those of DHT and oestradiol, but not to those of the other steroids studied. On the other hand, cortisol levels were significantly correlated to those of pregnenolone, DHA, androstenedione and oestrone. In the same subjects, the levels of pregnenolone, DHA, androstenedione, testosterone and DHT, androstenedione and oestrone. In the same subjects, the levels of pregnenolone, DHA, androstenedione, testosterone and DHT in seminal plasma were also estimated; they were all significantly correlated to the levels of the corresponding steroid in the systemic blood withdrawn both before and after masturbation. As a practical consequence, the results indicate that whenever both blood and semen are analysed, blood sampling must precede semen collection.     

Effects of estrogens on adrenal 3 beta-hydroxysteroid dehydrogenase in ovariectomized women.

The acute and chronic effects of estradiol (E2) on the serum levels of four delta5,3-beta hydroxysteroids and their four delta4, 3-keto products were studied in four ovariectomized women with and without adrenal stimulation by ACTH. Six hour infusions of saline and of synthetic 1-24 ACTH were administered and later repeated with a two hour infusion of E2 50 mug/h. The patients were then given 50 mug of ethinyl estradiol (EE2) p.o. for 4 to 6 weeks and the control and ACTH infusions were again repeated. Levels of pregnenolone3 (Pe), 17alpha-hydroxypregnenolone (17 Pe), progesterone (Po), 17alpha-hydroxyprogesterone (17 Po), dehydroepiandrosterone (DHEA), androstenedione (Adione), androstenediol (Adiol), and testosterone (T), as well as cortisol and DHEA-sulfate were measured by radioimmunoassay on serum samples taken at 1200 and 1300 h. There was no significant effect of E2 or EE2 in the doses administered with or without exogenous ACTH on 3 betaOHSD activity as reflected in absolute steroid levels or in the ratio of concentrations of each delta5:delta4 steroid pair. During the 4th and 5th hour of ACTH infusion, the plasma level of 17 Pe (mean 22.5-fold stimulation) was most elevated, followed by 17 Po (12.5-fold), Pe (10-fold), cortisol (5.9-fold) and Po (4.5-fold), with smaller increases for the other steroids. These results, as well as the pattern of change in plasma levels in one of the subjects in whom fifteen minute samples were measured, provide further evidence suggesting that the major pathway for cortisol biosynthesis in vivo proceeds from Pe via 17 Pe, and not via Po.     

INDICES OF GONADAL FUNCTION IN THE HUMAN MALE

A radioimmunoassay technique for the simultaneous measurement of eight unconjugated steroids (progesterone, pregnenolone, dehydroepiandrosterone, androstenedione, testosterone, dihydrotestosterone, oestrone and oestradiol) in the peripheral plasma of human males is described. Determinations of these steroids and of immunoreactive FSH and LH were carried out on the plasma of twenty-one normal individuals and the levels were compared to those of eleven and ten males exhibiting oligospermia and azoospermia, respectively. Mean values and tolerance limits for each hormone, based on a lognormal distribution of individual values, are presented for all groups. Oligospermia was associated with a significant reduction in plasma dihydrotestosterone and testosterone levels. Azoospermic subjects also exhibited decreased dihydrotestosterone levels but a normal range of testosterone concentrations. Mean peripheral plasma levels of FSH were significantly elevated in both pathological groups and this was paralleled in the azoospermic men by increased concentrations of plasma LH.     

The effect of flutamide on basal and ACTH-stimulated plasma levels of adrenal androgens in patients with advanced prostate cancer

The effect of flutamide on basal and ACTH-stimulated plasma levels of adrenal androgens was investigated in 6 patients with untreated advanced prostate cancer, aged 52-75 yr. Flutamide was administered (250 mg three times daily) for 10 days; before and after treatment, a synthetic ACTH1-24 stimulation test (250 micrograms im, with blood sampling immediately before and 60 min after the stimulus) was performed. Basal plasma 17OH-pregnenolone (delta 5-17OHP), 170H-progesterone (delta 4-17OHP), androstenedione (A), dehydroepiandrosterone (DHEA) and its sulphate (DHEAS) were unchanged by flutamide treatment. In contrast, basal plasma testosterone (T) concentrations significantly increased (p less than 0.05). The response of cortisol delta 4-17OHP, delta 5-17OHP, A and DHEA to ACTH, as well as the ACTH-stimulated delta 5-17OHP/delta 4-17OHP, delta 5-17OHP/DHEA, delta 4-17OHP/A and DHEA/A ratios, were unchanged by flutamide treatment. These findings indicate that: a) Short-term flutamide administration enhances testicular steroidogenesis, via augmented LH pulse frequency; b) Adrenal steroidogenesis seems to be not affected by the drug, since ACTH-stimulated plasma levels of adrenal androgens and precursors/products ratios were unchanged.     

Effect of exposure to long days on the secretion of oestradiol, oestrone, progesterone, testosterone, androstenedione, cortisol and follicle-stimulating hormone in intact and spayed ferrets

The changes in concentration of plasma oestradiol, oestrone, progesterone, androstenedione, testosterone, cortisol and FSH were followed in intact female ferrets brought into oestrus by extension of the photoperiod from 8 to 16 h daily. An additional group of spayed females was similarly exposed to the extended photoperiod. There was no change in the blood oestrone, androstenedione and testosterone levels in the spayed females; the concentration of oestradiol, progesterone and FSH fell, while that of cortisol rose after 6 weeks. The intact females showed no change in plasma oestrone and cortisol concentrations, a rise in plasma oestradiol associated with the onset of oestrus, and falls in the blood levels of testosterone, androstenedione, progesterone and FSH. These results indicate that the changes in plasma gonadal steroid levels after extension of the photoperiod differ markedly from those in rodents or ruminants.     

STEROIDS IN OVARIAN AND PERIPHERAL VENOUS BLOOD IN POLYCYSTIC OVARIAN DISEASE

Ovarian and peripheral venous blood samples were collected at operation in six patients with polycystic ovaries (PCO) and seven control subjects with normal ovarian function in the follicular phase of the cycle. Plasma concentrations of unconjugated testosterone, dihydrotestosterone (DHT), androsterone, androstenedione, dehydroepiandrosterone (DHEA), pregnenolone, progesterone, 17α-hydroxyprogesterone (17α-OH-P) and oestradiol were determined by specific radioimmunoassay techniques, and concentrations of DHEA, androsterone and pregnenolone sulphates by gas chromatography. In the control group, ovarian vein concentrations of all unconjugated steroids, except progesterone, were significantly higher than the corresponding peripheral vein concentrations, suggesting ovarian secretion. No significant differences were demonstrated between ovarian and peripheral plasma levels of steroid sulphates. Ovarian vein levels of androstenedione, testosterone and DHEA were markedly elevated in PCO patients compared with the control group, and the levels of DHT and androsterone to a lesser degree. Polycystic ovaries appear to secrete androsterone sulphate, but no significant secretion of DHEA sulphate could be demonstrated. Ovarian venous levels of oestradiol in the PCO group did not differ from those in the control group. Elevated ovarian venous androgen levels in the PCO group seemed to correlate with thecal cell hyperplasia as indicated by histological examination of ovarian biopsies. In one PCO patient, blood levels of different steroids were followed for a month after ovarian wedge resection. Testosterone fell to half the pre-operative value and a temporary fall was also noticed in other androgens. A marked rise in plasma progesterone concentration at the end of the follow-up period suggested that ovulation had occurred.     

Studies on the reproductive cycle on the female cobra, Naja naja. II. In vitro ovarian steroid synthesis.

The synthesis of steroids in vitro by minced ovarian tissue from the cobra, Naja naja, using [³H]pregnenolone and [³H]dehydroepiandrosterone([³H]DHA) as precursors was studied. From [³H]pregnenolone the major products were progesterone, pregnanolone (3α-hydroxy-5β-pregnan-20-one), 17α-hydroxyprogesterone, androstenedione, and testosterone. DHA and 17α-hydroxypregnenolone were tentatively identified, but insufficient material was available for positive characterization. From incubations using [³H]DHA as precursor, the only products identified were testosterone, androstenedione, and estradiol-17β. Significant amounts of radioactivity were associated with an estriol fraction from both the pregnenolone and the DHA incubations but were not further characterized. Time-lapse studies revealed an extremely rapid conversion of [³H] pregnenolone to progesterone, with a maximum occurring after 15 min in tissue taken from a cobra in April at the height of the reproductive period. Addition of cofactors to the medium markedly stimulated the synthesis of progesterone and pregnanolone from [³H]pregnenolone, but appeared to inhibit the production of other ovarian steroids. Mammalian LH, when added to the incubation medium, was found to stimulate the biosynthesis of 17α-hydroxyprogesterone, androstenedione, and testosterone from [³H]pregnenolone. Addition of fresh, homogenized snake pituitary or mammalian FSH appeared to increase the yield of testosterone but none of the precursors in the pathway, and there was a suggestion that FSH alone increased the rate of aromatization.     

Ketoconazole reverses hyperandrogenism in a patient with insulin resistance and acanthosis nigricans

We administered ketoconazole to a young woman with ovarian hyperandrogenism, insulin resistance, and acanthosis nigricans. While taking ketoconazole, her serum testosterone, androstenedione, dehydroepiandrosterone, and cortisol levels declined, while serum progesterone, 17-hydroxyprogesterone, and 11-deoxycortisol rose. Serum LH, FSH, and estradiol levels were intermittently higher during ketoconazole treatment, although LH and FSH responsiveness to GnRH did not change. Basal and stimulated serum insulin concentrations were high before and during ketoconazole therapy, while fasting glucose levels and glucose disappearance rate constants were normal throughout the study. A dramatic improvement in hirsutism occurred, and menses resumed after a 6-yr hiatus. Adverse drug effects or clinical evidence of adrenal insufficiency were not encountered. These results support a role for ketoconazole in the therapy of ovarian hyperandrogenism.     

Sex hormones in amenorrheic women with alcoholic liver disease

Urinary excretion of estrogens and plasma concentrations of estrone, estradiol, LH, FSH, PRL, progesterone, testosterone, and sex hormone binding globulin were measured in nine chronic alcoholic women with cirrhosis or alcoholic fatty liver. They were aged 24-40 yr and all had secondary amenorrhea which had lasted for at least 3 months. The response of pituitary gonadotropin secretion to administration of LHRH and estradiol benzoate and of PRL secretion to TRH were also investigated. Urinary excretion of estrogens in the alcoholic women with liver disease was similar to that in normal postmenopausal women and less than half that in normal women of the same age in the midfollicular phase of the menstrual cycle. Plasma estradiol levels in the alcoholic women were lower than in the menstruating women but higher than in the postmenopausal women, whereas their plasma estrone levels were higher than in the menstruating women. Plasma concentrations of progesterone and testosterone in the alcoholic women did not differ from those in the postmenopausal women but were lower than in the menstruating women. In spite of the relative estrogen deficiency plasma LH and FSH levels were not elevated in the alcoholic women. The responses of LH and FSH to LHRH were similar in the patients and in the menstruating women. Intramuscular administration of estradiol benzoate did not increase plasma LH and FSH concentrations in the alcoholic women. Hyperprolactinemia was not found and there were no differences in the PRL responses to TRH between the patients and the control groups. In conclusion, disturbed regulation of gonadotropin secretion is an important factor in the genesis of estrogen deficiency and amenorrhea in alcoholic women with liver disease, although ovarian function may also be directly impaired.     

Effects of intravenous administration of high dose-diethylstilbestrol diphosphate on serum hormonal levels in patients with hormone-refractory prostate cancer

The objective of this study was to elucidate the mechanism underlying the further suppression of serum testosterone (T) by diethylstilbestrol diphosphate (DES-DP) in patients with prostate cancer refractory to hormonal treatment. These patients received an LHRH agonist with or without a non-steroidal androgen-receptor blocker or a gestagen before DES-DP. We measured serum levels of total and free T, dihydrotestosterone (DHT), estradiol (E2), dehydroepiandrosterone sulfate (DHEA-S), dehydroepiandrosterone (DHEA), androstenedione, cortisol, aldosterone before and during intravenous administration of high doses of DES-DP (500 or 1000 mg/day). DES-DP administration suppressed the serum levels of FSH (p=0.04) and total T (p=0.02), and eliminated free T (p=0.04) and E2 (p=0.04) from serum, while reducing serum DHEA-S to approximately two-thirds of the pretreatment level (p=0.03). In contrast, serum levels of SHBG (p=0.02) and cortisol (p=0.02) were markedly increased after DES-DP administration. The latter had no significant effect on serum levels of LH, DHT, ACTH, 17alpha-hydroxypregnenolone, 17alpha-hydroxyprogesterone, DHEA, androstenedione, or aldosterone. The results suggest that the potent suppression of circulating total T by DES-DP is caused, in part, by the inhibitory effect of DES-DP on serum DHEA-S level. In most patients, high-dose DES-DP treatment completely suppressed the serum level of free T, while possibly elevating serum SHBG and decreasing serum total T. The mechanisms that maintain the serum level of serum DHT during DES-DP treatment require further elucidation.     

Plasma concentrations of luteinizing hormone, follicle-stimulating hormone and progesterone during the breeding season in ewes immunized against androstenedione or testosterone

Levels of plasma LH, FSH and progesterone during the breeding season were measured by radioimmunoassay in control ewes and ewes actively immunized against androstenedione-11 alpha-hemisuccinyl--bovine serum albumin or testosterone-3(O-carboxymethyl)oxime--bovine serum albumin. Immunization against androstenedione resulted in normal oestrous cycles with raised plasma LH and progesterone levels and a reduction in the concentration of FSH during the luteal phase. It is tentatively suggested that androstenedione, or its metabolites, could modify the oestrogenic control of LH secretion and facilitate the release of FSH in the ewe. Immunization against testosterone prevented oestrus and resulted in markedly increased levels of LH without alteration of the FSH concentration. Since evidence of increased binding of oestradiol-17 beta was found in the ewes immunized against testosterone, these results cannot be attributed solely to a reduction in the biologically active faction of testosterone.     

Corticotropin-releasing hormone: a potent androgen secretagogue in girls with hyperandrogenism after precocious pubarche

CRH is an adrenal androgen secretagogue in men and has been proposed as a candidate regulator of adrenarche. CRH also affects androgen production by theca cells and may be involved in the pathogenesis of ovarian hyperandrogenism (OH). Precocious pubarche (PP) in girls can precede adolescent OH, a condition characterized by a high ovarian 17-hydroxyprogesterone (17-OHP) response 24 h after GnRH agonist challenge. In adolescent girls with a history of PP, we assessed the early androgen response to CRH, as well as the CRH effect on the late ovarian response to GnRH agonist. Within a randomized cross-over design, saline or CRH (human CRH 1 microg/kg x h in saline) was infused over 3-h (1100-1400 h) into 12 adolescent girls (age 17+/-2 yr; body mass index 21.4+/-0.9 Kg/m2) who had been pretreated with dexamethasone (1 mg at 0 h) and GnRH agonist (leuprolide acetate 500 microg sc at 0800 h = time 0). All adolescents had hirsutism, irregular menses, hyperandrogenemia, and hyperinsulinemia after PP. Serum LH, FSH, androstenedione, dehydroepiandrosterone (DHEA), and DHEA-sulfate (DHEAS) were measured at time 0, 3, 6, and 24 h, and ACTH and 17-OHP were measured at time 0, 6, and 24 h. ACTH concentrations at the end of saline or CRH infusions were less than 45 pg/mL; neither saline nor CRH infusions evoked early changes in 17-OHP levels. Within 3 h of CRH infusion, DHEAS increased by 46%, on average; androstenedione increased 2.5-fold and DHEA increased 5-fold duringCRH infusion (all P < 0.0001 compared with saline). There was no detectable CRH effect on the responses of LH, FSH, DHEA, DHEAS, 17-OHP, androstenedione, testosterone, and estradiol 24 h after GnRH agonist administration; five of 12 girls had elevated 17-OHP responses suggestive of OH. In conclusion, CRH was found to be a potent adrenal androgen secretagogue in adolescent girls with hyperandrogenism after PP. In this study, CRH failed to detectably affect the ovarian androgen response to gonadotropins.