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Insulin resistance and its attendant hyperinsulinemia has been linked with hyperandrogenism. Insulin resistance is characteristic of the Pima Indians of the Gila River Indian community in central Arizona. Serum androgens, testosterone and dehydroepiandrosterone sulfate (DHEA-S) were quantitated at baseline and in response to low- and high-dose insulin infusion in 11 obese, hyperinsulinemic Pima Indian and 10 obese, hyperinsulinemic Caucasian women and were compared with baseline androgens in 16 nonobese Caucasian women. While there was no significant testosterone or DHEA-S response to short-term insulin infusion in either Pimas or obese Caucasians, both these groups had higher baseline testosterone concentrations (67 +/- 6.5 ng/dl in the Pimas, 55 +/- 5.9 ng/dl in the obese Caucasians) as compared with the nonobese Caucasians (28 +/- 2 ng/dl; p < 0.001). Baseline DHEA-S concentrations were not significantly different in the three groups. Given the hyperinsulinemic status of both the Pimas and the obese Caucasians, the finding of higher testosterone concentrations in these subjects as compared with nonobese Caucasians supports a role for insulin in ovarian androgen production and demonstrates that hormonal interactions that may be operating in obese hyperinsulinemic Caucasian subjects also operate in obese, hyperinsulinemic Pima Indians.

The aim was to study 3 alpha-androstanediol glucuronide (3AG) plasma levels and its relationship with 5-ene and 4-ene steroids in children with the benign form of precocious pubarche (precocious adrenarche). Sixty-five children with precocious adrenarche (PA), aged 3.6-8.2 yr (55 girls and 10 males) and 15 normal age-matched children were studied. We evaluated plasma androstenedione (A), dehydroepiandrosterone (DHA), its sulfate (DHA-S), testosterone (T), dihydrotestosterone (DHT), its glucuronide (DHTG), 3 alpha-androstanediol (3Ad) and its glucuronide (3AG) in all subjects. All androgens are expressed as mean +/- SD. We found significantly higher plasma levels not only in glandular androgens but also in peripheral androgens (A, 2.4 +/- 1.5 nM vs 0.79 +/- 0.46 nM, p < 0.001; DHA, 9.8 +/- 4.9 vs 2.7 +/- 0.76 ng/dl, p < 0.001; DHA-S, 3.4 +/- 2 microM vs 2.4 +/- 0.65 microM, p < 0.05; T, 0.74 +/- 0.5 nM vs 0.4 +/- 0.1 nM, p < 0.001; DHT, 0.36 +/- 0.13 nM vs 0.12 +/- 0.05 nM, p < 0.001; 3Ad, 0.13 +/- 0.1 nM vs 0.054 +/- 0.03 nM, p < 0.001; DHTG, 0.5 +/- 0.3 nM vs 0.26 +/- 0.09 nM p < 0.01). As far as the plasma 3AG levels are concerned we found significantly higher values in PA with respect to controls (1.17 +/- 0.7 nM vs 0.61 +/- 0.04 nM, p < 0.01), suggesting that 3AG may be considered a marker of skin androgen utilization.(ABSTRACT TRUNCATED AT 250 WORDS)

In order to evaluate the effect of postmenopausal estrogen replacement therapy on the plasma levels of the insulin-like growth factor-I (IGF-I) 12 postmenopausal women aged 44 to 59 years were studied. The control group consisted of 15 healthy premenopausal women aged 20-44 years. In the postmenopausal women the plasma levels of IGF-I, gonadotrophins and sex hormones were determined before and after 3 and 6 months cyclic replacement therapy with transdermal 17 beta-estradiol (E2 100 micrograms patches applied twice weekly) combined with oral chlormadinone acetate (2 mg daily for 7 days in each cycle). Basal levels of estradiol (E2), IGF-I, dehydroepiandrosterone sulphate (DHEA-S), testosterone and androstenedione were lower, but gonadotropin levels were higher in postmenopausal than in premenopausal women. In all the women studied age was inversely correlated with IGF-I levels (r = -0.793, p less than 0.001) and with DHEA-S concentrations (r = -0.435, p less than 0.02). In postmenopausal women transdermal estradiol administration restored the circulating E2 levels to the early follicular range and increased the IGF-I levels (from 76.4 +/- 9.2 micrograms/l to 141.8 +/- 20.8 micrograms/l; p less than 0.01). Transdermal estradiol decreased gonadotrophin levels without changes in concentration of DHEA-S, testosterone, androstenedione and SHBG. In postmenopausal women before and during replacement therapy a positive correlation was found between estradiol and IGF-I concentrations (r = -0.439, p less than 0.01). These results suggest that cyclic replacement therapy with transdermal 17 beta-estradiol in combination with chlormadinone acetate given orally increase the plasma levels of IGF-I in postmenopausal women.

Dehydroepiandrosterone sulphate plasma levels were measured in patients with benign breast disease and in healthy women. In addition the adrenal secretion of dehydroepiandrosterone sulphate was assessed by means of an ACTH stimulation test in some patients and control subjects. The results obtained demonstrate that dehydroepiandrosterone sulphate plasma levels of patients with benign breast disease overlap those found in controls and that the adrenal response to ACTH of patients with breast pathology does not differ from that of healthy women.

A 33 year old woman presented with recurrent Cushing's disease 4 years after complete remission induced by pituitary surgery. On relapse she exhibited the unusual pattern of elevated indices of cortisol secretion with markedly suppressed serum DHEA-S; urinary 17-ketosteroid excretion was also below the normal range. Biochemical testing was otherwise consistent with ACTH-mediated hypercortisolism, and adrenal histopathology showed bilateral hyperplasia with no evidence of tumor. This case illustrates that serum DHEA-S is not an infallible guide to the differential diagnosis of Cushing's syndrome, and it supports the existence of a pituitary-secreted adrenal androgen stimulating factor that is distinct from ACTH.

We have studied the variation of ACTH, cortisol and DHEA-S plasma levels in 6 patients before and up to 15 months after surgical remission of Cushing's syndrome in order to compare the relative dependency of cortisol and adrenal androgens towards ACTH. Three patients with adrenal adenoma were treated by unilateral adrenalectomy. Three other patients with Cushing's disease underwent transsphenoidal pituitary tumorectomy. Preoperative ACTH was undetectable in patients with adrenal adenoma and high-normal or elevated in patients with Cushing's disease. All patients became rapidly hypocortisolemic after surgery and ACTH and cortisol levels eventually recovered at different intervals. Patients with adrenal adenoma had an initially low DHEA-S which failed to normalize for the entire follow-up period. Patients with Cushing's disease had normal or high-normal DHEA-S which became low immediately after surgery, following ACTH decrease, and it remained low during the entire follow-up period. In conclusion, after removal of corticotropic inhibition secondary to excess cortisol, DHEA-S remains suppressed for a longer period of time than cortisol. Moreover it only takes a short period of relatively low ACTH (after pituitary tumor excision) to induce a long lasting DHEA-S inhibition. Therefore the DHEA-S secreting adrenal cells seem to be more sensitive to the lack of corticotropic stimulation than cortisol secreting cells.

Seven hirsute women were treated with 200 mg/12 h po of ketoconazole during 6 months. We evaluated clinical and hormonal effects during this period. Ketoconazole treatment decreased testosterone, androstenedione and dehydroepiandrosterone sulfate, while 17-alfahydroxyprogesterone increased. This finding suggests a steroidogenic blockade at the level of C17-20 lyase. We did not observe changes in LH, SHBG and cortisol values. In spite of this findings after 6 months treatment, hirsutism remained unmodified. We conclude that ketoconazole inhibits androgen synthesis in hirsute women, but the use of this drug as an alternative and effective treatment of hirsutism warrants further evaluation.

The aim of the present study was to evaluate the effects of estrogens and androgens on hypothalamic beta-endorphin (beta-EP) concentrations. Intact or castrated female rats were chronically (2 weeks) treated with estrogen (estradiol benzoate) and/or antiestrogens (clomiphene, cyclophenil or epimestrol), and with androgens (dihydrotestosterone or dehydroepiandrosterone sulphate) and/or antiandrogen (cyproterone acetate). A group of rats treated with vehicle were studied as comparison. The beta-EP concentrations were measured by radioimmunoassay on acidic extracts of rat hypothalami. The administration of clomiphene and cyclophenil significantly reduced hypothalamic beta-EP concentrations in intact rats, while both drugs or estradiol benzoate increased the peptide concentration in castrated rats. Both intact and castrated rats treated with epimestrol showed hypothalamic beta-EP concentrations higher than vehicle treated rats. The estradiol-induced increase of beta-EP was not changed by the concomitant administration of antiestrogens. The administration of dihydrotestosterone significantly decreased beta-EP concentrations in both intact and castrated female rats, while the treatment with dehydroepiandrosterone sulphate only slightly decreased beta-EP levels in intact female rats. The cyproterone acetate-chronically treated rats showed higher beta-EP concentrations than vehicle-treated rats and these changes were reversed by the concomitant addition of dihydrotestosterone or dehydroepiandrosterone sulphate. These results showed that estrogens play a positive role while androgens negatively influence the hypothalamic beta-EP concentrations in female rats, supporting the view that central beta-EP might be a target of gonadal steroid feedback signals.

A 34-year-old woman with excessive facial hirsutism and a 18-month history of amenorrhea was found to have an ovarian arrhenoblastoma of the intermediate type. The endocrine profile was determined before, during and after surgery. Determination of hormone levels indicated that, although both the delta 4 and delta 5 pathways were involved, the delta 4 pathway was probably predominant in androgen biosynthesis. Four weeks after removal of the tumor, the menstrual cycle was normalized and has subsequently remained regular. Six yr after operation, the patient had lost her hirsutism and neither radiological, palpatory nor endocrine signs of either recurrence or metastasis have been observed.

A design for the perfusion of one (monoperfusion) or two (parallelperfusion) cotyledos of one placenta was developed for studies of the metabolism of the precursor steroid dehydroepiandrosterone (DHA). Several parameters are used as viability criteria: vascular resistance, glucose and oxygen consumption, lactate/pyruvate ratio, activity of lactate-dehydrogenase (LDH) in the perfusate, extent of perfusion by dye infusion, and morphological description by electron microscopy. A dosage of 2 mg DHA with 2.5 microCi 14C-radioactive labelled marker is given for testing the metabolizing capacity of the placenta. The labelled metabolites DHA, androstenedione (A), testosterone (T), estrone (Oe 1), and estradiol-17 beta (Oe 2) are separated by thin-layer chromatography and measured by scanning and measurements of scraped radioactive spots by scintillation counting. The steroidogenesis is evaluated with the concentrations of Oe 1 at 15 min (Oe 1.15'), Oe 1 + Oe 2 at 90 min (Oe tot, 90'), total aromatization rate (from perfusate and homogenate after 120 min). Results comparable to DHA are found using DHA-sulphate (DHA-S) as precursor, higher amounts of estrogens are metabolized from A. Mature placentas metabolize DHA in relation to the initial DHA concentration: optimal aromatization is found at 250-350 pmol DHA/ml/g, decreased aromatization at higher or lower concentrations. Oe 1 represents the main placental metabolite.

The importance of the placental 3 beta-steroid sulfatase for placental biosynthesis of estrogens is demonstrated by a case report of a placental sulfatase deficiency. The absolute deficiency of this enzyme in our case is demonstrated in vivo by the intravenous dehydroepiandrosterone sulfate loading test and in vitro by placental enzyme tests. Steroid concentrations in serum after injection of dehydroepiandrosterone sulfate (DHEA-S) are compared with those in a group of pregnant women without placental enzyme defects and in a group of nonpregnant women. Placental in vitro tests demonstrate the intact 3 beta-hydroxysteroid dehydrogenase-delta 4,5 isomerase-aromatase-system in the placenta with sulfatase deficiency. The lack of placental hydrolysis results in low concentrations of estrone and estradiol-17 beta in the maternal serum, which are only 5.9% and 12.5%, respectively, of the mean values of the control group. This indicates that more than 90% of estrone and more than 85% of estradiol-17 beta measured in the maternal serum are from DHEA-S as precursor. The remaining concentrations are converted mainly from dehydroepiandrosterone (DHEA), which needs no hydrolysis. Maternal serum concentrations of estriol are under the detection limit of the radioimmunoassay. This is due to the absence of the so called "neutral pathway" and the "phenolic pathway" with 16 alpha-hydroxydehydroepiandrosterone sulfate (16 alpha-OH-DHEA-S) and DHEA-S respectively as precursors. The insignificance of the "placental pathway" for the total biosynthesis of estriol is demonstrated. The placental sulfatase seems to have no great importance for the biosynthesis of the C21-steroids.

In order to verify the relationship between insulin resistance and hyperandrogenism in Polycystic ovary disease (PCOD), circulating levels of insulin in response to oral glucose tolerance test (OGTT) were assessed in 23 PCOD patients and 10 matched control subjects without obesity, acanthosis nigricans and impaired glucose tolerance. In PCOD patients serum total testosterone (T), dehydroepiandrosterone sulfate (DHEA-S), LH and LH/FSH ratio were significantly higher than in control subjects; whereas urinary 17-ketosteroids (17-KS) and glycemic response to OGTT were not different. PCOD patients were clearly hyperinsulinemic before and during OGTT compared to the control group: mean +/- SD basal insulin (Io) (23.4 +/- 10.3 vs 11.3 +/- 4.6 microU/ml, p less than 0.001) and the sums of insulin levels (sigma I) during OGTT (341.4 +/- 148.9 vs 162.2 +/- 56 microU/ml, p less than 0.001). In the two groups serum T, but not DHEA-S, LH, urinary 17-KS and the degree of obesity, was strongly associated with Io (r = 0.458, p less than 0.01) and sigma I (r = 0.419, p less than 0.02), as well as with insulin resistance as assessed by basal (r = 0.425, p less than 0.02) and postglucose challenge (r = 0.384, p less than 0.05) insulin to glucose ratio. These results confirm that the hyperinsulinism and insulin resistance in PCOD is not related to obesity and suggest that the hyperandrogenism may be partially responsible of the observed imbalance in glucose-insulin homeostasis.

The response to ACTH stimulation, insulin-hypoglycemia and metyrapone in patients with suspected HPA axis dysfunction due to corticosteroid therapy (Group I, n = 10), or pituitary surgery (Group II, n = 7) and in a control population (Group III, n = 8) was studied. Group I patients had been maintained on a stable low dose of prednisone 5.0-7.5 mg/day for 1 month-16 yr (mean = 31 mos) prior to testing. Basal 08:00 h cortisol levels in this group were not different from control values. However, the mean responses to all three testing procedures were suppressed (Group I vs III, ACTH p less than 0.001, insulin p less than 0.01, metyrapone p less than 0.05). Group II patients had undergone surgery 1-26 months (mean = 10 mo) prior to testing and had been maintained subsequently on a stable dose of prednisone 5.0-7.5 mg/day. In this group basal mean 08:00 h cortisol and the cortisol response to ACTH and insulin-hypoglycemia were not significantly different from control values while the response to metyrapone was suppressed (Group II vs III p less than 0.02). Basal serum DHEA-S levels were suppressed in both Groups I and II when compared to Group III (p less than 0.001). Discordant responses to the three testing procedures were noted in 6 patients with suspected HPA dysfunction with abnormal test results in 1/6 using cortrosyn, 3/6 using insulin-hypoglycemia and 4/6 using metyrapone.(ABSTRACT TRUNCATED AT 250 WORDS)

A 30-year-old man presented with longstanding hypercortisolism and biochemical studies typical of pituitary-dependent Cushing's disease. After unsuccessful transsphenoidal surgery, plasma ACTH transiently became undetectable and adrenal computed tomography (CT) was consistent with macronodular hyperplasia. Serum dehydroepiandrosterone sulphate (DHEA-S) exceeded 10,000 ng/ml (normal 2,000-3,350 ng/ml). Despite either transient adrenal autonomy or variable adrenocortical ACTH hyperresponsiveness, urinary cortisol normalized within eight months following pituitary irradiation alone. Serum DHEA-S fell progressively but remained mildly elevated (4,000 ng/ml). Follow-up CT showed minimal residual adrenal nodularity. Given these findings and a review of the literature, we propose that chronic cosecretion of non-ACTH proopiomelanocortinderived peptides may have stimulated both hypersecretion of DHEA-S and adrenocortical macronodularity in this patient.

In 49 patients affected by PCO syndrome the serum levels of dehydroepiandrosterone-sulphate (DHEAs) were determined and correlated with the clinical presentation and the endocrine pattern. Twenty-three patients (47%) had high DHEAs levels (h-DHEAs patients). They presented a milder clinical presentation (low incidence of amenorrhea) than PCO patients with normal DHEAs levels (n-DHEAs patients). In h-DHEAs patients the finding of a normal DHEAs response to ACTH and of slightly increased 170HP serum levels suggested that the elevation of serum DHEAs was not due to an adrenal enzymatic deficiency but to a tonic hyperstimulation of the adrenals. Two subgroups of h-DHEAs patients were identified: in the first subgroup, PRL and estrone levels were increased and probably explained the DHEAs hypersecretion; in the second subgroup, the endocrine pattern was very similar to that observed in n-DHEAs patients and a clear explanation for DHEAs increase was not found, although the possibility of an exaggerated secretion of some pituitary hormones with adrenal androgen stimulating activity must be considered.

We investigated the effectiveness of D-Ser (TBU)6-EA10-LHRH (Buserelin) intranasally 600 micrograms/day given 6 times daily in desensitizing normal ovulatory women and patients with polycystic ovarian disease (PCOD) before initiation of ovarian stimulation for in vitro fertilization. We found that this regimen was sufficient to suppress the gonadotrophs in the normal women and in 8 out of 10 PCOD patients. In PCOD ovarian hormones became normal after Buserelin administration. Adrenal steroidogenesis was not affected by the GnRH agonist. We suggested that the frequency of administration of Buserelin was important to achieve a constant receptor binding and consequently a rapid desensitization. The choice of a monoclonal immunoradiometric assay for luteinizing hormone (LH) and follicle stimulating hormone (FSH) in association with the estradiol-benzoate provocation test were essential in evaluating desensitization.

The adrenal androgen secretion and testicular function were studied in 6 thalassemic boys aged between 16 and 20 years. Six normal boys of the same age and 6 at the same pubertal stage (P1 according to Tanner) were also studied as controls. Plasma testosterone levels were found significantly lower (p less than 0.001) in the thalassemic boys (0.8 +/- 0.1 ng/ml) than in healthy boys of the same age (3.4 +/- 1.01 ng/ml), but within the range of the healthy boys at the same pubertal stage (0.69 +/- 0.1 ng/ml). DHA-S, a marker of adrenal maturation, showed a similar pattern. The hCG test showed a significant (p less than 0.001) testosterone response in all 3 groups. The response of thalassemic boys (1.5 +/- 0.18 ng/ml) was similar to that of normal boys at stage P1 (1.8 +/- 0.31 ng/ml), but significantly lower (p less than 0.001) than the group of normal boys of the same age (12.5 +/- 3.2 ng/ml). The impaired adrenal and testicular activity is probably due to iron deposits in the endocrine glands.

A virilization syndrome in a normally menstruated 20--year-old woman, due to adrenocortical tumor, is reported. Preoperative basal hormonal study showed normal plasma gonadotropins, androstenedione (A) and cortisol, slightly elevated testosterone (T), markedly increased urinary 17 ketosteroids (17KS) excretion and plasma dehydroepiandrosterone-sulfate (DHEA-S) levels. Thus DHEA-S was the major constituent of the androgen excess. Urinary 17KS and plasma DHEA-S did not change after ACTH, whereas increased after dexamethasone (DXM)-hCG administration. PRL and LH responses to TRH and LHRH tests were exaggerated. Echotomography, pneumoperitoneum radiography and selective adrenal venous angiography showed a tumor in the left adrenal gland. After the tumor removal all abnormalities were corrected. Light and electron microscopy showed well differentiation of the tumoral cells with typical ultrastructural characteristics of androgen-secreting tissue. It is concluded that the absence of amenorrhea and of LH suppression does not exclude the possibility of an androgen-secreting tumor. Moreover, the unusual finding of slightly elevated T value may be reported to enzymatic defect at the neoplastic cellular level. Furthermore the paradoxical DXM-hCG androgen response may be due to spontaneous variations in hormone secretion by the tumor or to cell receptors alteration.

The Authors have evaluated the relationship between the secretion of dehydroepiandrosterone sulfate (DHA-S) by the adrenal glands and by the gonads in a group of prepubertal and pubertal subjects ("short normal"), both males and females. In the male subjects of a hCG test and an ACTH test were performed; in the female subjects only the latter test was carried out. The behavior of DHA-S under basal conditions was also assessed in both sexes and related to bone age and chronological age in the prepubertal period and during the early stages of puberty. Plasma levels of DHA-S in both sexes increase progressively with chronological age and bone age. A negative correlation was found between DHA-S and bone delay (expressed in percent relative to chronological age) in prepubertal subjects, both males and females. A significant increase in DHA-S after hCG stimulation was found both in prepubertal and pubertal boys. After ACTH stimulation DHA-S increased significantly in prepubertal and pubertal males and females; throughout the test no difference was found between prepubertal and pubertal subjects nor between male and female subjects. Our data confirm that DHA-S is produced both by the adrenals and by the testes.

Plasma levels of prolactin, before and after TRH stimulation, progesterone, estradiol, sex-hormone-binding-globulin, androstenedione, testosterone and dehydroepiandrosterone-sulphate were determined in a group of women with benign breast disease and in control group, in order to correlate a possible hormonal disorder to breast pathology. The hormonal pattern in the patients with benign breast disease was characterized by an increased responsiveness of lactotrophes to TRH stimulation and by higher levels of sex hormone binding globulin, probably sustained by an underlying hyperestrogenism.

A case of adrenal carcinoma with Cushing's syndrome was presented. Endocrinological and morphological investigations disclosed the presence of a functional adrenal carcinoma. This case was characterized by its unusual urinary 17-ketosteroid (17-KS) fractionation, i.e. a marked elevation of 17-KS was accompanied by the increments of etiocholanolone, but not of dehydroepiandrosterone (DHEA) or androsterone. Measurements of the plasma adrenocorticosteroids revealed normal DHEA and DHEA-S (sulfate) levels, moderately increased 17-OH-pregnenolone, and markedly increased (less than 100 times the normal) 11-deoxycortisol (cpd S). Therefore, it seems plausible that the normal urinary DHEA level in this patient would have occurred as a result of remarkably low C17-20 lyase activity sufficient to hamper DHEA production, and that markedly increased etiocholanolone might possibly have been converted from cpd S as well as from DHEA and androstenedione through 5 beta-reduction.

The purpose of the present investigation was to verify possible positive correlations between prolactin secretion and dehydroepiandrosterone sulphate levels in plasma of women with benign breast disease. Prolactin secretion was evaluated in terms of basal levels, maximum peak, percent increase above baseline levels, total integrated area, response area after TRH stimulation. No correlation was found between the parameters of prolactin secretion and dehydroepiandrosterone sulphate levels.

We report on a 17 year old female patient with amenorrhea, hirsutism and slight acne. Hormonal blood analyses showed markedly increased levels for dehydroepiandrosteronesulfate, testosterone and androstenedione. Ultrasound investigation revealed a large tumor above the left kidney and a small area above the right kidney, suspicious for a tumor on the contralateral side. This was confirmed by angiography. During surgery, bilateral tumors were removed. Pathological diagnosis was made as bilateral adenomas of the adrenal cortex. Postoperatively, an impressive normalization was observed, accompanied by a rapid decrease of the elevated hormone concentrations. This case is the first report of a bilateral occurrence of a virilizing tumor of the adrenal cortex.

Plasma levels of testosterone (T), LH, FSH, prolactin (PRL), cortisol (F), dehydroepiandrosterone sulfate (DHAS), noradrenaline (NA), NA sulfate (NAS), adrenaline (A) and A sulfate (AS) were measured in 7 adult males before and immediately after a marathon run as well as every morning for 5 days after the run. While plasma T levels fell significantly on the first and the second postmarathon day, those of LH rose significantly during the first 3 postrun days. Plasma PRL and F values increased significantly only at the end of the marathon. Plasma levels of NA and NAS rose significantly at the end of the run and again on days 2 and 5 postmarathon, respectively. A similar pattern was observed for A and AS except for the second peak of free A. These results show that a strenuous physical exercise leads to a persistent relative insensitivity to LH of the testicular T biosynthetic machinery, while the feedback mechanisms operating at the hypothalamic-pituitary level are normal. Furthermore, they suggest that catecholamines may be responsible for the prolonged inhibitory effect of stress on T biosynthesis.