Polycystic ovary syndrome after precocious pubarche: ontogeny of the low-birthweight effect.

OBJECTIVE: Young girls with precocious pubarche (PP) are at increased risk of developing polycystic ovary syndrome (PCOS), including hyperinsulinism, dyslipidaemia and ovarian hyperandrogenism, particularly if PP itself was preceded by a low birthweight. Resistance to insulin is thought to be a key factor in the pathogenesis of this sequence. We aimed to elucidate the peripubertal ontogeny of the low birthweight effect on hyperinsulinism, dyslipidaemia and ovarian dysfunction after PP. PATIENTS AND DESIGN: We obtained fully longitudinal data from 51 girls with a history of PP and compared normal-birthweight (n = 26) with low-birthweight (n = 25) girls (birthweight SD score 0.0 +/- 0-2 vs. - 2.4 +/- 0.2) for measurements obtained at diagnosis of PP (mean age 7.0 years), in early puberty (10.4 years) and after menarche (14.3 years). MEASUREMENTS: Fasting serum lipids and lipoproteins, together with insulin responses to an oral glucose load, were assessed at diagnosis of PP, in early puberty and after menarche; serum gonadotropins were measured in early puberty and after menarche; ovarian function was examined postmenarche. RESULTS: Comparisons of endocrine-metabolic results between normal- and low-birthweight PP girls showed no detectable differences before puberty. The hypertriglyceridaemia and elevated LDL-cholesterol levels characterizing low-birthweight PP girls became detectable by early puberty; reduced insulin sensitivity was not evident until postmenarche, when the tendency to ovarian dysfunction also became obvious. Body mass indices of normal- and low-birthweight subgroups were identical in early puberty and postmenarche. CONCLUSIONS: These longitudinal data show that, in PP girls, the endocrine-metabolic risk conferred by prenatal growth restraint is not readily detectable until puberty or postmenarche, and is not attributable to a higher body mass index.

Treatment of hirsutism, hyperandrogenism, oligomenorrhea, dyslipidemia, and hyperinsulinism in nonobese, adolescent girls: effect of flutamide.

Functional ovarian hyperandrogenism, a variant of polycystic ovary syndrome, is often associated with hyperinsulinism and dyslipidemia. The mechanisms interlinking this triad are poorly understood; both hyperandrogenism and hyperinsulinism have been proposed as factors involved in the pathogenesis of the dyslipidemia. Precocious pubarche (PP) in girls is a risk factor for subsequent anovulation, ovarian and adrenal hyperandrogenism, hyperinsulinism and dyslipidemia. Flutamide, a nonsteroidal antiandrogen, is known to be effective in reducing hirsutism in patients with ovarian hyperandrogenism. However, the effects of flutamide on the endocrine-metabolic correlates of hyperandrogenism are uncertain. We assessed the effects of low dose flutamide treatment (250 mg daily for 18 months) on hormonal and metabolic variables in 18 nonobese adolescent girls (age, 16.8 +/- 0.3 yr) with functional ovarian hyperandrogenism (diagnosis by GnRH agonist test) after PP. Flutamide treatment was accompanied by a marked decrease in the hirsutism score, free androgen index, and testosterone, androstenedione, and dehydroepiandrosterone levels and by an increase in sex hormone-binding globulin concentrations. However, there were no substantial changes in the pattern of menstrual cycles, gonadotropin, estradiol, or dehydroepiandrosterone sulfate concentrations, and there was no detectable effect on the 17-hydroxyprogesterone response to GnRH agonist. Serum triglycerides, total cholesterol, and low-density lipoprotein cholesterol levels decreased markedly during flutamide therapy, whereas high-density lipoprotein cholesterol, fasting glycemia/insulinemia, and the insulin response to a glucose load remained unchanged. Flutamide was well tolerated. In conclusion, low dose flutamide treatment was found to be an effective and safe approach to reduce hirsutism and circulating androgen, low-density lipoprotein cholesterol, and triglyceride levels in girls with functional ovarian hyperandrogenism after PP. However, flutamide failed to increase high-density lipoprotein cholesterol levels or decrease hyperinsulinemia, i.e. to affect two major risk factors for subsequent cardiovascular disease.

Ovarian hyporesponsiveness to follicle stimulating hormone in adolescent girls born small for gestational age.

Girls with reduced prenatal growth are known to have, at birth, a small ovarian fraction of primordial follicles and, in adolescence, a uterus and ovaries of small size. We have now examined whether reduced prenatal growth is also followed by changes in the relationships among FSH, inhibin B and estradiol in adolescent girls. We studied 48 post-menarcheal girls (age 13.6 +/- 1.4 yr) who were either born with an appropriate weight for gestational age (AGA; n=33; mean weight 3.3 Kg) or born small for gestational age (SGA; n=15; mean weight 2.4 Kg). Serum FSH, inhibin B and estradiol concentrations were measured in the early follicular phase (range: day 5 +/- 3). SGA girls had, compared to AGA girls, elevated serum FSH (7.2 +/- 0.7 vs 4.5 +/- 0.3 IU/mL; p=0.0002), similar inhibin B (62.1 +/- 8.1 vs 60.7 +/- 6.5 pg/mL) and lower estradiol concentrations (12.1 +/- 1.5 vs 21.2 +/- 2.4 pg/mL; p=0.02). SGA girls thus displayed, early after menarche, a pattern that points to hyporesponsiveness of the ovarian granulosa cell fraction and that is reminiscent of reproductive aging. In conclusion, the gynecological correlates of prenatal growth restriction are herewith extended to include ovarian hyporesponsiveness to FSH in adolescence.

Reduced uterine and ovarian size in adolescent girls born small for gestational age.

Reduced fetal growth is known to be associated with a reduced ovarian fraction of primordial follicles, with ovarian hyperandrogenism and anovulation in late adolescence. In this study, we examined whether adolescent girls born small for gestational age also present an abnormality in uterine or ovarian size. Standardized ultrasound measurements of the internal genitalia were performed in 36 healthy post-menarcheal girls (mean age 14 y) born with a size that was either appropriate for gestational age (AGA) or small (SGA), birth weight averaging 0.1 and -3.0 SD, respectively; clinical and endocrine characteristics were documented concomitantly. Compared with AGA girls, the SGA girls had a smaller uterus (mean difference of 20%; p < 0.006) and a reduced ovarian volume (mean difference of 38%; p < 0.0002). In conclusion, the gynecological correlates of prenatal growth restriction are herewith extended to include a reduced size of the uterus and the ovaries.

Premature adrenarche--normal variant or forerunner of adult disease?

Adrenarche is the puberty of the adrenal gland. The descriptive term pubarche indicates the appearance of pubic hair, which may be accompanied by axillary hair. This process is considered premature if it occurs before age 8 yr in girls and 9 yr in boys. The chief hormonal product of adrenarche is dehydroepiandrosterone (DHEA) and its sulfated product DHEA-S. The well documented evolution of adrenarche in primates and man is incompatible with either a neutral or harmful role for DHEA and implies most likely a positive role for some aspect of young adult pubertal maturation and developmental maturation. Premature adrenarche has no adverse effects on the onset and progression of gonadarche in final height. Both extra- and intraadrenal factors regulate adrenal androgen secretion. Recent studies have shown that premature adrenarche in childhood may have consequences such as functional ovarian hyperandrogenism, polycystic ovarian syndrome, and insulin resistance in later life, sometimes already recognizable in childhood or adolescence. Premature adrenarche may thus be a forerunner of syndrome X in some children. The association of these endocrine-metabolic abnormalities with reduced fetal growth and their genetic basis remain to be elucidated.

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.

Exaggerated adrenarche and hyperinsulinism in adolescent girls born small for gestational age.

Serum dehydroepiandrosterone-sulfate (DHEAS) is a classic marker for adrenarche and, subsequently, for the individual hormonal milieu. We have tested the hypothesis that prenatal growth reduction is followed by exaggerated adrenarche. Serum DHEAS, androstenedione and insulin concentrations were determined together with fasting glycemia in matched populations of asymptomatic, non-obese, post-menarcheal girls (mean age 14 yr) who were born either with a strictly appropriate weight for gestational age (AGA) or small for gestational age (SGA). When compared to AGA girls, the SGA girls had identical glucose levels, higher values for insulin and androstenedione (p<0.01), and a two-fold rise of DHEAS concentrations (p<0.0001). In conclusion, girls with prenatal growth reduction were found to be prone to develop, besides hyperinsulinism, a variant of exaggerated adrenarche. It remains to be verified whether the exaggerated adrenarche in adolescence is followed by adrenal hyperandrogenism throughout adulthood and senescence.

Sexual dimorphism in the maturation of the pituitary-gonadal axis, assessed by GnRH agonist challenge.

OBJECTIVE: To assess whether the maturational changes of the pituitary--gonadal axis in a healthy population show gender-specific changes and to establish normative data for the different Tanner stages. DESIGN: Prospective, cross-sectional study. METHODS: The GnRH agonist leuprolide acetate (500 microgram) was administered s.c. to 60 boys and 81 girls (age range, 5--17 years). Serum steroids and gonadotropins were determined at 0 and 24 h and at 0, 3 and 24 h after GnRH agonist challenge respectively, whereas IGF-I, IGF-binding protein-1 (IGFBP-1), IGFBP-3 and sex hormone-binding globulin were measured at baseline. RESULTS: Baseline and peak LH responses to the agonist in late puberty, and basal and peak FSH levels at all Tanner stages, were higher in girls than in boys. Girls showed higher IGF-I levels than boys throughout puberty, sharper decreases in IGFBP-1 and earlier and greater increases in 17-hydroxypregnenolone, dehydroepiandrosterone (DHEA) and DHEA-sulfate. Testosterone responses to the agonist increased during puberty in males, and showed no changes in females. Conversely, estradiol responses rose throughout puberty in females and remained unchanged until late puberty in males. CONCLUSION: Leuprolide acetate stimulates gonadotropin and gonadal steroid secretion during puberty in both sexes and increases FSH levels in prepubertal girls. Pubertal maturation of gonadotrope function is gender specific, as it appears to involve increases in both the releasable and reserve pools of LH in males, and of LH and FSH in females. The earlier increase in Delta(5)-steroids in girls may suggest a sharper rise in ovarian cytochrome P450c17 activity along the Delta(5)-steroid pathway, while the failure of estradiol to increase in response to leuprolide acetate in early pubertal males suggests a late maturation of aromatase activity.

A limited repertoire of mutations of the luteinizing hormone (LH) receptor gene in familial and sporadic patients with male LH-independent precocious puberty.

Herein, we report mutation analysis of the LH receptor gene in 17 males with LH-independent precocious puberty, of which 8 were familial and 9 had a negative family history. A total of 7 different mutations (all previously reported) were detected in 12 patients. Among 10 European familial male-limited precocious puberty (FMPP) patients who had a LH receptor gene mutation, none had the Asp578Gly mutation, which is responsible for the vast majority of cases in the U.S. The restricted number of activating mutations of the LH receptor observed in this and other studies of FMPP strongly suggests that an activating phenotype is associated with very specific sites in the receptor protein. Clinical follow-up of the 5 patients who did not have LH receptor mutations shows that such cases most likely do not have true FMPP. LH receptor mutation analysis provides a sensitive tool for distinguishing true FMPP from other causes of early-onset LH-independent puberty in males.

Endocrinology and metabolism after premature pubarche in girls.

The prevalence of functional ovarian hyperandrogenism, hyperinsulinism and dyslipidaemia is increased in adolescent girls with a history of premature pubarche, defined as the appearance of pubic hair before the age of 8 years. The ovarian hyperandrogenism is characterized by clinical signs of androgen excess and an exaggerated ovarian 17-hydroxyprogesterone response to gonadotrophin-releasing hormone agonist stimulation. The hyperinsulinism and dyslipidaemia are detectable before and during pubertal development, and they are commonly accompanied by low serum levels of insulin-like growth factor binding protein-1 (IGFBP-1) and sex hormone binding globulin, and by an increased prevalence of anovulation from late adolescence onwards. In girls, premature pubarche, hyperinsulinism, low serum levels of IGFBP-1, dyslipidaemia, anovulation and hyperandrogenism (or various combinations of these conditions) have been related to reduced fetal growth, indicating that these constellations or sequences may have a prenatal origin. These findings suggest that premature pubarche in girls should no longer be regarded as merely a normal variant of development, but rather as a childhood marker pointing to an increased risk of a polyendocrine-metabolic disorder of prenatal origin.

Premature pubarche, ovarian hyperandrogenism, hyperinsulinism and the polycystic ovary syndrome: from a complex constellation to a simple sequence of prenatal onset.

Adolescent girls with a history of premature pubarche have an increased incidence of functional ovarian hyperandrogenism [a form of polycystic ovary syndrome (PCOS)] at adolescence, which is usually associated with hyperinsulinemia and dyslipemia. The hyperinsulinemia and lipid disturbances can often be detected in the prepubertal period and throughout puberty, and are associated with an exaggerated ovarian androgen synthesis. Birthweight SD scores are lower in premature pubarche girls than in control girls, and particularly so in those girls who show hyperinsulinemia and subsequently develop ovarian hyperandrogenism. Therefore, although the mechanisms interlinking the triad of premature pubarche, hyperinsulinism and ovarian hyperandrogenism remain enigmatic, these data indicate that the triad may result, at least in part, from a common early origin, rather than from a direct interrelationship later in life.

Changes in growth, growth hormone, and insulin-like growth factor-I (IGF-I) after orthotopic liver transplantation.

Growth failure is an important consequence of chronic liver disease in childhood. Insulin-like growth factor-I (IGF-I), which is synthesized and released by the liver, plays an important role as a growth regulator in humans. We examined the growth hormone (GH)/IGF-I axis before and after orthotopic liver transplantation (LT) in 14 children aged between 2 and 11 years (mean 5.6 +/- 1.1 years). Pre-transplantation serum GH levels (7.5 +/- 1.2 ng/ml) were significantly higher (P < 0.001) compared with controls (5 +/- 0.5 ng/ml). However, post-transplantation levels (1.8 +/- 0.8 ng/ml) did not differ from those in the control group. Serum IGF-I levels showed a statistically significant increase after LT (20.1 +/- 9.4 vs 190 +/- 66.2 ng/ml; P < 0.001) and became indistinguishable from the levels in the control group (180 +/- 96 ng/ml). In comparison with pre-transplantation data (z - 2.70), there was an increase in height 4 years postoperatively (z - 1.68). Catch-up growth was highly significant, in particular during the 1st year after LT (z -1. 58 +/- 1.63 vs 2.59 +/- 5.29; P < 0.01). We conclude that a GH resistance state found in patients with severe chronic liver disease reverted following LT. Given that IGF-1 depends upon liver function, this could be one of the main factors in the significant catch-up growth in pediatric LT recipients.

Ovarian 17 alpha-hydroxyprogesterone responses to GnRH analog testing in oligomenorrheic insulin-dependent diabetic adolescents.

OBJECTIVE: To investigate the pituitary-ovarian function in adolescent girls with insulin-dependent diabetes mellitus (IDDM). DESIGN: Clinical case-control study. METHODS: The GnRH analog leuprolide acetate was administered subcutaneously to 16 adolescents with IDDM (seven eumenorrheic and nine oligomenorrheic) and 13 controls between 0800 and 0900 h. Blood samples were collected at baseline and 0.5, 3, 6 and 24 h after leuprolide to measure levels of gonadotropins, 17 alpha-hydroxyprogesterone (17-OHP), androgens and estradiol. RESULTS: Mean baseline serum LH levels were significantly higher in eumenorrheic compared with oligomenorrheic IDDM patients, while peak LH responses to GnRH analog testing were similar in all subjects. Oligomenorrheic IDDM girls showed, as a group, a distinct 17-OHP response to GnRH analog stimulation, which in five out of nine girls was in the range of functional ovarian hyperandrogenism (> or = 8.6 nmol/l). Androgen and estradiol levels were not significantly altered in any group. No correlation was found between steroid levels and HbA1c levels, although the latter were significantly higher in oligomenorrheic than in eumenorrheic patients. CONCLUSION: About 50% of the oligomenorrheic IDDM adolescents had an increased ovarian 17-OHP response to GnRH analog stimulation in the range of functional ovarian hyperandrogenism. Factors other than metabolic control, such as stress, may play an etiologic role in IDDM ovarian dysfunction.

Girls diagnosed with premature pubarche show an exaggerated ovarian androgen synthesis from the early stages of puberty: evidence from gonadotropin-releasing hormone agonist testing.

OBJECTIVE: To assess the gonadotropin and ovarian steroid responses to the GnRH agonist (GnRH-a) leuprolide acetate (LA) in premature pubarche girls and in Tanner stage- and bone age-matched controls to ascertain whether the ovarian 17-hydroxyprogesterone (17-OHP) hyper-response to GnRH-a challenge present in some subsets of adolescent premature pubarche girls is detectable during puberty and whether these patients have a distinct pattern of pituitary-ovarian maturation. DESIGN: Cross-sectional study. SETTING: A university teaching hospital. PATIENT(S): Seventy-six premature pubarche girls (early pubertal [B2; n = 31], midpubertal [B3; n = 15], late pubertal [B4; n = 12], and postmenarcheal [B5; n = 18]) and 45 controls. INTERVENTION(S): Gonadotropins and plasma steroid hormones (17-OHP, 17-OH-pregnenolone [17-Preg], androstenedione [A], T, DHEA, DHEAS, E2, and cortisol) were measured before and 3 and 24 hours, respectively, after LA challenge (500 micrograms SC). MAIN OUTCOME MEASURE(S): Ovarian-steroidogenic responses to GnRH-a challenge. RESULT(S): Luteinizing hormone responsiveness increased significantly during puberty in all subjects whereas FSH levels changed less consistently. Peak E2 levels differed among pubertal stages and were significantly higher in premature pubarche girls than in controls at B4 and at B5. Both peak and incremental increases of 17-Preg and DHEA throughout puberty and of 17-OHP and A at B4 were significantly higher in premature pubarche girls than in controls. This pattern of ovarian-steroidogenic response was most evident during midpuberty and late puberty and resembled the adrenal hyper-response to ACTH of exaggerated adrenarche, suggestive of increased ovarian activity of both the 17 alpha-hydroxylase and the 17,20 lyase functions of cytochrome P450c17 alpha. CONCLUSION(S): Pubertal girls with a history of premature pubarche show a distinct pattern of ovarian maturation characterized by an exaggerated ovarian androgen synthesis throughout puberty.

Ovarian 17-hydroxyprogesterone hyperresponsiveness to gonadotropin-releasing hormone (GnRH) agonist challenge in women with polycystic ovary syndrome is not mediated by luteinizing hormone hypersecretion: evidence from GnRH agonist and human chorionic gonadotropin stimulation testing.

Women with polycystic ovary syndrome (PCOS: hyperandrogenism and oligomenorrhea) have been shown to have exaggerated ovarian 17-hydroxyprogesterone (17-OHP) responses after GnRH agonist stimulation, suggestive of disordered ovarian cytochrome P450c17 alpha activity. However, most hyperandrogenic women also have an exaggerated LH response to both native GnRH and GnRH agonists. To assess whether the known LH hyperresponsiveness in PCOS patients mediates their exaggerated 17-OHP response to GnRH agonist challenge or whether the 17-OHP response can be duplicated by direct stimulation of the ovary with a fixed amount of hCG, 25 PCOS women [age, 20.6 +/- 1.1 yr; body mass index (BMI), 24.9 +/- 1.3 kg/m2] and 5 controls (age, 29.4 +/- 2.3 yr; BMI, 29.2 +/- 3.0) underwent both GnRH agonist (leuprolide acetate) and hCG testing. In addition, 23 normal women (age, 26.5 +/- 1.5 yr; BMI, 27.2 +/- 1.7 kg/m2) underwent hCG testing, and 21 other normal women (age, 19.3 +/- 0.5 yr; BMI, 23.0 +/- 0.8 kg/m2) underwent leuprolide acetate challenge. Blood was sampled before and 24 h after (the previously determined time of the peak response) leuprolide acetate (500 micrograms, sc) and hCG (5000 IU, im) stimulation tests. The tests were administered during the early follicular phase in women who were ovulatory and in randomized order in the subjects receiving both stimuli. Peak serum 17-OHP levels did not differ between leuprolide acetate or hCG stimulation in PCOS patients or controls when measured at 24 h (324.9 +/- 41.9 vs. 360.4 +/- 54.0 in PCOS; 183.2 +/- 19.6 vs. 141.2 +/- 11 ng/dL in controls). Peak 17-OHP levels after hCG challenge and GnRH agonist stimulation were highly correlated (r = 0.82; P < 0.001) in the subjects receiving both stimuli. Although leuprolide acetate elicited a higher estradiol (E2) response than hCG in all subjects, serum E2 levels increased significantly after hCG treatment in both patients and controls (P < 0.001 and P < 0.0001). The small, but significant, increase in serum E2 after hCG stimulation suggests that a rigid two-cell model of ovarian steroidogenesis may be an oversimplification of in vivo physiology. Our results suggest that exaggerated 17-OHP responses to GnRH agonist stimulation in hyperandrogenic women are not mediated by the known hyperresponsiveness of LH in these patients, but are due to increased ovarian androgen sensitivity to LH stimulation.

Source localization of androgen excess in adolescent girls.

Functional ovarian hyperandrogenism (FOH) is characterized by an abnormal ovarian response to challenge with the GnRH analogs nafarelin and leuprolide acetate, similar to that observed in women with well defined polycystic ovary syndrome, regardless of whether elevated LH levels or polycystic ovaries are present. We studied an unselected group of 42 hyperandrogenic adolescents (age range, 14-22 yr; mean, 18.1 +/- 2.5 yr) 1) to determine FOH incidence through the assessment of ovarian-steroidogenic response to a single dose of leuprolide acetate, 2) to assess the clinical characteristics of patients according to their responses to GnRH analog stimulation, and 3) to evaluate adrenal steroidogenic function and its relation to ovarian hyperandrogenism in patients with either normal or abnormal responses to leuprolide acetate challenge. All patients underwent leuprolide acetate and ACTH testing, dexamethasone and ovarian suppression tests, and pelvic ultrasonography. Twenty-four (58%) patients had supranormal plasma 17-hydroxyprogesterone (17-OHP) responses to leuprolide acetate characteristic of FOH, and in 18, the 17-OHP response was similar to that of controls (n = 24; age, 17.1 +/- 2.3 yr). Seven patients (5 with FOH and 2 with normal responses to leuprolide acetate) had an abnormal response to ACTH, but only 1 had conclusive evidence of 21-hydroxylase deficiency. In 16 patients, the response to both stimulation tests was normal. Only 13 (54%) of the 24 FOH patients had polycystic ovaries on ultrasonography, and in 11 (46%), basal plasma LH levels were elevated. In FOH patients, reduction in testosterone and androstenedione plasma levels was significantly greater after ovarian suppression than after dexamethasone challenge (P < 0.0005 and P < 0.02, respectively). Peak plasma 17-OHP levels postleoprolide acetate simulation correlated with dexamethasone-suppressed plasma testosterone concentrations, dexamethasone-suppressed plasma androstenedione levels, and the free androgen index postdexamethasone treatment (r = 0.4, P = 0.01; r+ 0.4, P < 0.05; and r = 0.41, P = 0.007, respectively), Plasma sex hormone-binding globulin levels after dexamethasone administration correlated negatively with the baseline free androgen index (r = -.0.67; P < 0.0001). Considering our diagnostic criteria, 26 (62%) of our collective of 42 patients had abnormal responses to one or both stimulation tests, whereas 16 (37%) had normal response. FOH is the most common cause in (58%) of androgen excess in adolescence. Short term leuprolide acetate stimulation is a reliable tool fro identification of the ovary as the source of their hyperandrogenism.

Ovarian suppression with triptorelin and adrenal stimulation with adrenocorticotropin in functional hyperadrogenism: role of adrenal and ovarian cytochrome P450c17 alpha.

OBJECTIVES: To validate combined ovarian suppression with triptorelin and adrenal stimulation with ACTH in the diagnosis of female hyperandrogenism and to provide new insights into the adrenal-ovarian relationship present in this disorder. DESIGN: Comparison of sexual steroids and basal and ACTH-stimulated steroid levels before and after ovarian suppression induced by triptorelin. SETTING: Department of Endocrinology, Hospital Ramón y Cajal, Madrid, Spain. PARTICIPANTS: Thirty-nine nonselected women with hyperandrogenism. MAIN OUTCOME MEASURES: Serum levels of T, 17-hydroxyprogesterone (17-OHP), 17-hydroxy-pregnenolone, DHEA and DHEAS, androstenedione (delta 4-A), 11-deoxycortisol, and cortisol. RESULTS: Elevated T independent of ovarian suppression pointed to an adrenal disorder in six patients (one with an androgen-producing adenoma, two with late-onset 21-hydroxylase deficiency, three with functional adrenal hyperandrogenism). Nineteen patients had functional ovarian hyperandrogenism as elevated T normalized after ovarian suppression and were subdivided into ovDHEAS+ (n = 7) and ovDHEAS = (n = 12) subgroups depending on the presence of DHEAS hypersecretion. Finally, 14 patients had idiopathic hirsutism according to normal T before and after ovarian suppression. Comparisons of initial hormonal values between groups and with reference values obtained from normal women (n = 11) disclosed in functional adrenal hyperandrogenism an elevation of T and basal and stimulated DHEAS, delta 4-A, and 17-OHP with respect to normal women. These abnormalities were also present in ovDHEAS+ except for basal delta 4-A, which was normal, whereas only T and stimulated 17-OHP were elevated in ovDHEAS =. In the idiopathic group all steroids were normal with the exception of a mild elevation in stimulated DHEAS. CONCLUSIONS: These results show a continuum of abnormalities in hyperandrogenic women, suggesting an enhanced cytochrome P450c17 alpha activity in the adrenal and the ovary as the shared mechanism between functional adrenal hyperandrogenism and functional ovarian hyperandrogenism.

Use of leuprolide acetate response patterns in the early diagnosis of pubertal disorders: comparison with the gonadotropin-releasing hormone test.

The effects of a single injection (500 micrograms sc) of the GnRH agonist leuprolide acetate on gonadotropin secretion and those induced by a GnRH test were analyzed in 32 children (11 males and 21 females) referred for possible pubertal developmental disorders and in 9 prepubertal controls [group C; 4 males and 5 females; chronological age (CA), 7.4 +/- 1.2 yr]. The pituitary-gonadal secretory responses to the GnRH agonist were characterized in all subjects and in a control group in early puberty [10 females (Tanner breast stage II; CA, 11.3 +/- 1.1 yr) and 6 males (Tanner pubertal stage II; CA, 13.5 +/- 0.4 yr); group D]. Twelve girls (CA, 7.1 +/- 0.7 yr) presented with precocious breast development, 11 patients [6 boys (CA, 10.9 +/- 0.4 yr) and 5 girls (CA, 9.3 +/- 0.5 yr)] had advanced puberty and predicted adult heights below -2.0 SD score, and 9 patients [5 boys (CA, 14.6 +/- 0.3 yr) and 4 girls (CA, 14.4 +/- 1.1 yr)] had delayed puberty. Less than 6 months had elapsed since the appearance of pubertal signs in all patients with pubertal development. After a follow-up period of 12.9 +/- 2.0 months, 20 patients showed progression of pubertal signs (group A, progressive puberty), and in 12, puberty regressed or did not progress (group B, nonprogressive puberty). The results of hormonal tests in all patients were analyzed retrospectively according to their clinical outcome. Patients in group A had a mean plasma peak LH response significantly higher after leuprolide acetate stimulation than after GnRH challenge (13.1 +/- 0.2 vs. 7.3 +/- 0.9 IU/L; P < 0.003). Those in groups B and C had similar peak LH responses after both tests (3.3 +/- 0.2 vs. 3.1 +/- 0.4, and 1.5 +/- 0.1 vs. 1.8 +/- 0.4 IU/L, respectively). No differences in basal and poststimulated LH levels were found between boys and girls in the same group. In patients in groups A and D, LH consistently peaked 3 h postleuprolide acetate challenge; in those in groups B and C, the LH peak occurred 3-6 h postinjection. Maximal gonadal responses were elicited 24 h poststimulation. No overlap in poststimulated estradiol or testosterone values occurred between patients in groups A and D and those in groups B and C.(ABSTRACT TRUNCATED AT 400 WORDS)

Ontogenesis of insulin receptors in human cerebral cortex.

This study examines the ontogenesis of insulin receptors in human cerebral cortex. Synaptosomal membrane fraction was obtained after subcellular fractionation of human brain tissue. The 24 cases studied were classified according to the statistical differences found in: Group I, pre-term, up to 30 weeks of gestation; group II, full-term and newborns; group III from one year to adulthood. Scatchard plots of insulin binding to brain membranes were curvilinear and showed a decrease in insulin receptor number as a function of age with slight differences in affinity. Receptor number were 3.0 +/- 0.8 pmol/mg in Group I, 0.6 +/- 0.14 pmol/mg and 0.2 +/- 0.024 pmol/mg in Groups II and III respectively. Values of 5'nucleotidase and Na+ K+ ATPase activities, were similar in all groups, which indicates that the purity of the fraction used for binding was similar in each group. According to the ontogenic profile in insulin binding described in this work, it may be assumed that the higher concentration of insulin receptors in human brain during the fetal period can determine some insulin action in this early stage of maturation, even though the functionality of these receptors remains to be elucidated.