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PubMed1997

Different dysregulations in adrenal steroid biosynthesis as a prevalent cause of hyperandrogenism in women from southern Italy.

OBJECTIVE: To investigate the presence of a dysregulation in steroid biosynthesis in women from southern Italy. DESIGN: Controlled clinical study. SETTING: Normal and hyperandrogenic women referred to the Endocrinology Unit of Federico II University Medical School of Naples. PATIENT(S): One hundred fifty untreated young hyperandrogenic women and 50 normal age-matched women. INTERVENTION(S): Morning (basal) blood samples obtained in the early follicular phase and after a long (360 minute) ACTH stimulation test. MAIN OUTCOME MEASURE(S): The adrenal maximal response was calculated as stimulus under curve areas (AUCa), and all steroids were assayed using RIA methods. RESULT(S): A dysregulation of 21-hydroxylase was found in 22 patients (14.7%), with a prevalent increase of 17 alpha-hydroxyprogesterone AUC, whereas in 9 hirsute women (6%), there was a prevalent significant increase in 11-deoxycortisol AUC. In 5 women (3.3%), DHEA and DHEAS basal and AUCs plasma levels were increased, suggesting an impaired 3 beta-olo-dehydrogenase activity. The remaining 114 hyperandrogenic women (76%) compose the nonadrenal group, with a probable diagnosis of primitive functional ovarian hyperandrogenism. CONCLUSION(S): Considering the high prevalence of hirsutism and oligomenorrhea in our female hyperandrogenic population, we suggest an adrenal hyperresponsiveness likely due to a dysregulation in enzymes related to androgen adrenal steroidogenesis.

17-alpha-Hydroxyprogesterone↗
PubMed1999

Do hyperandrogenic women with normal menses have polycystic ovary syndrome?

OBJECTIVE: To determine the prevalence of polycystic ovary syndrome (PCOS) among hyperandrogenic women who report normal menses. DESIGN: Prospective observational study. SETTING: Academic practice in reproductive endocrinology. PATIENT(S): Fifty-eight consecutively seen new patients with hyperandrogenism who reported normal menses. INTERVENTION(S): Ovulatory status was assessed with timed serum progesterone measurements. The following tests also were carried out: vaginal ultrasound examination; measurement of the ovarian response of 17-hydroxyprogesterone (17-OHP) after the administration of leuprolide acetate, 1 mg SC; and determination of fasting serum LH, FSH, E2, 17-OHP, insulin, and androgen levels. MAIN OUTCOME MEASURE(S): Determination of ovulatory status, polycystic appearance of ovaries, and increased response of 17-OHP to leuprolide acetate. RESULT(S): Twelve (20.7%) of the hyperandrogenic women were anovulatory and met the usual criteria for the diagnosis of PCOS. The ovulatory patients had lower serum total and unbound testosterone levels. Thirty-one (53.4%) of the ovulatory women had polycystic ovaries on ultrasound examination and/or an increased 17-OHP response to leuprolide acetate, suggesting the diagnosis of PCOS despite the presence of ovulation. Considering both the anovulatory and ovulatory patients, 74% of the hyperandrogenic women studied could have PCOS. CONCLUSION(S): The data suggest that most (74%) hyperandrogenic women who report normal menses have evidence for the diagnosis of PCOS.

17-alpha-Hydroxyprogesterone↗
PubMed1999

Insulin action during variable hyperglycemic-hyperinsulinemic infusions in hyperandrogenic anovulatory patients and healthy women.

OBJECTIVE: To determine whether 3-month GnRH analogue (GnRH-a) administration to hyperandrogenic anovulatory patients and healthy women affects glucose utilization or endogenous glucose production (EGP) in the postabsorptive state and during variable hyperglycemic-hyperinsulinemic infusions. DESIGN: Prospective, nonrandomized study. SETTING: Academic research environment. PATIENT(S): Twelve hyperandrogenic anovulatory patients and 11 healthy women matched by body mass index and waist to hip circumference ratio. INTERVENTION(S): Variable hyperglycemic-hyperinsulinemic infusions replicated physiological increases in circulating glucose and insulin levels before and after 3-month GnRH-a administration. MAIN OUTCOME MEASURE(S): Glucose utilization and EGP. RESULT(S): In the postabsorptive state, plasma glucose and insulin levels, glucose utilization, and EGP were similar in hyperandrogenic patients and healthy women. During variable hyperglycemic-hyperinsulinemic infusions, glucose use increased and EGP decreased to similar degrees in both groups of women. Three-month GnRH-a administration to hyperandrogenic patients and healthy women did not affect plasma glucose and insulin levels, glucose utilization and EGP in the postabsorptive state, or glucose utilization and EGP during variable hyperglycemic-hyperinsulinemic infusions. CONCLUSION(S): Glucose use and EGP in the postabsorptive state and during variable hyperglycemic-hyperinsulinemic infusions are similar in hyperandrogenic anovulatory patients and healthy women of similar body fat distribution and are unaffected by 3-month GnRH-a administration.

Adolescent↗
PubMed2003

Is ovarian and adrenal venous catheterization and sampling helpful in the investigation of hyperandrogenic women?

OBJECTIVE: To audit our practice of performing ovarian and adrenal venous catheterization and sampling in hyperandrogenic women who fail to suppress their elevated androgen levels following a 48-h low-dose dexamethasone suppression test (LDDST). We considered the technical success rate of catheterization, the extra information obtained in addition to the standard biochemical tests and imaging findings, and the impact of sampling on management decisions. DESIGN: A retrospective analysis of the results of all ovarian and adrenal venous catheterizations performed at St Bartholomew's Hospital, London, in the years 1980-1996. PATIENTS AND METHODS: Baseline ovarian and adrenal androgens were measured in all women presenting with symptoms and signs of hyperandrogenism. Those patients who failed to suppress their elevated testosterone (T), androstenedione (A4) and/or dehydroepiandrosterone-sulphate (DHEAS) levels following a LDDST to within the normal range or to less than 50% of the baseline value were investigated further with adrenal computed tomography (CT), ovarian ultrasound, and ovarian and adrenal venous catheterization and sampling. RESULTS: Results were available in 38 patients. The overall catheterization success rate was: all four veins in 27%, three veins in 65%, two veins in 87%. The success rate for each individual vein was: right adrenal vein (RAV) 50%, right ovarian vein (ROV) 42%, left adrenal vein (LAV) 87% and left ovarian vein (LOV) 73%. Eight patients were found to have tumours by means of imaging (adrenal CT and ovarian ultrasound), three adrenal and five ovarian, seven of which underwent operation. In six of these patients the clinical presentation was suggestive of the presence of a tumour; in addition, the combination of imaging findings allowed the detection of suspicious adrenal and ovarian masses in all eight cases. The five patients with ovarian tumours had serum testosterone levels > 4.5 nmol/l. In a further eight patients, laparotomy was performed based on a combination of diagnostic and therapeutic indications; in two of these patients the catheterization results were suggestive of an ovarian tumour. All these eight patients were shown histologically to have polycystic ovarian syndrome (PCOS), and no occult ovarian tumour was identified. None of the patients with nontumourous hyperandrogenism had a baseline testosterone level in excess of 7 nmol/l (median 4.4 nmol/l, range 2.5-7 nmol/l). CONCLUSIONS: Our results suggest that ovarian and adrenal venous catheterization and sampling should not be performed routinely in women presenting with symptoms and signs of hyperandrogenism, even if they fail to suppress their elevated androgen levels to a formal 48-h LDDST. All patients presenting with symptoms and signs of hyperandrogenism and elevated androgen levels, and where the suspicion of an androgen-secreting tumour is high, should have adrenal CT and ovarian ultrasound imaging to detect such a tumour. Venous catheterization and sampling should be reserved for patients in whom uncertainty remains, as the presence of a small ovarian tumour cannot be excluded on biochemical and imaging studies used in this series alone. Its use should be restricted to units with expertise in this area.

Adrenal Gland Neoplasms↗
PubMed2005

Extensive clinical experience: relative prevalence of different androgen excess disorders in 950 women referred because of clinical hyperandrogenism.

CONTEXT: We undertook this study to estimate the prevalence of the various androgen excess disorders using the new criteria suggested for the diagnosis of polycystic ovary syndrome (PCOS). SETTING: The study was performed at two endocrine departments at the University of Palermo (Palermo, Italy). PATIENTS: The records of all patients referred between 1980 and 2004 for evaluation of clinical hyperandrogenism were reevaluated. All past diagnoses were reviewed using the actual diagnostic criteria. To be included in this study, the records of the patients had to present the following available data: clinical evaluation of hyperandrogenism, body weight and height, testosterone (T), free T, dehydroepiandrosterone sulfate, 17-hydroxyprogesterone, progesterone, and pelvic sonography. A total of 1226 consecutive patients were seen during the study period, but only the scores of 950 patients satisfied all criteria and were reassessed for the diagnosis. RESULTS: The prevalence of androgen excess disorders was: PCOS, 72.1% (classic anovulatory patients, 56.6%; mild ovulatory patients, 15.5%), idiopathic hyperandrogenism, 15.8%; idiopathic hirsutism, 7.6%; 21-hydroxylase-deficient nonclassic adrenal hyperplasia, 4.3%; and androgen-secreting tumors, 0.2%. Compared with other androgen excess disorders, patients with PCOS had increased body weight whereas nonclassic adrenal hyperplasia patients were younger and more hirsute and had higher serum levels of T, free T, and 17-hydroxyprogesterone. CONCLUSIONS: Classic PCOS is the most common androgen excess disorder. However, mild androgen excess disorders (ovulatory PCOS and idiopathic hyperandrogenism) are also common and, in an endocrine setting, include about 30% of patients with clinical hyperandrogenism.

17-alpha-Hydroxyprogesterone↗
PubMed2001

Sensitization to insulin induces ovulation in nonobese adolescents with anovulatory hyperandrogenism.

In nonobese girls with an adolescent variant of polycystic ovary syndrome, insulin-sensitizing treatment reduces hyperinsulinism, dyslipidemia, and hyperandrogenism and restores eumenorrhea; however, the effect on anovulation is unknown. We assessed whether metformin treatment is capable of inducing ovulation in nonobese adolescents with anovulatory hyperandrogenism after precocious pubarche. The study population consisted of 18 adolescents (mean age, 16 yr; body mass index, 21.4 kg/m2; 3-7 yr beyond menarche) with hyperinsulinemic hyperandrogenism. All girls received metformin for 6 months in a daily dose of 1275 mg. Before inclusion, persistent anovulation was documented by weekly serum progesterone measurements less than 4 ng/ml (months -3 and -1); the ovulation rate was assessed similarly after 2, 4 and 6 months on metformin; a premenstrual progesterone level greater than 8 ng/ml was used as ovulation marker. Regular menses were reported by 16 of 18 girls within 4 months on metformin, and all girls were eumenorrheic after 6 months on metformin. Of the 18 girls, 1 (6%) ovulated after 2 months on metformin, 7 (39%) after 4 months, and 14 (78%) after 6 months; ovulation induction failed in the girls with the lowest birth weight or most severe hyperandrogenism. Metformin treatment was well tolerated. In conclusion, sensitization to insulin was found to be an effective approach to induce ovulation in nonobese adolescents with anovulatory hyperandrogenism.

Adolescent↗
PubMed1999

Adrenal 21-hydroxylase gene mutations in Slovenian hyperandrogenic women: evaluation of corticotrophin stimulation and HLA polymorphisms in screening for carrier status.

OBJECTIVE: To study the incidence of 21-hydroxylase deficiency in Slovenian hyperandrogenic women, at the gene level. Previous endocrine studies indicated large differences in the incidence of 21-hydroxylase deficiency in hyperandrogenic women. The predictive values of the 17-hydroxyprogesterone (17-OHP) response to ACTH stimulation and of HLA typing in screening for carrier status were re-evaluated. DESIGN: Molecular analysis of CYP21 gene, ACTH stimulation and human leucocyte antigen (HLA) typing were performed in 83 consecutive Slovenian hyperandrogenic women. MEASUREMENTS: Cortisol and 17-OHP concentrations were measured at baseline and 60 min after ACTH stimulation. Basal adrenal androgen concentrations were also measured. RESULTS: None of 83 hyperandrogenic patients was affected with non-classical 21-hydroxylase deficiency, but 12 of 81 patients (14.8%) had high concentrations of 17-OHP after stimulation, indicative of carrier status. The increase in 17-OHP concentrations could be explained by a carrier status for CYP21 gene mutations in only three of 12 patients (25%), whereas seven of 69 patients (10. 1%) with normal concentrations of 17-OHP after stimulation were found to be carriers of CYP21 gene mutations, indicating low positive predictive values of ACTH stimulation as a screening test for carriers of 21-hydroxylase deficiency. In total, 11 carriers were identified among 83 patients: seven CYP21 gene deletions/conversions, two Gln(318)Stop and one Val(281)Leu mutation and one gene conversion extending from exon 4 to exon 7 were found. The association between Val(281)Leu mutation and HLA-B14 antigen was confirmed in this Slovenian population. CONCLUSIONS: Basal or ACTH-stimulated 17-OHP concentrations are not a good indicator of the carrier status for 21-hydroxylase deficiency among Slovenian hyperandrogenic patients. Reliable screening for carriers of 21-hydroxylase deficiency is possible only by molecular analysis of the CYP21 gene.

17-alpha-Hydroxyprogesterone↗
PubMed2005

[Leptin level and the PPARgamma2 Pro12Ala and Pro115Gln polymorphisms in women with functional hyperandrogenism. Preliminary report].

UNLABELLED: Hyperandrogenism is a multifactoral chronic disease, characterised by an androgen excess, often connected with obesity, hirsutism, polycystic ovaries, hyperinsulinemia, insulin resistance and hyperleptynemia. Peroxisome proliferator activated receptors (PPARgamma) are one of the factors influencing insulin sensitivity. As a transcriptional factor it plays a crucial role in the regulation of genes involved in insulin action. The aim of this study was to evaluate the frequency of PPARgamma Pro12Ala and Pro115Gln polymorphisms in hyperandrogenic women. The additional aim was to investigate differences in leptin levels in healthy and FOH (functional ovarian hyperandrogenism) women (non-obese and obese). MATERIAL AND METHODS: we investigated 90 women: 72 healthy women (37 nonobese and 35 obese)--control group, and 18 women with FOH (9 nonobese and 9 obese)--FOH group. We performed anthropological examination: BMI, WHR and total-body densytomery, biochemical and hormonal estimations in the whole group. PPARgamma polymorphism was studied using PCR and RFLP. RESULTS: in the control group Pro12Pro ("wild" type) was observed in 45 women (26 obese and 19 nonobese) - 62.5% of the group. Heterozygosity Pro12Ala was observed in 15 women (20.8%): 4 obese and 11 with BMI < 30 kg/m2, homozygosity Ala12Ala was seen in 12 women (16.6%): 5 obese i 7 nonobese. In FOH group "wild" type was discovered in 9 women (4 obese and 5 nonobese) - 50% of FOH group, heterozygosity Pro12Ala was seen in 5 women (27.7%): 2 obese and 3 with BMI < 30 kg/m2, homozygosityAla12Ala was observed in 4 women (22.2%): 3 obese and in 1 non-obese. Ala allel frequency in control group was 28%. (37% in non-obese and 20% in obese). In FOH group Ala allel frequency was 36% (nonobese - 28%, obese - 44%). In the studied group we did not find Pro115Gln polymorphism. Leptin level in control group was 19.92 +/- 14.3 ng/ml, and in FOH group - 23.41 +/- 19.47 ng/ml. Depending on BMI leptin level in non-obese healthy group was 7.45 +/- 3.76 ng/ml, in non-obese FOH women - 18.33 +/- 16.54 ng/ml, p < 0.005. In obese controls leptin level was 43.6 +/- 17.28 ng/ml, and in obese FOH women - 45.72 +/- 14.89 ng/ml. CONCLUSIONS: Leptin level in non-obese FOH women is significantly higher than in lean healthy controls. This difference was not observed in obese women. However the Pro12Ala polymorphism is quite common; it does not seem to be directly related to the obesity connected with hyperandrogenism. Higher frequency of Ala allele In FOH women compared to healthy controls (36% vs 28%) may at least partially explain the beneficial effect of tiazolidinediones in the treatment of hyperandrogenism.

Adult↗
PubMed1993

3 beta-hydroxysteroid dehydrogenase deficiency in hyperandrogenism.

OBJECTIVE: Deficient adrenocortical 3 beta-hydroxysteroid dehydrogenase activity has been reported in 5% to 30% of hyperandrogenic women. Our objective was to determine the incidence and degree of 3 beta-hydroxysteroid dehydrogenase deficiencies in hyperandrogenism. STUDY DESIGN: A prospective study of adrenal function in patients with hyperandrogenism was performed in a tertiary care university medical center. Eighty-six consecutive patients with hirsutism or hyperandrogenic oligomenorrhea were studied; 26 healthy eumenorrheic women served as controls. All subjects underwent serum sampling at rest and a 1-hour adrenal stimulation test with 1 mg of intravenously corticotropin-(1-24). Dehydroepiandrosterone sulfate, androstenedione, sex hormone-binding globulin, total and free testosterone, and luteinizing and follicle-stimulating hormones were measured in basal serum; dehydroepiandrosterone, 17-hydroxyprogesterone, and 17-hydroxypregnenolone were measured in basal and corticotropin-stimulated serum. On the basis of experience with genetically defined 21-hydroxylase late-onset adrenal hyperplasia, patients were presumed to suffer from 3 beta-hydroxysteroid-deficient late-onset adrenal hyperplasia if they demonstrated a dehydroepiandrosterone or 17-hydroxypregnenolone response to corticotropin-(1-24) stimulation (absolute poststimulation level or net increment) greater than threefold the upper 95th percentile of controls. RESULTS: Three women of two families (2.3%) had a 17-hydroxyprogesterone response consistent with 21-hydroxylase-deficient late-onset adrenal hyperplasia and were excluded from further study. Eighteen (21%) of the remaining patients had a 17-hydroxypregnenolone poststimulation increment above the upper 95th percentile of controls (13.9 nmol/L), and two had an elevated dehydroepiandrosterone increment (> 19.5 nmol/L). However, no patient exceeded threefold the upper control limit for either steroid response. Patients with an exaggerated dehydroepiandrosterone or 17-hydroxypregnenolone increment had higher circulating dehydroepiandrosterone sulfate levels but similar basal total and free testosterone, sex hormone-binding globulin, luteinizing and follicle-stimulating hormone concentrations, basal or stimulated androstenedione, dehydroepiandrosterone/androstenedione, and 17-hydroxypregnenolone/17-hydroxyprogesterone than their less responsive counterparts. CONCLUSIONS: Although an exaggerated response of 17-hydroxypregnenolone to adrenal stimulation is common in hyperandrogenism, a response severe enough to merit consideration as 3 beta-hydroxysteroid dehydrogenase-deficient late-onset adrenal hyperplasia was not encountered in this unselected patient population, suggestive of the rarity of this disorder.

17-alpha-Hydroxypregnenolone↗
PubMed1982

The prognostic value of acute adrenal suppression and stimulation tests in hyperandrogenic women.

A group of 106 consecutively seen hyperandrogenic women were subjected to an acute adrenal suppression and stimulation test. The results of these tests were analyzed with respect to androgen suppression achieved after chronic glucocorticoid therapy in the same patients. The data suggested that an acute dexamethasone test may identify the group of hyperandrogenic women who respond poorly to chronic glucocorticoid therapy. This group of patients were found to have elevated luteinizing hormone (LH) levels and LH/follicle-stimulating hormone (FSH) ratios, suggesting the possibility of an LH-related hyperandrogenism. In patients whose elevated testosterone levels were suppressed by dexamethasone, adrenocorticotropic hormone (ACTH) induced a prompt return of the testosterone levels to baseline, suggesting an ACTH-dependent hyperandrogenism. In these patients, the degree of testosterone suppression after dexamethasone was not quantitatively related to the degree of testosterone suppression after chronic glucocorticoid therapy. In all cases chronic therapy resulted in a greater suppression of androgen levels than the acute dexamethasone test. In conclusion, an acute dexamethasone suppression test appears to be of clinical value in the management of the hyperandrogenic female, particularly in identification of women who will not respond to chronic glucocorticoid suppression therapy.

Adrenocorticotropic Hormone↗
PubMed1999

Screening for 21-hydroxylase-deficient nonclassic adrenal hyperplasia among hyperandrogenic women: a prospective study.

OBJECTIVE: To prospectively establish the specificity, sensitivity, and positive predictive value (PPV) of a basal 17-hydroxyprogesterone (17-HP) level for the screening of 21-hydroxylase-deficient nonclassic adrenal hyperplasia (NCAH) among hyperandrogenic women. DESIGN: Prospective observational trial. SETTING: Tertiary care academic medical centers. PATIENT(S): Eight healthy controls, 20 patients with NCAH, and 284 consecutively seen patients with hyperandrogenism. INTERVENTION(S): All controls and patients with NCAH, and select patients with hyperandrogenism, underwent acute ACTH (1-24) stimulation. MAIN OUTCOME MEASURE(S): Specificity was determined by measuring 17-HP every other day during one menstrual cycle in 8 healthy women with normal ovulation (107 samples). Sensitivity was determined by measuring 17-HP between 7 and 9 A.M. and 3 and 5 P.M. on the same day in 20 patients with genetically confirmed NCAH. The PPV was determined by prospectively measuring 17-HP in 284 consecutively seen hyperandrogenic women at their initial evaluation. The diagnosis of NCAH was established by a stimulated 17-HP level of >10 ng/mL. RESULT(S): Among controls, 17-HP levels of <2, <3, and <4 ng/mL all had a specificity of 100% when obtained in the follicular phase; when obtained in the luteal phase, they had specificities of 53%, 82%, and 82%, respectively. Among patients with NCAH, 17-HP levels of >2, >3, and >4 ng/mL had sensitivities of 100%, 90%, and 90%, respectively, for the detection of the disorder when obtained in the morning, and sensitivities of 95%, 90%, and 85%, respectively, when obtained in the afternoon. Among the 284 consecutively seen hyperandrogenic women, the PPVs of the first and second 17-HP levels were 7.3% and 19% for a cutoff level of >2 ng/mL, 13% and 43% for a cutoff level of >3 ng/mL, and 33% and 40% for a cutoff level of >4 ng/mL, respectively. CONCLUSION(S): A basal 17-HP level is a useful screening tool for NCAH. A cutoff level of 4 ng/mL has maximum specificity and PPV, with little loss in sensitivity if testing is performed in the morning and during the follicular phase. However, a lower cutoff level (e.g., 2 or 3 ng/mL) is preferable if testing is performed at odd hours of the day, as is common in many practices, and maximum sensitivity is desired.

17-alpha-Hydroxyprogesterone↗
PubMed1991

Lipid metabolism and hyperandrogenism.

Hyperandrogenism and lipid metabolism were shown to be related intimately. Any discussion of the nature of their relationship must include other clinical and metabolic variables such as hyperinsulinemia and UBO. Despite the many correlations among each of these factors, the appropriate sequence in the pathogenesis of these conditions has not been defined. Do conditions that result in insulin resistance (e.g., genetic defects, insulin receptor antibodies, and obesity) also lead to the development of hyperandrogenemia by direct or indirect ovarian stimulation by insulin? Does hyperandrogenism of ovarian or adrenal origin cause abnormal upper body fat distribution, in turn leading to lipid abnormalities and insulin resistance? Regardless of the issue of mechanism of causality, women with hyperandrogenism are thought to be at greater risk for cardiovascular morbidity and mortality than their normoandrogenic counterparts. These women often are obese, hypertensive, and sedentary; ingest diets high in saturated fats; and have glucose intolerance and/or insulin resistance. All these abnormalities are well known independent risk factors for the development of lipid abnormalities and cardiovascular disease. Whether hyperandrogenism is a secondary consequence of any of these or whether it is an independent contributor to lipid aberrations requires future study. Treatment strategies for hyperandrogenic women, however, should not only be directed toward alleviation of the cosmetic problem of hirsutism but also toward the prevention and treatment of cardiovascular morbidity using modalities aimed at eradicating hyperinsulinemia, hypertension, and dyslipidemia. These modalities should include modifications in diet, exercise, and weight in addition to pharmacologic and/or surgical manipulation. Weight reduction will reduce many cardiovascular risk factors. Obesity is easier to target because of the many risk factors that result in it.(ABSTRACT TRUNCATED AT 250 WORDS)

Androgens↗
PubMed1993

Gonadotropin-releasing hormone agonist as a probe for the pathogenesis and diagnosis of ovarian hyperandrogenism.

We have found that women with typical polycystic ovary syndrome have supranormal plasma 17-hydroxyprogesterone responses to a 100-micrograms test dose of the gonadotropin-releasing hormone agonist nafarelin without evidence of hindered estrogen secretion. To understand the basis of this response, we computed the apparent efficiency of the steps in steroid biosynthesis from the pattern of plasma steroids in response to nafarelin. The proximate cause appears to be excessive 17 alpha-hydroxylase activity and high, yet partially down-regulated, 17,20-lyase activity in the delta 4-pathway. These results suggest that this pattern of steroid secretion results from abnormal regulation (dysregulation) of these activities, possibly involving the enzyme cytochrome P450c17. To determine the usefulness of nafarelin testing for the diagnosis of ovarian hyperandrogenism, we then prospectively studied 40 hyperandrogenic women. The plasma 17-PROG response to nafarelin was supranormal in 58% of the women. The responses of 17-PROG to nafarelin and free testosterone to dexamethasone correlated well and were concordant in approximately 85% of cases. Baseline serum luteinizing hormone concentration was elevated in only 48% of cases. To understand ovarian structure-function relationships, we studied another 20 consecutive hyperandrogenic women. Among seven women with polycystic ovaries, five had an elevated LH level, and four of these five (80%) had an elevated 17-PROG response to nafarelin. Conversely, about half of patients with the PCOS-like disorder of ovarian function did not have polycystic ovaries. Ovarian stromal area, but not LH levels, correlated significantly (r = 0.45) with the 17-PROG response to nafarelin. Thus, both stromal hyperplasia and dysregulation of steroidogenesis seem to be manifestations of abnormal intraovarian regulation of cell growth and function. We conclude that a PCOS-like disorder of ovarian function in response to nafarelin testing is found in approximately half of hyperandrogenic women. The pathogenetic implication of our results is that abnormal intraovarian modulation of LH action seems to be a major factor in ovarian hyperandrogenism. The diagnostic implication of our data is that ovarian androgen excess will often be missed by use of common diagnostic criteria for PCOS.

Androgens↗
PubMed1980

The intraovarian sites of androgen and estrogen formation in women with normal and hyperandrogenic ovaries as judged by in vitro experiments.

The status of oocytes, the follicular fluid concentrations of steroids, and the in vitro steroidogenic capacities of stromal tissue, thecal tissue, and granulosa cells from a 15-yr-old girl with primary amenorrhea, ovarian hyperandrogenism, insulin-resistant diabetes mellitus, and acanthosis nigricans were compared to those from normal adult human ovaries. Most oocytes (95%) in the antral follicles recovered from the hyperandrogenic ovaries were degenerative, and the antral fluid levels of testosterone were 30- to 200-fold higher than those in normal ovaries. Granulosa cells from the hyperandrogenic ovaries produced mainly estradiol as did those from normal healthy follicles. The thecal tissues produced 2- to 6-fold more androgen than similar tissues from normal ovaries. However, the stroma from the hyperandrogenic ovaries produced 49- to 250-fold more testosterone than that generated by normal tissues. These data suggest that the removal of stromal tissue as well as follicular tissue from patients with certain types of hyperandrogenism may sometimes contribute to a reduction in androgen secretion.

Adolescent↗
PubMed1985

Acanthosis nigricans in obese women with hyperandrogenism. Characterization of an insulin-resistant state distinct from the type A and B syndromes.

Acanthosis nigricans and hyperandrogenism are commonly found in patients with extreme target cell resistance to insulin, as in the type A and B syndromes of insulin resistance. However, the significance of concurrent acanthosis nigricans and hyperandrogenism in other clinical settings is not clear. We observed acanthosis nigricans to be present in 5% (15 of 300) of patients being evaluated for hyperandrogenism, and carried out studies of insulin binding and action in a group (7) of these women. Although none were diabetic, all were insulin resistant as assessed by hyperinsulinemia when fasting and after oral glucose administration. All patients were obese (mean IBW, 169%). However, when matched to hyperandrogenized women of similar body weight, patients with acanthosis nigricans were clearly more hyperinsulinemic. Insulin binding to monocytes and red cells was decreased in patients with acanthosis, and the extent of decrease was predicted by the fasting insulin level. There was also marked resistance to exogenous insulin during euglycemic insulin clamp studies in the two patients so tested. Anti-insulin receptor antibodies were not detectable, ruling out the type B syndrome. Unlike the type A syndrome, insulin binding to monocytes of these patients increased after acute (2/2) and chronic (1/1) caloric restriction. In the latter patient, acanthosis nigricans remitted as insulin resistance and the insulin binding defect improved. We conclude that acanthosis nigricans is present in as many as 5% of women with clinically significant hyperandrogenism. These women, although not diabetic, have fairly marked insulin resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Acanthosis Nigricans↗
PubMed2000

Diagnosis of the polycystic ovary syndrome in adolescence: comparison of adolescent and adult hyperandrogenism.

We performed gonadotropin releasing hormone agonist (GnRHag) tests on 23 consecutive hyperandrogenic girls 9.9-17.5 years of age who were referred to our pediatric endocrinology clinic with symptoms suggestive of PCOS. They were compared to contemporaneously studied groups of adult normal and hyperandrogenic women. We found that hyperandrogenic adolescents had clinical and endocrine features similar to those of hyperandrogenic adults. However, there were some noteworthy unique features of adolescent hyperandrogenism, such as presentation in mid-childhood with premature pubarche and the occasional diagnosis before the age of 10 years. Some differences between adolescents and adults were statistically significant, for example, pelvic ultrasonography was not as helpful in the diagnosis of FOH as it is in adults. Nevertheless, a number of questions about the development of the ovarian dysfunction remain to be answered. For example, we are unable to diagnose ovarian dysfunction before puberty or in early puberty, and the relationship of "physiologic adolescent anovulation" to PCOS remains to be defined.

Adolescent↗
PubMed1998

Variants of the type II 3beta-hydroxysteroid dehydrogenase gene in children with premature pubic hair and hyperandrogenic adolescents.

To ascertain the potential role of heterozygosity for 3beta-hydroxysteroid (3beta-HSD) deficiency in children with premature pubic hair and adolescent girls with hyperandrogenism, we performed single-strand conformational polymorphism (SSCP) analysis of the 3beta-hydroxysteroid dehydrogenase type 2 (3beta-HSD2) gene in 34 hyperandrogenic patients. Three sequence variants, two missense mutations and a 3'-UTR sequence variant, were detected among seven patients and in none of 100 healthy control subjects. One of these seven patients carried Leu236 --> Ser on one 3beta-HSD2 allele and Glu318 --> STOP on one 21-hydroxylase (CYP21) allele. ACTH stimulation tests were performed in 5/7 patients with sequence variants and were compatible with decreased 3beta-hydroxysteroid dehydrogenase activity in three. Thus, 7 of 34 (20.6%) mildly hyperandrogenic patients carry heterozygous sequence variants of the 3beta-HSD2 gene. Since obligate heterozygotic carriers for congenital adrenal hyperplasia are typically asymptomatic, other genetic or environmental influences may contribute to the expression of hyperandrogenic symptoms in our patients.

17-Hydroxycorticosteroids↗
PubMed2006

Diagnosis of hyperandrogenism: biochemical criteria.

Biochemical derangements in ovarian, adrenal, and peripheral androgen production and metabolism play an important role in underlying causes of hyperandrogenism. Specific diagnostic serum markers such as testosterone (total) and dehydroepiandrosterone sulfate (DHEAS), respectively, may be helpful in the diagnosis of ovarian and adrenal hyperandrogenism, respectively. Validated immunoassays or mass spectrometry assays should be used to quantify testosterone, DHEAS and other principal androgens. Free testosterone measurements, determined by equilibrium dialysis or the calculated method, are advocated for routine evaluation of more subtle forms of hyperandrogenism. The skin, with its pilosebaceous units (PSUs), is an important site of active androgen production. A key regulator in PSUs is 5alpha-reductase, which transforms testosterone or androstenedione to dihydrotestosterone (DHT). DHT in blood is not effective in indicating the presence of hyperandrogenism. However, distal metabolites of DHT have been shown to be good markers of clinical manifestations of hirsutism, acne and alopecia. Assays for these peripheral markers need improvement for routine clinical testing.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗