cosyntropin and Hyperandrogenism

Moderate forms of 21-hydroxylase deficiency (D21OH-NC), the so-called non-classical or late-onset forms are a frequently reported cause of hyperandrogenism in women [1-5]. The purpose of this collective and synthetic work was to provide the endocrinologist, gynecologist and dermatologist with consensual information so as to detect the maximum cases with acceptable cost-benefit ratio and to define the main lines of optimal patient management, given the data currently available in medical literature.

Topics: Adrenal Hyperplasia, Congenital; Adrenal Insufficiency; Cosyntropin; Female; Genetic Counseling; Glucocorticoids; Hirsutism; Hormone Replacement Therapy; Humans; Hyperandrogenism; Infertility, Female; Steroid 21-Hydroxylase

Increased peripheral metabolism of cortisol may explain compensatory ACTH-dependent adrenal steroidogenesis and hence hyperandrogenism in polycystic ovary syndrome (PCOS). Previous studies have described an increased 5alpha-reduction of cortisol or impaired regeneration of cortisol by 11beta-HSD1 in PCOS. However, these observations may be confounded by obesity. Moreover, the relationship between alterations in cortisol metabolism and the extent of adrenal androgen hyper-secretion in response to ACTH has not been established. This study aimed to examine the association between cortisol metabolism and ACTH-dependent adrenal hyperandrogenism in PCOS, independently of obesity.. We compared 90 PCOS women (age 18-45 yr) stratified by adrenal androgen responses to ACTH1-24 and 45 controls matched for age and body weight.. PCOS women were stratified as normal responders (NR), intermediate responders (IR), and high responders (HR) to 250 microg ACTH1-24: NR (no.=27) had androstenedione and DHEA responses within 2 SD of the mean in controls; IR (no.=43) had DHEA responses >2 SD above controls; HR (no.=20) had both androstenedione and DHEA responses >2 SD above controls.. All groups were similar for age, body weight, and body fat distribution. Basal testosterone, androstenedione, and 5alpha-dihydrotestosterone plasma levels were similarly elevated among the 3 groups of PCOS compared with controls, whereas basal DHEA-S was higher in HR (2.8+/-1.2 microg/ml) and IR (2.4+/-1.1 microg/ml) than in NR (1.8+/-0.8 microg/ml) and controls (1.7+/-0.6 microg/ml). The HR group had the lowest basal plasma cortisol levels (101+/-36 ng/ml vs IR 135+/-42 ng/ml, NR 144+/-48 ng/ml, and controls 165+/-48 ng/ml; all p<0.01), but the greatest cortisol response to ACTH1-24 (Delta(60-0)cortisol 173+/-60 ng/ml vs IR 136+/-51 ng/ml, NR 114+/-50 ng/ml, and controls 127+/-50 ng/ml; all p<0.01), and the highest urinary excretion of total and 5beta-reduced cortisol metabolites (eg 5beta-tetrahydrocortisol/ cortisol ratio 25.2+/-15.3 vs IR 18.8+/-10.7, NR 19.7+/-11.4, and controls 17.2+/-13.7; all p<0.05). There were no differences in urinary excretion of 5alpha-reduced cortisol metabolites or in 5alpha-dihydrotestosterone/testosterone ratio between groups.. Adrenal androgen excess in PCOS is associated with increased inactivation of cortisol by 5beta-reductase that may lower cortisol blood levels and stimulate ACTH-dependent steroidogenesis.

Topics: Adolescent; Adrenocortical Hyperfunction; Adult; Androstenedione; Basal Metabolism; Cosyntropin; Dehydroepiandrosterone; Female; Humans; Hydrocortisone; Hyperandrogenism; Middle Aged; Oxidoreductases; Pituitary-Adrenal Function Tests; Polycystic Ovary Syndrome; Up-Regulation; Young Adult

To determine if the (tttta)(n) repeat polymorphism in the promoter region of CYP11a gene is associated with hirsutism and hyperandrogenism in women from Spain.. Controlled clinical study.. Tertiary-care institutional hospital.. Ninety-two hirsute women and 33 healthy control women.. Basal and adrenocorticotropin-stimulated serum samples and genomic DNA extracted and purified from whole-blood samples were obtained during the follicular phase of the menstrual cycle.. CYP11a (tttta)(n) repeat-polymorphism genotype and serum ovarian and adrenal androgen levels.. None of the CYP11a (tttta)(n) polymorphic alleles was associated with hirsutism. The absence of the four-repeat-units allele (4R-- genotype), which has been reported by other authors to be associated with polycystic ovary syndrome (PCOS), was found in 22.4% of the women studied here and was equally distributed among patients and controls, independently of the presence of PCOS and/or ovarian or adrenal hyperandrogenism. No differences were observed in serum hormone concentrations in 4R-- individuals as compared with subjects with at least one four-repeat-units allele.. The (tttta)(n) repeat polymorphism in the promoter region of CYP11a does not appear to play any significant role in the pathogenesis of hirsutism and hyperandrogenism in women from Spain.

Topics: Adult; Base Sequence; Cholesterol Side-Chain Cleavage Enzyme; Cortodoxone; Cosyntropin; Dehydroepiandrosterone Sulfate; Dexamethasone; Estradiol; Female; Follicle Stimulating Hormone; Genotype; Hirsutism; Humans; Hyperandrogenism; Luteinizing Hormone; Menstrual Cycle; Microsatellite Repeats; Polycystic Ovary Syndrome; Polymorphism, Genetic; Progesterone; Promoter Regions, Genetic; Reference Values; Sex Hormone-Binding Globulin; Testosterone

To test the hypothesis that in women with polycystic ovary syndrome (PCOS), adrenal cytochrome P450c 17alpha activity is different after physiologic vs. pharmacologic ACTH stimulation and that ovarian activity promotes adrenal hyperactivity that is different after physiologic vs. pharmacologic ACTH stimulation.. Prospective controlled pilot study.. Reproductive endocrinology unit of an academic medical center.. Six women with PCOS who had adrenal hyperandrogenism were compared with four women with normal ovulation.. Adrenal dynamic blood sampling was performed before and after 6 months of GnRH agonist administration.. Comparison of physiologic and pharmacologic ACTH-stimulated levels of progesterone, 17-hydroxyprogesterone, and androgens before and after ovarian steroid modulation.. In women with PCOS, exaggerated responses of androstenedione and 11beta-hydroxyandrostenedione as well as elevated ratios of 17-hydroxyprogesterone to progesterone and of androstenedione to 17-hydroxyprogesterone after physiologic ACTH stimulation did not persist after GnRH-agonist administration. Three of the six women with PCOS had an increased response of androstenedione and a ratio of androstenedione to 17-hydroxyprogesterone that were >2 SD above the mean of those in the women with normal ovulation after pharmacologic ACTH stimulation; this finding persisted after GnRH-agonist administration.. In women with PCOS, increases in adrenal androgen sensitivity after physiologic ACTH stimulation reflected in both arms of cytochrome P450c 17alpha activity may be influenced by ovarian activity. However, 17,20-lyase hyperactivity in a subset after pharmacologic ACTH stimulation may be an intrinsic adrenal disorder.

Topics: Adrenocorticotropic Hormone; Adult; Cosyntropin; Female; Gonadotropin-Releasing Hormone; Hormones; Humans; Hyperandrogenism; Leuprolide; Ovary; Pilot Projects; Polycystic Ovary Syndrome; Steroid 17-alpha-Hydroxylase

To comprehensively phenotype parents identified with nonclassic congenital adrenal hyperplasia (NCCAH) by family genetic studies, termed here as cryptic NCCAH and to define the incidence of cryptic NCCAH in the parents of a large cohort of patients with 21-hydroxylase deficiency.. Genotyping was performed on 249 parents of 145 unrelated congenital adrenal hyperplasia (CAH) patients. Parents with two CYP21A2 mutations underwent extensive evaluation.. Of the 249 parents, ten (4%; seven females and three males) were identified as having cryptic NCCAH. The majority was of ethnicities previously reported to have a higher incidence of NCCAH. Cosyntropin stimulation performed in eight parents provided biochemical confirmation (17-hydroxyprogesterone range 56-364 nmol/l) and cortisol response was ≤500 nmol/l in three parents (38%). Of the seven women (27-54 years) with cryptic NCCAH, four had prior infertility, two reported irregular menses, two had treatment for hirsutism, one had androgenic alopecia. Men were asymptomatic. All cryptic NCCAH parents reported normal puberty and had normal height. Adrenal hypertrophy and a small adrenal myelolipoma were observed in two parents; testicular adrenal rest tissue was not found.. Parents diagnosed with NCCAH by genetic testing are mostly asymptomatic. Temporary female infertility and suboptimal cortisol response were commonly observed. Ongoing glucocorticoid therapy is not indicated in adults with CAH identified by family genotype studies unless symptomatic, but glucocorticoid stress coverage should be considered in select cases. Parents of a child with CAH have a 1:25 risk of having NCCAH; if the mother of a child with CAH has infertility, evaluation for NCCAH is indicated.

Topics: Adrenal Glands; Adrenal Hyperplasia, Congenital; Adult; Aged; Anthropometry; Bayes Theorem; Body Height; Cosyntropin; DNA; Female; Hormones; Humans; Hyperandrogenism; Infertility; Male; Middle Aged; Parents; Phenotype; Puberty; Steroid 21-Hydroxylase; Testis; Tomography, X-Ray Computed

This study investigated the prevalence and consequences of heterozygous CYP21A2 mutations in premature pubarche (PP) girls.. We investigated 36 French Mediterranean girls with isolated PP. We performed synacthen testing with 17OHP and 21-deoxycortisol evaluation, along with molecular analysis of the CYP21A2 gene in girls with abnormal elevation of one of these two adrenal steroids. Three girls (8.3%) had nonclassical adrenal hyperplasia, secondary to compound heterozygosity that associated at least one severe mutation for the three girls. A heterozygous mutation of the CYP21A2 gene was confirmed by molecular biology in eight girls (22%); a deletion of the CYP21A2 gene was found in one of them. Biological hyperandrogenism was found in the prepubertal CYP21A2 mutation carriers, whereas the four heterozygous girls who were followed long enough to have reached pubertal age presented biological and clinical hyperandrogenism.. We underline the high prevalence of heterozygous CYP21A2 mutations in girls with PP and demonstrate the usefulness of systematic screening by synacthen testing, both to improve their future clinical management and to prevent the transmission of classical adrenal hyperplasia to future offspring. Because of the severe metabolic and cardiovascular consequences of hyperandrogenism, long-term follow-up of these heterozygous patients is mandatory.

Topics: 17-alpha-Hydroxyprogesterone; Adolescent; Child; Child, Preschool; Cortodoxone; Cosyntropin; Dehydroepiandrosterone Sulfate; Female; France; Heterozygote; Humans; Hyperandrogenism; Mediterranean Region; Mutation; Puberty, Precocious; Steroid 21-Hydroxylase; Testosterone

The exaggerated 17-hydroxyprogesterone response to GnRH agonists, which reflects functional ovarian hyperandrogenism (FOH), is believed to be the prominent abnormality in women with polycystic ovary syndrome (PCOS).. Our objectives were to quantify the prevalence of PCOS with FOH and to evaluate whether the presence of FOH may distinguish different clinical and biochemical phenotypes.. We conducted an observational study at an academic hospital that included 148 PCOS women and 22 healthy age-matched normal-weight control women.. A hormone profile was taken at baseline and in response to (1-24)ACTH and to a GnRH agonist, buserelin, administered during dexamethasone suppression.. Based on the data obtained in the control subjects, the PCOS patients were divided into two groups, one with a normal (NR-PCOS, n = 78) and one with a high 17-hydroxyprogesterone response (HR-PCOS, n = 70) to buserelin. The two groups of PCOS subjects had similar anthropometric parameters and clinical signs of hyperandrogenism. Age and body weight at menarche were significantly lower and higher, respectively, in the HR-PCOS group than the NR-PCOS group. Moreover, the HR-PCOS group had higher basal testosterone (P < 0.001), free androgen index (P < 0.01), 17-hydroxyprogesterone (P < 0.05), estrogens (P < 0.05), area under the curve for insulin (insulin(AUC)) (P < 0.05), and C-peptide(AUC) (P < 0.01) and lower insulin sensitivity (as composite insulin sensitivity index) (P < 0.05) than the NR-PCOS group. The response of 17-hydroxyprogesterone to (1-24)ACTH (as percent variation) was lower in the HR-PCOS group with respect to the NR-PCOS group (P < 0.05), whereas the response of cortisol, androstenedione, and dehydroepiandrosterone was similar. Finally, the HR-PCOS group had lower percent suppression of androstenedione (P < 0.001) and 17-hydoxyprogesterone (P < 0.05) to dexamethasone. In a multiple regression model applied in all PCOS women, insulin(AUC) but not androgens or markers of insulin resistance predicted the 17-hydroxyprogesterone response to buserelin to a highly significant extent (t = 3.269; P < 0.01).. This study indicates that the paradigm that FOH is a specific feature of the PCOS status can no longer be sustained. We have shown that women with an exaggerated 17-hydroxyprogesterone response to a GnRH agonist, buserelin, are characterized by more severe hyperandrogenemia, glucose-stimulated beta-cell insulin secretion, and worse insulin resistance than those without evidence of FOH. Our data may be consistent with the hypothesis that excess insulin may represent a candidate factor responsible for FOH in these women, through the overactivation of the cytochrome P450 17alpha-hydroxylase/17,20-lyase (CYP17) enzyme pathway.

Topics: 17-alpha-Hydroxyprogesterone; Adolescent; Adult; Anthropometry; Blood Glucose; Buserelin; C-Peptide; Cosyntropin; Dexamethasone; Female; Glucose Tolerance Test; Gonadotropin-Releasing Hormone; Hormones; Humans; Hyperandrogenism; Insulin; Middle Aged; Ovarian Diseases; Phenotype; Polycystic Ovary Syndrome; Prospective Studies

A 60-year-old woman presented with diffuse scalp alopecia, hirsutism, and clitorimegaly, and the mean serum testosterone levels were greater than 200 ng/dL. Findings on computed tomography of both adrenal glands were normal. After bilateral oophorectomy, a unique histological picture consisting of diffuse stromal Leydig cell hyperplasia was found. Reinke crystals were present, but neither hilus cell hyperplasia nor stromal hyperthecosis was noted. Sequencing of the 11 exons of the gene for the luteinizing hormone receptor revealed no abnormality. Relevant data suggest that treatment of the postmenopausal woman with hyperandrogenism and virilization is bilateral laparoscopic oophorectomy if she has no pronounced ovarian enlargement or adrenal tumor on imaging. In this setting, an intensive endocrine evaluation or a search for metastatic disease seems to be unnecessary.

Topics: Cosyntropin; Diagnosis, Differential; Female; Gonadal Steroid Hormones; Humans; Hyperandrogenism; Hyperplasia; Leydig Cells; Male; Middle Aged; Postmenopause; Virilism

To evaluate whether ovarian function might have an influence on the adrenal hyperandrogenism present in patients with functional ovarian hyperandrogenism.. Controlled clinical study.. Tertiary institutional hospital.. Twenty-nine hirsute women with functional ovarian hyperandrogenism and 12 normal controls.. The ACTH and GnRH tests were performed before and during triptorelin-induced ovarian suppression in patients. The normal women served as controls for the ACTH test.. Basal and ACTH-stimulated steroid values.. All patients presented elevated T and free androgen index, which normalized after triptorelin. Patients with functional ovarian hyperandrogenism and adrenal hyperandrogenism, defined by elevated basal DHEAS (n = 10), presented enhanced delta 4-17, 20-lyase activity, which persisted during ovarian suppression. delta 4-17,20-lyase activity was normal in the functional ovarian hyperandrogenism patients without adrenal hyperandrogenism (n = 19). No correlation was observed between the any of the indexes of the adrenal enzymatic activities evaluated and plasma E2 or T.. Increased adrenal delta 4-17,20-lyase activity is present in functional ovarian hyperandrogenism women with adrenal hyperandrogenism. No influence of the excess ovarian androgens or estrogens was found on any of the adrenal enzymatic pathways explored.

Topics: Adolescent; Adrenocortical Hyperfunction; Adult; Androgens; Cohort Studies; Cosyntropin; Delayed-Action Preparations; Female; Follicular Phase; Gonadotropin-Releasing Hormone; Humans; Hyperandrogenism; Luteolytic Agents; Ovarian Diseases; Reference Values; Steroid 17-alpha-Hydroxylase; Steroids; Triptorelin Pamoate

Many women with androgen excess demonstrate elevated circulating insulin levels independent of obesity. In addition, in these women some investigators have demonstrated a negative correlation between the circulating levels of the adrenal androgens, dehydroepiandrosterone or dehydroepiandrosterone sulfate and insulin. The mechanism by which insulin decreases adrenal androgens is unclear. The objective of this study was to determine whether chronic hyperinsulinemia in hyperandrogenic women results in an alteration in the adrenocortical response to corticotropin, resulting in decreased androgen secretion.. We studied seven hyperandrogenic women with severe chronic hyperinsulinemia and eight hyperandrogenic normoinsulinemic patients. Nine healthy women served as controls for the basal hormonal levels and the response to a 3-hour, 100 gm oral glucose tolerance test. In all subjects insulin and glucose were measured hourly during the oral glucose tolerance test and the baseline sample was assayed for total testosterone, dehydroepiandrosterone sulfate, dehydroepiandrosterone, androstenedione, sex hormone-binding globulin, and free testosterone. In hyperandrogenic women cortisol, dehydroepiandrosterone, and androstenedione were also measured, before and 60 minutes, after acute intravenous administration of 0.25 mg corticotropin (1-24).. There was no difference in the response of cortisol, dehydroepiandrosterone, or androstenedione to corticotropin-(1-24) stimulation between normoinsulinemic and hyperinsulinemic hyperandrogenic patients. As defined, the hyperinsulinemic patients had higher basal and peak insulin levels and areas under the insulin response curve compared with the normoinsulinemic patients or controls. Total testosterone and dehydroepiandrosterone did not differ among study groups. As expected, hyperandrogenic patients demonstrated lower sex hormone-binding globulin activity and higher free testosterone, androstenedione, and dehydroepiandrosterone sulfate basal levels compared with controls.. The results of this study do not support the hypothesis that chronic hyperinsulinemia in hyperandrogenic patients significantly inhibits the andrenocortical secretion of dehydroepiandrosterone or androstenedione in response to corticotropin stimulation or the basal circulating adrenal androgen levels. Additional studies, including a greater number of patients, may be needed to fully establish these conclusions.

Topics: Adrenal Cortex; Adult; Analysis of Variance; Androgens; Blood Glucose; Chronic Disease; Cosyntropin; Female; Glucose Tolerance Test; Humans; Hydrocortisone; Hyperandrogenism; Hyperinsulinism; Insulin; Peptide Fragments; Sex Hormone-Binding Globulin

Some investigators have suggested that "dysregulation" of cytochrome P450c17 alpha may result in the exaggerated secretion of ovarian androgens in hyperandrogenism. Although the majority of hyperandrogenic (HA) patients demonstrate an ovarian source for their androgens, approximately 50% also display adrenocortical hyperactivity and adrenal androgen excess. To determine whether 17-hydroxylase (17-OH) and/or 17,20-lyase dysregulation is responsible for the adrenocortical abnormalities noted in many HA patients, we studied 92 consecutive women with hirsutism and/or HA oligomenorrhea; 26 healthy eumenorrheic nonhirsute women served as controls. The basal levels of total and free testosterone (T), sex hormone-binding globulin, and dehydroepiandrosterone sulfate were measured, and pregnenolone, 17-hydroxypregnenolone, progesterone, 17-hydroxyprogesterone, dehydroepiandrosterone, and androstenedione were measured 0 and 60 min after the acute iv administration of ACTH-(1-24). Controls and HA patients did not differ in mean age or body mass, but HA women had higher basal T, free T, dehydroepiandrosterone sulfate, androstenedione, and LH/FSH and lower sex hormone-binding globulin levels. The mean estimated basal 17-OH activity was higher among HA patients than in controls. Although 52 HA patients demonstrated solely an exaggerated basal delta 5-17-OH activity estimate, few HA patients had an exaggerated estimate for either basal delta 4-17-OH or ACTH-stimulated 17-OH activity. No HA patient demonstrated an exaggerated 17,20-lyase basal activity, whereas 14 demonstrated an exaggerated delta 4-17,20-lyase ACTH-stimulated activity only. There was no association between these estimates of 17-OH and 17,20-lyase activities and the circulating adrenal androgen levels in HA women. Importantly, none of the patients demonstrated an increase in the basal activities of both 17-OH and 17,20-lyase, and only 4 patients demonstrated an exaggerated ACTH-stimulated activity of both 17-OH and 17,20-lyase. In conclusion, the steroidogenic profile observed in this population of HA women before and after ACTH-(1-24) stimulation is not consistent with dysregulation of cytochrome P450c17 alpha and probably represents a generalized alteration of adrenocortical control or biosynthesis.

Topics: Adrenal Glands; Adult; Aldehyde-Lyases; Androgens; Cosyntropin; Cytochrome P-450 Enzyme System; Female; Humans; Hyperandrogenism; Incidence; Peptide Fragments; Reference Values; Steroid 17-alpha-Hydroxylase

To determine whether the ovary influences adrenal androgen secretion in polycystic ovary syndrome (PCOS).. The adrenal androgen secretion was evaluated before and during ovarian suppression with a long-acting GnRH agonist.. Department of Obstetrics and Gynecology, Pisa, Italy.. Women with PCOS and high (10 subjects) and normal (12 subjects) DHEAS levels and 6 normal women.. After 1 mg dexamethasone, an ACTH-(1-24) stimulation test was performed in the early follicular phase of the menstrual cycle. The test was repeated after two injections of a long-acting GnRH analogue (GnRH-a).. Basal plasma levels of gonadotropins, E2, T, androstenedione (A), 17 alpha-hydroxyprogesterone (17-OHP), DHEAS, and cortisol (F) were evaluated before the evening administration of dexamethasone. Serum A, T, 17-OHP, DHEAS, and F were measured 9 hours after dexamethasone and in samples collected 60 and 120 minutes after ACTH IV injection.. In the high DHEAS group the maximum increases in T, A, 17-OHP, and DHEAS in response to ACTH were significantly higher than in normal DHEAS PCOS women and in normal women. The GnRH-a modified the A and T responses to ACTH in the high DHEAS group.. Ovarian steroids, or other extra-ovarian factors, seem to be responsible for the increased A and T responses to the corticotropin stimulation demonstrated in some PCOS women.

Topics: Adolescent; Adrenal Glands; Adult; Androgens; Cosyntropin; Dexamethasone; Female; Gonadotropin-Releasing Hormone; Humans; Hyperandrogenism; Ovary; Peptide Fragments; Polycystic Ovary Syndrome

Our purpose was to establish the incidence of point mutations of the 21-hydroxylase gene (CYP21) in hyperandrogenic women with and without a 17-hydroxyprogesterone response to corticotropin stimulation above normal but below those levels associated with nonclassic adrenal hyperplasia.. We studied 22 patients with hirsutism or hyperandrogenic oligoovulation: eight with an exaggerated net increase in 17-hydroxyprogesterone (i.e., change in 17-hydroxyprogesterone between 8.8 and 36 nmol/L) and 14 with a normal change in 17-hydroxyprogesterone. Large deletions of the 21-hydroxylase gene were evaluated by laser densitometry. Point mutations were detected with the polymerase chain reaction and dot blot hybridization analysis and included 30 Leu, intron-2 (G), 8 bp deletion exon-3, 172 Asn, 236-237-239 exon-6, 281 Leu, 318 stop, 339 His, 341 Trp, 356 Trp, and 453 Ser.. Four patients with an increase in 17-hydroxyprogesterone carried a 281 Leu mutation, one patient had an intron-2 (G) mutation, and one had a complete deletion of CYP21. Only two of these patients demonstrated no obvious abnormality of CYP21. In contrast, only one of the control patients demonstrated a CYP21 abnormality, a significant difference (p < 0.001).. These findings suggest that the majority of hyperandrogenic women with an exaggerated 17-hydroxyprogesterone response to corticotropin stimulation are heterozygotes (carriers) for inherited defects of CYP21. Whether these mutations are incidental to the androgen excess or predispose to the development of this disorder remains to be determined.

Topics: 17-alpha-Hydroxyprogesterone; Adrenal Glands; Adult; Case-Control Studies; Cosyntropin; Female; Heterozygote; Hirsutism; Humans; Hydroxyprogesterones; Hyperandrogenism; Mutation; Oligomenorrhea; Peptide Fragments; Point Mutation; Steroid 21-Hydroxylase