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Biomedical subjects

R Azziz

Publications and source records attributed to R Azziz.

At least 55 records · Page 3Linked to original sources
PubMed1999

Prevalence of polycystic ovary syndrome in women seeking treatment from community electrologists. Alabama Professional Electrology Association Study Group.

OBJECTIVE: To determine the prevalence of the polycystic ovary syndrome (PCOS) among women seeking electrology, clients presenting to nine electrology centers completed a questionnaire. STUDY DESIGN: Women with potential risk factors were referred to the University of Alabama at Birmingham. They underwent a detailed history and physical examination, including hirsutism scoring by a modified Ferriman-Gallwey (F-G) method. Serum was assayed for total testosterone, sex hormone binding globulin and dehydroepiandrosterone sulfate. RESULTS: Three hundred fifteen (40%) of 779 patients had potential risk factors for hyperandrogenism and were referred. Eighty-two (26%) completed their evaluation. Six were excluded secondary to prepubertal or menopausal status. Of the remaining 76 patients, 20% had F-G scores of 7 or 8, 13% had scores of 9 or 10, and 21% had scores > 10. Forty-nine (64%) patients reported irregular menstrual cycles. Sixty-four patients were not receiving hormonal therapy: 25 reported regular menstrual cycles, and 39 reported irregular cycles. Seventeen (68%) of the 25 had at least one abnormal androgen value, while 33 (85%) of the 39 women had at least one abnormal value (nonsignificant difference). Overall, PCOS was evident in 39 of the 76 women, or 12% of the 315 patients who were referred for further evaluation. CONCLUSION: Thirty-nine of the 315 referred patients (12%) fulfilled the diagnostic criteria for PCOS. However, they were not receiving medical care for this condition. In addition, this percentage is a conservative estimate in that 74% of the referred patients did not pursue a medical evaluation. Therefore, efforts to educate both electrologists and their clients of the possibility of underlying endocrine disorders and subsequent metabolic morbidity should be undertaken.

Adult↗
PubMed1998

Identification and characterization of cytosolic sulfotransferases in normal human endometrium.

Understanding the factors which alter estrogen metabolism and activity in endometrial tissue is important because unopposed estrogen stimulation is an important risk factor in the development of endometrial carcinoma. The cyclic progression of the endometrium through proliferative and secretory phases is normally under the control of the ovarian hormones beta-estradiol (E2) and progesterone. One mechanism by which progesterone inhibits the activity of E2 in secretory endometrium is by elevating the degree of E2 sulfation, thereby reducing its ability to bind to the estrogen receptor and elicit a cellular response. Our laboratories have investigated the cytosolic sulfotransferases (STs) found in biopsies of both proliferative and secretory endometrium obtained from five normal pre-menopausal women who were not taking any drugs or steroids. Two of the human cytosolic STs were detected in human endometrial tissues. The phenol-sulfating form of phenol ST (P-PST) was found at varying levels in cytosol from both proliferative and secretory endometrium in all of the women studied but with no consistent correlation to the phase of the menstrual cycle. In contrast, estrogen ST (EST) was not detected in the proliferative endometrial cytosol of any of the women studied but was consistently found in all of the secretory endometrial cytosols. The presence and levels of these STs was confirmed by ST activity studies, immunoblot analysis and Northern blot analysis. These results indicate that the expression of EST in human endometrial tissues varies with the phase of the menstrual cycle and is most likely regulated by progesterone secreted from the ovaries.

Adult↗
PubMed1998

Measurement of total serum testosterone levels using commercially available kits: high degree of between-kit variability.

OBJECTIVE: The measurement of total serum testosterone has an established clinical role in the management of male hypogonadism and female androgen excess disorders. We studied the between-kit variability and precision of six different commercially available testosterone assays and compared them with an established in-house method. DESIGN: Laboratory observational prospective study. SETTING: Tertiary university medical center clinical laboratory. PATIENT(S): Three groups of samples each of men (n = 36) and women (n = 15) who had high, normal, or low levels of sex hormone-binding globulin (SHBG), respectively, were studied. INTERVENTION(S): Individual and pooled (male and female) serum samples were analyzed for total testosterone concentration using six different commercially available assays and one in-house method. MAIN OUTCOME MEASURE(S): The between-kit variability and the effect of the mean (+/- SD) SHBG level were determined, the results obtained with the use of the kits and the in-house method were compared, and the intraassay variability (i.e., precision) was evaluated. RESULT(S): Male samples demonstrated a 26.3%-40.8% variance in the results obtained with different kits, which was greatest for samples with the lowest SHBG levels. For female samples, between-kit variability ranged from 57%-115% (average, 77%). The percent deviation of the results obtained with the use of commercial methods from those obtained with the use of our in-house assay was greater for men (mean variance, 194%) than for women (mean variance, 67%). The female pool intraassay coefficient of variation was 3.8% with the use of the in-house method and ranged from 8.9%-21.2% with the use of the commercial kits. The male pool intraassay coefficient of variation was 3.1% with the use of the in-house method and ranged from 3.3%-5.5% with the use of the commercial kits. CONCLUSION(S): Most commercially available kits for measuring the total serum testosterone level demonstrated significant between-kit variability, which was greatest for female samples. Further, samples with the lowest SHBG levels had the highest between-kit variances. These data strongly suggest that the measurement of total serum testosterone using commercial kits may have limited utility, particularly for the detection of hyperandrogenemia.

Cohort Studies↗
PubMed1998

Role of the ovary in the adrenal androgen excess of hyperandrogenic women.

OBJECTIVE: To test the hypothesis that ovarian hormones in women with hyperandrogenism alter adrenocortical steroidogenesis. DESIGN: Combination of two prospective studies. SETTING: Academic medical centers. PATIENT(S): Eighteen hyperandrogenic patients demonstrating hirsutism with either hyperandrogenemia, oligomenorrhea, or both. Eighteen healthy nonhirsute eumenorrheic untreated women served as controls. INTERVENTIONS: Blood sampling basally and after acute adrenal stimulation with ACTH, before and after 20-24 weeks of leuprolide administration. Nine patients also received 0.625 mg/d of oral conjugated esterified estrogens and 10 mg of medroxyprogesterone acetate days 1-12 of the month (i.e., estrogen replacement therapy [ERT]), whereas the remaining nine did not. MAIN OUTCOME MEASURE(S): Before and after the administration of the GnRH agonist (GnRH-a), the basal concentrations of DHEAS; and the levels of androstenedione (A4), DHEA, androstenediol, 11 beta-hydroxyandrostenedione (11-OHA4), and cortisol before and 60 minutes after acute adrenal stimulation, were measured. RESULT(S): Levels of DHEAS, androstenediol, and 11-OHA4 decreased by 15%-30%, regardless of whether patients initially had or did not have DHEAS excess. However, only hyperandrogenic patients with elevated levels of DHEAS showed a significant decrease in basal DHEA levels. No statistically significant difference in the response of either androgen to ACTH (1-24) stimulation was noted with ovarian suppression, regardless of initial DHEAS level or use of ERT. CONCLUSION(S): We found no evidence that ovarian hormone secretion affected adrenal steroidogenesis, and those women with the highest adrenal androgen levels had the least response to GnRH-a suppression. These findings further support the concept of an intrinsic, and possibly primary, abnormality of adrenocortical steroidogenesis in a subset of hyperandrogenic women that is independent of ovarian abnormalities.

Adolescent↗
PubMed1998

Idiopathic hirsutism: an uncommon cause of hirsutism in Alabama.

OBJECTIVE: To determine the prevalence of idiopathic hirsutism among a population of consecutive hirsute patients. DESIGN: Prospective cohort study. SETTING: University-based clinic. PATIENT(S): Premenopausal women with a complaint of hirsutism who were not receiving hormonal therapy. INTERVENTION(S): Evaluations for total and free testosterone, (T), 17-hydroxyprogesterone (17-HP), and DHEAS serum levels. MAIN OUTCOME MEASURE(S): Ovulatory function in women with cycles of < or =35 days in length was assessed with a basal body temperature (BBT) calendar and day 22-24 progesterone levels. RESULT(S): Of 132 consecutive hirsute women studied, 68 had cycles of >35 days in length. Of the remaining 64 patients, 25 also had oligo/anovulation by BBT and day 22-24 progesterone level. Of the 39 patients with hirsutism and regular ovulatory function, 22 had total and free T and DHEAS levels within normal limits. CONCLUSION(S): If idiopathic hirsutism is defined by the presence of hirsutism, regular ovulation, and normal androgen levels, only 17% of consecutive hirsute patients can be diagnosed with the disorder. Alternatively, if idiopathic hirsutism is based solely on the presence of hirsutism and regular ovulation, regardless of androgen levels, then 29% of the total hirsute population can be considered as having idiopathic hirsutism. Importantly, 40% of hirsute patients with a history of "regular cycles" were actually oligo/anovulatory, indicating the need to objectively assess ovulatory function in such patients.

Adolescent↗
PubMed1998

The effect of 17 beta-estradiol on adrenocortical sensitivity, responsiveness, and steroidogenesis in postmenopausal women.

Aging in women is associated with reduced production of adrenal androgens (AAs); this decrease may in part be the result of menopausal hypoestrogenism. To determine the effects of physiological concentrations of estradiol (E2) on adrenocortical sensitivity and responsiveness in postmenopausal women, we determined steroid responses to a continuous incremental ACTH-(1-24) infusion (0, 20, 40 80, 160, 320, 640, and 1280 ng/1.5 m2/h), followed by an ACTH-(1-24) bolus of 0.25 mg, after overnight dexamethasone suppression before and after 3 months of E2 therapy (transdermal E2, 0.05 mg/day) in 14 postmenopausal women. After E2 treatment, subjects demonstrated an increase in serum E2 concentrations from 29.8 +/- 2.6 to 49.9 +/- 6.0 pg/mL (P < 0.005) and a decline in mean FSH levels from 83.1 +/- 24.4 to 57.5 +/- 17.3 mIU/mL (P < 0.004). E2 administration had no effect on basal, postdexamethasone, or maximally stimulated serum levels of cortisol (F), dehydroepiandrosterone (DHEA), androstenedione (A4), or 17-hydroxyprogesterone (17-OHP). Furthermore, E2 did not affect adrenal sensitivity or responsiveness to ACTH-(1-24) stimulation. Finally, the steroid ratios reflecting 3 beta-hydroxysteroid dehydrogenase (i.e. the A4/DHEA ratio) and delta 417,20-lyase (i.e. the A4/17-OHP ratio) activities also were unaffected by E2 therapy. The responsiveness of F to ACTH was significantly greater than that of DHEA, A4, or 17-OHP regardless of the circulating E2 levels. Furthermore, F and A4 were significantly more sensitive to ACTH stimulation than were 17-OHP and DHEA, and this was not altered by E2 administration. We conclude that transdermal E2 replacement to postmenopausal women does not significantly alter AA sensitivity or responsiveness to ACTH. Hence, it is unlikely that the hypoestrogenism of menopause contributes to the decline in AAs noted with age. Furthermore, menopausal estrogen replacement, at least in physiological amounts administered transdermally, cannot be expected to reverse the suppressed production of these androgens.

17-alpha-Hydroxyprogesterone↗
PubMed1998

Development of a health-related quality-of-life questionnaire (PCOSQ) for women with polycystic ovary syndrome (PCOS).

OBJECTIVE: To develop a self-administered questionnaire for measuring health-related quality of life (HRQL) in women with polycystic ovary syndrome (PCOS). METHODS: We identified a pool of 182 items potentially relevant to women with PCOS through semistructured interviews with PCOS patients, a survey of health professionals who worked closely with PCOS women, and a literature review. One hundred women with PCOS completed a questionnaire in which they told us whether the 182 items were relevant to them and, if so, how important the issue was in their daily lives. We included items endorsed by at least 50% of women in the analysis plus additional items considered crucial by clinicians and an important subgroup of patients in a factor analysis. We chose items for the final questionnaire taking into account both item impact (the frequency and importance of the items) and the results of the factor analysis. RESULTS: Over 50% of the women with PCOS labelled 47 items as important to them. Clinicians chose 5 additional items from the infertility domain, 4 of which were identified as important by women who were younger, less educated, married, and African-American. The Cattell's Scree plot from a factor analysis of these 51 items suggested 5 factors that made intuitive sense: emotions, body hair, weight, infertility, and menstrual problems. We chose the highest impact items from these 5 domains to construct a final questionnaire, the Polycystic Ovary Syndrome Questionnaire (PCOSQ), which includes a total of 26 items and takes 10-15 minutes to complete. CONCLUSIONS: We have used established principles to construct a questionnaire that promises to be useful in measuring health-related quality of life. The questionnaire should be tested prior to, or concurrent with, its use in randomized trials of new treatment approaches.

Adult↗
PubMed1998

Adrenal androgen excess in the polycystic ovary syndrome: sensitivity and responsivity of the hypothalamic-pituitary-adrenal axis.

Over 50% of patients with the polycystic ovary syndrome (PCOS) demonstrate excess levels of adrenal androgens (AAs), particularly dehydroepiandrosterone sulfate (DHS). Nonetheless, the mechanism for the AA excess remains unclear. It has been noted that in PCOS the pituitary and ovarian responses to their respective trophic factors (i.e. GnRH and LH, respectively) are exaggerated. Similarly, we have postulated that excess AAs in PCOS arises from dysfunction of the hypothalamic-pituitary-adrenal axis, due to 1) exaggerated pituitary secretion of ACTH in response to hypothalamic CRH, 2) excess sensitivity/responsivity of AAs to ACTH stimulation, or 3) both. To test this hypothesis we studied 12 PCOS patients with AA excess (HI-DHS; DHS, > 8.1 mumol/L or 3000 ng/mL), 12 PCOS patients without AA excess (LO-DHS; DHS, < 7.5 mumol/L or 2750 ng/mL), and 11 controls (normal subjects). Each subject underwent an acute 90-min ovine CRH stimulation test (1 microgram/kg) and an 8-h incremental i.v. stimulation with ACTH-(1-24) at doses ranging from 20-2880 ng/1.5 m2.h) with a final bolus of 0.25 mg. All patient groups had similar mean body mass indexes and ages, and both tests were performed in the morning during the follicular phase (days 3-10) of the same menstrual cycle, separated by 48-96 h. During the acute ovine CRH stimulation test, no significant differences in the net maximal response (i.e. change from baseline to peak level) for ACTH, dehydroepiandrosterone (DHA), androstenedione (A4), or cortisol (F) or for the DHA/ACTH, A4/ACTH, or F/ACTH ratios was observed. Nonetheless, the net response of DHA/F and the areas under the curve (AUCs) for DHA and DHA/F indicated a greater response for HI-DHS vs. LO-DHS or normal subjects. The AUC for A4 and A4/F and the delta A4/delta F ratio (delta = net maximum change) indicated that HI-DHS and LO-DHS had similar responses, which were greater than that of the normal subjects, although the difference between LO-DHS patients and normal subjects reached significance only for the AUC of the A4 response. No difference in the sensitivity (i.e. threshold or minimal stimulatory dose) to ACTH was noted between the groups for any of the steroids measured. Nonetheless, the average dose of ACTH-(1-24) required for a threshold response was higher for DHA than for F and A4 in all groups. No difference in mean responsivity (slope of response to incremental ACTH stimulation) was observed for DHA and F between study groups, whereas the responsivity of A4 was higher in HI-DHS patients than in normal or LO-DHS women. The net maximal and the overall (i.e. AUC) responses of DHA were greater for HI-DHS than for normal or LO-DHS women. The response of A4 and the delta A4/delta F ratio were greater for HI-DHS patients than for LO-DHS patients or normal subjects. Alternatively, HI-DHS and LO-DHS patients had similar overall responses (i.e. AUC) for A4 or A4/F, although both were greater than those of normal subjects. The relative differences in response to incremental ACTH stimulation between steroids was consistent for all subject groups studied, i.e. A4 > F or DHA. In conclusion, our data suggest that AA excess in PCOS patients is related to an exaggerated secretory response of the adrenal cortex for DHA and A4, but not to an altered pituitary responsivity to CRH or to increased sensitivity of these AAs to ACTH stimulation. Whether the increased responsivity to ACTH for these steroids is secondary to increased zonae reticularis mass or to differences in P450c17 alpha activity, particularly of the delta 4 pathway, remains to be determined.

Adrenal Cortex Hormones↗
PubMed1998

Androgen response to hypothalamic-pituitary-adrenal stimulation with naloxone in women with myotonic muscular dystrophy.

Myotonic muscular dystrophy (MMD) is a disease of autosomal dominant inheritance characterized by multisystem disease, including myotonia, muscle-wasting and weakness of all muscular tissues, and endocrine abnormalities attributed to a genetic abnormality causing a defective cAMP-dependent kinase. We have previously reported that MMD patients demonstrate ACTH hypersecretion after endogenous CRH release stimulated by naloxone administration while manifesting a normal cortisol (F) response. Additionally, others have reported a reduced adrenal androgen (AA) response to exogenous ACTH administration in MMD patients. As ACTH stimulates the secretion of both AAs and F, it is possible that the discordant relationship of these hormones in MMD patients results from a defect of adrenocortical ACTH receptor function or postreceptor signaling or subsequent biochemical events. Furthermore, the molecular abnormality seen in MMD patients may suggest that the mechanism underlying the frequently observed discordances in the secretion of glucocorticoids and AAs (e.g. adrenarche, surgical trauma, severe burns, or intermittent glucocorticoid administration) are explainable solely via an alteration in the function of the ACTH receptor or postreceptor signaling. To ascertain whether the responses of F and AAs to endogenous ACTH diverged in this disorder, we prospectively studied the responses of these hormones to naloxone-stimulated CRH release in nine premenopausal women with MMD and seven healthy age and weight-matched control women. After naloxone infusion (125 micrograms/kg, i.v.), blood sampling was performed at baseline (i.e. -5 min) and at 30 and 60 min. In addition to the absolute hormone level at each time, we calculated the net increment (i.e. change) at 30 and 60 min and the area under the curve (AUC) for F, ACTH, dehydroepiandrosterone (DHA), and androstenedione (A4). Consistent with our previous study, MMD patients demonstrated higher ACTH levels at all sampling times except [minud]5 min. AUC analysis revealed the ACTHAUC values were significantly higher in MMD than in control women (457 +/- 346 vs. 157 +/- 123 pmol/min.L; P < 0.03), whereas the FAUC response did not differ between MMD and controls (13860 +/- 3473 vs. 13375 +/- 3465 nmol/min.L; P > 0.5). Despite the greater ACTH secretion, the baseline circulating dehydroepiandrosterone sulfate levels were significantly lower in MMD compared with control women (18 +/- 23 vs. 61 +/- 23 mumol/L; P < 0.002). The serum concentrations of A4 at baseline, 30 min, and 60 min and DHA levels at 30 and 60 min were also significantly lower in MMD vs. control women. Additionally, the A4AUC and DHAAUC values were significantly lower in MMD patients than in controls. Furthermore, the net response of DHA at 60 min to the endogenous ACTH increase was also reduced in MMD patients compared with that in control subjects (2.3 +/- 2.1 vs. 5.6 +/- 2.6 nmol/L; P < 0.02). In conclusion, in addition to ACTH hypersecretion to CRH-mediated stimuli, these data suggest that MMD patients have a defect in the adrenocortical response to ACTH, reflected in normal F and reduced DHA and A4 secretion. Whether this defect is inherent to the disease or simply reflects adaptive changes to chronic disease remains to be demonstrated. However, it is possible that further studies of the response of MMD patients to ACTH may reveal a mechanism that explains the frequently observed dichotomy in the secretion of glucocorticoids and AAs.

Adrenal Cortex↗
PubMed1998

Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study.

Estimates of the prevalence of the polycystic ovary syndrome (PCOS) in the general population have ranged from 2-20%. The vast majority of these reports have studied White populations in Europe, used limited definitions of the disorder, and/or used bias populations, such as those seeking medical care. To estimate the prevalence of this disorder in the United States and address these limitations, we prospectively determined the prevalence of PCOS in a reproductive-aged population of 369 consecutive women (174 White and 195 Black; aged 18-45 yr), examined at the time of their preemployment physical. Body measures were obtained, and body hair was quantified by a modified Ferriman-Gallwey (F-G) method. All exams were initially performed by 2 trained nurses, and any subject with an F-G score above 3 was reexamined by a physician, the same for all patients. Of the 369 women, 277 (75.1%) also agreed to complete a questionnaire and have additional blood drawn. Subjects were studied regardless of current estrogen/progestin hormonal use (28.5%). PCOS was defined as 1) oligoovulation, 2) clinical hyperandrogenism (i.e. hirsutism) and/or hyperandrogenemia, and 3) exclusion of other related disorders, such as hyperprolactinemia, thyroid abnormalities, and non-classic adrenal hyperplasia. Hirsutism was defined by a F-G score of 6 or more, and hyperandrogenemia was defined as a total or free testosterone, androstenedione, and/or dehydroepiandrosterone sulfate level above the 95th percentile of control values [i.e. all eumenorrheic women in the study, who had no hirsutism (F-G < or = 5) or acne and were receiving no hormonal therapy; n = 98]. Considering all 369 women studied, White and Black women had similar mean ages (29.4 +/- 7.1 and 31.1 +/- 7.8 yr, respectively), although White women had a lesser body mass than Black women (24.9 +/- 6.1 vs. 29.2 +/- 8.1 kg/m2, respectively; P < 0.001). Of these 7.6%, 4.6%, and 1.9% demonstrated a F-G score of 6 or more, 8 or 10, respectively, and there was no significant racial difference, with hirsutism prevalences of 8.0%, 2.8%, and 1.6% in Whites, and 7.1%, 6.1%, and 2.1% in Blacks, respectively. Of the 277 women consenting to a history and hormonal evaluation, 4.0% had PCOS as defined, 4.7% (6 of 129) of Whites and 3.4% (5 of 148) of Blacks. In conclusion, in our consecutive population of unselected women the prevalence of hirsutism varied from 2-8% depending on the chosen cut-off F-G score, with no significant difference between White and Black women. Using an F-G score of 6 or more as indicative of hirsutism, 3.4% of Blacks and 4.7% of Whites had PCOS as defined. These data suggest that PCOS may be one of most common reproductive endocrinological disorders of women.

Acne Vulgaris↗
PubMed1998

Differential binding of estradiol and testosterone to SHBG. Relation to circulating estradiol levels.

OBJECTIVE: Sex hormone-binding globulin (SHBG) binds testosterone (T) to a greater degree than it does estradiol (E2), acting as an amplifier of E2 action. However, it is not known whether the relative capacity of SHBG for E2 vs. T is altered by the hormonal milieu. We hypothesized that an increase in circulating E2 levels results in a compensatory increase in the relative binding capacity of SHBG for these hormones, dampening the E2 amplification effect in hyperestrogenic conditions. STUDY DESIGN: Retrospective. RESULTS: As expected, during hMG stimulation there was a significant increase in total and free E2 (28 to 1,986 pg/mL, P < .001; and 0.3 to 20.8 pg/mL, P < .001, respectively) and total T levels (40.3 vs. 78.3 ng/dL, P < .001) from basal to late stimulation. Free T levels increased, but the difference did not reach significance. The binding capacity of SHBG for both E2 and T increased in a proportional manner (980 +/- 340 vs. 1,434 +/- 449 nmol/L, P < .009; and 352 +/- 190 vs. 512 +/- 128 nmol/L, P < .02; respectively) since the ratio of SHBG binding to E2 and T was unchanged. Although the SHBG molar concentration appeared increased, the difference did not reach significance (821 +/- 542 to 1,099 +/- 254 nmol/L). CONCLUSION: A short-term, although profound, increase in circulating E2 does not seem to be associated with an increase in the relative binding capacity of the carrier protein for either E2 or T, although an overall increase in binding for both steroids was observed. It is possible that longer periods of exposure to E2 may be necessary to demonstrate a change in the differential binding of this carrier protein with an alteration in the hormonal milieu.

Adult↗
PubMed1997

Prevalence of hyperandrogenemia among nonhirsute oligo-ovulatory women.

OBJECTIVE: To test the hypothesis that oligo-ovulatory ovulation is associated with hyperandrogenemia in the absence of other clinical signs of androgen excess. DESIGN: Retrospective cohort controlled. SETTING: Tertiary care university-based outpatient clinic. PATIENT(S): Thirty-two consecutive nonhirsute oligo-ovulatory women and 37 healthy eumenorrheic controls. INTERVENTION(S): All study subjects underwent a physical exam and blood sampling in the follicular phase of the menstrual cycle. MAIN OUTCOME MEASURE(S): Serum was assayed for total T, sex hormone-binding globulin (SHBG), androstenedione (A), and DS, and the free T level was calculated. RESULT(S): Mean free T was higher and SHBG was lower in oligo-ovulatory patients compared with controls. The oligo-ovulatory patients were subdivided according to severity of menstrual abnormalities into those with cycles < 45 days (n = 19, oligo-ovulatory-short) and > or = 45 days (n = 13, oligo-ovulatory-long). Oligo-ovulatory-long and -short patients had similar mean DS, A, and total T levels; but mean free T was higher and SHBG was lower in oligo-ovulatory-long patients compared with either oligo-ovulatory-short women or controls. Five of 13 (38%) oligo-ovulatory-long patients had at least one abnormal androgen value compared with 1 of 19 (5%) oligo-ovulatory-short patients, which was a significant difference. CONCLUSION(S): Approximately 40% of nonhirsute oligo-ovulatory women with cycle intervals > or = 45 days demonstrate at least one abnormally elevated androgen level, suggesting that they may have a discrete form of the polycystic ovary syndrome. Furthermore, this data brings into question the sensitivity of hirsutism as a marker for hyperandrogenemia.

Adult↗
PubMed1997

CYP11B1 mutations causing non-classic adrenal hyperplasia due to 11 beta-hydroxylase deficiency.

Steroid 11 beta-hydroxylase deficiency is the second most common cause of congenital adrenal hyperplasia, the inherited inability to synthesize cortisol. Severely affected patients carry mutations in the CYB11B1 gene that destroy enzymatic activity. Such patients have signs of androgen excess and usually have hypertension. Mild or non-classic 11 beta-hydroxylase deficiency has been reported previously but not studied genetically. In this study we report analysis of the CYP11B1 genes of three patients thought to suffer from non-classic 11 beta-hydroxylase deficiency. Mutations were detected in the CYP11B1 genes of two patients. One was a compound heterozygote for missense mutations N133H and T319M, whereas the other carried a nonsense mutation (Y423X) on one allele and a missense mutation (P42S) on the other. All three missense mutations affected enzymatic activity when expressed in vitro. No mutations were detected in the coding regions or intron-exon boundaries of the CYP11B1 genes of the other putative non-classic patient. In addition, we were unable to detect CYP11B1 mutations in two hirsute women with mildly elevated levels of 11 beta-hydroxylase precursors who had previously been identified in a screening study of patients in a reproductive endocrinology clinic. We conclude that nonclassic 11 beta-hydroxylase deficiency is a rare disorder. It is not a significant cause of hyperandrogenism in women and relatively stringent criteria should be used to prevent its misdiagnosis.

Adrenal Glands↗
PubMed1997

Impact of overnight dexamethasone suppression on the adrenal androgen response to an oral glucose tolerance test in women with and without polycystic ovary syndrome.

In order to test the hypothesis that adrenocortical overactivity, possibly related to the stress of testing, may impact on the measurement of circulating androgen concentrations during glucose-induced hyperinsulinaemia, we prospectively screened 10 patients with the polycystic ovary syndrome (PCOS) and nine healthy control women with an oral glucose tolerance test (OGTT), before and after the administration of dexamethasone. Blood sampling was performed at 0, 30, 60, 90, and 120 min following the oral ingestion of 75 g of glucose, before and after the administration of 1.0 mg dexamethasone on the evening prior to testing. Total and free testosterone, androstenedione, dehydroepiandrosterone (DHEA), DHEA sulphate (DHEAS), cortisol, glucose and insulin were assessed during the 2 h OGTT. Women with PCOS had increased basal concentrations of free testosterone, total testosterone, androstenedione, and insulin compared to control women. In women with PCOS an acute decline in circulating concentrations of DHEAS occurred during the OGTT. In PCOS women there were no changes in other ovarian or adrenal androgens during OGTT before or following dexamethasone administration. In control women DHEA concentrations declined during the OGTT. Following overnight dexamethasone suppression in control women, circulating concentrations of DHEAS and testosterone also declined. It is concluded that: (i) in PCOS women only the concentration of circulating DHEAS decreased during glucose-induced hyperinsulinaemia and dexamethasone administration did not further alter androgen responses to an OGTT; (ii) it is possible that, in these hyperandrogenic patients, the insulin-related suppression of adrenocortical testosterone and DHEA is negated by their much greater ovarian secretion of these androgens; (iii) in control women DHEA concentrations acutely declined during the OGTT and the administration of dexamethasone resulted in the acute decline of DHEA, DHEAS, and testosterone; (iv) it appears that the stress related to testing impacts on the androgen response to OGTT, at least in healthy women.

Adrenal Cortex↗
PubMed1997

Carriers of 21-hydroxylase deficiency are not at increased risk for hyperandrogenism.

A deficiency of 21-hydroxylase activity is one of the most commonly inherited genetic disorders in man, with heterozygosity for CYP21 mutations affecting approximately 1 in 60 of the non-Jewish Caucasian population. We have hypothesized that heterozygosity for CYP21 mutations in women increases their risk of developing clinically evident hyperandrogenism, and that this risk is related to the severity of the mutation of CYP21 and/or the 17-hydroxyprogesterone (17-OHP) response to ACTH stimulation. To test these hypotheses, we studied 38 obligate carriers for 21-hydroxylase deficiency (i.e. mothers of children with congenital adrenal hyperplasia or nonclassic congenital adreanl hyperplasia), comparing them to 27 weight-, parity-, and age-matched controls. Premenopausal carriers, not receiving hormonal treatment (n = 27), had higher mean total and free testosterone [T; 2.02 +/- 0.55 vs. 1.56 +/- 0.65 nmol/L (P < 0.007) and 0.018 +/- 0.007 vs. 0.012 +/- 0.006 nmol/L (P < 0.007), respectively] and lower mean sex hormone-binding globulin (214 +/- 62 vs. 277 +/- 129 nmol/L; P < 0.03) levels compared to controls. There was no difference in the mean basal levels of dehydroepiandrosterone sulfate, androstenedione (A4), or 17-OHP between carriers and controls. As expected, carriers exhibited higher stimulated and net increment 17-OHP levels than controls [21.1 +/- 27.1 vs. 6.2 +/- 3.1 nmol/L (P < 0.01) and 19.0 +/- 26.5 vs. 4.4 +/- 2.8 nmol/L (P < 0.009), respectively]. However, no difference was observed in the response of A4 to ACTH-(1-24) stimulation. Of the 27 carriers studied biochemically, 2 (7.4%) had a stimulated 17-OHP value between 30.3-60.6 nmol/L, and 1 (3.7%) had a 17-OHP level above 60.6 nmol/L, suggestive of nonclassic adrenal hyperplasia. Of all carriers studied genetically (n = 36), 50.0% (18 of 36) had 1, 33% (12 of 36) had 2, and 16.7% (6 of 36) had 3 or more mutations. In 27.8% (10 of 36) of carriers, the mutations were contiguous, consistent with a large gene conversion. All 38 carriers were examined for historical and physical features of hyperandrogenism. Hirsutism was defined as a Ferriman-Gallwey score of 6 or more, menstrual/ovulatory dysfunction as a history of menstrual cycles of more than 35-day, and hyperandrogenemia as total or free T, A4, and/or dehydroepiandrosterone sulfate levels above the upper 95th percentile of control values. Further, defining functional androgen excess (FAE) as the presence of at least 2 of the 3 hyperandrogenic features, 4 of 38 (10.5%) of carriers appeared to be affected (95% confidence interval, 2.9-24.8%). Assuming an expected prevalence rate of FAE in the general population of 5-20%, the frequency of FAE among our carriers was not significantly higher than expected. In conclusion, heterozygosity for CYP21 mutations does not appear to increase the risk of clinically evident hyperandrogenism, although carrying the defect was associated with higher mean and free T levels. Finally, due to the low frequency of androgen excess in our heterozygote population, we were unable to correlate the severity of the CYP21 mutation and/or the 17-OHP response to ACTH stimulation with the presence of the phenotype.

Adrenal Hyperplasia, Congenital↗