Steroid Screening Tools Differentiating Nonclassical Congenital Adrenal Hyperplasia and Polycystic Ovary Syndrome.

PURPOSE: To analyze the performance of basal 17OH-progesterone (17OHP) levels versus the basal 17OHP/cortisol ratio in nonclassical congenital adrenal hyperplasia (NCAH) and polycystic ovary syndrome (PCOS) differential diagnosis. Basal 17OHP levels >10 ng/mL have been used to confirm NCAH diagnosis without the adrenocorticotropic hormone (ACTH) test; however, the optimal cutoff value is a matter of debate. METHODS: A cross-sectional study was performed at the endocrinology and gynecological endocrinology outpatient clinics of a tertiary hospital. A total of 361 patients with PCOS (age 25.0 ± 5.3 years) and 113 (age 19.0 ± 13.6 years) patients with NCAH were enrolled. Basal and ACTH-17OHP levels were measured by radioimmunoassay, and CYP21A2 molecular analysis was performed to confirm hormonal NCAH diagnosis. Receiver operating characteristic curve analysis compared basal 17OHP levels and the 17OHP/cortisol ratio between NCAH and PCOS patients. RESULTS: Basal 17OHP levels were higher in NCAH patients than in those with PCOS (8.85 [4.20-17.30] vs 1.00 [0.70-1.50] ng/mL; P < 0.0001), along with 17OHP/cortisol ratio (0.86 [0.47-1.5]) vs 0.12 [0.07-0.19]; P < 0.0001, respectively). Basal 17OHP levels and the 17OHP/cortisol ratio were strongly correlated in both groups (rho = 0.82; P < 0.0001). Areas under the curves for basal 17OHP levels (0.9528) and the 17OHP/cortisol ratio (0.9455) were not different to discriminate NCAH and PCOS (P > 0.05). Basal 17OHP level >5.4 ng/mL and 17OHP/cortisol ratio >2.90 had 100% specificity to identify NCAH. MAIN CONCLUSIONS: Basal 17OHP levels >5.4 ng/mL can be used to perform differential diagnoses between NCAH and PCOS, dismissing the ACTH test. The basal 17OHP/cortisol ratio was not superior to basal 17OHP levels in this scenario.

Molecular CYP21A2 diagnosis in 480 Brazilian patients with congenital adrenal hyperplasia before newborn screening introduction.

BACKGROUND: Most congenital adrenal hyperplasia (CAH) patients carry CYP21A2 mutations derived from conversion events involving the pseudogene, and the remaining carry new mutations. OBJECTIVE: To review causal mutations and genotype-phenotype correlation in 480 Brazilian patients. METHODS: DNA was extracted from 158 salt-wasters (SWs), 116 simple virilizing (SV), and 206 nonclassical (NC) patients. Fourteen point mutations were screened by allele-specific PCR, large rearrangements by Southern blotting/MLPA, and sequencing was performed in those with incomplete genotype. The gene founder effect was analyzed by microsatellite studies. Patients were divided into six genotypes (Null; A: <2%; B: 3-7%; C: >20% of residual enzymatic activity (EA); D: unknown EA; E: incomplete genotype). RESULTS: Targeted methodologies defined genotype in 87.6% of classical and in 80% of NC patients and the addition of sequencing in 100 and 83.5%, respectively. The most frequent mutations were p.V281L (26.6% of alleles), IVS2-13A/C>G (21.1%), and p.I172N (7.5%); seven rare mutations and one novel mutation (p.E351V) were identified. Gene founder effect was observed in all but one (p.W19X) mutation. Null, A, B, and C genotypes correlated with SW (88%), SW (70%), SV (98%), and NC forms (100%), respectively. In group D, the p.E351V mutation correlated with classical form and group E comprised exclusively NC-patients. ACTH-stimulated 17OHP level of 44.3ng/mL was the best cutoff to identify NC-patients carrying severe mutations. CONCLUSIONS: We identified a good genotype-phenotype correlation in CAH, providing useful data regarding prediction of disease's severity; moreover, we suggest that ACTH-stimulated 17OHP levels could predict carrier status for severe mutations. Sequencing is essential to optimize molecular diagnosis in Brazilian CAH patients.

Association of glucocorticoid receptor polymorphisms with clinical and metabolic profiles in polycystic ovary syndrome.

OBJECTIVES: We aimed to investigate whether glucocorticoid receptor gene polymorphisms are associated with clinical and metabolic profiles in patients with polycystic ovary syndrome. Polycystic ovary syndrome is a complex endocrine disease that affects 5-8% of women and may be associated with metabolic syndrome, which is a risk factor for cardiovascular disease. Cortisol action and dysregulation account for metabolic syndrome development in the general population. As glucocorticoid receptor gene (NR3C1) polymorphisms regulate cortisol sensitivity, we hypothesized that variants of this gene may be involved in the adverse metabolic profiles of patients with polycystic ovary syndrome. METHOD: Clinical, metabolic and hormonal profiles were evaluated in 97 patients with polycystic ovary syndrome who were diagnosed according to the Rotterdam criteria. The alleles of the glucocorticoid gene were genotyped. Association analyses were performed using the appropriate statistical tests. RESULTS: Obesity and metabolic syndrome were observed in 42.3% and 26.8% of patients, respectively. Body mass index was positively correlated with blood pressure, triglyceride, LDL-c, total cholesterol, glucose and insulin levels as well as HOMA-IR values and inversely correlated with HDL-c and SHBG levels. The BclI and A3669G variants were found in 24.7% and 13.4% of alleles, respectively. BclI carriers presented a lower frequency of insulin resistance compared with wild-type subjects. CONCLUSION: The BclI variant is associated with a lower frequency of insulin resistance in women with polycystic ovary syndrome. Glucocorticoid gene polymorphism screening during treatment of the syndrome may be useful for identifying subgroups of at-risk patients who would benefit the most from personalized treatment.

Association of glucocorticoid receptor polymorphisms with clinical and metabolic profiles in polycystic ovary syndrome

OBJECTIVES: We aimed to investigate whether glucocorticoid receptor gene polymorphisms are associated with clinical and metabolic profiles in patients with polycystic ovary syndrome. Polycystic ovary syndrome is a complex endocrine disease that affects 5-8% of women and may be associated with metabolic syndrome, which is a risk factor for cardiovascular disease. Cortisol action and dysregulation account for metabolic syndrome development in the general population. As glucocorticoid receptor gene (NR3C1) polymorphisms regulate cortisol sensitivity, we hypothesized that variants of this gene may be involved in the adverse metabolic profiles of patients with polycystic ovary syndrome. METHOD: Clinical, metabolic and hormonal profiles were evaluated in 97 patients with polycystic ovary syndrome who were diagnosed according to the Rotterdam criteria. The alleles of the glucocorticoid gene were genotyped. Association analyses were performed using the appropriate statistical tests. RESULTS: Obesity and metabolic syndrome were observed in 42.3% and 26.8% of patients, respectively. Body mass index was positively correlated with blood pressure, triglyceride, LDL-c, total cholesterol, glucose and insulin levels as well as HOMA-IR values and inversely correlated with HDL-c and SHBG levels. The BclI and A3669G variants were found in 24.7% and 13.4% of alleles, respectively. BclI carriers presented a lower frequency of insulin resistance compared with wild-type subjects. CONCLUSION: The BclI variant is associated with a lower frequency of insulin resistance in women with polycystic ovary syndrome. Glucocorticoid gene polymorphism screening during treatment of the syndrome may be useful for identifying subgroups of at-risk patients who would benefit the most from personalized treatment. .

A premenopausal woman with virilization secondary to an ovarian Leydig cell tumor.

BACKGROUND: A 33-year-old woman presented to an endocrinology clinic with a 5-year history of secondary amenorrhea. 2 years before presentation, she had noticed progressively worsening signs of virilization. INVESTIGATIONS: Measurement of levels of serum free and total testosterone, androstenedione, dehydroepiandrosterone sulfate and gonadotropins; transvaginal ultrasonography, abdominal and pelvic MRI and (18)F-fluorodeoxyglucose PET imaging. DIAGNOSIS: Virilization secondary to an ovarian Leydig cell tumor. MANAGEMENT: The patient underwent a left salpingo-oophorectomy that confirmed the diagnosis of a unilateral Leydig cell tumor. Complete normalization of androgens and gonadotropin levels was achieved after surgery.

Dyslipidemia in women with polycystic ovary syndrome: incidence, pattern and predictors.

One hundred forty-two women with polycystic ovary syndrome (PCOS) with an average body mass index (BMI) of 29.1 kg/m(2) and average age of 25.12 years were studied. By BMI, 30.2% were normal, 38.0% were overweight and 31.6% were obese. Thirty-one eumenorrheic women matched for BMI and age, with no evidence of hyperandrogenism, were recruited as controls. The incidence of dyslipidemia in the PCOS group was twice that of the Control group (76.1% versus 32.25%). The most frequent abnormalities were low high-density lipoprotein cholesterol (HDL-C; 57.6%) and high triglyceride (TG) (28.3%). HDL-C was significantly lower in all subgroups of women with PCOS when compared to the subgroups of normal women. No significant differences were seen in the total cholesterol (p = 0.307), low-density lipoprotein cholesterol (LDL-C; p = 0.283) and TGs (p = 0.113) levels among the subgroups. An independent effect on HDL-C was detected for glucose (p = 0.004) and fasting insulin (p = 0.01); on TG for age (p = 0.003) and homeostatic model assessment insulin resistance (p = 0.03) and on total cholesterol and LDL-C for age (p = 0.02 and p = 0.033, respectively). In conclusion, dyslipidemia is common in women with PCOS, mainly due to low HDL-C levels. BMI has a significant impact on this abnormality.

Metabolism of triglyceride-rich lipoproteins and lipid transfer to high-density lipoprotein in young obese and normal-weight patients with polycystic ovary syndrome.

OBJECTIVE: To clarify whether the metabolism of triglyceride-rich lipoproteins and lipid transfer to high-density lipoprotein (HDL) are altered in patients with polycystic ovary syndrome (PCOS). DESIGN: Case-control study. SETTING: Endocrinology clinics. PATIENT(S): Eight normal-weight (NW) and 15 obese (Ob) patients with PCOS were compared with 10 NW and 10 Ob women without PCOS paired for age and body mass index. INTERVENTION(S): Determination of triglyceride-rich lipoprotein metabolism and lipid transfer to HDL. MAIN OUTCOME MEASURE(S): Participants were injected triglyceride-rich emulsions labeled with (14)C-cholesteryl esters and (3)H-triglycerides and the fractional clearance rate (FCR, in min(-1)) of labels was determined. Lipid transfer from artificial nanoemulsions to HDL was performed by incubating radioactively labeled lipid nanoemulsions with plasma during 1 hour, followed by radioactive counting of HDL-containing supernatant after chemical precipitation. RESULT(S): Lipolysis estimated by triglyceride FCR was equal in PCOS groups (NW = 0.043 +/- 0.032, Ob = 0.033 +/- 0.009) and respective controls (NW = 0.039 +/- 0.015, Ob = 0.044 +/- 0.019). However, the remnant removal as estimated by cholesteryl ester FCR was reduced in both PCOS groups (NW = 0.005 +/- 0.006, Ob = 0.005 +/- 0.005) compared with controls (NW = 0.016 +/- 0.006, Ob = 0.011 +/- 0.072). Lipid transfer rates were not different among groups, but triglyceride transfer rates were positively correlated with homeostasis model assessment estimate of insulin resistance in PCOS. CONCLUSION(S): PCOS patients showed decreased removal of atherogenic remnants even when fasting glucose was <100 mg/dL. This reinforces the usefulness of the measures taken to prevent cardiovascular events in PCOS patients.

Ovarian hyperthecosis in the context of an adrenal incidentaloma in a postmenopausal woman.

Adrenal incidentaloma is not infrequent and can be found in hirsute women. We report a case of a 54-year-old woman with amenorrhea and hirsutism of abrupt onset and mild signs of virilization that had an adrenal incidentaloma coexisting with ovarian hyperthecosis. Basal total and free testosterone were 191 ng/dL and 179 pmol/L. Pelvic ultrasonography disclosed a right ovary with 10.3 cc and a left ovary with 9.8 cc without nodules or cysts, and computerized tomography of the abdomen disclosed a normal right adrenal gland. On the left adrenal gland a solid nodule with 0.8 cm was seen. After GnRHa administration, total testosterone was 23 ng/dL and free testosterone was 17 pmol/L. In view of a suppression of testosterone by GnRHa, the patient was submitted to a hystero-oophorectomy by laparoscopy. Symmetrically enlarged ovaries were seen. No tumor was apparent. Histology showed hyperthecosis, with foci of luteinized stromal cells. Only atretic follicles were detected. No hilar cell hyperplasia was seen. In conclusion, the presence of an adrenal mass in a hirsute woman can lead to a wrong diagnosis. In this case the suppression GnRHa test was fundamental to determine the origin of hyperandrogenemia.

Ovarian hyperthecosis in the context of an adrenal incidentaloma in a postmenopausal woman / Coexistência de incidentaloma adrenal e hipertecose de ovário em mulher menopausada

Adrenal incidentaloma is not infrequent and can be found in hirsute women. We report a case of a 54-year-old woman with amenorrhea and hirsutism of abrupt onset and mild signs of virilization that had an adrenal incidentaloma coexisting with ovarian hyperthecosis. Basal total and free testosterone were 191 ng/dL and 179 pmol/L. Pelvic ultrasonography disclosed a right ovary with 10.3 cc and a left ovary with 9.8 cc without nodules or cysts, and computerized tomography of the abdomen disclosed a normal right adrenal gland. On the left adrenal gland a solid nodule with 0.8 cm was seen. After GnRHa administration, total testosterone was 23 ng/dL and free testosterone was 17 pmol/L. In view of a suppression of testosterone by GnRHa, the patient was submitted to a hystero-oophorectomy by laparoscopy. Symmetrically enlarged ovaries were seen. No tumor was apparent. Histology showed hyperthecosis, with foci of luteinized stromal cells. Only atretic follicles were detected. No hilar cell hyperplasia was seen. In conclusion, the presence of an adrenal mass in a hirsute woman can lead to a wrong diagnosis. In this case the suppression GnRHa test was fundamental to determine the origin of hyperandrogenemia.

Os incidentalomas adrenais não são infreqüentes e podem ser encontrados em pacientes com hirsutismo. Nesse relato, apresentamos o caso de coexistência de um incidentaloma adrenal com hipertecose de ovário, em uma mulher com 54 anos de idade com amenorréia e hirsutismo de início abrupto e sinais leves de virilização. As testosteronas total e livre basal foram de 191 ng/dL e 179 pmol/L, respectivamente. O ultra-som pélvico demonstrou o ovário direito com 10,3 cc e ovário esquerdo com 9,8 cc, sem nódulos ou cistos e a tomografia computadorizada de abdome demonstrou adrenal direita adrenal e nódulo sólido de 0,8 cm na adrenal esquerda. Após a administração de análogo de GnRH, as testosteronas total e livre foram de 23 ng/dL e 17 pmol/L, respectivamente. Considerando a supressão da concentração de testosterona pelo análogo de GnRH, a paciente foi submetida a histeroooforectomia por via laparoscópica. O diagnóstico histológico foi de hipertecose, com focos de células estromais luteinizadas. Somente folículos atréticos foram visualizados. Não se detectou hiperplasia de células hilares. Em conclusão, a presença de massa adrenal em uma paciente com hirsutismo pode levar ao diagnóstico errado. Neste caso, o teste de supressão com análogo de GnRH foi fundamental para se determinar a origem da hiperandrogenemia.

Impact of body mass index on blood pressure levels in patients with polycystic ovary syndrome.

As there is controversy about the prevalence of hypertension in patients with polycystic ovary syndrome (PCOS) and, up to the present moment, no studies have evaluated the impact of body mass index (BMI) on blood pressure levels (BP) in these patients, we studied retrospectively sixty-nine patients with PCOS, with BMI of 29.0 +/- 6.7 kg/m(2) and aged 25.6 +/-5.6 yr, subdivided into three groups according to BMI (normal, overweight and obese) and evaluated regarding BP (mercury sphygmomanometer), basal hormonal profile, fasting glucose, and insulin sensitivity (HOMA-IR). Mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) were normal (118.1 +/- 17.0 and 74.7+/- 11.5 mmHg, respectively), with a hypertension prevalence of 20.3%. Of these patients, 78.6% were obese and 21.4% were overweight. When the groups were compared according to BMI, a significant increase in SBP and DBP was observed (higher in overweight and obese patients for SBP and higher in obese for DBP), as well as a significant progressive increase in glucose, insulin, homeostatic model assessment, and a significant progressive decline in LH levels. When the patients were subdivided as normotensive or hypertensive, a significant difference was observed only for BMI (28.2 +/- 6.1 and 34.7 +/- 8.6 kg/m(2), respectively; p = 0.007). In conclusion, we observed a significant and progressive impact of BMI on blood pressure levels in our patients with polycystic ovary syndrome.

Impact of body mass index on blood pressure levels in patients with polycystic ovary syndrome

As there is controversy about the prevalence of hypertension in patients with polycystic ovary syndrome (PCOS) and, up to the present moment, no studies have evaluated the impact of body mass index (BMI) on blood pressure levels (BP) in these patients, we studied retrospectively sixty-nine patients with PCOS, with BMI of 29.0 ± 6.7 kg/m² and aged 25.6 ± 5.6 yr, subdivided into three groups according to BMI (normal, overweight and obese) and evaluated regarding BP (mercury sphygmomanometer), basal hormonal profile, fasting glucose, and insulin sensitivity (HOMA-IR). Mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) were normal (118.1 ± 17.0 and 74.7 ± 11.5 mmHg, respectively), with a hypertension prevalence of 20.3 percent. Of these patients, 78.6 percent were obese and 21.4 percent were overweight. When the groups were compared according to BMI, a significant increase in SBP and DBP was observed (higher in overweight and obese patients for SBP and higher in obese for DBP), as well as a significant progressive increase in glucose, insulin, homeostatic model assessment, and a significant progressive decline in LH levels. When the patients were subdivided as normotensive or hypertensive, a significant difference was observed only for BMI (28.2 ± 6.1 and 34.7 ± 8.6 kg/m², respectively; p = 0.007). In conclusion, we observed a significant and progressive impact of BMI on blood pressure levels in our patients with polycystic ovary syndrome.

Como há controvérsia sobre a prevalência de hipertensão arterial em pacientes com a síndrome dos ovários policísticos (SOP) e, até o momento, nenhum estudo avaliou o impacto do índice de massa corporal (IMC) sobre a pressão arterial (PA), foram estudados retrospectivamente 69 pacientes com a SOP, com IMC de 29,0 ± 6,7 kg/m² e idade de 25,6 ± 5,6 anos, subdivididos em 3 grupos de acordo com o IMC (normal, sobrepeso e obesos) e avaliados com relação à PA, perfil hormonal basal, glicemia de jejum e sensibilidade à insulina (HOMA-IR). As médias das pressões arteriais sistólica (PAS) e diastólica (PAD) foram normais (118,1 ± 17,0 e 74,7 ± 11,5 mmHg, respectivamente), com uma prevalência de hipertensão de 20,3 por cento. Das pacientes hipertensas, 78,6 por cento eram obesas e 21,4 por cento apresentavam sobrepeso. Quando os grupos, subdivididos de acordo com o IMC, foram comparados, aumento significativo da PAS e PAD foi observado (PAS maior nas pacientes com sobrepeso e obesas e PAD maior nas pacientes obesas), assim como um aumento progressivo da glicemia, insulina e HOMA-IR, e um decréscimo significante e progressivo de LH. Quando as pacientes foram subdivididas em normotensas e hipertensas, diferença significativa foi observada somente para IMC (28,2 ± 6,1 e 34,7 ± 8,6 kg/m², respectivamente; p = 0,007). Em conclusão, observamos um impacto significativo e progressivo do IMC sobre os níveis pressóricos em nossas pacientes com a síndrome dos ovários policísticos.

Prevalence of abnormalities of glucose metabolism in patients with polycystic ovary syndrome.

Patients with polycystic ovary syndrome (PCOS) present a higher risk for abnormalities of glucose metabolism (AGM). For to study this in our population, we submitted 85 patients, with body mass index (BMI) of 28.5 +/- 6.6 kg/m(2) and aged 25.5 +/- 5.4 years old, to an oral glucose tolerance test (OGTT), and assessed the impact of BMI on the prevalence of impaired glucose tolerance (IGT) and of diabetes mellitus (DM). The states of glucose tolerance were classified considering fasting plasma glucose (FPG) according to the American Diabetes Association (ADA) criterion and plasma glucose at 120 minutes according to the Word Health Organization (WHO) criterion. According to the ADA criteria, 83.5% classified as normal and 16.5% as with AGM, with 15.3% presenting impaired fasting glucose and 1.2% DM, while according to the WHO criteria, 68.2% were classified as normal and 31.8% as with AGM, with 27.0% of them presenting IGT and 4.8% DM. Seventy-three percent of PCOS patients with IGT by WHO criterion had normal FPG by ADA criterion. The prevalence of AGM for both criteria increased with the body mass index. In conclusion, we found a higher prevalence of AGM in PCOS patients than that found in the general population, being the highest in obese patients. Glycemia at 120 minutes on the OGTT identified more patients with AGM than fasting glycemia. We recommended that the assessment of AGM must be done by the OGTT in all patients with PCOS.

Microconversion between CYP21A2 and CYP21A1P promoter regions causes the nonclassical form of 21-hydroxylase deficiency.

CONTEXT: Most mutations causing 21-hydroxylase deficiency originate from microconversions between CYP21 pseudogenes and active genes. However, around 20% of the alleles in the nonclassical form (NC-21OHD) remain without identified mutations, suggesting the involvement of regulatory regions. The pseudogene promoter is 80% less active than the CYP21A2 due to the presence of -126C>T, -113G>A, -110T>C, and -103A>G mutations. Additionally, mutations in the steroidogenic factor-1 binding sites of the CYP21 distal regulatory region, located at 4676 bases upstream from the cap site of the CYP21A2 gene, decrease its transcription to 35%. OBJECTIVE: The objective of the study was to investigate the CYP21A2 promoter/regulatory regions in NC-21OHD patients with undetermined genotype. SUBJECTS: The study included 17 NC-21OHD patients and 50 controls. METHODS: Promoter/regulatory regions were sequenced from peripheral leukocytes' genomic DNA. The identified substitutions were evaluated through EMSA using -132/-97 wild-type and mutant probes and nuclear extracts from NCI-H295A cells. Transcriptional activity studies were performed with wild-type and mutant constructions transfected in NCI-H295A cells. RESULTS: No mutations were identified in the distal regulatory regions. The -126C>T, -113G>A, -110T>C promoter mutations were found in compound heterozygosity with the V281L mutation in one patient and the -126C>T mutation in compound heterozygosity with the I2 splice in another. The -126T mutation decreases the transcriptional activity to 52%, compatible with the patient's nonclassical phenotype. EMSA demonstrated that the -132/-121 region is important for the DNA interaction with the specificity protein-1 transcription factor. CONCLUSION: Microconversions between CYP21A2 and CYP21A1P promoters could be involved in the nonclassical phenotype. Therefore CYP21A2 promoter analysis should be included in genetic studies of 21OHD.

Metformin in normal-weight hirsute women with polycystic ovary syndrome with normal insulin sensitivity.

Fifteen normal-weight (body mass index (BMI) 21.50 +/- 1.65 kg/m(2)) hirsute women with polycystic ovary syndrome and normal insulin sensitivity were treated with 850 mg metformin orally, three times daily, for 4 months. Before and at the end of the treatment, clinical data as well as serum concentrations of sex steroid hormones, gonadotropins, fasting plasma glucose and insulin, insulin resistance - homeostasis model assessment (HOMA-IR), carbohydrate tolerance and the area under the curve for insulin (AUC(insulin)) were analyzed. Three patients withdrew from the study. Seven of the remaining 12 patients presented menstrual pattern improvement, followed by ovulatory cycles at the end of the treatment period. There were no changes in BMI and hirsutism score. A significant (p < 0.05) decrease in luteinizing hormone (LH) (from 8.18 +/- 4.34 to 5.05 +/- 1.53 IU/ml), testosterone (from 104.66 +/- 27.54 to 82.00 +/- 23.05 ng/dl), fasting insulin (from 9.66 +/- 4.79 to 7.83 +/- 3.06 microIU/ml), AUC(insulin) (from 9239 +/- 3285 to 7660 +/- 2565 microUI/ml x min) and HOMA-IR (from 2.15 +/- 1.2 to 1.67 +/- 0.74), and a significant increase in follicle-stimulating hormone (FSH) (from 4.05 +/- 1.53 to 5.96 +/- 2.13 IU/ml), were observed at the end of the treatment period. A higher LH and a lower FSH predicted clinical improvement, while basal insulin and AUC(insulin) showed lower predictive value.

Prevalence of abnormalities of glucose metabolism in patients with polycystic ovary syndrome

Patients with polycystic ovary syndrome (PCOS) present a higher risk for abnormalities of glucose metabolism (AGM). For to study this in our population, we submitted 85 patients, with body mass index (BMI) of 28.5 ± 6.6 kg/m² and aged 25.5 ± 5.4 years old, to an oral glucose tolerance test (OGTT), and assessed the impact of BMI on the prevalence of impaired glucose tolerance (IGT) and of diabetes mellitus (DM). The states of glucose tolerance were classified considering fasting plasma glucose (FPG) according to the American Diabetes Association (ADA) criterion and plasma glucose at 120 minutes according to the Word Health Organization (WHO) criterion. According to the ADA criteria, 83.5 percent classified as normal and 16.5 percent as with AGM, with 15.3 percent presenting impaired fasting glucose and 1.2 percent DM, while according to the WHO criteria, 68.2 percent were classified as normal and 31.8 percent as with AGM, with 27.0 percent of them presenting IGT and 4.8 percent DM. Seventy-three percent of PCOS patients with IGT by WHO criterion had normal FPG by ADA criterion. The prevalence of AGM for both criteria increased with the body mass index. In conclusion, we found a higher prevalence of AGM in PCOS patients than that found in the general population, being the highest in obese patients. Glycemia at 120 minutes on the OGTT identified more patients with AGM than fasting glycemia. We recommended that the assessment of AGM must be done by the OGTT in all patients with PCOS.

Pacientes com a síndrome dos ovários policísticos (SOP) têm um risco maior para desenvolver anormalidades do metabolismo da glicose (AMG). Para avaliarmos a prevalência dessas anormalidades na nossa população, submetemos 85 pacientes, com índice de massa corporal (IMC) de 28,5 ± 6,6 kg/m² e média etária de 25,5 ± 5,4 anos, a teste de tolerância oral à glicose (TTOG). Os estados de tolerância à glicose foram classificados considerando a glicemia de jejum (GJ; American Diabetes Association - ADA) e glicemia aos 120 minutos (G120; Organização Mundial de Saúde - OMS). De acordo com a ADA, 83,5 por cento das pacientes foram normais e 16,5 por cento com AMG, com 15,3 por cento apresentando glicemia de jejum imprópria e 1,2 por cento diabetes mellitus (DM). De acordo com a OMS, 68,2 por cento foram normais e 31,8 por cento com AMG, com 27,0 por cento apresentando intolerância à glicose (IG) e 4,8 por cento DM. Observamos que 73 por cento das pacientes com IG pelos critérios da OMS apresentavam GJ normal pelos critérios da ADA. A prevalência de AMG para ambos os critérios foi maior entre as pacientes com IMC mais elevado. Conclusão: encontramos maior prevalência de AMG nas pacientes com a SOP do que na população geral, sendo mais elevada entre as pacientes obesas. Além disso, a G120 no TTOG identificou maior número de pacientes com AMG do que a GJ. Assim, recomendamos avaliação de AMG através do TTOG para todas as pacientes portadoras da SOP.

Variable ACTH-stimulated 17-hydroxyprogesterone values in 21-hydroxylase deficiency carriers are not related to the different CYP21 gene mutations.

The currently used cutoff level for ACTH-stimulated 17- hydroxyprogesterone (17OHP) for the diagnosis of the nonclassical (NC) form of 21-hydroxylase deficiency (21OHD), established before molecular studies, is based on the mean + 2 SD of 17OHP levels of obligate heterozygotes. However, carriers of CYP21 mutations present variable ACTH-stimulated 17OHP levels, ranging from normal values up to 30 nmol/liter. The aim of this study was to determine whether ACTH-stimulated 17OHP levels in obligate carriers for 21OHD would be correlated with the impairment of the enzyme activity caused by these mutations, which would affect the 17OHP cutoff level for the diagnosis of the NC form. Fifty-nine parents of patients with the classical and NC forms of 21OHD had their DNA screened for the mutations found in the index case and were divided into three mutation groups according to the impairment of enzyme activity (A = 0%, B = 3%, and C > 20%). All parents carried mutations in one allele (29 of group A, 9 of group B, and 21 of group C). Blood samples were collected at baseline condition and 60 min after ACTH (250 microg i.v.) to measure 17OHP levels. The levels among groups A, B, and C were compared using the Kruskall Wallis test. ACTH-stimulated 17OHP levels identified 39% of the carriers (9 in group A, 2 in group B and 12 in group C). The mean +/- SD basal 17OHP levels in groups A, B, and C were: 2.94 +/- 1.89, 1.77 +/- 0.81 and 3.90 +/- 2.43 nmol/liter, respectively (P > 0.05) and for ACTH-stimulated levels were 12.6 +/- 7.2, 13.2 +/- 12.9 and 16.8 +/- 7.8 nmol/liter, respectively (P > 0.05). Two carriers presented ACTH-stimulated 17OHP levels between 30 and 45 nmol/liter and their entire CYP21 sequencing revealed only one mutation in heterozygous state indicating that the current cutoff level might overestimate the diagnosis of the NC form. We conclude that the variable ACTH-stimulated 17-OHP levels in carriers are not related to CYP21 gene mutations with different impairment of enzyme activity.

O espectro clínico e laboratorial da forma näo clássica de hiperplasia adrenal congênita por deficiência da 21-hidroxilase / The clinical and laboratorial spectrum of the non-classic way of congenital adrenal hyperplasia by 21-hydroxilase deficiency

Foram estudadas 9 pacientes portadoras da forma nao clássica de hiperplasia adrenal congênita por deficiência de 2l-hidroxilase (2l-FNC). O diagnóstico baseou-se na resposta da 17-hidroxiprogesterona (l7-OHP) 60 minutos após estímulo com 250 ug de ACTH sintético por via EV. Em relaçao à reserva de glicocorticóide, observamos somente uma paciente com resposta deficiente de cortisol ao estímulo com ACTH. A concentraçao basal de 17-OHP foi altamente variável, tanto em relaçao a mesma paciente como entre as pacientes. Em duas delas, observamos concentraçao basal de 17-OHP normal, após estímulo com ACTH, observamos uma hiperresposta de 17-OHP, compatível com o diagnóstico de 2l-FNC. As pacientes foram subdivididas em três grupos de acordo com o diagnóstico clínico: Grupo I: Pubarca precoce (n= 1); Grupo II: Hirsutismo com ciclos menstruais regulares e ovulatórios (n= 4); e Grupo III: Hirsutismo com alteraçao menstrual (n= 3). Nao observamos qualquer diferença entre os três grupos tanto em relaçao à reserva de glicocorticóide adrenal e a concentraçao de 17-OHP, basal ou pós-estímulo, nem com relaçao à parâmetros clínicos, como obesidade, menarca ou idade de início do hirsutismo nas pacientes dos grupos II e III, sugerindo que a manifestaçao clínica da 2l -FNC esteja na dependência de fatores extra-adrenais, excetuando-se a pubarca precoce.