Does obesity diminish the positive effect of oral contraceptive treatment on hyperandrogenism in women with polycystic ovarian syndrome?
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Polycystic ovarian syndrome (PCOS) is an obvious indication for long-term treatment. Combined oral contraceptives (COC) remain the first choice for the treatment of hyperandrogenism in most patients. However, differences in endocrine and metabolic parameters between obese and lean patients have been postulated. This is the first study evaluating the effect of COC treatment in obese versus non-obese PCOS patients. In total, 28 lean [body mass index (BMI) <25 kg/m(2))] and 15 obese (BMI >30 kg/m(2)) women patients were enrolled in the study. The concentrations of androgens, sex hormone-binding globulin (SHBG) and lipids were measured before and after 6 months of treatment with COC containing low-androgenic progestins. Clinical androgenic symptoms were monitored. There was a lower concentration of SHBG in obese patients, but there were no differences in androgen concentrations between both groups before the study. Highly significant changes in concentrations of testosterone (P < 0.001), androstenedione (P < 0.0001), SHBG (P < 0.001) and LH (P = 0.01) were demonstrated in lean patients, with only less significant changes in SHBG (P < 0.01) and testosterone (P < 0.05) in obese patients during the study. Clinical androgenic symptoms improved significantly (P = 0.05) only in the group of lean women. No reduction in low-density lipoprotein-cholesterol/high-density lipoprotein-cholesterol ratio was observed in either group. In conclusion, the positive effect of COC treatment on androgen production, serum androgen binding capacity, and clinical androgenic symptoms was negatively influenced by an increased BMI. (+info)
HAIR-AN syndrome: a multisystem challenge.
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HAIR-AN syndrome is an acronym for an unusual multisystem disorder in women that consists of hyperandrogenism (HA), insulin resistance (IR) and acanthosis nigricans (AN). The precipitating abnormality is thought to be insulin resistance, with a secondary increase in insulin levels and subsequent overproduction of androgens in the ovaries. Long periods of hyperinsulinism and, some suspect, hyperandrogenism can result in the cutaneous manifestation of acanthosis nigricans. Patients are often concerned about the physical manifestations of this disorder, including virilization and acanthosis nigricans, and may be less aware of systemic problems. Physicians should assess women with these problems for an underlying endocrine abnormality. Although a treatment regimen for the HAIR-AN syndrome has not been established, antiandrogen therapy and weight loss are useful. (+info)
Human sex hormone-binding globulin variants associated with hyperandrogenism and ovarian dysfunction.
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The access of testosterone and estradiol to target tissues is regulated by sex hormone-binding globulin (SHBG) in human blood. Serum SHBG levels are low in patients with hyperandrogenism, especially in association with polycystic ovarian syndrome (PCOS) and in individuals at risk for diabetes and heart disease. Here, we identify SHBG coding region variations from a compound heterozygous patient who presented with severe hyperandrogenism during pregnancy. Serum SHBG levels in this patient measured 2 years after her pregnancy were exceptionally low, and her non-protein-bound testosterone concentrations greatly exceeded the normal reference range. A single-nucleotide polymorphism within the proband's maternally derived SHBG allele encodes a missense mutation, P156L, which allows for normal steroid ligand binding but causes abnormal glycosylation and inefficient secretion of SHBG. This polymorphism was identified in four other patients with either PCOS, ioiopathic hirsutism, or ovarian failure. The proband's paternal SHBG allele carries a single-nucleotide deletion within exon 8, producing a reading-frame shift within the codon for E326 and a premature termination codon. CHO cells transfected with a SHBG cDNA carrying this mutation fail to secrete the predicted truncated form of SHBG. To our knowledge, these are the first examples of human SHBG variants linked to hyperandrogenism and ovarian dysfunction. (+info)
Maternal serum androgens in pregnant women with polycystic ovarian syndrome: possible implications in prenatal androgenization.
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BACKGROUND: The aim of this study was to evaluate the peripheral serum androgen concentrations in normal and polycystic ovarian syndrome (PCOS) women during pregnancy, in order to establish if PCOS may induce gestational hyperandrogenism and therefore constitute a potential source of androgen excess for the fetus. METHODS: Twenty pregnant PCOS (PPCOS) women and 26 normal pregnant (NP) women of similar age with singleton pregnancies were selected for the study. During gestational weeks 10-16 and 22-28, a 2 h, 75 g oral glucose tolerance test (OGTT) was performed. For the OGTT, glucose and insulin were measured in each sample and testosterone, androstenedione, dehydroepiandrosterone sulphate (DHEAS), estradiol, progesterone and sex hormone-binding globulin were determined in the fasting sample. RESULTS: In the first study period (gestational weeks 10-16), the levels of androstenedione, testosterone and DHEAS and the free androgen index tended to be higher in the PCOS group. These differences became significant in the second study period (gestational weeks 22-28). In this second period, 2 h insulin concentrations were also significantly higher in PPCOS than in NP women. CONCLUSIONS: The present study demonstrates a significant increase in androgen concentrations during pregnancy in PCOS women. We propose that these androgen concentrations could provide a potential source of androgen excess for the fetus, without leading to fetal virilization. (+info)
Molecular defects of the CYP21 gene in Spanish girls with isolated precocious pubarche.
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OBJECTIVE: To determine the frequency of mutant alleles in the CYP21 gene in Spanish girls presenting with precocious pubarche (PP) and to assess the relationships between genotype and endocrine-metabolic variables. DESIGN: Fifty-three unrelated girls with a history of PP (14 prepubertal, 8 pubertal and 31 postmenarcheal) and 35 controls were studied. METHODS: Genomic DNA was extracted from peripheral blood leukocytes. After selection against the pseudogen, an allele-specific PCR was used to identify 14 known mutations in the CYP21 gene. The mutations studied were Pro30Leu, splice intron 2, Ilel72Asn, Cluster E(6), Glyl92Ser, Ins T, GT-CT, Gln318-stop, Arg357Trp, Trp406-stop, Pro453Ser, Arg483Pro, Arg483 frameshift and Val281Leu. A standard 2-h oral glucose tolerance test was performed in all PP girls. Ovarian 17-hydroxyprogesterone (17-OHP) responses to gonadotrophin-releasing hormone-agonist stimulation was assessed in postmenarcheal PP girls. RESULTS: Thirteen PP girls and eight control girls were heterozygous for one of the mutations studied. The frequency of the carrier status was 25% and 23% in the PP and control groups respectively. Severe mutations were found in 33% of the carrier girls. Serum 17-OHP responses to ACTH stimulation were similar in carriers and non-carriers (351+/-65 vs 334+/-22 ng/dl). The presence of ovarian hyperandrogenism and/or hyperinsulinism was also not related to the carrier status. CONCLUSION: The incidence of molecular defects in the CYP21 gene in the present study was comparable in the PP and control groups. We found no relationship between the presence of carrier status and endocrine-metabolic abnormalities. Prospective studies of larger cohorts of PP girls are needed to ascertain the long-term clinical relevance of CYP21 heterozygosity. (+info)
Physiopathological determinants of human infertility.
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Successful management of infertility involves the use of appropriate diagnostic tests and treatments, and knowledge of prognostic factors such as age of the female partner and duration of infertility. The assessment of infertility may reveal disorders that cause morbidity in the normally fertile population, which might or might not contribute to the infertility. Endocrine dysfunction is a significant cause of infertility due to amenorrhoea and dysfunctional uterine bleeding, and hirsutism is a familiar problem in the normal population. Some genetic abnormalities cause infertility in males and females and create implications for the progeny of infertile couples. Sexually transmitted diseases cause illness and healthcare expenditure among young adults, and can also result in tubal infertility. Congenital disorders of the uterus and fibromyomas are not rare and they are frequently asymptomatic, but in some cases uterine anomalies may contribute to infertility and pregnancy loss. Autoimmunity underlies some common diseases, especially among females, and it can also be associated with pregnancy loss. When such widely distributed factors are identified during the diagnostic assessment of subfertile couples, it is important to distinguish between a coincidental association and a specific relationship to the infertility. (+info)
Low-dose combination of flutamide, metformin and an oral contraceptive for non-obese, young women with polycystic ovary syndrome.
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BACKGROUND: The endocrine-metabolic status of non-obese, young women with polycystic ovary syndrome (PCOS) is normalized more effectively by combined treatment with flutamide and metformin than by either of these drugs in monotherapy. In this follow-up study, we assess whether the endocrine-metabolic benefits of combined flutamide-metformin treatment are maintained in the presence of a low-dose oral contraceptive (OC). METHODS: To a population of non-obese, young PCOS women already receiving flutamide-metformin (125 mg/day and 1275 mg/day), a low-dose OC (ethinyl estradiol 20 microg + gestodene 75 microg) was administered to reduce the risk of pregnancy. A total of 12 women elected to receive the OC and this subgroup (OC+) was matched to a subgroup continuing on flutamide-metformin alone (OC-), for a total study population of 24 women (mean age +/- SEM 18.7 +/- 0.3 years; body mass index, 21.8 +/- 0.5 kg/m(2)). Endocrine-metabolic indices were assessed before any treatment (0 months), on flutamide-metformin (12 months), and again after a further 6 months with or without additional OC (18 months). RESULTS: In OC- and OC+ women, the beneficial effects of flutamide-metformin on hyperandrogenaemia, hyperinsulinaemia and dyslipidaemia were maintained. In OC+ women, there was an additional increase in sex hormone-binding globulin (SHBG), and thus a further drop in the free androgen index. CONCLUSION: When a low-dose OC is administered with a low-dose flutamide-metformin combination in women with PCOS, the beneficial effects are maintained on hyperinsulinaemia-dyslipidaemia, which are key determinants of long-term complications. Hence, in daily practice, such a low-dose quatuor may become a therapeutic option of first choice for young women with PCOS. (+info)
Obesity in transgenic female mice with constitutively elevated luteinizing hormone secretion.
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Transgenic (TG) female mice, expressing a chimeric bovine luteinizing hormone (LH) beta-subunit/human chorionic gonadotropin beta-subunit COOH-terminal extension (bLHbeta-CTP) gene, produce high levels of circulating LH and serve as a model for functional ovarian hyperandrogenism and follicular cysts. We report here that obesity is a typical feature of these female mice. The mean body weight of the bLHbeta-CTP females was significantly higher than in controls at, and beyond 5 wk of age, and at 5 mo, it was 32% increased. At this age, the amount of white adipose tissue in the bLHbeta-CTP females was significantly increased, as reflected by the weight difference of the retroperitoneal fat pad. In addition, the expression of leptin mRNA in white adipose tissue of the TG females was elevated about twofold. Serum leptin and insulin levels, and food intake, were also increased significantly in the TG females. Brown adipose tissue (BAT) thermogenic activity, as measured by GDP binding to BAT mitochondria, was reduced (P < 0.05). Ovariectomy at the age of 3 wk totally prevented the development of obesity. In summary, the present results show that intact female bLHbeta-CTP mice are obese, have increased food consumption, and reduced BAT thermogenic activity. The weight gain can be explained partly by elevated androgens but is probably also contributed to the increased adrenal steroidogenesis. Hence, the bLHbeta-CTP mice provide a useful model for studying obesity related to elevated LH secretion, with consequent alterations in ovarian and adrenal function. (+info)