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Query: UMLS:C0011849 (diabetes)
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Congenital adrenal hyperplasia (CAH) is caused by a defect in the biosynthesis of cortisol that results in maximal activity of the hypothalamic-pituitary adrenal axis with hyperplasia of the adrenals and hyperandrogenism due to the accumulation of androgen precursors. In the salt-wasting subtype of the disorder, which accounts for appr. 75 % of patients with classical CAH, patients are unable to synthesise sufficient amounts of aldosterone and are prone to life-threatening salt-losing crises, whereas the simple virilising form is predominantly characterized by clitoris hypertrophy and posterior labial fusion. In addition, a non-classical variant can be discerned which in most cases is diagnosed at the time of puberty or early adolescence when hirsutism and menstrual irregularities may occur. The vast majority of CAH patients have 21-hydroxylase deficiency (90 - 95 %). Less common forms, such as 11beta-hydroxylase deficiency, will not be discussed in this review. Unfortunately, a considerable number of CAH patients is lost to regular and competent follow-up once they move out of paediatric care. This is most probably the result of insufficient co-operation between paediatric and adult endocrinologists at the time of transition from adolescence to adulthood. Furthermore, there is a lack of clinical guidance regarding psychosexual development in these patients. In this overview we will focus on special aspects of CAH treatment in adolescence and adulthood, and report on our 10-year experience with a transfer system for endocrine patients from paediatric to internal medical care, known as the "Kieler Modell". For practical purposes, we here provide charts for follow-up of CAH patients that can be adapted for use in any endocrine outpatient clinic.
Exp Clin Endocrinol Diabetes 2004 Jul
PMID:Congenital adrenal hyperplasia - how to improve the transition from adolescence to adult life. 1523 19

Polycystic ovary syndrome (PCOS) is probably the most prevalent endocrinopathy in women and the most common cause of anovulatory infertility. Patients with PCOS have clinical and biochemical features consistent with the ultrasound diagnosis and they are likely to face the problems of hyperandrogenism, subfertility and recurrent miscarriage. The aim of the present review is to summarize our present knowledge on the hormonal background of this very prevalent syndrome and to give some clinical examples how the present knowledge can be applied to treat PCOS patients according to their current problem, such as menstrual cycle disorder, hirsutism, infertility or to prevent late consequences as diabetes mellitus. The etiology and pathogenesis of PCOS is still a matter of controversies, but it is apparent that inappropriate gonadotropin secretion, obesity, hyperinsulinism and insulin resistance are the major determining factors in the development of ovarian hyperandrogenism an chronic anovulation. Reversal of insulin resistance in PCOS constitutes the fundamental goal in the management of hyperandrogenic anovulatory infertility and in the prevention of long-term consequences. The value of the insulin sensitizer metformin therapy awaits further evaluation and it should be integrated in the spectrum of therapeutical options that include the discussed surgical methods and GnRH analogues as well.
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PMID:Endocrine characteristics of polycystic ovary syndrome (PCOS). 1525 72

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, chronic anovulation, and insulin resistance; long-term consequences include diabetes mellitus type 2. The aim of this randomized, double-blind, controlled trial was to investigate whether the thiazolidinedione derivative pioglitazone diminishes insulin resistance and hyperandrogenism and enhances ovulation rates in women with PCOS. Forty premenopausal women with PCOS were randomly allocated to treatment with either pioglitazone (30 mg/d) or placebo for periods of 3 months. Administration of pioglitazone resulted in a remarkable decline in both fasting serum insulin levels (P < 0.02) and the area under the insulin response curve after an oral glucose load (P < 0.02). This represented an increase in insulin sensitivity and a decrease in insulin secretion (P < 0.05). Furthermore, pioglitazone increased serum SHBG (P < 0.05), resulting in a significant decrease in the free androgen index (P < 0.05 compared with placebo). Treatment with pioglitazone was also associated with higher ovulation rates (P < 0.02). Thus, pioglitazone significantly improved insulin sensitivity, hyperandrogenism, and ovulation rates in women with PCOS, thereby providing both metabolic and reproductive benefits.
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PMID:Effect of the insulin sensitizer pioglitazone on insulin resistance, hyperandrogenism, and ovulatory dysfunction in women with polycystic ovary syndrome. 1529 14

The prenatally androgenised female rhesus monkey has become a model for polycystic ovary syndrome (PCOS) in women, with early prenatal androgenisation entraining a permanent PCOS-like phenotype characterised by luteinising hormone (LH) hypersecretion due to reduced hypothalamic sensitivity to steroid negative feedback and relative insulin excess associated with increased abdominal adiposity. These combined reproductive and metabolic abnormalities occur in combination with ovarian hyperandrogenism and follicular arrest in adulthood, and with premature follicle differentiation and impaired embryo development during gonadotrophin therapy for in vitro fertilization (IVF). The ability of prenatal androgen excess in fetal rhesus monkeys to entrain multiple organ systems in utero provides evidence that the hormonal environment of intrauterine life programmes target tissue differentiation, raising the possibility that hyperandrogenism in human fetal development promotes PCOS in adulthood. This hypothesis developed in prenatally androgenised female rhesus monkeys, however, also must include data from clinical studies of PCOS to clarify the homology between human and non-human primates in intrafollicular steroidogenesis and its impact on oocyte developmental competency. By doing so, future studies promise to develop new clinical strategies that will lead to improved pregnancy outcome and reduced pregnancy loss in women with disorders of insulin action, including PCOS, obesity and diabetes mellitus.
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PMID:Early origins of polycystic ovary syndrome. 1574 43

Ovary is the main source of the hyperandrogenism in polycystic ovary syndrome (PCOS). Adrenal glands may also be involved in the pathogenesis of the development of PCOS. To investigate this possibility and to find out if buserelin test is able to distinguish PCOS patients from the patients with idiopathic hirsutism (IH), ACTH and buserelin tests were performed in 29 women with PCOS, 21 women with IH, and 20 control subjects (CS). We also aimed to determine the role of dysregulation of 17 hydroxylase in the development of PCOS. Basal and stimulated dehydroepiandrosterone sulfate (DHEA-S) and stimulated cortisol (F) levels after ACTH administration were significantly higher in PCOS group than in IH and CS groups (p<0.0001 and p<0.05, respectively). PCOS patients also possessed significantly higher basal and stimulated 17-hydroxyprogesterone (17-OH P) levels, including the peak levels (p<0.02), during buserelin testing when compared with IH patients and CS. There was no significant correlation between the ACTH-stimulated and the buserelin-stimulated peak 17-OH P values. In conclusion, significantly higher basal and ACTH-stimulated levels of F and DHEA-S in PCOS compared with controls and patients with IH, reflect that adrenal hyperactivity also plays a role in hyperandrogenemia seen in PCOS. Because of the lack of the correlation between ACTH-stimulated and buserelin-stimulated 17-OH P levels, it is hard to say that adrenal hyperactivity seen in PCOS is the result of the dysregulation of cytochrome P450c17-alpha enzyme. Our results suggest that buserelin test which is an GnRH analogue could distinguish at least some of the patients with PCOS from the other patients presenting with the common symptoms of hyperandrogenemia.
Exp Clin Endocrinol Diabetes 2005 Feb
PMID:Role of ovary and adrenal glands in hyperandrogenemia in patients with polycystic ovary syndrome. 1577 4

Lipodystrophies represent a group of diseases characterized by altered body fat repartition and major metabolic alterations with insulin resistance. Genetic forms of partial lipodystrophy are currently recognized as two syndromes with subcutaneous lipoatrophy but preserved or increased fat at the level of face and neck (Dunnigan syndrome or FPLD due to LMNA mutations) and/or abdomen (PPARgamma-linked forms) and are both transmitted as dominant diseases. FPLD is further characterized by muscular hypertrophy, hyperandrogenism, acanthosis nigricans, hepatomegaly with steatosis and at the biological level, marked hypertriglyceridaemia, low HDL cholesterol, insulin resistance and altered glucose tolerance or diabetes. These signs occur after puberty and their prevalence and severity are more marked in female than in male patients. At the genetic level, LMNA mutations concern in most cases the type-A lamin C-terminal domain and more than 80% are heterozygous substitutions located at position 482 (R482W/Q/L). The other locations are G465D, K486N, R582H and R584H. The presence of signs evocative of limb-girdle muscular dystrophy has been reported in patients with typical forms of FPLD. In addition, forms presenting with lipodystrophy and myopathy have been reported for patients with mutations at position R28W, R60G, R62G or R527P. In addition, lipodystrophy, either partial or generalized, can be associated with syndromes of premature ageing like Hutchinson-Gilford progeria or acromandibular dysplasia, but also with other phenotypes, as we described in a patient bearing the LMNA R133L heterozygous substitution.
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PMID:A-type lamin-linked lipodystrophies. 1577 53

Obstructive sleep apnea (OSA) is a prevalent disorder particularly among middle-aged, obese men, although its existence in women as well as in lean individuals is increasingly recognized. Despite the early recognition of the strong association between OSA and obesity, and OSA and cardiovascular problems, sleep apnea has been treated as a 'local abnormality' of the respiratory track rather than as a 'systemic illness.' In 1997, we first reported that the pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNFalpha) were elevated in patients with disorders of excessive daytime sleepiness (EDS) and proposed that these cytokines were mediators of daytime sleepiness. Also, we reported a positive correlation between IL-6 or TNFalpha plasma levels and the body-mass-index (BMI). In subsequent studies, we showed that IL-6, TNFalpha, and insulin levels were elevated in sleep apnea independently of obesity and that visceral fat, was the primary parameter linked with sleep apnea. Furthermore, our findings that women with the polycystic ovary syndrome (PCOS) (a condition associated with hyperandrogenism and insulin resistance) were much more likely than controls to have sleep disordered breathing (SDB) and daytime sleepiness, suggests a pathogenetic role of insulin resistance in OSA. Other findings that support the view that sleep apnea and sleepiness in obese patients may be manifestations of the Metabolic Syndrome, include: obesity without sleep apnea is associated with daytime sleepiness; PCOS and diabetes type 2 are independently associated with EDS after controlling for SDB, obesity, and age; increased prevalence of sleep apnea in post-menopausal women, with hormonal replacement therapy associated with a significantly reduced risk for OSA; lack of effect of continuous positive airway pressure (CPAP) in obese patients with apnea on hypercytokinemia and insulin resistance indices; and that the prevalence of the metabolic syndrome in the US population from the Third National Health and Nutrition Examination Survey (1988-1994) parallels the prevalence of symptomatic sleep apnea in general random samples. Finally, the beneficial effect of a cytokine antagonist on EDS in obese, male apneics and that of exercise on SDB in a general random sample, supports the hypothesis that cytokines and insulin resistance are mediators of EDS and sleep apnea in humans. In conclusion, accumulating evidence provides support to our model of the bi-directional, feed forward, pernicious association between sleep apnea, sleepiness, inflammation, and insulin resistance, all promoting atherosclerosis and cardiovascular disease.
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PMID:Sleep apnea is a manifestation of the metabolic syndrome. 1589 51

Particular forms of polycystic ovary syndrome with severe hyperandrogenism, acanthosis nigricans, and marked insulin resistance, defining the type A insulin resistance syndrome, are due to insulin receptor gene mutations. However, the majority of affected individuals do not have such mutation, arguing for the genetic heterogeneity of this syndrome. The familial partial lipodystrophy of the Dunnigan type, one of the diseases due to mutations in the lamin A/C (LMNA) gene, is characterized by a lipodystrophic phenotype and shares some clinical and metabolic features with the type A syndrome. We describe here the case of a nonobese 24-year-old woman affected with type A syndrome without clinical lipodystrophy. We linked this phenotype to a novel heterozygous missense mutation in the LMNA, predicting a G602S amino acid substitution in lamin A. This mutation cosegregated with impaired glucose tolerance, insulin resistance, and acanthosis nigricans in the absence of clinical lipodystrophy in the family. The skin fibroblasts from the proband exhibited nuclear alterations similar to those described in other laminopathies, and showed several defects in the insulin transduction pathway. This study further extends the vast range of diseases linked to LMNA mutations and identifies another genetic cause for the type A insulin resistance syndrome.
Diabetes 2005 Jun
PMID:Type A insulin resistance syndrome revealing a novel lamin A mutation. 1591 11

Polycystic ovary syndrome (PCOS), defined as the combination of oligoanovulation and hyperandrogenism, affects more than 5% of women of reproductive age. Insulin resistance and hyperinsulinemia appear to play an important role in its pathogenesis. Here, we will present a characterization of a PCOS cohort from North Rhine-Westphalia in Germany. Clinical features, family history as well as endocrine and metabolic parameters were prospectively recorded from 200 successive patients. All patients were evaluated for insulin resistance and beta-cell-function by oral glucose tolerance test. Patient data were compared with those of 98 age-matched control women. PCOS patients showed significantly higher BMI, body fat mass and androgen levels as well as impaired glucose and insulin metabolism. A positive family history of PCOS and diabetes was more frequent in PCOS patients. Insulin resistance (71%) was the most common metabolic abnormality in PCOS patients followed by obesity (52%) and dyslipidemia (46.3%), with an incidence of 31.5% for the metabolic syndrome. C-reactive protein and other cardiovascular risk factors were frequently elevated even in young PCOS patients. While the clinical characteristics and endocrine parameters of this German PCOS cohort were heterogeneous, they were comparable to those from other Caucasian populations.
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PMID:Clinical and biochemical characterization of women with polycystic ovary syndrome in North Rhine-Westphalia. 1603 17

Polycystic ovary syndrome (PCOS) is a common endocrine condition with reproductive and metabolic implications. In the current setting there is an evolving, yet inadequate, understanding of the pathophysiology, long-term health implications and ideal therapies for women with PCOS. Insulin resistance, secondary to both genetic and lifestyle factors, is integrally involved in the pathogenesis, the metabolic and clinical features and the long-term sequelae of PCOS in a majority of patients. Therapeutic strategies targeting insulin resistance ameliorate clinical features and may reduce long-term sequelae of PCOS, including diabetes. The main benefit of improved insulin resistance is to improve fertility and potentially to improve clinical features of hyperandrogenism and lower androgen levels. Insulin sensitisers also have the potential to delay the development of diabetes and cardiovascular disease in PCOS. Lifestyle therapy is indicated as the first intervention; however, metformin as an insulin sensitising agent has a role in first-line medical therapy in women with PCOS. Further research is needed to define the role of insulin sensitisers in PCOS and to determine the long-term risks and benefits of these therapies.
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PMID:Insulin-sensitisers in the treatment of polycystic ovary syndrome. 1625 73


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