Succinate dehydrogenase mutations: paraganglioma imaging and at-risk population screening.

Paragangliomas are rare vascular tumours of the autonomic nervous system. They can be classified as sympathetic or parasympathetic. Sympathetic paragangliomas, which include phaeochromocytomas, tend to be functional and symptomatic. Parasympathetic paragangliomas are usually non-functional and may present with mass effect. Forty percent of paragangliomas are linked to genetic syndromes, most commonly due to mutations of the succinate dehydrogenase (SDH) enzyme complex and are collectively known as paraganglioma syndromes, of which five are described. Genetic testing is recommended for all patients, and their first-degree relatives, diagnosed with paragangliomas. When SDH mutations are discovered, biochemical screening and imaging surveillance is indicated. There is currently no consensus on imaging surveillance protocols. Most advocate full-body imaging, but the choice of technique and frequency varies. If paragangliomas are demonstrated, functional imaging to look for synchronous tumours or metastases is indicated. 2-[18F]-fluoro-2-deoxy-d-glucose (18F-FDG) positron-emission tomography (PET)-computed tomography (CT) is the technique of choice for metastatic evaluation, but [123I]-metaiodobenzylguanidine or [111In]-DTPA-octreotide scintigraphy are also utilised. Current research into emerging positron-emitting radiolabelled somatostatin analogues have yielded promising results, which is likely to be reflected in future guidelines. As genetic testing becomes increasingly prevalent, the need to answer the remaining questions regarding surveillance imaging is paramount.

Identification of asymptomatic frailty vertebral fractures in post-menopausal women.

PURPOSE: Vertebral fractures are associated with persistent pain, disability and mortality. However, around two thirds of women with vertebral fractures are unaware of them. We aimed to analyze which factors could mostly be associated to the presence of vertebral fractures in post-menopausal women, and evaluate the effectiveness of current screening criteria for the detection of vertebral fractures in an outpatient setting. METHODS: We evaluated 1132 post-menopausal women referred to the osteoporosis outpatient clinic of the Geriatrics Department of Padova. For each participant we assessed: anthropometric data, femoral and lumbar bone mineral density (BMD), dorso-lumbar X-rays, bone metabolism markers. Current recommendations for X-ray examinations by SIOMMMS (Società Italiana di Osteoporosi, Metabolismo Minerale e Malattie dello Scheletro) and ISCD (International Society of Clinical Densitometry) versus routine X-ray examinations were considered, and fracture risk was assessed through the derived FRAX (DeFRA) tool. RESULTS: Of the women included in our study, 28% presented vertebral fractures, most of these previously unknown (82.8%). Lumbar BMD did not differ between patients with and without vertebral fractures. According to SIOMMMS guidelines, 50% of patients <60 years with unknown vertebral fractures would have been excluded from spinal X-ray examination. According to ISCD recommendations, the number of patients excluded reached 94.6% in the <60 age-group and 84.9% in the 60-70 age-group. The under-identification of vertebral fractures led to the 10-year risk of fractures computed by DeFRA being underestimated by around 15%. CONCLUSIONS: BMD, particularly in the lumbar site, may not properly predict the presence of vertebral fractures in post-menopausal women. Improvement of the current recommendations for spinal X-ray examination may lead to early identification and better management of patients with vertebral fractures.

Papillary carcinoma of the thyroid in patients with primary hyperparathyroidism: Is there a link?

Primary hyperparathyroidism (PHPT) is present in up to 0.1% of the general population. The incidence is higher in women and increases with age. The majority of the cases is asymptomatic and up to 85% are due to single gland adenoma. Parathyroidectomy is the treatment of choice after localization of the hyperactive gland. Papillary Thyroid Carcinoma (PTC) is the most common cancer of the thyroid and constitutes more than 70% of thyroid malignancies. PTC can present as a single nodule or can be Multifocal. The incidence is higher in women. Early treatment favors a good prognosis. PTC with PHPT has been reported in 2.3-4.3% of patients undergoing surgery for PHPT. The coexistence of parathyroid adenoma and incidental PTC is thought to be rare. The mechanisms underlying the relationship between PHPT and PTC have not been established. We suggest a possible hypothesis for the relationship based on shared embryological origin and genes, high parathyroid hormone (PTH), low 1,25 hydroxy vitamin D, hypercalcemia resulting in high levels of angiogenic growth factors. This promotes the formation of parathyroid adenomas and papillary thyroid carcinoma. Presence of these two diseases can complicate patient management due to untreated hypercalcemia, unrecognized thyroid cancer and need for second surgery if not screened for both diseases carefully.

A case of co-existing paraganglioma and thymoma.

BACKGROUND: Head and neck paragangliomas are rare tumours and can arise as a part of inherited syndromes. Their association with thymic tumour is not well known. CASE DESCRIPTION: This report describes a female patient who presented with right sided neck paragangliomas. The histology of the tumour was consistent with paraganlioma. Few years later her MRI scan of the chest revealed presence of an anterior mediastinal mass that corresponded to the location of the thymus. Review of her previous scans showed that the mass was present all along and had gradually increased in size. Patient developed symptoms including fatigue, dyspnoea, migratory polyarthritis, Raynaud's phenomenon and erythema nodosum. She had sternotomy and excision of mediastinal mass. The histology was consistent with cortical thymoma (WHO type B2) and she had radiotherapy. After treatment her constitutional symptoms improved. Her paraganglioma susceptibility genes are negative. DISCUSSION AND EVALUATION: To our knowledge this is only the second case report in the literature of coexistence of carotid body tumour and thymoma. The first case reported was bilateral carotid body tumour, thyroid gland adenoma and thymoma. This case also highlights the importance of long term surveillance, multidisciplinary management and being aware of associated pathologies in patients with isolated paraganglioma.

Vitamin K antagonists' use and fracture risk: results from a systematic review and meta-analysis.

BACKGROUND: Although vitamin K antagonists (VKAs) lower serum values of bone deposition markers, the link with osteoporosis and fractures remains controversial. OBJECTIVES: To assess whether the use of VKAs is associated with an increased prevalence and/or incidence of osteoporosis, fractures, or lower bone mineral density (BMD) values. METHODS: We conducted a systematic PubMed and EMBASE literature search until August 31, 2014, and a meta-analysis of cross-sectional and longitudinal studies investigating fractures and BMD, comparing patients treated with VKAs and healthy controls (HCs) or with patients with medical illness (medical controls, MCs). Standardized mean differences ± 95% and confidence intervals (CIs) were calculated for BMD, and risk ratios (RRs) were calculated for prevalent and incident fractures. RESULTS: Of 4597 initial hits, 21 studies were eligible, including 79 663 individuals treated with VKAs vs. 597,348 controls. Compared with HCs, VKA-treated individuals showed significantly higher fracture risk in cross-sectional (three studies; RR = 1.24; 95% CI: 1.12-1.39, P < 0.0001) and longitudinal studies (seven studies; RR = 1.09; 95% CI: 1.01-1.18, P = 0.03) and more incident hip fractures (four studies; RR = 1.17; 95% CI: 1.05-1.31, P = 0.003). Analyzing studies that matched VKA participants with HCs (four studies), both these findings in longitudinal studies became non-significant. Notably, the VKA and MC group had similar BMD values at all investigated sites. Compared with HCs, a single study showed significantly lower spine T-scores in the VKA-treated group (standardized mean difference = - 0.45; 95% CI: - 0.75, - 0.14, P = 0.004). CONCLUSION: VKAs neither increased prospectively-assessed fracture risk compared with MCs when matching eliminated confounding factors nor reduced BMD beyond effects of medical illness. Future studies, using careful matching and/or adequate MC groups, are needed to further clarify the short- and long-term effects of VKAs on bone health.

Dual effect of metformin on growth inhibition and oestradiol production in breast cancer cells.

Evidence has been accumulating for a role for metformin in reducing breast cancer risk in post-menopausal women. It inhibits growth of breast cancer cells via several mechanisms, primarily the AMPK/mTOR signalling pathway. Another possible protective mechanism may be the ability of metformin to inhibit aromatase activity. In the present study, we investigated the effects of metformin on the basal growth of MCF-7 cells, after oestradiol (E2) stimulation and after the inhibition of mTOR by rapamycin. Secondly, we investigated the effects of metformin on the activity of a number of steroidogenic enzymes and the mRNA expression of aromatase and steroid sulphatase (STS). High doses of metformin significantly inhibited both basal and oestrogen-stimulated cell division. Low-dose rapamycin (10-10 M) did not inhibit growth, but the addition of metformin induced a significant reduction in growth. High-dose rapamycin (10-8 M) inhibited growth, and this was further attenuated by the addition of metformin. Exposure to low (10-7 M) and high (10-4 M) doses of metformin for 7-10 days significantly reduced the conversion of androstenedione (ANDRO) and testosterone (TESTO) (both requiring aromatase), but not the conversion of oestrone or oestrone sulphate (ES) via 17ß-hydroxysteroid dehydrogenase/sulphatase to E2. This attenuation was via a downregulation in the expression of total aromatase mRNA and promoter II, whilst the expression of sulphatase was unaffected by metformin. In conclusion, plasma levels of metformin have a dual therapeutic action, first by directly inhibiting cell proliferation which can be augmented by rapamycin analogues, and secondly, by inhibiting aromatase activity and reducing the local conversion of androgens to E2.

A complex endocrine conundrum.

We describe a case of recurrent primary hyperparathyroidism, manifested as 3 metachronous parathyroid adenomata, in a 50 year-old woman who also had Hashimoto hypothyroidism, gastric gastrointestinal stromal tumour (GIST), cysts in liver and kidneys, 5 intestinal polyps (one of these a villous adenoma), diverticulitis and telangiectasia of lips. She did not have medullary thyroid carcinoma (MTC). Genetic analysis of the CDC73 gene [for Hyperparathyroidism-jaw tumor (HPT-JT)], MEN1 for Multiple Endocrine Neoplasia Type1, CDKN1B for MEN4, SDHB and SDHD for Paraganglioma/Pheochromocytoma susceptibility, VHL for von Hippel-Lindau Syndrome, BMPR1A and SMAD4 for Juvenile Polyposis Syndrome (JPS) (sequencing and MLPA), karyotype and array CGH (44 K) were all normal. She was found to be homozygous for a synonomous germline variant in exon 14 (p. Ser836Ser) of the RET oncogene. This RET variant is of unclear clinical significance, and has been previously reported both in normal individuals and in individuals with MTC. It is unlikely that homozygosity for the RET variant has been casual in the multiple pathologies that our patient has developed.

Laparoscopic adrenalectomy for co-secreting aldosterone and cortisol adenomas.

There are few published data on aldosterone and cortisol co-secreting adrenal tumours. Failure to perform comprehensive preoperative endocrine investigations in patients with adrenal "incidentalomas" or in those thought to be secreting only one hormone may account for this. Clinically patients with such lesions may have evidence of hypertension and hypokalaemia with no features of cortisol excess. Preoperative diagnosis of such lesions with accurate endocrinological work up is essential to prevent adrenal insufficiency and haemodynamic crises following removal of such glands. We present a series of 4 patients with co-secreting tumours treated by laparoscopic adrenalectomy between September 2010 and March 2011. Our experience suggests that dual secretors are more common than originally thought. A high index of suspicion and adequate endocrine work up is paramount in diagnosing such tumours and in experienced hands, laparoscopic adrenalectomy with appropriate substitutive steroid cover is safe, feasible and curative for these functioning adrenal tumours.

A new long term hepatic complication in survivors of childhood haematological malignancy.

Hepatic abnormalities have been documented in survivors of childhood malignancies and a spectrum of liver diseases has been described in this group The risk factors for liver disease include: hepatic surgery; radiotherapy to field including liver; total body irradiation (TBI); chemotherapy, multiple blood transfusions and use of hematopoietic cell transplantation. We report three cases of hepatic adenomatosis (HA) in young women who had been treated for haematological malignancy as children and had bone marrow transplant. These women were on estrogen and growth hormone replacement. They had mild abnormalities of liver function tests. The diagnosis of HA was made on liver imaging and confirmed by liver biopsy. We also propose a hypothesis for the pathogenesis of hepatic adenomatosis in these patients which vascular damage, estrogen replacement and growth hormone deficiency.

Experimental study of the asymmetric charge transfer reaction between Ar+ ions and Fe atoms.

We investigate the Ar(+)-Fe asymmetric charge transfer (ACT) reaction using a combination of plasma diagnostics methods and a kinetic model of the afterglow plasma, which allow monitoring of the temporal evolution of the densities of different species. The iron vapor is created inside a discharge cell by cathode sputtering; its density is measured by atomic absorption spectroscopy. The rate coefficient of the reaction is evaluated from the emission intensity decay of Fe(+)∗ lines pumped by the ACT process in the He-Ar-Fe and Ar-Fe afterglow plasmas. The measurements yield a rate coefficient k = 7.6( ± 3.0) × 10(-9) cm(3) s(-1) at T = 300 K.

Pit-1 mutation and lipoedema in a family.

BACKGROUND: A 23-year-old male was referred to our clinic with diagnosis of idiopathic isolated growth hormone deficiency. A detailed family history revealed short stature and swelling of legs which only affected females in four generations of his family. METHODS: Combined pituitary function tests revealed growth hormone deficiency, secondary hypothyroidism and hypoprolactinemia in the proband. His mother had hypoprolactinemia and growth hormone deficiency. A diagnosis of inherited combined pituitary deficiency due to a PIT-1 mutation was suspected in view of the short stature with associated multiple pituitary hormone deficiencies. RESULTS: A mutation was identified in PIT-1 (POU1F1), 196C>T, which produces the amino acid change P24L in exon 1. The mutation was also found in the mother of the proband but not in his phenotypically normal half-sister. CONCLUSION: The case shows a novel association of two rare conditions Pit-1 mutation and lipoedema in a family that has not been described before. It also allows formulation of hypothesis on the interaction of growth hormone and sex steroids resulting in abnormal fat distribution in predisposed subjects at the time of puberty.

Latent autoimmune diabetes in the young.

This case represents latent autoimmune diabetes in the young (LADY), and demonstrates that autoimmune diabetes can be slowly progressive even in younger patients with insulin independency period lasting for more than two years.

Testosterone selectively increases primary follicles in ovarian cortex grafted onto embryonic chick membranes: relevance to polycystic ovaries.

Histological studies have demonstrated that polycystic ovaries (PCO) contain increased numbers of preantral follicles with a specific increase in primary follicles. Polycystic ovary syndrome is associated with hyperandrogenism and pre- and postnatal androgenization of primates increases the pool of growing follicles producing changes resembling PCO. In vitro studies could test the hypothesis that androgens alter early folliculogenesis, but conventional culture techniques for small follicles are generally unsuitable in non-rodent species. Our objective was to develop and use a method to investigate the effects of testosterone on early folliculogenesis. We adapted an in ovo technique in which lamb cortical ovarian fragments were grafted onto the chorioallantoic membrane of fertilised chick eggs. Optimal experimental conditions for vascularisation and survival of tissue were determined and the model then used to investigate the effects of testosterone on follicle growth. Eggs were inoculated with testosterone at the time of implantation of the ovarian tissue, which was retrieved 5 days later. Tissue was sectioned and follicles staged and counted. There was no wholesale initiation of primordial follicle growth over the 5-day in ovo culture. Importantly, the proportion of primordial, primary and secondary follicles remained similar to those in unimplanted tissue. Testosterone increased the number of primary follicles by 50% compared with controls, an effect that was largely due to a reduction in atresia. In conclusion, incubation of ovarian cortex with testosterone reproduces the changes in early folliculogenesis reported in histological studies of PCO.

Large area mass analyzer instrument for the chemical analysis of interstellar dust particles.

A new instrument to analyze the chemical composition of dust particles in situ in space has been developed. The large target area ( approximately 0.2 m(2)) makes this instrument well suited for detecting a statistically significant number of interstellar dust grains or other dust particles with a low flux. The device is a reflectron-type time-of-flight mass spectrometer that uses only flat electrodes for the generation of the parabolic potential. The instrument analyzes the ions from the impact generated plasma due to hypervelocity dust impacts onto a solid target surface. The SIMION ion optics software package is used to investigate different potential field configurations and optimize the mass resolution and focusing of the ions. The cylindrically symmetric instrument operates with six ring electrodes and six annular electrodes biased to different potentials to create the potential distribution of the reflectron. The laboratory model of the instrument has been fabricated and tested. Hypervelocity dust impacts are simulated by laser ablation using a frequency doubled Nd:YAG laser with approximately 8 ns pulse length. The experimental data show typical mass resolution m/Deltam approximately 200.

Insulin resistance and endothelial dysfunction in the brothers of Indian subcontinent Asian women with polycystic ovaries.

BACKGROUND: Ultrasonographic appearances of polycystic ovaries (PCO) are found in 50% of South London Indian subcontinent Asians, a population at high risk of coronary disease and type 2 diabetes (DM). PCO is a familial condition but the genetics remain to be clarified. At present, the only characteristic documented in male family members is premature male pattern balding before the age of 30 years. Our aim was to quantify insulin resistance and endothelial cell function in the brothers of Indian subcontinent Asian women with PCO and/or a family history of type 2 DM. METHODS: Indian subcontinent Asian women (n = 40, age 16-40 years) with a brother available for study were recruited from the local population. They were stratified into four groups according to the ultrasound appearances of PCO and/or a family history of type 2 DM. Control subjects had no PCO and no family history of DM. Insulin sensitivity (KITT) was measured using a short insulin tolerance test and endothelial function using brachial artery ultrasound to measure flow-mediated dilatation (FMD). FINDINGS: Groups were well matched for age, body mass index (BMI) and waist-hip circumference ratios. Asian women with PCO demonstrated insulin resistance independent of BMI or family history of diabetes. Women with PCO and a family history of DM have reduced FMD, though PCO alone was not a marker. The brothers of women with PCO also have insulin resistance, comparable to that associated with a family history of type 2 DM. This was associated with elevations of blood pressure, abnormalities in serum lipid concentrations and impaired endothelial cell function. Endothelial cell function was particularly impaired in those subjects with both a sister with PCO and a family history of DM. INTERPRETATION: In an ethnic minority population at higher risk of coronary heart disease, brothers of women with PCO have evidence of insulin resistance and endothelial cell dysfunction in early adult life. Further study is required to establish whether these findings are associated with an increased incidence of cardiovascular events in this population.

Is the defect in pro-hormone processing in Type 2 diabetes mellitus restricted to the beta cell?

AIMS: To investigate whether the defect in pro-hormone processing in people with Type 2 diabetes mellitus is restricted to the pancreatic beta cell or whether there is evidence of a more generalized abnormality. METHODS: Ten Indian subcontinent Asian women with diet-controlled Type 2 diabetes were compared with a control group of nine non-diabetic Asian women who were matched for body mass index. All subjects underwent a standard 75 g oral glucose tolerance test during which plasma glucose, insulin, proinsulin and 32,33 split proinsulin were measured. Subjects in both groups then underwent an intravenous corticotrophin-releasing hormone (CRH) test with 100 microg human CRH. Plasma cortisol, adrenocorticotrophic hormone (ACTH) and ACTH precursors were measured. RESULTS: Basal levels of insulin were lower in diabetic subjects (32.5 (12.5-52) pmol/l) than in the control group (42.2 (21.4-63.0) pmol/l); normalized geometric mean (95% confidence interval), P<0.05; as were the levels at 30 min (29.5 (3.7-55.3) pmol/l) and (34.4 (10.7-58.2) pmol/l), P<0.05. The levels at 60 min were (26.7 (6.4-47.0) pmol/l) in subjects with diabetes and (13.6 (-11.3-38.5) pmol/l) in controls, P<0.05 and at 90 min these were (43.4 (19.4-67.4) pmol/l) and (19.3 (-4.6-43.3) pmol/l), P<0.05, respectively, after the 75-g oral glucose load. The acute insulin response was markedly reduced in the subjects with diabetes (1.8 (0.60-3.1) pmol insulin/ mmol glucose), compared with the control group (31.4 (8.0-54) pmol/l insulin/mmol glucose), P<0.005. Intact proinsulin was much higher in the diabetic subjects (23.9 (10.1-37) pmol/1) than in the control group (7.2 (3.9-10) pmol/1), P<0.002, as was the percentage of proinsulin-like molecules (28 (14-42) and 12 (8-17)%), respectively, P<0.01. There were no differences between basal or stimulated levels of ACTH precursors, ACTH or cortisol between the diabetic subjects and the controls. CONCLUSIONS: The defect in insulin secretion in Indian subcontinent Asian women with Type 2 diabetes is similar to that described in other populations with an increased prevalence of Type 2 diabetes. The absence of any defect in the processing of cortisol precursors in the women with Type 2 diabetes suggests that they do not have a generalized defect of hormone processing.

Reduced bone mineral density after surgical treatment for obesity.

OBJECTIVE: To investigate whether osteoporosis occurs after surgical treatment for obesity. DESIGN: A cross-sectional study of five groups of subjects who had undergone surgical treatment for obesity: five pre-menopausal women; 13 post-menopausal women; seven post-menopausal women taking oestrogen replacement (HRT); five men; and six women who had undergone surgical reversal (mean time 7 y). SUBJECTS: Thirty-six Caucasian subjects who had undergone jejunoileal or pancreaticobiliary bypass surgery at St George's Hospital between 1971 and 1992. Their mean age was 50.8 y (range 32-69 y) and the median time since the operation was 14.8y (range 4-23 y). MEASUREMENTS: A clinical questionnaire was used to exclude possible factors, which might influence bone mineral density. A single blood sample was collected for measurement of calcium, phosphate, alkaline phosphatase, albumin, magnesium, zinc, creatinine, thyroxine, 25-hydroxy-vitamin D, sex steroids, gonadotrophins and IGF-1 and 24 h urine calcium excretion was measured. Bone mineral density (BMD) was measured in the lumbar (L2-L4) spine (LS) and femoral neck (FN) by dual energy X-ray absorptiometry (DEXA). RESULTS: There was no difference in serum calcium, alkaline phosphatase, IGF-1, 25-hydroxy-vitamin D (25-OH vitamin D), magnesium or zinc concentrations between the five groups. The LS-BMD T score was lower (P < 0.05) in male subjects ( -2.08 +/- 1.04 mean 1.0 +/- s.d) and post-menopausal women not taking HRT ( -1.21 +/- 1.33) compared to the surgically reversed group (0.87 +/- 2.36). The male group was most severely affected, despite normal serum testosterone concentrations. Two of the five men studied, had a LS-BMD T score < -2.5 and two had a LS-BMD T score between -1.0 and -2.5. In contrast, six of the seven post-menopausal women on HRT had an LS BMD T score > - 1.0. There was no difference in the FN-BMD between the five groups. The presence of low BMD was not related to age, duration of bypass, or degree of postoperative weight loss. Iliac crest bone biopsies in three subjects with low BMD, confirmed the presence of osteoporosis. CONCLUSIONS: Reduced bone mineral density is a complication of jejunoileal bypass surgery.

Polycystic ovaries and associated metabolic abnormalities in Indian subcontinent Asian women.

OBJECTIVES: To determine the prevalence of polycystic ovaries (PCO) in Asian women living in England who are of Indian subcontinent origin or ancestry and to investigate the relationship between the presence of PCO and/or non-insulin dependent diabetes mellitus (NIDDM) and insulin sensitivity and other metabolic parameters. DESIGN: A random sample of Indian subcontinent Asian women was obtained from the lists of local General Practitioners and a translating service. These women were invited to attend for a medical history questionnaire, examination, venous blood sample for hormonal assessment and transvaginal ovarian ultrasonography. Groups of women without PCO or NIDDM, with NIDDM but not PCO, with PCO but not NIDDM and with both NIDDM and PCO were drawn at random from this population and from Indian subcontinent Asian women attending the Diabetes Unit. They underwent further studies, including measurement of insulin sensitivity using a short intravenous insulin tolerance test. SUBJECTS: 212 Indian subcontinent Asian women aged 18-40 took part in the initial study. Insulin sensitivity was measured in 13 women without PCO or NIDDM, 13 women with NIDDM but not PCO, 15 women with PCO but not NIDDM and 12 women with both NIDDM and PCO. MEASUREMENTS: The main outcome measures were prevalence of polycystic ovaries, clinical features of hyperandrogenism, fertility, blood pressure, serum gonadotrophins, testosterone and sex hormone binding globulin, fasting blood lipids, glucose and insulin, and insulin sensitivity. RESULTS: The prevalence of PCO in Indian subcontinent Asian women was 52% (110/212). There were significant associations between PCO and menstrual irregularity; infertility; the Ferriman and Gallwey score for body hair distribution; the presence of acanthosis nigricans and the fasting blood glucose concentration. There were no differences between women with PCO and those with normal ovarian morphology with respect to systolic and diastolic blood pressure, fasting total, HDL and LDL cholesterol and triglyceride concentrations. The subgroup of women without PCO or NIDDM had the highest insulin sensitivity (189.1 +/- 46.4 mumol glucose/l/min, mean +/- SD) and the women with both PCO and NIDDM had the lowest insulin sensitivity (80.5 +/- 30.9 mumol glucose/l/min). There was no significant difference in insulin sensitivity between those with PCO but not NIDDM (125.0 +/- 59.5 mumol glucose/l/min) and those with NIDDM but not PCO (120.8 + 38.0 mumol glucose/l/min). The effects of NIDDM and PCO on insulin sensitivity were independent; the effect of PCO on insulin sensitivity was -60 mumol glucose/l/min (95% confidence interval -100 to -21, P = 0.004) and the effect of NIDDM was -68 mumol glucose/l/min (95% confidence interval -105 to -31, P < 0.001). There were no significant relationships between insulin sensitivity and fasting plasma insulin, systolic or diastolic blood pressure, fasting serum cholesterol or triglyceride. CONCLUSIONS: The prevalence of polycystic ovaries in Indian subcontinent Asian women is very high and it has significant clinical associations. Polycystic ovaries and non-insulin dependent diabetes mellitus are associated with similar degrees of reduced insulin sensitivity in this population. Their effects are independent suggesting that these changes in insulin sensitivity involve different mechanisms. Polycystic ovaries unlike non-insulin dependent diabetes mellitus, are not associated with a defect in the secretion of insulin.