Gul Bano

Health-related quality of life in women with polycystic ovary syndrome: a comparison with the general population using the Polycystic Ovary Syndrome Questionnaire (PCOSQ) and the Short Form-36 (SF-36).

Background. We examined whether women with polycystic ovary syndrome (PCOS) have poorer health-related quality of life (HRQoL) than women in the general population and than patients with other medical conditions. Method. Women with PCOS were recruited from an outpatient clinic and a control group was recruited from a family planning clinic. Both groups completed the Short Form-36 (SF-36) and the Polycystic Ovary Syndrome Questionnaire (PCOSQ). SF-36 data from the Oxford Health and Lifestyle Survey were used to compare PCOS with other conditions. Results. Twenty-two women with PCOS and 96 control women took part. Women with PCOS scored lower in both summary scores of the SF-36 and in all domains of the PCOSQ. After adjusting for body mass index, the differences between the groups in the SF-36 disappeared, while those in the PCOSQ remained. When compared with asthma, epilepsy, diabetes, back pain, arthritis and coronary heart disease, our PCOS group had the same or better physical HRQoL but poorer psychological HRQoL. The PCOSQ showed good internal reliability, good concurrent validity and good discriminant validity. Conclusions. PCOS has a negative impact on HRQoL even when compared with other serious health conditions. The PCOSQ is reliable and valid for clinical use.

Tenofovir-linked hyperparathyroidism is independently associated with the presence of vitamin D deficiency.

Background:To determine patient and treatment characteristics associated with vitamin D deficiency (VDD) in an UK inner city HIV-1-positive adult cohort. Methods:Two hundred twenty-seven HIV-positive patients attending prospectively for routine blood tests in winter had serum 25-hydroxyvitamin D and parathyroid hormone (PTH) concentrations and other routine chemistry measured. Those with and without VDD were defined as having serum 25-hydroxyvitamin D concentrations <50 nmol/L and >75 nmol/L, respectively. Characteristics were compared between patients with and without VDD. The effects of VDD, tenofovir use, and their interaction on chemical measures were investigated. Results:VDD was found in 57% (131 of 227) of patients. Independent associations included nonwhite ethnicity [adjusted odds ratio (95% confidence interval): 7.40 (2.52 to 21.7)], higher random blood glucose [2.38 (1.24 to 4.57) per mmol/L], higher estimated glomerular filtration rate [eGFR: 1.04 (1.01 to 1.06)], and higher PTH [1.19 (1.00 to 1.42)]. PTH was higher in those receiving tenofovir (median 7.2 pmol/L) than other patients (4.3; P < 0.001) overall, but high PTH with tenofovir occurred only in the context of VDD. Tenofovir use was not associated with serum creatinine or eGFR overall but interacted with vitamin D status (P = 0.05 and P = 0.08, respectively), being linked to somewhat higher creatinine and lower eGFR among patients without VDD but higher eGFR in VDD patients. Conclusions:25(OH) VDD is associated with tenofovir-linked hyperparathyroidism and also with higher eGFR.

Large Genomic Deletions in AIP in Pituitary Adenoma Predisposition

CONTEXT Germline mutations in AIP have been recently shown to cause pituitary adenoma predisposition (PAP). Subsequently, many intragenic germline mutations have been reported, both in familial and in sporadic settings. OBJECTIVE Our objective was to evaluate the possible contribution of large genomic germline AIP deletions, an important mutation type in tumor predisposition syndromes, in PAP. DESIGN Here, we applied the multiplex ligation-dependent probe amplification assay to examine whether large genomic AIP or MEN1 alterations account for a subset of PAP cases. PATIENTS The study was performed on familial and sporadic pituitary adenoma cases of European origin, which had previously tested negative for germline AIP and MEN1 mutations by sequencing. RESULTS Two of 21 pituitary adenoma families (9.5%) were found to harbor an AIP deletion. No copy number changes were detected among 67 sporadic pituitary adenoma patients. No MEN1 deletions were found. CONCLUSIONS The present study shows that large genomic AIP deletions account for a subset of PAP. Therefore, in suspected PAP cases undergoing counseling and AIP genetic testing, multiplex ligation-dependent probe amplification could be considered if direct sequencing does not identify a mutation.

IVF/ICSI in a woman with active acromegaly: Successful outcome following treatment with pegvisomant

A 29 year old woman with difficult to control acromegaly and a pituitary macroadenoma responded to pegvisomant therapy and subsequently conceived with her first cycle of in-vitro fertilization and intra-cytoplasmic sperm injection. Pregnancy was complicated by gestational diabetes, pituitary gland enlargement and deteriorating visual fields. Conservative management with elective cesarean section was performed at 32 weeks gestation. A healthy boy was delivered who remains developmentally normal at 1 year. This complex case required intricate care by a multi-disciplinary team and is likely to represent the first in many cases of assisted conception on pegvisomant therapy for active acromegaly.

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 androgenisation 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.

Glucose homeostasis, obesity and diabetes

Plasma glucose levels are maintained within a narrow range in normal individuals. Both insulin-dependent and insulin-independent processes contribute to fasting and postprandial plasma glucose regulation. The brain and nervous system are insulin independent. Muscle and adipose tissue are responsive to insulin and can use either glucose or ketones and free fatty acids as their primary metabolic fuel. The essential components of metabolic syndrome are obesity, glucose intolerance, insulin resistance, lipid disturbances, and hypertension. The risk of type 2 diabetes increases exponentially as body mass index increases above about 25 kg/m2. The links between obesity and type 2 diabetes include proinflammatory cytokines, insulin resistance, deranged fatty acid metabolism, and cellular processes. Modest weight reduction can improve glycaemic control and reduce diabetes risk. Obesity also leads to hyperinsulinaemia and insulin resistance, with a progressive decrease in insulin secretory function. Ageing is another important risk factor for metabolic disorders, including obesity, impaired glucose tolerance, and type 2 diabetes.

Breakpoint determination of X;autosome balanced translocations in four patients with premature ovarian failure.

Premature ovarian failure (POF) is a disorder characterized by amenorrhea and elevated serum gonadotropins before 40 years of age. As X chromosomal abnormalities are often recognized in POF patients, defects of X-linked gene may contribute to POF. Four cases of POF with t(X;autosome) were genetically analyzed. All the translocation breakpoints were determined at the nucleotide level. Interestingly, COL4A6 at Xq22.3 encoding collagen type IV alpha 6 was disrupted by the translocation in one case, but in the remaining three cases, breakpoints did not involve any X-linked genes. According to the breakpoint sequences, two translocations had microhomology of a few nucleotides and the other two showed insertion of 3–8 nucleotides with unknown origin, suggesting that non-homologous end-joining is related to the formation of all the translocations.

Mutational analysis of the adaptor protein 2 sigma subunit (AP2S1) gene: search for autosomal dominant hypocalcemia type 3 (ADH3).

CONTEXT Autosomal dominant hypocalcemia (ADH) types 1 and 2 are due to calcium-sensing receptor (CASR) and G-protein subunit-α11 (GNA11) gain-of-function mutations, respectively, whereas CASR and GNA11 loss-of-function mutations result in familial hypocalciuric hypercalcemia (FHH) types 1 and 2, respectively. Loss-of-function mutations of adaptor protein-2 sigma subunit (AP2σ 2), encoded by AP2S1, cause FHH3, and we therefore sought for gain-of-function AP2S1 mutations that may cause an additional form of ADH, which we designated ADH3. OBJECTIVE The objective of the study was to investigate the hypothesis that gain-of-function AP2S1 mutations may cause ADH3. DESIGN The sample size required for the detection of at least one mutation with a greater than 95% likelihood was determined by binomial probability analysis. Nineteen patients (including six familial cases) with hypocalcemia in association with low or normal serum PTH concentrations, consistent with ADH, but who did not have CASR or GNA11 mutations, were ascertained. Leukocyte DNA was used for sequence and copy number variation analysis of AP2S1. RESULTS Binomial probability analysis, using the assumption that AP2S1 mutations would occur in hypocalcemic patients at a prevalence of 20%, which is observed in FHH patients without CASR or GNA11 mutations, indicated that the likelihood of detecting at least one AP2S1 mutation was greater than 95% and greater than 98% in sample sizes of 14 and 19 hypocalcemic patients, respectively. AP2S1 mutations and copy number variations were not detected in the 19 hypocalcemic patients. CONCLUSION The absence of AP2S1 abnormalities in hypocalcemic patients, suggests that ADH3 may not occur or otherwise represents a rare hypocalcemic disorder.

Maternally inherited diabetes and deafness (MIDD): Diagnosis and management

Maternally inherited diabetes with deafness is rare diabetes caused by a mitochondrial DNA defect. 85% of cases are associated with m.3243A>G mutation. It is important to diagnose this form of diabetes because of the unique management issues and associated comorbidities. A very strong family history of diabetes, deafness and presence of retinal dystrophy should prompt an investigation for MIDD. Microvascular complications out of keeping with duration of diabetes are another clue to the diagnosis. Retinal and renal manifestations of mitochondrial disease may be confused for diabetic complications. Glutamic acid decarboxylase (GAD) autoantibody negativity in a nonobese diabetic is another clue. Cardiac conduction defects and GDM may also raise suspicion as to the diagnosis. Recognizing this etiology of DM should promote family screening, genetic counseling, screening of associated comorbidities, avoidance of metformin, and cautious use of statins. We report a 77 years old lady with MIDD who was being followed up as insulin requiring type 2 diabetes. We then identified 5 more patients with MIDD in the same clinic. They all had A3243 mutation with characteristic clinical presentation. The pharmacological approaches discussed in the paper are unlikely to work in these patients as they were diagnosed late.

Carney triad versus Carney Stratakis syndrome: two cases which illustrate the difficulty in distinguishing between these conditions in individual patients.

Carney triad is a usually sporadic association of pulmonary chondroma, gastrointestinal stromal tumours, and paraganglioma. The majority of patients have two of these tumours, the gastric and pulmonary tumours being the most common combination. Carney Stratakis syndrome is an association of familial paraganglioma and gastric stromal sarcoma and it is considered to be a distinct condition from Carney triad as it is dominantly inherited and not associated with pulmonary chondroma. We report two unrelated patients each with two components of Carney triad. A pathological mutation in succinate dehydrogenase subunit B gene was identified in one and a variant in the same gene was identified in the other. This report demonstrates the difficulty in distinguishing between Carney triad and Carney Stratakis syndrome due to the rarity of the individual components. The fact that most patients with Carney triad have only two components of the Triad, and the long interval often seen between the occurrence of the first and the second component makes it difficult to differentiate confidently between the two conditions. Molecular information should improve the diagnosis of Carney triad.