Gerard S. Conway

Risk factors for coronary artery disease in lean and obese women with the polycystic ovary syndrome

OBJECTIVE The evidence that some women with the polycystic ovary syndrome (PCOS) are hyperinsulinaemic has brought into question their risk of developing early coronary artery disease. We have focused on three cardiac risk factors which have been associated with hyperinsullnaemia by measuring glucose tolerance, fasting serum lipid concentrations and blood pressure in women with PCOS.

Linkage and association of insulin gene VNTR regulatory polymorphism with polycystic ovary syndrome

BACKGROUND Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting up to 10% of women of reproductive age. Women with anovulatory PCOS have hyperinsulinaemia, insulin resistance, and dyslipidaemia, and the syndrome is associated with greatly increased risks of non-insulin-dependent diabetes mellitus and cardiovascular disease and it often clusters in families. The VNTR (variable number of tandem repeats) locus upstream of the insulin gene (INS) regulates insulin expression. We have studied INS VNTR as a candidate genetic locus for susceptibility to PCOS. METHODS We evaluated linkage of PCOS to the INS VNTR locus on chromosome 11p15.5 in 17 families with several cases, and looked for an association between VNTR and PCOS in two additional clinic populations. VNTR genotypes were designated I/I, I/III, and III/III and linkage disequilibrium mapping was used to test the primary role of the VNTR. FINDINGS In a group of PCOS/male pattern baldness families, we obtained positive evidence for linkage to 11p15.5 (p = 0.002). The INS VNTR III/III genotype was associated with an increased risk of PCOS in two independent case-control studies (odds ratios 8.20 [p = 0.005] and 5.70 [p = 0.043]). Multilocus linkage disequilibrium mapping suggests that VNTR itself is the predisposing locus. INTERPRETATION Mapping of susceptibility to PCOS to the INS VNTR implies that PCOS is due, in part, to an inherited alteration in insulin production. The data suggest a mechanistic link between type 2 diabetes and PCOS, which is a risk factor for diabetes later in life.

Functional imaging of neuroendocrine tumors with combined PET/CT using 68Ga-DOTATATE (DOTA-DPhe1,Tyr3-octreotate) and 18F-FDG.

The aim was to assess the relevant distribution of the novel PET tracer 68Ga‐DOTATATE in neuroendocrine tumors (NETs) with combined positron emission tomography / computed tomography (PET/CT) and compare its performance with that of 18F‐FDG PET/CT.

Spatial abilities following prenatal androgen abnormality: targeting and mental rotations performance in individuals with congenital adrenal hyperplasia.

In most mammals, behaviors that show sex differences are influenced by androgen during early life. In the current study, the hypothesis that androgen influences the development of human spatial abilities was investigated. Participants included 40 females and 29 males with congenital adrenal hyperplasia (CAH), a genetic disorder that causes overproduction of adrenal androgens beginning prenatally, and 29 unaffected female and 30 unaffected male relatives of individuals with CAH. Participants ranged in age from 12-45 years. Measures of spatial abilities included two mental rotations tasks and two targeting tasks, all of which showed large sex differences favoring males in the unaffected relative controls. Females with CAH (exposed to higher than normal levels of androgen prenatally) performed better than unaffected females on the targeting tasks, and resembled unaffected males and males with CAH in this respect. However, females with CAH did not perform better than unaffected females on the measures of mental rotations abilities. Males with CAH showed unaltered performance on the targeting tasks, and impaired performance on the mental rotations tasks. Results are discussed in terms of differences in experiential and hormonal contributions to different spatial abilities, as well as in terms of possible differences in critical periods for hormonal influences on targeting versus mental rotations abilities. Specifically, we speculate that, although androgen may influence targeting abilities prenatally, if hormones influence the development of mental rotations ability, they do so at some other time, perhaps during the first six months of postnatal life.

The pathophysiology of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder of uncertain aetiology, which affects between 6 and 10% of women of the reproductive age. The heterogeneity of both the ovarian morphology and clinical findings in women with polycystic ovaries has been well recognized since Stein & Leventhal’s (1935) first report and gradually led to the establishment of the term polycystic ovary syndrome. The many features of this syndrome can be broadly divided into three categories: clinical, endocrine and metabolic. The clinical features include menstrual abnormalities, hirsutism, acne, alopecia, anovulatory infertility and recurrent miscarriages. The endocrine features include elevated androgens, luteinizing hormone, oestrogen and prolactin levels. The metabolic aspects of this syndrome include insulin resistance, obesity, lipid abnormalities and an increased risk for impaired glucose tolerance and type 2 diabetes mellitus (type 2 DM). Controversy persists regarding the criteria used for PCOS diagnosis. Currently, the recommended diagnostic criteria for PCOS are hyperandrogenism and ovulatory dysfunction with the exclusion of specific disorders, such as nonclassic adrenal 21hydroxylase deficiency, Cushing’s syndrome, hyperprolactinaemia and androgen-producing tumours. This clinical definition reflects a 1990 National Institutes of Health–National Institute of Child Health and Development Consensus Conference (Zawadeski & Dunaif, 1992) in which there was poor agreement among the 58 specialists who completed a questionnaire on the diagnostic criteria for PCOS, with no single criterion endorsed as ‘definite or probable’ by more than 64% of respondents. Interestingly, the conclusion of this meeting was that the polycystic ovary morphology is consistent with, but not essential for, the diagnosis of the syndrome. Sonographic criteria for polycystic ovaries have been refined with advances in technology (Fox, 1999; Atiomo et al ., 2000) and transvaginal ultrasound is currently the gold standard for diagnosing polycystic ovaries. Using the most conservative criteria based on transabdominal ultrasound, the presence of 10 or more cysts, 2–8 mm in diameter, arranged either peripherally around a dense core of stroma or scattered throughout an increased amount of stroma (Adams et al ., 1985), up to 23% of normal volunteer women meet the sonographic criteria for polycystic ovaries (Clayton et al ., 1992). On the other hand, many investigators have maintained that ovaries from women with PCOS may be sonographically normal (Hann et al ., 1984; Timor-Tritsch & Rottem, 1998). Thus, the ovarian morphological changes must be distinguished from the endocrine syndrome of PCOS and be considered as a sign rather and not a disease.

The polycystic ovary syndrome: a position statement from the European Society of Endocrinology.

Polycystic ovary syndrome (PCOS) is the most common ovarian disorder associated with androgen excess in women, which justifies the growing interest of endocrinologists. Great efforts have been made in the last 2 decades to define the syndrome. The presence of three different definitions for the diagnosis of PCOS reflects the phenotypic heterogeneity of the syndrome. Major criteria are required for the diagnosis, which in turn identifies different phenotypes according to the combination of different criteria. In addition, the relevant impact of metabolic issues, specifically insulin resistance and obesity, on the pathogenesis of PCOS, and the susceptibility to develop earlier than expected glucose intolerance states, including type 2 diabetes, has supported the notion that these aspects should be considered when defining the PCOS phenotype and planning potential therapeutic strategies in an affected subject. This paper offers a critical endocrine and European perspective on the debate on the definition of PCOS and summarises all major aspects related to aetiological factors, including early life events, potentially involved in the development of the disorder. Diagnostic tools of PCOS are also discussed, with emphasis on the laboratory evaluation of androgens and other potential biomarkers of ovarian and metabolic dysfunctions. We have also paid specific attention to the role of obesity, sleep disorders and neuropsychological aspects of PCOS and on the relevant pathogenetic aspects of cardiovascular risk factors. In addition, we have discussed how to target treatment choices based according to the phenotype and individual patients needs. Finally, we have suggested potential areas of translational and clinical research for the future with specific emphasis on hormonal and metabolic aspects of PCOS.

Idiopathic gonadotrophin deficiency: genetic questions addressed through phenotypic characterization*

OBJECTIVE The association of idiopathic hypogonadotrophic hypogonadism (IHH) with congenital olfactory deficit defines Kallmanns syndrome (KS). Although a small proportion of IHH patients have been found to harbour defined genetic lesions, the genetic basis of most IHH cases remains to be elucidated. Genes currently recognized to be involved comprise KAL (associated with X‐linked‐KS), the GnRH receptor (associated with resistance to GnRH therapy), DAX 1 (associated with adrenohypoplasia congenita) and three loci also associated with obesity, leptin (OB), leptin receptor (DB) and prohormone convertase (PC1). Because of the rarity of the condition and the observation that patients are almost universally infertile without assistance, familial transmission of IHH is encountered infrequently and pedigrees tend to be small. This has constrained the ability of conventional linkage studies to identify other candidate loci for genetic IHH. We hypothesized that a systematic clinical evaluation of a large patient sample might provide new insights into the genetics of this rare disorder. Specifically, we wished to examine the following propositions. First, whether normosmic (nIHH) and anosmic (KS) forms of IHH were likely to be genetically discrete entities, on the basis of quantitative olfactory testing, analysis of autosomal pedigrees and the prevalence of developmental defects such as cryptorchidism and cleft palate. Second, whether mirror movements and/or unilateral renal agenesis were specific phenotypic markers for X‐linked‐KS.

The prevalence of polycystic ovaries in women with type 2 diabetes mellitus

Polycystic ovary syndrome (PCOS) and type 2 diabetes mellitus are both common conditions associated with insulin resistance and compensatory hyperinsulinaemia. Previous reports have noted that impaired glucose tolerance and diabetes are common in women with PCOS. In this report we present the results of the converse study: the prevalence of polycystic ovaries in premenopausal women presenting with type 2 diabetes mellitus.

Premature Ovarian Failure

The diagnosis of premature ovarian failure is based on the finding of amenorrhoea before age 40 associated with follicle-stimulating hormone levels in the menopausal range. Screening for associated autoimmune disorders and karyotyping, particularly in early onset disease, constitute part of the diagnostic work up. There is no role for ovarian biopsy or ultrasound in making the diagnosis. Management essentially involves hormone replacement and infertility treatment, the most successful being assisted conception with donated oocytes. Embryo cryopreservation, ovarian tissue or oocyte cryopreservation and in vitro maturation of oocytes hold promise in cases where ovarian failure is foreseeable as in women undergoing cancer treatments.

Hypertension is a major risk factor for aortic root dilatation in women with Turner's syndrome

Women with Turners syndrome (TS) have a threefold increase in mortality, primarily as a result of their cardiovascular complications. Recently, the risk of fatal aortic dissection has come to light as a major cause of mortality in women with TS. The aim of this study was to assess the prevalence of aortic root dilatation in a group of women with TS and to investigate the factors contributing to its development.