Fourteen Caucasian families with 81 affected individuals have been assessed in which polycystic ovaries/male pattern baldness (PCO/MPB) segregates as an autosomal dominant phenotype (1). The gene CYP17, coding for P450c17 alpha (17 alpha-hydroxylase; 17/20 lyase) on chromosome 10q24.3 is the rate-limiting step in androgen biosynthesis. We have identified a new single base change in the 5' promoter region of CYP17 by heteroduplex analysis. This creates an additional SP1-type (CCACC box) promoter site, which may cause increased expression. This base change also creates a recognition site for the restriction enzyme MspA1 allowing a simple screening procedure. There is a significant association between the presence of this base change (A2) and the affected state for consecutively identified Caucasian women with PCO as compared either to consecutively matched controls (P = 0.03) with an odds ratio for those with at least one A2 allele of 3.57, or to a random population (P = 0.02) with an odds ratio of 2.50. Within the fourteen families, members with PCO or MPB have a significant association with the occurrence of at least one A2 allele compared to their normal relatives, with an odds ratio of 2.20 (P = 0.05). The base change does not cosegregate with the affected phenotype within the families showing association, demonstrating that this mutation of CYP17 does not cause PCO/MPB. Variation in the A2 allele of the CYP17 gene is a significant factor modifying the expression of PCO/MPB in families where it has been demonstrated to segregate as a single gene disorder, but it is excluded as the primary genetic defect.

Two hundred and sixty-three women with ultrasound-diagnosed polycystic ovary syndrome were studied of whom 91 (35%) were obese (BMI greater than 25 kg/m2). Obese women with PCOS had a greater prevalence of hirsutism (73% compared with 56%) and menstrual disorders than non-obese subjects. Total testosterone and androstenedione concentrations in serum were similar in the two subgroups but SHBG concentrations were significantly lower, and free testosterone levels higher, in obese compared with lean subjects. In addition, concentrations of androsterone glucuronide, a marker of peripheral 5 alpha-reductase activity, were higher in obese than in non-obese women with PCOS. There were no significant correlations of either SHBG or free testosterone with androsterone glucuronide suggesting that obesity has independent effects on transport and on metabolism of androgen. There were no significant differences between the subgroups in either baseline gonadotrophin concentrations or the pulsatile pattern of LH and FSH secretion studied over an 8-h period. There was, however, an inverse correlation of FSH with BMI, but only in the obese subgroup. In conclusion, the increased frequency of hirsutism in obese compared with lean women with PCOS is associated with increased bio-availability of androgens to peripheral tissues and enhanced activity of 5 alpha-reductase in obese subjects. The mechanism underlying the higher prevalence of anovulation in obese women remains unexplained.

No abstract

Clomiphene citrate is the treatment of first choice in the management of infertility in normally oestrogenized, anovulatory women (WHO group II). The majority of women with 'pure' anovulatory infertility respond to treatment with clomiphene citrate. The rates of pregnancy and miscarriage are close to those expected in a normal fertile population. Basal hormone concentrations do not predict outcome. An increased body mass index is the only factor which is consistently associated with a decreased response to clomiphene citrate; it follows therefore, that weight reduction should be an important part of therapy in anovulatory women. According to our data, only an increased luteinizing hormone value immediately post clomiphene citrate predicted an adverse pregnancy outcome in women who conceived. Clomiphene citrate, along with other ovulation induction therapies, can cause multiple follicular development, with a risk of ovarian hyperstimulation and multiple pregnancy. Ultrasound monitoring of treatment is important in order to choose the appropriate dose of clomiphene citrate in subsequent cycles and to minimize the risks of hyperstimulation and multiple pregnancy. When couples with other factors contributing to subfertility are excluded, the cumulative conception rate continues to rise after 6 months of treatment with clomiphene citrate, reaches a plateau by treatment cycle 12 and approaches that of the normal population. It has been reported that prolonged use of clomiphene citrate may be associated with an increased risk of a borderline or invasive ovarian tumour. Taking into consideration these observations, we recommend that anovulatory women responsive to clomiphene citrate should be treated for at least 6 cycles before considering more complex or invasive methods of ovulation induction, and that treatment should probably be limited to a maximum of 12 cycles.

Biochemical data implicate an underlying disorder of androgen biosynthesis and/or metabolism in the aetiology of polycystic ovary syndrome (PCOS). We have examined the segregation of the genes coding for two key enzymes in the synthesis and metabolism of androgens, cholesterol side chain cleavage (CYP11a) and aromatase (CYP19), with PCOS in 20 multiply-affected families. All analyses excluded CYP19 cosegregation with PCOS, demonstrating that this locus is not a major determinant of risk for the syndrome. However, our results provide evidence for linkage to the CYP11a locus (NPL score = 3.03, p = 0.003). Parametric analysis using a dominant model suggests genetic heterogeneity, generating a maximum HLOD score of 2.7 (alpha = 0.63). An association study of 97 consecutively identified Europids with PCOS and matched controls demonstrates significant allelic association of a CYP11a 5' UTR pentanucleotide repeat polymorphism with hirsute PCOS subjects (p = 0.03). A strong association was also found between alleles of this polymorphism and total serum testosterone levels in both affected and unaffected individuals (p = 0.002). Our data demonstrate that variation in CYP11a may play an important role in the aetiology of hyperandrogenaemia which is a common characteristic of polycystic ovary syndrome.

No abstract

Following a single blind, cross-over and non-randomized design we investigated the effect of 7-day use of chlorhexidine (CHX) mouthwash on the salivary microbiome as well as several saliva and plasma biomarkers in 36 healthy individuals. They rinsed their mouth (for 1 min) twice a day for seven days with a placebo mouthwash and then repeated this protocol with CHX mouthwash for a further seven days. Saliva and blood samples were taken at the end of each treatment to analyse the abundance and diversity of oral bacteria, and pH, lactate, glucose, nitrate and nitrite concentrations. CHX significantly increased the abundance of Firmicutes and Proteobacteria, and reduced the content of Bacteroidetes, TM7, SR1 and Fusobacteria. This shift was associated with a significant decrease in saliva pH and buffering capacity, accompanied by an increase in saliva lactate and glucose levels. Lower saliva and plasma nitrite concentrations were found after using CHX, followed by a trend of increased systolic blood pressure. Overall, this study demonstrates that mouthwash containing CHX is associated with a major shift in the salivary microbiome, leading to more acidic conditions and lower nitrite availability in healthy individuals.Chlorhexidine (CHX) has been commonly used in dental practice as antiseptic agent since 1970, due to its long-lasting antibacterial activity with a broad-spectrum of action 1 . Since then, many clinical trials have shown effective results of CHX for the clinical management of dental plaque and gingival inflammation and bleeding 2-4 . This is supported by other studies using in vitro methods and reporting positive results of CHX in reducing the proliferation of bacterial species associated with periodontal disease, such as Enterobacteria, Porphyromonas gingivalis, Fusobacterium nucleatum, as well as different species of Actinomyces and Streptococcus, including Streptococcus mutans, which is considered the main etiological agent of dental caries 4,5 . Other studies have also reported that the use of CHX was effective in the treatment of halitosis, especially in reducing the levels of halitosis-related bacteria colonising the dorsal surface of the tongue 6 .The anti-microbial activity of CHX however, has been extensively studied using in vitro culture methods, which limit the identification and cultivation of all microorganisms in the environment 4 . To the best of our knowledge, only one recent study has investigated the effect of CHX mouthwash on mixed bacterial communities (microbiome) of the tongue using new genome sequencing techniques such as 16 S rRNA 7 . The study found differences in over 10 different species colonizing the tongue, and a lower microbial diversity after using CHX for a week, but did not analyse other parameters related to oral health such as pH, lactate production or buffering capacity 7 . Additionally, we and others have recently shown that the use of CHX in healthy subjects can attenuate the nitrate-reducing activity of oral bacteria by at least 80% 8-11 . This in turn leads to lo...

Metformin does not improve weight loss or menstrual frequency in obese patients with PCOS. Weight loss alone through lifestyle changes improves menstrual frequency.