BACKGROUND: Genetic association studies have reported single nucleotide polymorphisms (SNPs) at Chromosome 19q13.3 to be associated with prostate cancer (PCa) risk. Recently, the rs61752561 SNP (Asp84Asn substitution) in exon-3 of the kallikrein-related peptidase 3 (KLK3) gene encoding Prostate-Specific Antigen (PSA), was reported to be strongly associated with PCa risk (P=2.3×10−8). However, biological contribution of the rs61752561 SNP to PCa risk, has not been elucidated. METHODS: Recombinant PSA proteins were generated to assess the SNP-mediated biochemical changes by stability and substrate activity assays. PC3 cell-PSA overexpression models were established to evaluate the effect of the SNP on PCa pathogenesis. Genotype-specific correlation of the SNP with total PSA (tPSA) levels and free/total (F/T) PSA ratio were determined from serum samples. RESULTS: Functional analysis showed that the rs61752561 SNP impacts on PSA stability, structural conformation and creates an extra-glycosylation site. This PSA variant had reduced enzymatic activity and ability to stimulate proliferation and migration of PCa cells. Interestingly, the minor allele is associated with lower tPSA levels and high F/T PSA ratio in serum samples, indicating that the aminoacid substitution may impact PSA immunoreactivity to antibodies used in the clinical immunoassays. CONCLUSIONS: Our assessment on the biological effects of the rs61752561 showed this SNP to have a potential role in PCa pathogenesis by changing the glycosylation, protein stability, PSA activity and may also impact on the clinically measured F/T PSA ratio. Accounting for these effects on the tPSA and F/T PSA ratio may help to improve the accuracy of the current PSA test.

Inactive free : total prostate speci®c antigen ratios in ejaculate from men with suspected and known prostate cancer, compared with young control men Objective To measure free : total prostate speci®c antigen (PSA) ratios in ejaculate from men with suspected and known prostate cancer, and in young control men, to determine if this ratio might be useful in discriminating benign from malignant prostatic conditions. Patients, subjects and methods Forty-seven men with prostate cancer (positive biopsies), 52 men with suspected prostate cancer but who had negative biopsies and 28 young men (<30 years old) and with no family history of cancer, provided either a single ejaculate specimen (total 59) or multiple specimens (total 193) on subsequent occasions. Free and total PSA were measured using appropriate assays. All specimens were diluted in a PSA-negative female serum pool. Results The median free : total PSA ratios were 0.76±0.81 among the patient groups and control men, and there was no statistical difference between the groups. These data presumably only re¯ect the inactive component of free PSA, given that any a 2 -macroglobulin or a 1 -antichymotrypsin in the assay serum diluent was likely to have bound the active free PSA component in these samples. Similar results were obtained from those providing single and multiple samples, suggesting that a single specimen is suf®cient to re¯ect the seminal plasma free : total PSA ratio over that period. There was no relationship between seminal plasma free : total PSA ratio and age for the controls or the positive biopsy group, although there was a negative relationship (i.e. a decline with age) that almost reached signi®cance in those with negative biopsies (P=0.058, R 2 =0.07). Conclusions This is the ®rst report of free : total PSA ratios in the ejaculate of men with suspected and known prostate cancer compared with young control men. Although no signi®cant changes were detected in the free : total PSA ratios in ejaculate, these results may be confounded by differences in ratios with age, as is the case for serum PSA or different molecular forms of PSA. Indeed, these data suggest that a large proportion of free PSA in seminal plasma may be inactive. Further studies are needed to determine the potential utility of measuring free : total PSA, or other candidate markers, in ejaculate to better discriminate benign from malignant prostate disease.

Antenatal screening for fetal anomalies has provided women and their partners with information to make reproductive choices based on the risk of serious chromosomal or structural defects since the 1990s. Alternative tests include first-trimester screening (combined ultrasound and maternal serum markers), second-trimester maternal serum markers and noninvasive cell-free DNA testing. The recent recommendations by the Royal Australian and New Zealand College of Obstetrics and Gynaecology and the Human Genetics Society of Australasia against second-trimester triple testing are based on unsound performance criteria, raise several contestable issues around access and equity and challenge the principles of governments providing affordable options.

Objective: To determine whether hormone treatment of women during the menopause transition induces changes in body weight, blood pressure, lipoprotein levels, antithrombin Ill activity, and the endometrium. Design: Prospective, randomised, placebo‐controlled, double‐blind, 12‐month study, with crossover at 6 months. Setting: Outpatient clinic of a city hospital. Participants: 105 apparently healthy women in the menopause transition (40–52 years), with menstrual function, who were experiencing minor menopausal symptoms, were selected from the general population by advertising. Interventions: Active arm ‐ oral conjugated oestrogens (0.625 mg daily) and cyclic medroxyprogesterone acetate (10mg daily) on Day 14–27 of each menstrual cycle; placebo arm ‐ placebos of both medications. Main outcome measures: Excess change from baseline associated with active compared with placebo treatment for all variables; effect of order of treatment. Results: Baseline biochemical values were similar for both treatment‐order groups, but baseline blood pressures and body weights were higher in the group receiving placebo first. With treatment, there were no differences in overall values for body weight and blood pressure (P>0.4), and order of treatment had no significant influence (P>0.3). There were no differences in total and low density lipoprotein cholesterol levels, overall or with order of treatment. Active treatment increased high density lipoprotein (HDL) cholesterol levels (overall and when placebo was given first; P=0.001), and triglyceride levels (when active treatment was given first; P=0.03). There was no overall treatment effect, but a significant order‐of‐treatment effect, on antithrombin Ill activity (mean levels were decreased by active treatment to a greater extent when it was given first; P=0.02). The endometrium showed only physiological changes regardless of treatment. Conclusions: The lack of significant excess change in anthropometry, lipoprotein levels, antithrombin Ill activity, and endometrial histology in women given hormone treatment compared with placebo is reassuring. The increase in HDL cholesterol level is an extra benefit. Our study provides conclusive evidence that hormone treatment does not produce weight gain in women during the menopause transition.

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