Neuropeptide S receptor 1 is a nonhormonal treatment target in endometriosis.

Endometriosis is a common chronic inflammatory condition causing pelvic pain and infertility in women, with limited treatment options and 50% heritability. We leveraged genetic analyses in two species with spontaneous endometriosis, humans and the rhesus macaque, to uncover treatment targets. We sequenced DNA from 32 human families contributing to a genetic linkage signal on chromosome 7p13-15 and observed significant overrepresentation of predicted deleterious low-frequency coding variants in NPSR1, the gene encoding neuropeptide S receptor 1, in cases (predominantly stage III/IV) versus controls (P = 7.8 × 10-4). Significant linkage to the region orthologous to human 7p13-15 was replicated in a pedigree of 849 rhesus macaques (P = 0.0095). Targeted association analyses in 3194 surgically confirmed, unrelated cases and 7060 controls revealed that a common insertion/deletion variant, rs142885915, was significantly associated with stage III/IV endometriosis (P = 5.2 × 10-5; odds ratio, 1.23; 95% CI, 1.09 to 1.39). Immunohistochemistry, qRT-PCR, and flow cytometry experiments demonstrated that NPSR1 was expressed in glandular epithelium from eutopic and ectopic endometrium, and on monocytes in peritoneal fluid. The NPSR1 inhibitor SHA 68R blocked NPSR1-mediated signaling, proinflammatory TNF-α release, and monocyte chemotaxis in vitro (P < 0.01), and led to a significant reduction of inflammatory cell infiltrate and abdominal pain (P < 0.05) in a mouse model of peritoneal inflammation as well as in a mouse model of endometriosis. We conclude that the NPSR1/NPS system is a genetically validated, nonhormonal target for the treatment of endometriosis with likely increased relevance to stage III/IV disease.

Childhood adversity and traumatic exposures during deployment as predictors of mental health in Australian military veterans.

OBJECTIVE: To examine whether the relationship between traumatic exposure on deployment and poor mental health varies by the reported level of childhood adversity experienced in Australian military veterans deployed to the Bougainville or East Timor military operations. METHODS: Cross-sectional self-reported survey data were collected in 2008 from 3,564 Australian military veterans who deployed to East Timor or Bougainville on their deployment experiences, health and recall of childhood events. Multivariable logistic regression was used to investigate the association between childhood adversity, deployment exposures and mental health. RESULTS: The most common childhood adversity reported was 'not having a special teacher, youth worker or family friend who looked out for them while growing up'. On average, responders reported experiencing 3.5 adverse childhood experiences (SD 2.7) and averaged 5.3 (SD 4.9) traumatic exposures on deployment. Both childhood adversity and traumatic exposures on deployment were associated with higher odds of poorer mental health. However, there was no evidence that level of childhood adversity modified the association between traumatic exposure and mental health. CONCLUSIONS/IMPLICATIONS: These findings suggest that military personnel who recalled a higher level of childhood adversity may need to be monitored for poor mental health and, if required, provided with appropriate support.

Common variants in the CYP2C19 gene are associated with susceptibility to endometriosis.

OBJECTIVE: To follow-up previous studies highlighting a possible role for cytochrome P450, family 2, subfamily C, 19 (CYP2C19) in susceptibility to endometriosis by searching for additional variants in the CYP2C19 gene that may be associated with the disease. DESIGN: Case-control study. SETTING: Academic research. SUBJECT(S): The cases comprised 2,271 women with surgically confirmed endometriosis; the controls comprised 939 women with self-report of no endometriosis and 1,770 unscreened population samples. INTERVENTION(S): Sequencing of the CYP2C19 region and follow-up of 80 single nucleotide polymorphisms (SNPs) in two case-control samples. MAIN OUTCOME MEASURE(S): Allele frequency differences between cases and controls. RESULT(S): Sequencing of the CYP2C19 gene region resulted in the detection of a large number of known and novel SNPs. Genotyping of 80 polymorphic SNPs in 901 endometriosis cases and 939 controls resulted in study-wide significant association signals for SNPs in moderate or complete linkage disequilibrium with rs4244285, a functional SNP in exon 5 that abrogates CYP2C19 function through the creation of an alternative splice site. Evidence of association was also detected for another functional SNP in the CYP2C19 promoter, rs12248560, which was highlighted in our previous study. CONCLUSION(S): Functional variants in CYP2C19 may contribute to endometriosis susceptibility in both familial and sporadic cases.

Explaining variance in the cumulus mammographic measures that predict breast cancer risk: a twins and sisters study.

BACKGROUND: Mammographic density, the area of the mammographic image that appears white or bright, predicts breast cancer risk. We estimated the proportions of variance explained by questionnaire-measured breast cancer risk factors and by unmeasured residual familial factors. METHODS: For 544 MZ and 339 DZ twin pairs and 1,558 non-twin sisters from 1,564 families, mammographic density was measured using the computer-assisted method Cumulus. We estimated associations using multilevel mixed-effects linear regression and studied familial aspects using a multivariate normal model. RESULTS: The proportions of variance explained by age, body mass index (BMI), and other risk factors, respectively, were 4%, 1%, and 4% for dense area; 7%, 14%, and 4% for percent dense area; and 7%, 40%, and 1% for nondense area. Associations with dense area and percent dense area were in opposite directions than for nondense area. After adjusting for measured factors, the correlations of dense area with percent dense area and nondense area were 0.84 and -0.46, respectively. The MZ, DZ, and sister pair correlations were 0.59, 0.28, and 0.29 for dense area; 0.57, 0.30, and 0.28 for percent dense area; and 0.56, 0.27, and 0.28 for nondense area (SE = 0.02, 0.04, and 0.03, respectively). CONCLUSIONS: Under the classic twin model, 50% to 60% (SE = 5%) of the variance of mammographic density measures that predict breast cancer risk are due to undiscovered genetic factors, and the remainder to as yet unknown individual-specific, nongenetic factors. IMPACT: Much remains to be learnt about the genetic and environmental determinants of mammographic density.

Genome-wide association meta-analysis identifies new endometriosis risk loci.

We conducted a genome-wide association meta-analysis of 4,604 endometriosis cases and 9,393 controls of Japanese and European ancestry. We show that rs12700667 on chromosome 7p15.2, previously found to associate with disease in Europeans, replicates in Japanese (P = 3.6 × 10(-3)), and we confirm association of rs7521902 at 1p36.12 near WNT4. In addition, we establish an association of rs13394619 in GREB1 at 2p25.1 with endometriosis and identify a newly associated locus at 12q22 near VEZT (rs10859871). Excluding cases of European ancestry of minimal or unknown severity, we identified additional previously unknown loci at 2p14 (rs4141819), 6p22.3 (rs7739264) and 9p21.3 (rs1537377). All seven SNP effects were replicated in an independent cohort and associated at P <5 × 10(-8) in a combined analysis. Finally, we found a significant overlap in polygenic risk for endometriosis between the genome-wide association cohorts of European and Japanese descent (P = 8.8 × 10(-11)), indicating that many weakly associated SNPs represent true endometriosis risk loci and that risk prediction and future targeted disease therapy may be transferred across these populations.

Genome-wide linkage and association analyses implicate FASN in predisposition to Uterine Leiomyomata.

Uterine leiomyomata (UL), the most prevalent pelvic tumors in women of reproductive age, pose a major public health problem given their high frequency, associated morbidities, and most common indication for hysterectomies. A genetic component to UL predisposition is supported by analyses of ethnic predisposition, twin studies, and familial aggregation. A genome-wide SNP linkage panel was genotyped and analyzed in 261 white UL-affected sister-pair families from the Finding Genes for Fibroids study. Two significant linkage regions were detected in 10p11 (LOD = 4.15) and 3p21 (LOD = 3.73), and five additional linkage regions were identified with LOD scores > 2.00 in 2q37, 5p13, 11p15, 12q14, and 17q25. Genome-wide association studies were performed in two independent cohorts of white women, and a meta-analysis was conducted. One SNP (rs4247357) was identified with a p value (p = 3.05 × 10(-8)) that reached genome-wide significance (odds ratio = 1.299). The candidate SNP is under a linkage peak and in a block of linkage disequilibrium in 17q25.3, which spans fatty acid synthase (FASN), coiled-coil-domain-containing 57 (CCDC57), and solute-carrier family 16, member 3 (SLC16A3). By tissue microarray immunohistochemistry, we found elevated (3-fold) FAS levels in UL-affected tissue compared to matched myometrial tissue. FAS transcripts and/or protein levels are upregulated in various neoplasms and implicated in tumor cell survival. FASN represents the initial UL risk allele identified in white women by a genome-wide, unbiased approach and opens a path to management and potential therapeutic intervention.

No evidence for genetic association with the let-7 microRNA-binding site or other common KRAS variants in risk of endometriosis.

STUDY QUESTION: Is there a contribution of the minor allele at the KRAS single nucleotide polymorphism (SNP) rs61764370 in the let-7 microRNA-binding site to endometriosis risk? SUMMARY ANSWER: We found no evidence for association between endometriosis risk and rs61764370 or any other SNPs in KRAS. WHAT IS KNOWN ALREADY: The rs61764370 SNP in the 3' untranslated region of the KRAS gene is predicted to disrupt a complementary binding site (LCS6) for the let-7 microRNA, and was recently reported to be at a high frequency (31%) in 132 women of varying ancestry with endometriosis compared with frequencies in a database of population controls (up to 7.6% depending on ancestry), suggesting a strong effect of this KRAS SNP in the aetiology of endometriosis. STUDY DESIGN, SIZE AND DURATION: This was a case-control study with a total of 11 206 subjects. The study was performed between February 2012 and July 2012. PARTICIPANTS/MATERIALS, SETTINGAND METHODS: We first investigated a possible association between common markers in KRAS and endometriosis risk from our genome-wide association (GWA) data in 3194 surgically confirmed endometriosis cases and 7060 controls of European ancestry. Although rs61764370 was not genotyped on the GWA arrays, five SNPs typed in the study were highly correlated with this variant. The rs61764370 and two SNPs highly correlated with rs61764370 were then genotyped in 933 endometriosis cases and 952 controls using the Sequenom MassARRAY platform. MAIN RESULTS AND THE ROLE OF CHANCE: There was no evidence for an association between rs61764370 and endometriosis risk P = 0.411 and odds ratio = 1.10 (95% confidence intervals: 0.88-1.36). We also found no evidence for an association between the highly correlated SNP rs17387019 and endometriosis. Their minor allele frequencies in cases and controls were of 0.087-0.091 similar to the population frequency reported previously for this variant in controls. Analyses of endometriosis cases with revised American Fertility Society stage III/IV disease also showed no evidence for an association between these SNPs and endometriosis risk. LIMITATIONS AND REASONS FOR CAUTION: The GWA and genotyped data sets were not independent since individuals and cases from some families overlap. Controls in our GWA study were not screened for endometriosis. WIDER IMPLICATIONS OF THE FINDINGS: The key SNP, rs61764370, was genotyped in a subset of samples. Our results do not support the suggestion that carrying the minor allele at rs61764370 contributes to a significant number of endometriosis cases and rs61764370 is, therefore, unlikely to be a useful marker of endometriosis risk. STUDY FUNDING/COMPETING INTEREST(S): The research was funded by grants from the Australian National Health and Medical Research Council and Wellcome Trust. None of the authors has competing interests for the study.

Traumatic events, other operational stressors and physical and mental health reported by Australian Defence Force personnel following peacekeeping and war-like deployments.

BACKGROUND: The association between stressful events on warlike deployments and subsequent mental health problems has been established. Less is known about the effects of stressful events on peacekeeping deployments. METHODS: Two cross sectional studies of the Australian Defence Force were used to contrast the prevalence of exposures reported by a group deployed on a peacekeeping operation (Bougainville, n = 1704) and those reported by a group deployed on operations which included warlike and non-warlike exposures (East Timor, n = 1333). A principal components analysis was used to identify groupings of non-traumatic exposures on deployment. Multiple regression models were used to assess the association between self-reported objective and subjective exposures, stressors on deployment and subsequent physical and mental health outcomes. RESULTS: The principal components analysis produced four groups of non-traumatic stressors which were consistent between the peacekeeping and more warlike deployments. These were labelled 'separation', 'different culture', 'other people' and 'work frustration'. Higher levels of traumatic and non-traumatic exposures were reported by veterans of East Timor compared to Bougainville. Higher levels of subjective traumatic exposures were associated with increased rates of PTSD in East Timor veterans and more physical and psychological health symptoms in both deployed groups. In Bougainville and East Timor veterans some non-traumatic deployment stressors were also associated with worse health outcomes. CONCLUSION: Strategies to best prepare, identify and treat those exposed to traumatic events and other stressors on deployment should be considered for Defence personnel deployed on both warlike and peacekeeping operations.

Does government subsidy for costs of medical and pharmaceutical services result in higher service utilization by older widowed women in Australia?

BACKGROUND: In Australia, Medicare, the national health insurance system which includes the Medical Benefits Scheme (MBS) and Pharmaceutical Benefits Scheme (PBS), provides partial coverage for most medical services and pharmaceuticals. For war widows, the Department of Veterans' Affairs (DVA) covers almost the entire cost of their health care. The objective of this study was to test whether war widows have higher usage of medical services and pharmaceuticals. METHODS: Data were from 730 women aged 70-84 years (mostly World War II widows) participating in the Australian Longitudinal Study on Women's Health who consented to data linkage to Medicare Australia. The main outcome measures were PBS costs, claims, co-payments and scripts presented, and MBS total costs, claims and gap payments for medical services in 2005. RESULTS: There was no difference between the war widows and similarly aged widows in the Australian population without DVA support on use of medical services. While war widows had more pharmaceutical prescriptions filled they generated equivalent total costs, number of claims and co-payments for pharmaceuticals than widows without DVA support. CONCLUSIONS: Older war widows are not using more medical services and pharmaceuticals than other older Australian women despite having financial incentives to do so.

The association between mammographic density measures and aspirin or other NSAID use.

There is evidence that aspirin use reduces the risk of breast cancer. Increased mammographic density is known to be associated with increased breast cancer risk. Little is known about the association between mammographic density and aspirin or other non-steroidal anti-inflammatory drug (NSAID) use, but it is possible that the association between aspirin use and breast cancer risk might be due to the effect of aspirin on mammographic density. Multiple linear regression was used to investigate the association between measures of mammographic density and the use, frequency, and duration of aspirin and other NSAIDs such as paracetamol (acetaminophen), arthritis medication, and other over-the-counter or doctor-prescribed pain medications in 3286 women from the Australian Mammographic Density Twins and Sisters Study and the Genes Behind Endometriosis Study. We found no association between either dense area or percent dense area with any of the NSAIDs examined (all P > 0.06). If aspirin is reducing the breast cancer risk in women, it is likely doing so via a different pathway other than mammographic density measures that predict breast cancer risk.

Comparison of self-reported and audiometrically-measured hearing loss in the Australian Defence Force.

OBJECTIVE: To investigate the relationship between self-reported and audiometrically-measured hearing loss in a sample of Australian Defence Force personnel. DESIGN: Responses to a question regarding hearing problems were compared with contemporaneous audiometric data. STUDY SAMPLE: 3335 members of the Australian Defence Force for whom anonymised medical records were available. RESULTS: The sensitivity of self-report data to identify higher-frequency hearing loss was lower than sensitivity at other frequencies, and positive predictive values were moderate to poor at all frequencies. Performance characteristics of self-report compared with audiometric data also varied with age, sex, and rank. CONCLUSIONS: While self-report hearing loss data have good performance characteristics for estimating prevalence of hearing loss as defined by audiometric criteria, this study indicates that the usefulness of self-report data in identifying individuals with hearing loss may be limited in this population.

Self-reported tinnitus and ototoxic exposures among deployed Australian Defence Force personnel.

The objective of this study was to investigate the effect of chemical and environmental exposures during deployment on tinnitus among Australian Defence Force personnel previously deployed to Bougainville and East Timor. Participants were asked to self-report recent occurrence and severity of "ringing in the ears," and identify any chemical and environmental exposures during their deployment. Self-reported exposure to loud noises, heavy metals, intense smoke, engine exhaust, solvents and degreasing agents, and chemical spills increased the risk of self-assessed moderate or severe tinnitus. Daily exposure to 4 or more ototoxic factors was associated with 2- to 4-fold increase in the risk. In addition to loud noises, chemical exposures may also play a role in the development of tinnitus among Australian Defence Force personnel serving overseas.

High-density fine-mapping of a chromosome 10q26 linkage peak suggests association between endometriosis and variants close to CYP2C19.

OBJECTIVE: To refine a previously reported linkage peak for endometriosis on chromosome 10q26, and conduct follow-up analyses and a fine-mapping association study across the region to identify new candidate genes for endometriosis. DESIGN: Case-control study. SETTING: Academic research. PATIENT(S): Cases=3,223 women with surgically confirmed endometriosis; controls=1,190 women without endometriosis and 7,060 population samples. INTERVENTION(S): Analysis of 11,984 single nucleotide polymorphisms on chromosome 10. MAIN OUTCOME MEASURE(S): Allele frequency differences between cases and controls. RESULT(S): Linkage analyses on families grouped by endometriosis symptoms (primarily subfertility) provided increased evidence for linkage (logarithm of odds score=3.62) near a previously reported linkage peak. Three independent association signals were found at 96.59 Mb (rs11592737), 105.63 Mb (rs1253130), and 124.25 Mb (rs2250804). Analyses including only samples from linkage families supported the association at all three regions. However, only rs11592737 in the cytochrome P450 subfamily C (CYP2C19) gene was replicated in an independent sample of 2,079 cases and 7,060 population controls. CONCLUSION(S): The role of the CYP2C19 gene in conferring risk for endometriosis warrants further investigation.

Risk of adverse health outcomes associated with frequency and duration of deployment with the Australian Defence Force.

The operational tempo of the Australian Defence Force has increased over the last two decades. We examine the relationship between health of personnel and the frequency and duration of their deployment. Self-reported health measures (number of symptoms, Kessler Psychological Distress Scale, and Post Traumatic Stress Disorder Checklist) were compared for people who had never deployed to those who had deployed only once and for those who had deployed at least twice with at least one deployment to East Timor and one deployment to Afghanistan or Iraq. Comparisons were also made between people who had deployed for at least one month and those who had deployed for longer periods. Frequency of deployment but not duration of deployment was associated with poorer health.

Evaluation of polymorphisms in predicted target sites for micro RNAs differentially expressed in endometriosis.

Previous microarray analyses identified 22 microRNAs (miRNAs) differentially expressed in paired ectopic and eutopic endometrium of women with and without endometriosis. To investigate further the role of these miRNAs in women with endometriosis, we conducted an association study aiming to explore the relationship between endometriosis risk and single-nucleotide polymorphisms (SNPs) in miRNA target sites for these differentially expressed miRNAs. A panel of 102 SNPs in the predicted miRNA binding sites were evaluated for an endometriosis association study and an ingenuity pathway analysis was performed. Fourteen rare variants were identified in this study. We found SNP rs14647 in the Wolf-Hirschhorn syndrome candidate gene1 (WHSC1) 3'UTR (untranslated region) was associated with endometriosis-related infertility presenting an odds ratio of 12.2 (95% confidence interval = 2.4-60.7, P = 9.03 × 10(-5)). SNP haplotype AGG in the solute carrier family 22, member 23 (SLC22A23) 3'UTR was associated with endometriosis-related infertility and more severe disease. With the individual genotyping data, ingenuity pathways analysis identified the tumour necrosis factor and cyclin-dependant kinase inhibitor as major factors in the molecular pathways. Significant associations between WHSC1 alleles and endometriosis-related infertility and SLC22A23 haplotypes and the disease severe stage were identified. These findings may help focus future research on subphenotypes of this disease. Replication studies in independent large sample sets to confirm and characterize the involvement of the gene variation in the pathogenesis of endometriosis are needed.

Genome-wide association study identifies a locus at 7p15.2 associated with endometriosis.

Endometriosis is a common gynecological disease associated with pelvic pain and subfertility. We conducted a genome-wide association study (GWAS) in 3,194 individuals with surgically confirmed endometriosis (cases) and 7,060 controls from Australia and the UK. Polygenic predictive modeling showed significantly increased genetic loading among 1,364 cases with moderate to severe endometriosis. The strongest association signal was on 7p15.2 (rs12700667) for 'all' endometriosis (P = 2.6 × 10⁻7, odds ratio (OR) = 1.22, 95% CI 1.13-1.32) and for moderate to severe disease (P = 1.5 × 10⁻9, OR = 1.38, 95% CI 1.24-1.53). We replicated rs12700667 in an independent cohort from the United States of 2,392 self-reported, surgically confirmed endometriosis cases and 2,271 controls (P = 1.2 × 10⁻³, OR = 1.17, 95% CI 1.06-1.28), resulting in a genome-wide significant P value of 1.4 × 10⁻9 (OR = 1.20, 95% CI 1.13-1.27) for 'all' endometriosis in our combined datasets of 5,586 cases and 9,331 controls. rs12700667 is located in an intergenic region upstream of the plausible candidate genes NFE2L3 and HOXA10.

Smoking prevalence, its determinants and short-term health implications in the Australian Defence Force.

The objectives of this study were to determine the prevalence of smoking, identify the effects of deployment on smoking behavior and risk factors for smoking, and determine the short-term health outcomes associated with smoking in Australian Defence Force (ADF) personnel. Participants were randomly sampled from ADF members who deployed to the Solomon Islands between 2003 and 2005 and from a nondeployed comparison group. In total, 435 of 995 (44%) eligible individuals completed the study questionnaires. The prevalence of current smoking was highest in those who had completed less formal education and those who served in the Navy. Nearly two-thirds (63%) of current or former smokers smoked more while on overseas deployment. Current smokers were more likely to report current wheeze, shortness of breath, and persistent cough compared with nonsmokers. The ADF should continue to address cigarette smoking through its health promotion and health review programs and implement activities to reduce cigarette smoking on deployment.

Common genetic variants associated with breast cancer and mammographic density measures that predict disease.

Mammographic density for age and body mass index (BMI) is a heritable risk factor for breast cancer. We aimed to determine if recently identified common variants associated with small gradients in breast cancer risk are associated with mammographic density. We genotyped 497 monozygotic and 330 dizygotic twin pairs and 634 of their sisters from 903 families for 12 independent variants. Mammographic dense area, percent dense area, and nondense area were measured by three observers using a computer-thresholding technique. Associations with mammographic density measures adjusted for age, BMI, and other determinants were estimated (a) cross-sectionally using a multivariate normal model for pedigree analysis (P(x)), (b) between sibships, and (c) within sibships using orthogonal transformations of outcomes and exposures. A combined test of association (P(c)) was derived using the independent estimates from b and c. We tested if the distributions of P values across variants differed from the uniform distribution (P(u)). For dense area and percent dense area, the distributions of P(c) values were not uniform (both P(u) <0.007). Consistent with their breast cancer associations, rs3817198 (LSP1) and rs13281615 (8q) were associated with dense area and percent dense area (all P(x) and P(c) <0.05), and rs889312 (MAP3K1), rs2107425 (H19), and rs17468277 (CASP8) were marginally associated with dense area (some P(x) or P(c) <0.05). All associations were independent of menopausal status. At least two common breast cancer susceptibility variants are associated with mammographic density measures that predict breast cancer. These findings could help elucidate how those variants and mammographic density measures are associated with breast cancer susceptibility.

Early menstrual characteristics associated with subsequent diagnosis of endometriosis.

OBJECTIVE: The aim of this study was to investigate the association between early menstrual characteristics, before symptom onset, and later diagnosis of endometriosis. STUDY DESIGN: This was a case-control study of 268 Australian women with surgically confirmed moderate-to-severe endometriosis (cases) and 244 women without endometriosis (controls). Early menstrual cycle characteristics, before age at symptom onset, were analyzed. RESULTS: Menarche after age 14 years was strongly and inversely associated with endometriosis (odds ratio, 0.3; 95% confidence interval, 0.1-0.6). A history of dysmenorrhea was associated with subsequent endometriosis (odds ratio, 2.6; 95% confidence interval, 1.1-6.2). Despite a suggestive trend, shorter menstrual cycle length was not associated with endometriosis. Duration of natural menstruation and heaviness of flow were not associated with subsequent risk of endometriosis; neither was the reported type of sanitary protection used nor history of sexual intercourse during menstruation. CONCLUSION: There is a decreased risk of endometriosis with late age at menarche and an increased risk in women who report an early history of dysmenorrhea.

Familial correlations in postmenopausal serum concentrations of sex steroid hormones and other mitogens: a twins and sisters study.

BACKGROUND: Serum concentrations of some hormones are risk factors for certain cancers, but little is known about their familial associations especially for females. METHODS: We measured serum concentrations of estradiol (E(2)), testosterone (T), SHBG, prolactin, and IGF-I for 645 Australian female postmenopausal twins and their sisters [182 monozygotic (MZ) and 107 dizygotic (DZ) pairs and 67 nontwin sisters] using well-established immunoassays. After suitable transformation and adjusting for age, body mass index (BMI), and time since menopause, familial correlations and proportions of variance attributed to genetic (h(2)) and nongenetic factors common to sisterships (c(2)) were estimated under the classic twin multivariate normal model using FISHER. RESULTS: For all serum concentrations except prolactin, MZ, DZ, and sister pairs were correlated (P < 0.001). MZ correlations were in the range 0.5-0.7, and for all serum concentrations, there were no differences between DZ and sister correlations. MZ correlations were greater than DZ and sister correlations for log SHBG (P = 0.0001), IGF-I (P = 0.0002), and square-root T (P = 0.007) but not log E(2) (P = 0.3), and the respective h(2) estimates were 0.56 (SE = 0.14), 0.53 (0.17), 0.39 (0.14), and 0.14 (0.16). For log E(2) and square-root T, c(2) estimates were 0.39 (0.14) and 0.22 (0.12). CONCLUSION: There are strong familial correlations in postmenopausal SHBG, IGF-I, and to a lesser extent T, which are consistent with a genetic etiology. For E(2), and to a lesser extent T, correlations are consistent with substantial nongenetic familial factors. The latter might include maternal effects.