Parabens effects on female reproductive health - Review of evidence from epidemiological and rodent-based studies.

Parabens have been used as antimicrobial preservatives since the 1920s. The prevalent use of parabens increases their detection in the environment and in women's biological samples including reproductive tissues. Recent studies suggest parabens may alter endocrine function and thus female reproductive health may be affected. In this literature review, we summarize findings on parabens and female reproduction while focusing on epidemiological and rodent-based studies. The topics reviewed include paraben effects on cyclicity, pregnancy, newborn and pubertal development, reproductive hormones, and ovarian and uterine specific outcomes. Overall, the scientific literature on paraben effects on female reproduction is limited and with some conflicting results. Yet, some epidemiological and/or rodent-based experimental studies report significant findings in relation to paraben effects on cyclicity, fertility, gestation length, birth weight, postnatal development and pubertal onset, hormone levels, and hormone signaling in reproductive tissues. Future epidemiological and experimental studies are needed to better understand paraben effects on female reproduction while focusing on human related exposures including mixtures, physiologic concentrations of parabens, and multi-generational studies.

Parabens and Menopause-Related Health Outcomes in Midlife Women: A Pilot Study.

Background: Parabens are antimicrobial agents prevalently found in daily-use products that can interfere with the endocrine and reproductive systems. In this study, we examined the cross-sectional associations of parabens with hot flashes, hormone concentrations, and ovarian volume in a subsample of 101 nonsmoking, non-Hispanic 45- to 54-year-old women from the Midlife Women's Health Study. Materials and Methods: Women self-reported their hot flash history and underwent a transvaginal ultrasound to measure ovarian volume. Participants provided blood for quantification of serum hormones (by enzyme-linked immunosorbent assay or radioimmunoassay) and urine samples for measurements of urinary paraben biomarker levels (by high-performance liquid chromatography negative-ion electrospray ionization-tandem mass spectrometry). Linear or logistic regression models evaluated associations of specific gravity-adjusted paraben biomarker concentrations with hot flashes, hormone concentrations, and ovarian volume. Results: We observed marginal associations of propylparaben, methylparaben, and ∑parabens biomarkers (molar sum of four parabens) with hot flashes and follicle-stimulating hormone (FSH) concentrations, and of these paraben biomarkers and ethylparaben with ovarian volume. For example, women tended to have 32% (95% confidence intervals [CI]: 0.9 to 1.81), 40% (95% CI: 1.0 to 1.95), and 40% (95% CI: 0.98 to 2.01) higher odds of having recent, monthly, and mild hot flashes, respectively, for every two-fold increase in ∑parabens. Similarly, women tended to have 14.54% (95% CI: -0.10 to 31.32) higher FSH concentrations, but 5.67% (95% CI: -12.54 to 1.75) reduced ovarian volume for every two-fold increase in ∑parabens Conclusions: Overall, our preliminary findings suggest that urinary paraben biomarkers may be associated with menopause-related outcomes in midlife women. Additional studies in larger and diverse populations are needed to expand on these findings.

Early-Life Exposure to Environmental Contaminants Perturbs the Sperm Epigenome and Induces Negative Pregnancy Outcomes for Three Generations via the Paternal Lineage.

Due to the grasshopper effect, the Arctic food chain in Canada is contaminated with persistent organic pollutants (POPs) of industrial origin, including polychlorinated biphenyls and organochlorine pesticides. Exposure to POPs may be a contributor to the greater incidence of poor fetal growth, placental abnormalities, stillbirths, congenital defects and shortened lifespan in the Inuit population compared to non-Aboriginal Canadians. Although maternal exposure to POPs is well established to harm pregnancy outcomes, paternal transmission of the effects of POPs is a possibility that has not been well investigated. We used a rat model to test the hypothesis that exposure to POPs during gestation and suckling leads to developmental defects that are transmitted to subsequent generations via the male lineage. Indeed, developmental exposure to an environmentally relevant Arctic POPs mixture impaired sperm quality and pregnancy outcomes across two subsequent, unexposed generations and altered sperm DNA methylation, some of which are also observed for two additional generations. Genes corresponding to the altered sperm methylome correspond to health problems encountered in the Inuit population. These findings demonstrate that the paternal methylome is sensitive to the environment and that some perturbations persist for at least two subsequent generations. In conclusion, although many factors influence health, paternal exposure to contaminants plays a heretofore-underappreciated role with sperm DNA methylation contributing to the molecular underpinnings involved.

Paraben exposure alters cell cycle progression and survival of spontaneously immortalized secretory murine oviductal epithelial (MOE) cells.

The mammalian oviduct is a central organ for female reproduction as it is the site of fertilization and it actively transports the embryo to the uterus. The oviduct is responsive to ovarian steroids and thus, it is a potential target of endocrine disrupting chemicals. Parabens are antimicrobial compounds that are prevalently found in daily-used products. However, recent studies suggest that some parabens can impact female reproductive health. Yet, their effects on the oviduct are unknown. Here, we hypothesized that in vitro exposure of immortalized murine oviductal secretory epithelial (MOE) cells to methylparaben or propylparaben will result in disrupted cell cycle progression and increased cell death by dysregulation of molecular mechanisms that involve the cell cycle and apoptosis. Thus, we examined the effects of exposure to parabens on cell proliferation, cell cycle progression by flow cytometry, and mRNA levels of major cell cycle regulators and apoptotic factors, in MOE cells. Protein levels of estrogen and progesterone receptors were also quantified. Differences between treatments and controls were analyzed by linear mixed model followed by Dunnett post-hoc tests. The results indicate that methylparaben and propylparaben selectively reduce MOE cellular proliferation and colony numbers, compared to controls. Additionally, paraben exposure selectively dysregulates the progression through the cell cycle and decreases the levels of cell cycle regulators, compared to controls. Last, paraben selectively alters the levels of progesterone receptor. Overall, these findings suggest that parabens can affect mouse oviductal secretory epithelial cell proliferation and survival.

Potential Role of Lycopene in the Prevention of Postmenopausal Bone Loss: Evidence from Molecular to Clinical Studies.

Osteoporosis is a metabolic bone disease characterized by reduced bone mineral density, which affects the quality of life of the aging population. Furthermore, disruption of bone microarchitecture and the alteration of non-collagenous protein in bones lead to higher fracture risk. This is most common in postmenopausal women. Certain medications are being used for the treatment of osteoporosis; however, these may be accompanied by undesirable side effects. Phytochemicals from fruits and vegetables are a source of micronutrients for the maintenance of bone health. Among them, lycopene has recently been shown to have a potential protective effect against bone loss. Lycopene is a lipid-soluble carotenoid that exists in both all-trans and cis-configurations in nature. Tomato and tomato products are rich sources of lycopene. Several human epidemiological studies, supplemented by in vivo and in vitro studies, have shown decreased bone loss following the consumption of lycopene/tomato. However, there are still limited studies that have evaluated the effect of lycopene on the prevention of bone loss in postmenopausal women. Therefore, the aim of this review is to summarize the relevant literature on the potential impact of lycopene on postmenopausal bone loss with molecular and clinical evidence, including an overview of bone biology and the pathophysiology of osteoporosis.

Propylparaben inhibits mouse cultured antral follicle growth, alters steroidogenesis, and upregulates levels of cell-cycle and apoptosis regulators.

Propylparaben is prevalently used in cosmetics, pharmaceuticals, and foods; yet, its direct effects on the mammalian ovary are unknown. We investigated the direct effects of propylparaben on the growth and steroidogenic function of mouse antral follicles. Antral follicles were isolated from the ovaries of Swiss mice (age: 32-42 days) and cultured in media with dimethylsulfoxide vehicle control or propylparaben (0.01-100 µg/mL) for 24-72 h. Follicle diameter was measured every 24 h to assess growth. Follicles and media were collected at 24 and 72 h for gene expression and hormone measurements. Propylparaben (100 µg/mL) significantly inhibited follicle growth (48-72 h). Further, propylparaben exposure increased expression of cell cycle regulators (Cdk4, Cdkn1a), an apoptotic factor (Bax), and a key steroidogenic regulator (Star). In media, propylparaben decreased accumulation of dehydroepiandrosterone-sulfate, but increased testosterone and 17ß-estradiol. Overall, our findings suggest that propylparaben disrupts antral follicle growth and steroidogenic function by altering the cell-cycle, apoptosis, and steroidogenesis pathways.

Pretty Good or Pretty Bad? The Ovary and Chemicals in Personal Care Products.

Personal care products (PCP) contain a myriad of chemicals generally formulated to provide a safe and beneficial use. Nonetheless, an increasing amount of laboratory animal and human studies indicate that some chemicals in PCP are associated with decreased hormone production, diminished ovarian reserve, ovarian cancer, and early pregnancy loss. The ovary is key to female fertility by providing the eggs and sex steroid hormones for fertilization and maintenance of reproductive function, respectively. Thus, understanding how chemicals in PCP affect the ovary will shed some light on their potential effects on female fertility. In this review, we provide an overview of: (1) ovarian function as a determinant of fertility in females, (2) the status of knowledge regarding the effects of seven common chemicals in PCP on the ovary, and (3) significant gaps in the literature along with opportunities to eliminate some of the gaps. Findings from the limited existing data suggest that chemicals in PCP such as dibutyl phthalate can reach the ovary in humans and impact its function in animal models. Unfortunately, it is still difficult to assess how relevant findings of experimental studies are to women because of lack of human exposure data for most of these chemicals and the lack of studies that mimic real-life exposures. In contrast to chemicals such as bisphenol A and dioxin, the investigation of the effects of chemicals in PCP on reproductive function is still limited and warrants further investigation to fill existing data gaps.

The effects of in utero bisphenol A exposure on ovarian follicle numbers and steroidogenesis in the F1 and F2 generations of mice.

Bisphenol A (BPA) is a commonly used plasticizer. Previous studies show that in utero exposure to BPA affects reproductive outcomes in the F1-F3 generations of mice. However, its multigenerational effects on ovarian histology and steroidogenesis over the reproductive lifespan are unknown. Thus, we tested the hypothesis that BPA has multigenerational effects on follicle numbers and steroidogenesis. Mice were exposed in utero to vehicle control or BPA (0.5, 20, and 50µg/kg/day). Ovaries were collected for histological and gene expression analyses and sera were collected for hormone assays. In utero BPA exposure decreased preantral follicle numbers, cytochrome P450 aromatase mRNA levels, and estradiol levels in the F1 generation, whereas it decreased testosterone levels and altered steroidogenic acute regulatory protein, cytochrome P450 cholesterol side-chain cleavage, 3ß-hydroxysteroid dehydrogenase 1, and cytochrome P450 aromatase mRNA levels in the F2 generation. These data suggest that BPA has multigenerational effects on the ovary in mice.

Bisphenol A Exposure, Ovarian Follicle Numbers, and Female Sex Steroid Hormone Levels: Results From a CLARITY-BPA Study.

Bisphenol A (BPA) is an industrial chemical found in thermal receipts and food and beverage containers. Previous studies have shown that BPA can affect the numbers and health of ovarian follicles and the production of sex steroid hormones, but they often did not include a wide range of doses of BPA, used a small sample size, focused on relatively short-term exposures to BPA, and/or did not examine the consequences of chronic BPA exposure on the ovaries or steroid levels. Thus, this study was designed to examine the effects of a wide range of doses of BPA on ovarian morphology and sex steroid hormone production. Specifically, this study tested the hypothesis that prenatal and continuous BPA exposure reduces ovarian follicle numbers and sex steroid hormone levels. To test this hypothesis, rats were dosed with vehicle, ethinyl estradiol (0.05 and 0.5 µg/kg body weight/d), or BPA (2.5, 25, 250, 2500, and 25,000 µg/kg body weight/d) from gestation day 6 until 1 year as part of the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA). Ovaries and sera were collected on postnatal days 1, 21, and 90, and at 6 months and 1 year. The ovaries were subjected to histological evaluation of follicle numbers and the sera were subjected to measurements of estradiol and progesterone. Collectively, these data indicate that BPA exposure at some doses and time points affects ovarian follicle numbers and sex steroid levels, but these effects are different than those observed with ethinyl estradiol exposure and some previous studies on BPA.

The Midlife Women's Health Study - a study protocol of a longitudinal prospective study on predictors of menopausal hot flashes.

BACKGROUND: The Midlife Women's Health Study (MWHS) was developed to address some of the gaps in knowledge regarding risk factors for hot flashes among generally healthy midlife women during their menopausal transition. This manuscript describes the methods from the study and the main findings that were published to date, with a focus on predictors of hot flashes. This study was initially funded to test the hypothesis that obesity is associated with an increased risk of hot flashes through mechanisms that involve ovarian failure, altered sex steroid hormone levels, and selected genetic polymorphisms. METHODS/DESIGN: The MWHS was conducted between 2006 and 2015 as a prospective longitudinal population-based study of generally healthy midlife women (ages 45 to 54 years) during their natural menopausal transition. Women were eligible if they had intact uteri and both ovaries and reported having at least 3 menstrual periods in the last 12 months. Exclusion criteria included pregnancy, cancer, and use of hormonal/hormone-like supplements. Overall, 780 women were recruited into the study. The majority of study participants were followed for 4 to 7 years. At annual visits, women donated blood and urine samples, completed questionnaires, had a vaginal ultrasound, and had their anthropometric measurements taken. DISCUSSION: Several risk factors for menopausal hot flashes were identified or confirmed, including older age, perimenopausal status, current and former cigarette smoking, lower estradiol levels, lower progesterone levels, black race, and depressive symptoms. Factors that were associated with decreased odds of hot flashes included moderate alcohol consumption and more than 5 years of cessation of cigarette smoking. Body mass index was not associated with hot flashes. The MWHS has provided important information regarding hot flashes. The study methods are rigorous and can be easily adopted by research groups investigating naturally occurring menopausal hot flashes.

Evidence for bisphenol A-induced female infertility: a review (2007-2016).

We summarized the scientific literature published from 2007 to 2016 on the potential effects of bisphenol A (BPA) on female fertility. We focused on overall fertility outcomes (e.g., ability to become pregnant, number of offspring), organs that are important for female reproduction (i.e., oviduct, uterus, ovary, hypothalamus, and pituitary), and reproductive-related processes (i.e., estrous cyclicity, implantation, and hormonal secretion). The reviewed literature indicates that BPA may be associated with infertility in women. Potential explanations for this association can be generated from experimental studies. Specifically, BPA may alter overall female reproductive capacity by affecting the morphology and function of the oviduct, uterus, ovary, and hypothalamus-pituitary-ovarian axis in animal models. In addition, BPA may disrupt estrous cyclicity and implantation. Nevertheless, further studies are needed to better understand the exact mechanisms of action and to detect potential reproductive toxicity at earlier stages.

Phthalate metabolite levels and menopausal hot flashes in midlife women.

During the menopausal transition, a woman's reproductive capacity declines, her hormone milieu changes, and her risk of hot flashes increases. Exposure to phthalates, which can be found in personal care products, can also result in altered reproductive function. Here, we investigated the associations between phthalate metabolite levels and midlife hot flashes. Eligible women (45-54 years of age) provided detailed information on hot flashes history and donated urine samples (n=195). Urinary phthalate metabolite levels were measured by HPLC-MS/MS. A higher total sum of phthalate metabolites commonly found in personal care products was associated with an increased risk of ever experiencing hot flashes (odds ratio (OR)=1.45; 95% confidence interval (CI)=1.07-1.96), hot flashes in the past 30days (OR=1.43; 95%CI=1.04-1.96), and more frequent hot flashes (OR=1.47; 95%CI=1.06-2.05). These data suggest that some phthalate exposures from personal care products are associated with menopausal hot flashes in women.

The effects of in utero bisphenol A exposure on the ovaries in multiple generations of mice.

Bisphenol A is used in polycarbonate plastics and epoxy resins. Previous studies show that in utero BPA exposure inhibits germ cell nest breakdown in the F1 generation of mice, but its effects on germ cell nest breakdown and on the ovary in the F2-F3 generations were unknown. Thus, we tested the hypothesis that BPA has transgenerational effects on the ovary. Mice were exposed to BPA in utero (BPA 0.5, 20, or 50µg/kg/day), and ovaries were collected at postnatal days (PND) 4 and 21 from the F1-F3 generations and subjected to histological evaluation and gene expression analyses. In utero BPA exposure did not have transgenerational effects on germ cell nest breakdown and gene expression on PND 4, but it caused transgenerational changes in expression in multiple genes on PND 21. Collectively, these data indicate that in utero BPA exposure has some transgenerational effects in mice.

The effects of in utero bisphenol A exposure on reproductive capacity in several generations of mice.

In utero bisphenol A (BPA) exposure affects reproductive function in the first generation (F1) of mice; however, not many studies have examined the reproductive effects of BPA exposure on subsequent generations. In this study, pregnant mice (F0) were orally dosed with vehicle, BPA (0.5, 20, and 50 µg/kg/day) or diethylstilbestrol (DES; 0.05 µg/kg/day) daily from gestation day 11 until birth. F1 females were used to generate the F2 generation, and F2 females were used to generate the F3 generation. Breeding studies at the ages of 3, 6, and 9 months were conducted to evaluate reproductive capacity over time. Further, studies were conducted to evaluate pubertal onset, litter size, and percentage of dead pups; and to calculate pregnancy rate, and mating, fertility, and gestational indices. The results indicate that BPA exposure (0.5 and 50 µg/kg/day) significantly delayed the age at vaginal opening in the F3 generation compared to vehicle control. Both DES (0.05 µg/kg/day) and BPA (50 µg/kg/day) significantly delayed the age at first estrus in the F3 generation compared to vehicle control. BPA exposure reduced gestational index in the F1 and F2 generations compared to control. Further, BPA exposure (0.5 µg/kg/day) compromised the fertility index in the F3 generation compared to control. Finally, in utero BPA exposure reduced the ability of female mice to maintain pregnancies as they aged. Collectively, these data suggest that BPA exposure affects reproductive function in female mice and that some effects may be transgenerational in nature.

A potentially functional variant in the serotonin transporter gene is associated with premenopausal and perimenopausal hot flashes.

OBJECTIVE: An increase in the use of selective serotonin reuptake inhibitors (SSRIs) and/or serotonin-norepinephrine reuptake inhibitors (SNRIs) to relieve menopausal hot flashes (HFs) has been observed recently. However, response to them has been heterogeneous. We hypothesized that this heterogeneity might be partially attributed to genetic variations in genes encoding the serotonin and/or norepinephrine transporters (SLC6A4 and SLC6A2). As a first step in testing the role of genetics in response to SSRIs/SNRIs, we examined the association between HFs and genetic variants within these two genes. METHODS: We tested 29 haplotype-tagging single nucleotide polymorphisms within SLC6A4 and SLC6A2 for their association with HFs separately for European-American (396 cases and 392 controls) and African-American (125 cases and 81 controls) premenopausal and perimenopausal women. RESULTS: We found that the minor allele of SLC6A4_rs11080121 was associated with protection against HFs (odds ratio, 0.75; 95% CI, 0.60-0.94) only in European-American women. Bioinformatics analyses indicated that rs11080121 is fully correlated with rs1042173 in the 3' untranslated region of SLC6A4. The minor allele of rs1042173 seems to disrupt a conserved binding site for hsa-miR-590-3p microRNA. CONCLUSIONS: Disruption of a microRNA binding site leads to higher expression of SLC6A4, higher expression of SLC6A4 leads to depletion of serotonin in synaptic clefts, and depletion of serotonin triggers the presynaptic autoreceptor feedback mechanism to produce more serotonin, which is protective against HFs. This is the first study to test the association between HFs in both European-American and African-American premenopausal and perimenopausal women and genetic variants in two neurotransmitter transporter genes, SLC6A2 and SLC6A4. This information can be used in tailoring the pharmaceutical use of SSRIs/SNRIs for HF relief.

Bisphenol A inhibits cultured mouse ovarian follicle growth partially via the aryl hydrocarbon receptor signaling pathway.

Bisphenol A (BPA) is an endocrine disruptor that inhibits growth of mouse ovarian follicles and disrupts steroidogenesis at a dose of 438µM. However, the effects of lower doses of BPA and its mechanism of action in ovarian follicles are unknown. We hypothesized that low doses of BPA inhibit follicular growth and decrease estradiol levels through the aryl hydrocarbon receptor (AHR) pathway. Antral follicles from wild-type and Ahr knock-out (AhrKO) mice were cultured for 96h. Follicle diameters and estradiol levels then were compared in wild-type and AhrKO follicles ± BPA (0.004-438µM). BPA inhibited follicle growth (110-438µM) and decreased estradiol levels (43.8-438µM) in wild-type and AhrKO follicles. However, at BPA 110µM, inhibition of growth in AhrKO follicles was attenuated compared to wild-type follicles. These data suggest that BPA may inhibit follicle growth partially via the AHR pathway, whereas its effects on estradiol synthesis likely involve other mechanisms.

Genetic polymorphisms in the aryl hydrocarbon receptor-signaling pathway and sleep disturbances in middle-aged women.

OBJECTIVE: We aimed to determine if selected genetic polymorphisms in the aryl hydrocarbon receptor (AHR)-signaling pathway and circadian locomotor output cycles kaput (CLOCK) are associated with insomnia and early awakening in middle-aged women. METHODS: Women aged 45 to 54years (n=639) were recruited into a middle-aged health study and agreed to complete questionnaires and donate blood samples. Questionnaires were used to assess sleep outcomes. Blood samples were processed for genotyping for the selected polymorphisms: AHR (rs2066853), AHR repressor (AHRR) (rs2292596), aryl hydrocarbon nuclear translocator (ARNT) (rs2228099), and CLOCK (rs1801260). Data were analyzed using multivariable logistic regression. RESULTS: Women heterozygous for the AHRR alleles (GC) had decreased odds of insomnia compared to women homozygous for the AHRR_C allele (adjusted odds ratio [aOR], 0.69; 95% confidence interval [CI], 0.49-0.96). Women with at least one of the AHRR_G or CLOCK_C alleles had significantly decreased odds of insomnia compared to women homozygous for the AHRR_C and CLOCK_T alleles (aOR, 0.64; 95% CI, 0.43-0.96). Additionally, women homozygous for the AHRR_G and CLOCK_C alleles had significantly decreased odds of insomnia compared to women homozygous for the AHRR_C and CLOCK_T alleles (aOR, 0.56; 95% CI, 0.35-0.89). None of the selected single nucleotide polymorphisms (SNPs) or combinations of SNPs were significantly associated with early awakening. CONCLUSIONS: Selected genetic polymorphisms in the AHR-signaling pathway (i.e., AHRR) and CLOCK may play a role in decreasing the risk for experiencing insomnia during the menopausal transition.

Di-n-butyl phthalate disrupts the expression of genes involved in cell cycle and apoptotic pathways in mouse ovarian antral follicles.

Di-n-butyl phthalate (DBP) is present in many consumer products, such as infant, beauty, and medical products. Several studies have shown that DBP causes reproductive toxicity in rodents, but no studies have evaluated its effects on ovarian follicles. Therefore, we used a follicle culture system to evaluate the effects of DBP on antral follicle growth, cell cycle and apoptosis gene expression, cell cycle staging, atresia, and 17ß-estradiol (E(2)) production. Antral follicles were isolated from adult CD-1 mice and exposed to DBP at 1, 10, 100, and 1000 µg/ml for 24 or 168 h. Follicles treated with vehicle or DBP at 1-100 µg/ml grew over time, but DBP at 1000 µg/ml significantly suppressed follicle growth. Regardless of effect on follicle growth, DBP-treated follicles had decreased mRNA for cyclins D2, E1, A2, and B1 and increased p21. Levels of the proapoptotic genes Bax, Bad, and Bok were not altered by DBP treatment, but DBP 1000 µg/ml increased levels of Bid and decreased levels of the antiapoptotic gene Bcl2. DBP-treated follicles contained significantly more cells in G(1) phase, significantly less cells in S, and exhibited a trend for fewer cells in G(2). Although DBP did not affect E(2) production and atresia at 24 h, follicles treated with DBP had reduced levels of E(2) at 96 h and underwent atresia at 168 h. These data suggest that DBP targets antral follicles and alters the expression of cell cycle and apoptosis factors, causes cell cycle arrest, decreases E(2), and triggers atresia, depending on dose.

Genetic polymorphisms in the aryl hydrocarbon receptor signaling pathway as potential risk factors of menopausal hot flashes.

OBJECTIVE: We sought to determine if genetic polymorphisms in the aryl hydrocarbon receptor signaling pathway are associated with menopausal hot flashes via hormone levels. STUDY DESIGN: Women (n = 639) aged 45-54 years completed a study survey and provided blood for genetic and hormone analyses. The associations were analyzed using multivariable logistic regression and generalized linear models. RESULTS: Women carrying CYP1B1 (rs1800440) GG genotype had 3-fold greater odds of experiencing hot flashes for ≥1 year compared to the AA genotype (adjusted odds ratio [OR], 3.05; 95% confidence interval [CI], 1.12-8.25). Adding serum estradiol concentrations to the confounder-adjusted model resulted in a nonsignificant association (adjusted OR, 2.59; 95% CI, 0.91-7.18). Carriers of both CYP1B1 (rs1800440) G and CYP1B1 (rs1058636) G alleles had higher odds of experiencing hot flashes for ≥1 year compared to women homozygous for the major alleles (adjusted OR, 1.77; 95% CI, 1.06-2.96), even after adjustment for serum estradiol. CONCLUSION: CYP1B1 is associated with menopausal hot flashes via pathways that may involve changes in serum estradiol concentration.

A genetic polymorphism in the CYP19A1 gene and the risk of hypertension among midlife women.

OBJECTIVE: To test whether a synonymous single nucleotide polymorphism (A→G; rs700518) in the CYP19A1 gene, which encodes the enzyme aromatase, is associated with an increased risk for hypertension of midlife women. METHODS: In a cross-sectional study, 639 midlife women were recruited. Eligible women had their blood pressure, weight and height measured, and donated a blood sample for hormone and genetic analyses. The participants also completed a detailed study survey. Women were grouped according to their genotype, blood pressure measurements, and medical history. The data were analyzed using logistic and linear regression models. The study had 80% power to detect small differences in mean systolic blood pressure (SBP; 4.5 mmHg) and diastolic blood pressure (DBP; 3 mmHg). RESULTS: The selected polymorphism was significantly associated with hypertension and SBP in unadjusted analyses. Interestingly, women with hypertension were more likely to be homozygous for the A allele (AA) compared to women who were not categorized as having hypertension. Further, the mean SBP was significantly higher for women who were homozygous for the A allele when compared to women carrying the other genotypes (AG or GG). The unadjusted association between DBP values and genotype was of borderline statistical significance (p=0.07). However, after adjustment for potential confounders (age, race, body mass index (BMI), smoking and physical activity), the associations between genotype and hypertension/blood pressure were attenuated and not statistically significant. CONCLUSION: The rs700518 polymorphism in the CYP19A1 is not associated with hypertension in our sample of midlife women. Other factors, including race and BMI, appear to play a greater role.