Associations between per- and polyfluoroalkyl substances (PFAS) and female sexual function in a preconception cohort.

We used cross-sectional data from Pregnancy Study Online (PRESTO), a North American prospective preconception cohort study. Female participants were eligible if they were 21–45 years and trying to conceive without the use of fertility treatments. The Boston University Medical Center (BUMC) Institutional Review Board approved study protocols. Involvement of the Centers for Disease Control and Prevention (CDC) did not constitute human subjects research. We invited participants who lived or worked in the Boston and Detroit metropolitan areas to visit our clinics at BUMC or Henry Ford Health System to provide urine and blood samples within 2 weeks of enrollment ( Koenig et al., 2022 ). We stored non-fasting serum samples at study clinics at −80°C and shipped samples to the U.S. CDC overnight on dry ice. Using solid phase extraction-high performance liquid chromatography-isotope-dilution-mass spectrometry, as described previously ( Kato et al., 2018 ), CDC investigators measured serum concentrations of perfluorohexanesulfonic acid (PFHxS), linear and branch isomers of perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA), and 2-(N-methyl-perfluorooctane sulfonamido) acetic acid (MeFOSAA). Four PFAS with detection frequencies ≥60% (limit of detection [LOD]=0.1 ng/mL) were included in the analysis: PFHxS, PFOS, PFOA, and PFNA. PFOS and PFOA reflected summed concentrations of their respective linear and branched isomers. There were few concentrations <LOD (PFHxS=3, PFOS=1, PFOA=1, PFNA=5); concentrations <LOD were imputed as the L O D / 2 ( Hornung and Reed, 1990 ). Most (n=40) serum samples were collected in 2023; the remaining samples were collected in 2016 (n=9), 2020 (n=18), or 2021 (n=11). We invited participants to complete an optional sexual health questionnaire 30 days after enrollment. Sixty percent of participants completed the optional survey, and non-participation was not appreciably associated with key demographic and clinical factors ( Bond et al., 2022 ). We used a modified version of the 6-item Female Sexual Function Index (FSFI-6) ( Isidori et al., 2010 ), which is an abbreviated version of the Female Sexual Function Index ( Rosen et al., 2000 ). The Female Sexual Function Index has been used for over 20 years to identify female sexual dysfunction both in clinical practice and epidemiologic research ( Meston et al., 2020 ). It uses 19 questions to assesses self-reported function over the past 4 weeks on six different domains of sexual function: perceived levels of sexual desire, arousal, and satisfaction, orgasm frequency, degree of vaginal lubrication, and occurrence of painful intercourse. Participants respond to questions using a Likert scale, with 1 indicating low function and 5 high function. Scores are summed, and there are established cut points that have been demonstrated to be highly sensitive and specific for clinically-confirmed female sexual dysfunction ( Meston et al., 2020 ; Rosen et al., 2000 ). The abbreviated FSFI-6 uses one question for each of the 6 domains of sexual function, and also has an established cut point that has high sensitivity (0.93) and specificity (0.94) for clinically-confirmed female sexual dysfunction. The scale also has high internal reliability, with a Cronbach’s alpha of 0.789 ( Isidori et al., 2010 ). We modified the original FSFI-6, replacing a question about vaginal lubrication frequency with a question about difficulty achieving vaginal lubrication from the full Female Sexual Function Index ( Rosen et al., 2000 ). Responses to the new question, which we perceived as having higher specificity in capturing true sexual function issues, were highly correlated (r=0.79) with responses to the original question ( Bond et al., 2024 ). We summed responses to the modified FSFI-6 were and calculated summed scores, with lower scores reflecting poorer function (possible range=2–30; sample range=2–29). The Cronbach’s alpha within our sample was 0.736. In secondary analyses, we used the Female Sexual Distress Scale (FSDS), a validated 12-item scale, to assess distressing feelings about sexual function ( Derogatis et al., 2011 ). This scale captures the degree of negative feelings related to a respondent’s sex life (e.g., embarrassment, shame, frustration) using Likert responses scored from 0 (no distress) to 4 (high distress). The scale is typically used to create a binary variable indicative of clinically-relevant distress related to sexual function, using a validated cut point. In validation studies, Cronbach’s alpha ranged from 0.86–0.93 ( Derogatis et al., 2011 ). Distress related to sexual functioning, specifically negative feelings about one’s sex life, is necessary for a diagnosis of female sexual dysfunction ( American Psychiatric Association, 2013 ) but is not captured by the FSFI-6. Thus, use of a validated questionnaire assessing distress is recommended in combination with the Female Sexual Function Index ( Meston et al., 2020 ). We summed scores for each question, with higher scores indicative of more distress (possible range=0–48; range in PRESTO=0–36). Cronbach’s alpha within our sample was 0.94. Participants reported socioeconomic, demographic, reproductive history, and anthropometric data on a baseline questionnaire. Covariates included age (<25–29 years, 30–34 years, ≥35 years), annual household income (<$50,000-$99,000, $100,000-$149,000, ≥$150,000), educational attainment (<college degree, college degree, graduate school), parity (parous vs. nulliparous), and body mass index (BMI, kg/m 2 ). The current analysis included 78 participants with complete PFAS biomarker and sexual health data. We first evaluated distributions and calculated summary statistics (medians, 25 th -75 th percentiles, percentages [%]) for all variables and estimated Spearman correlation coefficients between the PFAS. We assessed linearity of PFAS-FSFI score and PFAS-FSDS score associations using Generalized Additive Models (GAMs); there was no evidence of non-linear associations, and PFAS were modeled continuously in subsequent regression models. Using a directed acyclic graph informed by the literature, we selected age, household income, educational attainment, parity, and BMI for inclusion in all statistical models ( Berg et al., 2014 ; DeLuca et al., 2023 ; McCool-Myers et al., 2018 ; Park et al., 2019 ; Sagiv et al., 2015 ; Wise et al., 2021 ). We fit multivariable linear regression models to estimate mean differences (with 95% confidence intervals [CIs]) in FSFI-6 scores per interquartile range (IQR) increase in PFAS concentrations, adjusting for hypothesized confounders. We further fit linear regression models in datasets stratified by parity (parous vs. nulliparous) to evaluate potential effect measure modification by parity because 1) menstruation, pregnancy, and breastfeeding are important elimination routes for PFAS ( Kang et al., 2021 ; Mondal et al., 2014 ; Park et al., 2019 ; Sagiv et al., 2015 ; Upson et al., 2022 ; Wise et al., 2021 ), and 2) parity adversely affects aspects of female sexual health ( Botros et al., 2006 ; McCool-Myers et al., 2018 ). We included calendar year at serum collection as a covariate in sensitivity analyses to adjust for potential time trends in PFAS concentrations. In secondary analyses, we fit multivariable linear regression models to estimate associations between an IQR increase in serum PFAS concentrations and log-transformed FSDS scores, adjusting for hypothesized confounders, among participants who completed the FSDS (n=74). We back-transformed beta coefficients (with 95% CIs) as percent differences in FSFD scores.

At baseline, most participants were aged 30–34 years (50.0%), had household incomes ≥$100,000 (78.2%), and had graduate degrees (67.9%; Table 1 ). Notably, all participants in the analytic sample had attained a college degree. The median (25 th -75 th %) BMI was 23.9 (22.0–28.2) kg/m 2 . Nulliparous participants tended to be younger and have higher household incomes, higher educational attainment, and lower BMIs compared with parous participants. Median (25 th -75 th percentile) scores for the FSFI-6 and FSDS were 22.5 (20.0–25.0) and 5.0 (2.0–12.0), respectively, and nulliparous participants tended to have scores indicative of lower function and higher distress ( Table 1 ; see also Figure S1 ). Median (25 th -75 th percentile) serum PFAS concentrations ranged from 0.3 ng/mL (PFNA; 0.2–0.4 ng/mL) to 1.9 ng/mL (PFOS; 1.2–2.8 ng/mL; Table 1 ). PFAS concentrations were consistently higher among nulliparous participants. Spearman correlation coefficients between the PFAS ranged from 0.56 (PFHxS-PFNA) to 0.82 (PFOS-PFNA). An IQR increase in serum PFHxS concentrations was associated with a 1.0-point decrease (95% CI=−1.8, −0.1) in modified FSFI-6 scores ( Figure 1 ). Higher serum PFAS concentrations were consistently associated, though imprecisely, with lower modified FSFI-6 scores among parous participants: an IQR increase in PFHxS, PFOS, PFOA, and PFNA was associated with a 3.2-point (95% CI=−6.2, −0.1), 4.4-point (95% CI=−7.3, −1.6), 2.6-point (95% CI=−7.0, 1.9), and 3.7-point (95% CI=−6.6, −0.9) decrease in modified FSFI-6 scores ( Figure 1 ), respectively. Associations were null among nulliparous participants, except for PFHxS (β=−0.9; 95% CI=−1.9, 0.0). Additional adjustment for calendar year at serum collection did not materially affect our primary findings because calendar year was not a strong predictor of sexual function ( Table S1 ). In secondary analyses, higher serum PFAS concentrations were consistently associated with greater sexual distress, operationalized using continuous FSFD scores, though these associations were imprecise ( Figure 2 ). Notably, an IQR increase in PFHxS and PFOS was associated with a 50.3% (95% CI=−18.2%, 176.0%) and 53.9% (95% CI=−18.4%, 190.5%) increase in FSFD scores, respectively, consistent with findings from the FSFI-6.

In a cohort of U.S. pregnancy planners, higher preconception serum concentrations of some PFAS were associated with poorer self-reported female sexual function, assessed using a modified version of the FSFI-6 ( Isidori et al., 2010 ), and greater sexual distress, evaluated using the FSFD ( Derogatis et al., 2011 ). Associations were consistently stronger, albeit also more imprecise, among parous participants compared with nulliparous participants. Although limited by the sample size, our findings nonetheless support the hypothesis that PFAS exposure may affect sexual function in reproductive-aged females. To our knowledge, this is the first study investigating associations between PFAS and female sexual function. Our findings are generally consistent with two previous studies that evaluated phthalates, another EDC class, and female sexual health in U.S. pregnant individuals (n=360) and Slovakian university students (n=68). Notably, both studies reported associations between higher urinary biomarker concentrations of certain phthalates, including di-(2-ethylhexyl) phthalate, and poorer sexual function (i.e., vaginal dryness, issues with sexual desire) ( Barrett et al., 2014 ; Kolena et al., 2024 ). Like PFAS ( Barrett et al., 2015a ; Harlow et al., 2021 ), phthalates can affect hormonal systems and have been associated with altered levels of reproductive hormones important for sexual function ( Chiang et al., 2020 ; Deng et al., 2019 ; Li et al., 2012 ; Liu et al., 2014 ; Pfaus, 2009 ; Reinsberg et al., 2009 ; Salonia et al., 2010 ; Svechnikov et al., 2010 ; Treinen et al., 1990 ; Zhu et al., 2022 ). Together with the current findings, these studies support the hypothesis that exposure to EDCs may adversely affect female sexual function. Our findings are further supported by toxicological data. PFAS have established neurotoxic mechanisms that may affect multiple aspects of sexual function (desire, arousal, orgasm, and pain). For example, PFAS can affect neurotransmission by dysregulating Ca 2+ ion signaling, altering levels of neurotransmitter or receptor levels, and inducing oxidative stress, leading to poorer functional connectivity, in regions of the brain that modulate sexual function (e.g., hippocampus, amygdala, prefrontal cortex) ( Brown-Leung and Cannon, 2022 ; Foguth et al., 2020 ; Pfaus, 2009 ; Salgado et al., 2016 ; Starnes et al., 2022b ). PFAS exposure has also been shown to reduce circulating levels of kisspeptin (produced in the hypothalamus, hippocampus, and amygdala), a protein that stimulates gonadotropin releasing hormone and regulates sexual desire ( Comninos et al., 2017 ; Starnes et al., 2022b ). PFAS also have documented effects on hormonal systems and exposure can alter levels of hormones (estrogen, oxytocin, progesterone) that are important for maintaining pelvic floor musculature and supporting genital blood flow and vaginal lubrication, with implications for sexual desire, arousal, and pain ( Azadzoi and Siroky, 2010 ; Calabrò et al., 2019 ; Dennerstein et al., 2007 ; Elaine Waetjen et al., 2018 ). Interestingly, PFAS-FSFI associations were stronger among parous participants despite higher PFAS concentrations among nulliparous participants. Parity has been shown to act as an effect measure modifier on associations between PFAS and reproductive hormones (estrogen, progesterone) important for sexual function ( Barrett et al., 2015b ; Harlow et al., 2021 ; Salonia et al., 2010 ). For example, PFAS were more strongly associated with lower progesterone levels in nulliparous 25–35-year-old Norwegian females compared with parous females ( Barrett et al., 2015b ). Higher progesterone levels generally decrease female sexual desire ( Cappelletti and Wallen, 2016 ), suggesting that reduced progesterone levels following PFAS exposure may increase desire, which may explain, in part, why we observed stronger negative associations between PFAS and sexual function among parous participants. Evidence is less clear for estrogen ( Harlow et al., 2021 ), but these data nonetheless suggest that parity may be an important effect measure modifier of PFAS-reproductive hormone associations, and thus PFAS-sexual function associations. The potential role of reproductive hormones in PFAS-sexual health associations warrants additional research. In addition, stronger associations among parous participants may reflect effect measure modification by psychosocial or relationship factors that correlate with both parity and sexual health ( Malina and Suwalska-Barancewicz, 2021 ; McCool-Myers et al., 2018 ). However, our stratified analysis was limited by its sample size and narrow concentration ranges for several PFAS ( Table 1 ), and these findings should be corroborated in future studies. Our study has many strengths, particularly that it is one of the first studies to consider female sexual function as a health endpoint in relation to any EDC exposure. We investigated this research question in an established preconception cohort that collected data on female sexual function using validated instruments ( Derogatis et al., 2011 ; Isidori et al., 2010 ). We further assessed PFAS exposure objectively using serum PFAS concentrations, as a proxy for exposure, quantified in samples collected prior to pregnancy. However, as noted, our sample size was small, particularly for parous participants, limiting our statistical precision and ability to adjust for all potentially important confounders, especially prior breastfeeding duration and menstruation, which have been associated with PFAS concentrations ( Wise et al., 2022 ) and sexual function ( McCool-Myers et al., 2018 ). Our analysis was also cross-sectional. We therefore cannot rule out the possibility of residual confounding or clarify the directionality of associations in the current study. We also do not know the clinical significance of small changes in sexual function as assessed by the scales we used. These scales have established cut points to identify clinically-relevant FSD ( Isidori et al., 2010 ) and distress ( Derogatis et al., 2011 ), respectively, but we used these scales as continuous outcome variables because of limited sample size. Nonetheless, both of these scales are well established, having been used extensively in clinical and epidemiologic research into female sexual dysfunction and distress for over 20 years ( Derogatis et al., 2011 ; Meston et al., 2020 ). Despite the noted influences of sexual function on quality of life, mental health, and relationship quality ( Diamond and Huebner, 2012 ; Flynn et al., 2016 ; Gianotten et al., 2021 ), little research has evaluated the association between environmental toxicants and female sexual dysfunction. The dearth of research on this topic highlights a need for innovative research using established tools. In conclusion, we reported inverse associations between serum PFAS concentrations and female sexual function, an understudied outcome in environmental health research. Female sexual function is important for overall quality of life, relationship satisfaction, and sexual wellbeing, and adverse effects of EDCs on sexual function therefore have implications for positive female sexual expression and overall health. Due to our limited sample and cross-sectional study design, additional studies with prospective designs and larger sample sizes are needed to support our findings.

Female sexual function, the ability to participate in and enjoy sexual activity, is important for female sexual well-being, fertility, relationship satisfaction, and general health ( Diamond and Huebner, 2012 ; Flynn et al., 2016 ; Gianotten et al., 2021 ; Loy et al., 2021 ). The etiology of female sexual dysfunction (FSD), which can manifest as distressing issues with sexual desire/interest, arousal, orgasm, and pain during sexual activity and affects ~40% of premenopausal individuals ( American Psychiatric Association, 2013 ; McCool et al., 2016 ; Parish et al., 2021 ), has not been fully characterized. Some studies indicate that exposure to endocrine-disrupting chemicals (EDCs) (i.e., phthalates) may deleteriously affect sexual function ( Barrett et al., 2014 ; Kolena et al., 2024 ). EDCs are defined by their ability to dysregulate hormonal functions important for reproductive health ( Ahn and Jeung, 2023 ; Diamanti-Kandarakis et al., 2009 ). Although multiple studies have been devoted to understanding the role of EDCs, including per- and polyfluoroalkyl substances (PFAS), on adverse reproductive (e.g., uterine fibroids, endometriosis, polycystic ovarian syndrome) and perinatal (e.g., birthweight, miscarriage, preterm birth, breastfeeding) outcomes ( Ahn and Jeung, 2023 ; Bariani et al., 2020 ; Criswell et al., 2020 ; Huang et al., 2017 ; Jensen et al., 2015 ; Katz et al., 2016 ; Peterson et al., 2022 ; Rickard et al., 2022 ; Upson et al., 2013 ; Wesselink et al., 2021 ; Wolff et al., 2008 ; Yu et al., 2022 ; Zhang et al., 2021 ), female sexual function remains an understudied outcome in the environmental health field. PFAS are a class of EDCs characterized by strong carbon-fluorine bonds that make them highly resistant to environmental degradation ( Fenton et al., 2021 ). Individuals can be exposed to PFAS through diet, drinking water consumption, and from PFAS uses in industrial/military applications (e.g., firefighting foams) and consumer goods (e.g., food packaging, stain- and water-resistant textiles, personal care products) ( Glüge et al., 2020 ; Smalling et al., 2023 ). In the U.S., human exposure to PFAS is widespread; it is estimated that >97% of Americans have detectable concentrations of PFAS in their blood, including legacy PFAS that have been banned or phased out given their environmental and biological persistence ( Brennan et al., 2021 ; U.S. CDC, 2023 ). PFAS, like other EDCs, have documented hormonal effects in the body and have been associated with altered circulating levels of reproductive hormones that modulate female sexual function (e.g., lower estradiol, lower progesterone, and higher testosterone levels) ( Barrett et al., 2015a ; Harlow et al., 2021 ; Heffernan et al., 2018 ). Because of their known endocrine-disrupting properties, it has been hypothesized that exposure to EDCs may adversely affect female sexual function. Of note, PFAS may deleteriously affect female sexual health by interfering with hormones (e.g., estradiol, progesterone) and inducing neurotoxicity in regions of the brain that mediate aspects of female sexual function, including vulvar blood flow, vaginal lubrication, and pelvic floor contractility ( Azadzoi and Siroky, 2010 ; Brown-Leung and Cannon, 2022 ; Calabrò et al., 2019 ; Dennerstein et al., 2007 ; Elaine Waetjen et al., 2018 ; Salgado et al., 2016 ; Starnes et al., 2022a ). To date, only two previous epidemiological studies have investigated associations of EDCs (phthalates) with female sexual health in U.S. pregnant individuals (n=360) or Slovakian university students (n=68) ( Barrett et al., 2014 ; Kolena et al., 2024 ). Both studies reported associations between higher urinary biomarker concentrations of certain phthalates (e.g., di-(2-ethylhexyl) phthalate) and poorer sexual function, defined as issues with sexual desire, vaginal dryness, or poorer scores on a derived sexuality score ( Barrett et al., 2014 ; Kolena et al., 2024 ). Despite study limitations, such as use of non-validated measures of sexual function, these studies support the hypothesis that EDC exposure can affect female sexual function. However, no previous study has investigated associations between PFAS exposure and female sexual function, despite their documented toxicological effects on female reproductive systems and pervasiveness of human exposure ( Barrett et al., 2015a ; Harlow et al., 2021 ; U.S. CDC, 2023 ). The aim of the current study was to assess associations between preconception serum PFAS concentrations and female sexual function on two validated measures (Female Sexual Function Index-6 and Female Sexual Distress Scale) in a cohort of North American pregnancy planners.