Endocrine disrupting chemicals and female sexual health: An emerging research priority.

Despite the toxicological evidence supporting the potential role of EDCs in the etiology of FSD, we are aware of only four previous epidemiologic studies that have investigated any EDC class in relation to female sexual function, three of which focused on phthalates 7 , 8 , 10 and one that focused on PFAS. 9 Barrett et al. investigated associations of urinary phthalate metabolites with self-reported interest in sexual activity and vaginal dryness among U.S. pregnant women (n=360). 7 This study reported associations between phthalate exposure and lack of interest in sexual activity, but not vaginal dryness. 7 Consistently, Kolena et al. reported associations between urinary phthalate metabolites and lower sexuality scores (reflecting poorer sexual function) in 68 Slovakian university students. 8 In contrast, in a sample of 347 pregnancy planners, Schildroth et al. reported generally null or weak associations between phthalate biomarkers and female sexual function as measured by the Female Sexual Function Index-6 (FSFI-6). 10 In a separate study, Schildroth et al. reported associations between serum PFAS concentrations and lower scores on the FSFI-6 among 78 North American pregnancy planners. 9 While these studies support the hypothesized role of EDC exposure in the etiology of FSD, they were limited by their cross-sectional designs and sample size. To our knowledge, our studies were the first to evaluate EDCs and sexual health using a validated instrument of sexual function (the FSFI-6). 117 While there are several validated scales to assess female sexual function, 118 many have been criticized as overly emphasizing vaginal intercourse, being less relevant in gender- and sexual-minority people, and having less utility among those not in partnered sexual relationships. 119 , 120 Finally, three of these studies did not consider personal lubricant use as a potentially important covariate. 7 – 9 Personal lubricants are effective at reducing vaginal pain during intercourse and are commonly used by women experiencing painful intercourse. 121 However, personal lubricants may represent a source of chemical exposure, given EDCs are often detected in personal care products, including menstrual products, cosmetics, and other vaginal products (i.e., douches). 122 – 126 This potentially important source of confounding or reverse causation should be considered carefully. Additional research is therefore needed to confirm findings from these studies, and to explore other factors that may contribute to the effects of EDCs on female sexual function. Because female sexual function is largely understudied in environmental health, there are broad needs for future epidemiologic studies. Notably, longitudinal studies, especially those with large sample sizes from established cohorts, are necessary to firmly establish the temporality of associations observed in prior cross-sectional studies. Where possible, established cohorts with data on EDC exposure should leverage data on female sexual health or dysfunction measured on instruments already employed in study protocols, like the FSFI-6, 117 Uterine Fibroid Symptom and Health-related Quality of Life (UFS-QOL) questionnaire, 127 or Endometriosis Impact Questionnaire (EIQ). 128 Ongoing cohorts with active data collection should also consider adding validated measures of female sexual function to their protocols to support investigation of EDC-sexual health associations. We focused our discussion on three commonly studied EDC classes--PFAS, phthalates, and environmental metals--because the current literature supports 1) possible adverse effects of these classes on female reproductive health, and 2) ubiquity of exposure among reproductive-aged women. 35 However, other chemical classes to which women are commonly exposed with known hormonal and neurotoxic mechanisms that could influence sexual function – for example, flame retardants, pesticides, phenols, and parabens 35 , 129 – should also be considered in future work. It is difficult to denote which EDC classes should be prioritized for study in relation to female sexual function given the paucity of research on female sexual function in the environmental health field. Future efforts should consider EDC classes with evidence of reproductive toxicity, particularly classes for which existing data in prospective cohorts is available. Studies actively collecting data could also consider emerging contaminants of concern, such as short-chain or alternative fluorinated compounds. Future research studies should also address potential joint or interactive effects of EDC mixtures, given that women are commonly exposed to multiple EDCs that may have overlapping mechanisms of toxicity. 130 – 134 Previous studies measured EDCs cross-sectionally among reproductive-aged women, including during pregnancy and in the preconception period. 7 – 9 However, consideration should be given to exposure timing in future studies, with an emphasis on prospectively evaluating the effects of EDCs during potentially vulnerable periods of exposure across the life course (i.e., menarche, phases of the menstrual cycle, pregnancy, menopause). Notably, during pregnancy and postpartum, individuals often experience decreases in sexual desire, orgasms, and sexual satisfaction, as well as increased pain with intercourse. 135 Concurrently, female sexual function is dynamic across the menstrual cycle: desire, for example, typically increases during the ovulatory period and sexual activity decreases in the luteal phase. 136 , 137 Female sexual function is further affected by hormonal changes in menopause, such that sexual desire and vaginal lubrication decrease, accompanied by increases in pain, among menopausal women. 138 While less research has investigated sexual function during adolescence, EDC exposure during puberty may lead to early menarche and alter reproductive hormone levels, 139 , 140 with potential implications for sexual health later in life. Taken together, these data suggest that the timing of EDC exposure is important to consider for female sexual health, where menarche, pregnancy, menopause, and certain phases of the menstrual cycle may be periods of susceptibility to EDC toxicity. Longitudinal studies with female sexual function measured at multiple time points are needed to identify potential critical periods of EDC exposure. Previous epidemiologic studies of EDCs and female sexual function did not investigate specific sexual function domains (e.g., desire, arousal, orgasm, and pain). 7 – 9 Because these domains are mediated by different physiological processes, as described in the Introduction, it is plausible that EDC exposure may differentially affect each sexual function domain, and may influence some domains but not others. Exploring the relationship between EDC exposures and individual domains of sexual function would help to 1) elucidate potential mechanisms of action of EDCs on sexual health, which remain largely uncharacterized, and 2) inform clinical practice. In addition, previous epidemiologic studies included few females from racial and ethnic minorities. 7 – 9 However, there are documented inequities in exposure to certain EDC classes, 141 in part, because of racist historical and environmental policies and practices, such as redlining, 142 zoning of toxic industrial sites, 143 and workplace discrimination (e.g., policies restricting natural hairstyles). 144 , 145 Moreover, some studies reported that minoritized racial and ethnic groups (e.g., Black, Hispanic females) are more likely to report lower FSFI scores, 146 less frequent sexual activity, 147 greater sexual pain, 148 and poorer medical care. 149 Therefore, EDC exposure may contribute to racial inequities in female sexual health, though this hypothesis has not yet been investigated in any epidemiologic study to our knowledge. Further, prior studies of EDCs and sexual function did not explicitly include individuals with diverse genders or sexual orientations (i.e., only included cisgender straight women). 7 – 9 Generally, sexual function is understudied in gender and sexual minority populations, 150 , 151 highlighting an important research gap for sexual function and reproductive health more broadly. Future studies investigating environmental determinants of female sexual function should aim to include more diverse populations in terms of race, ethnicity, and sexual and gender identity. Finally, to our knowledge, no prior study has considered psychosocial factors as potential effect measure modifiers or mediators of EDC-sexual health associations. 7 – 9 Psychosocial factors (e.g., high stress levels) can adversely influence levels of sexual desire and satisfaction and reduce the frequency of sexual activity. 152 , 153 Concurrently, EDCs may activate the stress response by dysregulating the hypothalamic-pituitary-adrenal axis and inducing neurotoxicity in the prefrontal cortex and limbic system, leading to greater perceived stress levels, anxiety, and depressive symptoms. 59 , 63 , 154 – 161 These data suggest that psychosocial factors may modify or mediate associations between EDCs and female sexual health, and should be investigated in future work. Future research efforts will need to address several study design challenges inherent to epidemiological research, generally, and EDC research specifically. As noted previously, all prior epidemiological studies of EDCs and sexual function were cross-sectional in design and may therefore be influenced by bias from reverse causation or time-varying confounding. Longitudinal studies are needed. In addition, future research efforts will need to address possible exposure measurement error inherent in studying EDCs with short biological half-lives and episodic exposures; resulting misclassification biases may be particularly pertinent for sexual health, given sexual function is multi-factorial and can be influenced by other transient factors (e.g., relationship satisfaction). Because sexual function is affected by multiple physiological, social, and psychological factors, disentangling the effect of EDCs on sexual function will be challenging and require adequately designed studies. Outcome misclassification is another important consideration, as FSD is often captured using validated questionnaires that collapse assessment of function across different domains of sexual function into a single measure (i.e., the Female Sexual Function Index). 162 It is possible that environmental exposures like EDCs affect different sexual function domains differently, necessitating validated measures of individual domains which are currently lacking. 163 , 164 In addition to longitudinal designs, studies of EDCs and sexual function should consider: 1) employing multiple exposure measurements over time to reduce misclassification and assess exposure at critical windows (e.g., across the menstrual cycle); 2) collecting extensive sociodemographic, relationship, behavioral, and psychosocial information to adjust for potential confounding and explore effect measure modification; and 3) use validated measures of sexual function, with an eye towards domain-specific measures where possible, to improve sensitivity and specificity of the outcome. Positive sexual expression is an enriching part of life for many individuals and is an important aspect of a female’s overall reproductive health and general well-being. 3 In particular, sexual satisfaction has been positively associated with increased relationship satisfaction and longevity, 165 , 166 and more regular sexual activity has been associated with delayed menopause. 167 Better sexual function has also been associated with other important health outcomes, including faster time-to-pregnancy. 168 Despite its importance, the etiology of FSD remains incompletely characterized. Because of the ubiquity of human exposure to EDCs, 35 understanding the relationship between exposure to environmental toxicants and FSD has the potential to elucidate an important cause of population-level sexual health issues, which may affect millions of women in the U.S. (i.e., >40% of premenopausal women). 5 Identifying environmental determinants of FSD can, in turn, inform interventions aimed at improving female sexual function through 1) implementation of individual-level exposure reduction strategies that have been shown to decrease biomarker levels of some EDCs 169 , 170 ; 2) structural policy changes limiting EDCs in consumer products, especially those that may have contact with sensitive vaginal tissue (e.g., personal lubricants, menstrual products) 125 , 126 ; 3) informing clinical practice, with a special emphasis on educating physicians on the potential for vaginal lubricants to contain EDCs 126 ; and 4) identifying subpopulations at particular risk. Elucidation of any relationship between EDCs and FSD and the underlying biological mechanisms has the potential to shed important insights into groups at higher risk of FSD caused by EDCs. For example, it is possible that the effects of EDCs are more potent among women at different points in the life course (e.g., menarche or menopause), among those with hormonal or metabolic disorders, or less access to healthcare or resources to support sexual wellness. In conclusion, female sexual function is an understudied outcome in environmental health research, despite its importance for female sexuality and quality of life. We provided an overview of the biological processes underlying female sexual function, described possible toxicological effects of EDCs on female sexual function, and outlined directions for future research, highlighting the importance of considering female sexual health as a distinct health endpoint in environmental health research.

Positive sexual expression has been associated with relationship satisfaction 1 and myriad health benefits 2 and is an important component of overall quality of life. 3 Sexual dysfunction refers to persistent difficulty in participating in desired sexual activity that is distressing to the person experiencing it. 4 Female sexual dysfunction (FSD), an umbrella term for a wide range of sexual dysfunctions in females, affects an estimated 40% of premenopausal women globally. 5 FSD encompasses issues in different domains of sexual function, including sexual desire, arousal, orgasm, and pain with sexual activity, 6 and may be adversely affected by exposure to endocrine disrupting chemicals (EDCs). 7 – 10 For example, several studies have reported associations between exposure to per- and polyfluoroalkyl substances (PFAS) and phthalates, two classes of EDCs that are ubiquitous in the environment, 10 – 15 and worse sexual function. 7 – 10 These studies are supported by epidemiologic and toxicological data illustrating the ability for EDCs to interfere with hormonal systems and neurological function underpinning sexual function, 16 – 23 and in vivo studies demonstrating altered sexual behaviors in female animals following EDC exposure. 24 – 26 Yet, female sexual function remains understudied in environmental health research, which is especially noteworthy given the relatively larger existing body of research on environmental exposures and male sexual function. 27 – 30 Therefore, our aim in this commentary is to highlight female sexual function as an important research priority in environmental health, particularly in relation to EDC exposure. Sexual function is appropriately contextualized within a complex, multi-level web of biological, psychological, and social factors, 31 , 32 but we focus this commentary on the basic biological processes that underlie sexual function 33 and may be sensitive to EDC toxicity. However, it is important to note that EDCs are best understood as one potential contributor to a complex condition and may interact with any number of other potential causes, including other environmental exposures or psychosocial circumstances, to influence sexual function. The first part of the commentary is organized into four sections, each focusing on one of four primary domains of sexual function: desire, arousal, orgasm, and pain. 6 Within each section, we highlight key physiological systems necessary for sexual function and describe the potential vulnerability to EDC exposures. We then discuss the current state of the epidemiologic literature and future directions for research. Because sexual function has been most comprehensively described and conceptualized in a cisgender context (i.e., people who were assigned female at birth and identify as women), 34 we use both “female” and “women” in this commentary to refer to cisgender women. However, we recognize the underrepresentation of gender-diverse individuals (e.g., people whose gender identity is different from their sex assigned at birth) in environmental health research and the need to fill important scientific gaps in this research area. Few previous studies have characterized the toxicological effects of EDCs on female sexual function, but some studies in animal models suggest that EDCs may influence sexual behavior in females. 24 – 26 Based on the current known toxicological mechanisms of EDCs, we hypothesize that EDC exposure may induce deleterious effects on sexual function by influencing the physiologic systems underling desire, arousal, orgasm, and pain. It bears noting that components of sexual function are interrelated and affect one another. We organize this commentary into individual sexual function domains, but functional issues in one domain can contribute to the development of functional issues in other domains, and therefore issues often co-occur across domains. 6 We focus our discussion on three EDC classes to which females are commonly exposed, PFAS, phthalates, and environmental metals, 35 though we recognize that other EDC classes may also adversely affect sexual function and should be considered in future research. We contextualize the hypothesized toxicological mechanisms of EDCs on sexual function into two categories: 1) neurotoxicity, including direct effects in areas of the brain mediating sexual function and indirect effects through psychosocial factors; and 2) interference with key hormonal systems. Sexual desire is a complex psychological state that integrates physical, cognitive, emotional, and relational elements. 36 Desire is believed to result from an interplay of excitement and inhibition. 37 Indeed, neuroimaging studies support the hypothesis that certain brain areas are hyper- or hypo-activated in the context of sexual desire and low desire disorders. 38 The hypothalamus and limbic system are key components of sexual desire, and they respond to steroid hormone activity (i.e., androgens, estrogens, and progestins) to prime the brain to respond to sexual stimuli. 39 Specific neurotransmitters, including dopamine, norepinephrine, melanocortin, and oxytocin, act within the hypothalamus and limbic region to cue attention to, and feelings of, desire in response to sexual cues and stimulation. 39 On the other hand, serotonin is believed to create a sense of satiety and decreased sexual desire, which may underlie the high prevalence of low sexual desire among individuals taking selective serotonin reuptake inhibitors. 40 The involvement of the hypothalamus and limbic system in sexual desire is notable because EDCs (phthalates, metals, PFAS) have been shown to affect Ca2+ ion signaling, induce oxidative stress, alter functional connectivity, and reduce neuronal plasticity in the limbic system (i.e., hippocampus), hypothalamus, and prefrontal cortex, leading to altered neurotransmission, neuroinflammation, and apoptosis. 23 , 41 – 45 EDCs, especially metals and PFAS, can alter neurotransmitter levels implicated in sexual desire (i.e., decrease dopamine or dopamine receptors, increase glutamate, increase serotonin). 23 , 44 , 46 – 50 The documented effects of EDCs on reproductive hormones important for sexual desire (i.e., estrogen, progesterone, oxytocin) in both humans and animal models is likely a key mechanism of toxicity. 16 – 22 Notably, exposure to PFAS, phthalates, and heavy metals has been consistently associated with reductions in estrogen, progesterone, and testosterone levels in humans and in animal models. 17 – 20 , 22 , 51 , 52 However, some studies reported positive associations with sex hormones, suggesting the effects of EDCs on reproductive hormones, and desire, is complex and may vary by exposure timing, exposure dose, or chemical/metabolite. 16 , 19 , 20 , 51 , 53 Several studies also reported that PFAS and phthalate exposure reduced kisspeptin expression, a hormone produced by the hippocampus, hypothalamus, and amygdala that plays a role in sexual desire by stimulating gonadotropin releasing hormone. 23 , 25 , 54 EDCs may further affect sexual desire indirectly by influencing psychosocial health. The adverse effects of stress, depression, and anxiety on sexual desire in women has been well established. 55 , 56 An emerging body of research suggests that exposure to some metals, phthalates, and PFAS may increase perceived stress levels, anxiety, and depressive symptoms in females, 57 – 63 which may in turn reduce sexual desire. Sexual arousal represents a combination of subjective and objective elements, specifically physical sensations of swelling, lubrication, and increased sensitivity of the vulva alongside subjective feelings of excitement. 64 Imaging studies in humans have identified areas of the brain that become active in response to sexually arousing stimuli, notably the hypothalamus, corpus striatum, and prefrontal cortex. 65 The temporal lobe, including the amygdala, is activated in response to prolonged visual sexual stimuli, but is deactivated in response to physical sexual stimuli. 66 Because the temporal lobe is hypothesized to inhibit sexual arousal, this decline in activity likely facilitates sexual arousal and response. 67 , 68 These brain areas and neural pathways are responsive to circulating steroid hormones, as demonstrated by brain imaging studies showing increased brain activity in response to sexual stimuli during the midluteal phase of the menstrual cycle, as compared with menstruation. 69 Physiologically, sexual arousal is accompanied by increased blood flow to the genitals. The release of two vasodilator neurotransmitters (vasoactive intestinal peptide and nitric oxide) result in increased blood flow and vasocongestion of the labia, clitoris, and vagina. 70 , 71 This vasocongestion creates the vaginal lubrication that accompanies sexual arousal. Specifically, the increased hydrostatic pressure inside capillaries in the aroused vagina forces out plasma transudate, which collects in the space around blood vessels until it passes through epithelial cells and into the vagina as lubrication. 65 Similar to desire, EDCs may influence arousal by inducing neurotoxicity (e.g., disrupting neurotransmission, inducing neuroinflammation) in regions of the brain (hypothalamus, striatum, amygdala, prefrontal cortex) and altering levels of reproductive hormones (i.e., steroid hormones) involved in arousal. 16 – 23 , 41 – 43 , 45 – 50 Moreover, hormones that mediate genital blood flow and vaginal lubrication may be sensitive to EDC exposure. For example, exposure to phthalates and some metals may decrease vasodilator (e.g., nitric oxide) levels, which may affect vaginal, vulvar, and clitoral blood flow. 72 – 74 EDC exposure has further been associated with depression and anxiety symptoms, 59 , 61 , 63 , 75 – 77 which have been strongly associated with poorer subjective arousal, 55 , 78 representing a possible indirect pathway. Orgasm is defined as a transient apex of pleasurable sensations, typically accompanied by an altered state of consciousness and involuntary contractions of pelvic musculature. 79 There is controversy about brain areas demonstrating increased activity during orgasm in humans. Some researchers suggest that the cerebellum displays consistently increased activity during orgasm, 65 , 66 while other researchers suggest non-uniform, widespread activation. 80 , 81 Dopamine facilitates orgasm, while serotonin inhibits orgasm. 81 Orgasm is often achieved via physical stimulation, particularly of the clitoris. 82 , 83 Animal studies suggest that estrogen 84 , 85 and testosterone 86 both play an important role in vulvar tactile sensitivity and clitoral muscular contraction, which are important for orgasmic experience. 87 Orgasm is accompanied by contractions of pelvic floor musculature, which enhance feelings of sexual pleasure. 81 Hypoactivity of pelvic floor muscles is associated with reduced feelings of pleasure during orgasm, 88 while hyperactivity is associated with painful intercourse. 89 Estrogen may also play a role in pelvic floor muscle function, with some scholars suggesting that estrogen deprivation adversely affects pelvic floor musculature, 90 , 91 though some studies suggest no connection. 92 EDCs may affect orgasm by inducing neuronal damage and altering levels of neurotransmitters or their receptors that mediate orgasm experience, notably dopamine and serotonin. For example, PFAS have been shown to increase serotonin levels and alter dopamine and dopamine receptor levels in animal models, though the direction of effect for dopamine varied across studies. 23 , 46 , 47 The dopaminergic toxicity of metals, especially heavy metals, has been established, with notable effects on dopamine neuron morphology and dopamine homeostasis in multiple brain regions. 44 , 49 , 93 Metals exposure can also affect serotonin homeostasis, 94 while some studies suggest phthalate exposure may increase serotonin levels and decrease dopamine levels in animal models. 95 , 96 The effect of EDCs on reproductive hormones also represents a key toxicological mechanism underlying potential influences on orgasm. Decreases in estrogen and testosterone levels following EDC exposure may adversely affect clitoral tissue and pelvic floor function, reducing orgasmic experience and sensation. 17 – 20 , 22 , 51 , 52 , 88 In addition, EDC-induced effects on psychosocial health may indirectly affect orgasm, 62 , 63 , 75 , 77 where depression has been associated with poor orgasm experience. 55 Sufficient vaginal lubrication, mediated by increased blood flow during sexual arousal, is necessary for painless vaginal penetration. 65 Low arousal, which may result in insufficient lubrication, could contribute to painful intercourse. Exogenous lubricants can improve feelings of sexual pleasure 97 and reduce pain, 98 though their chemical composition is not well characterized. Chronically reduced blood flow to vulvar and vaginal blood flow may result in hypoxia of vulvar tissue which has been associated with painful intercourse. 99 Sufficient exposure to estrogen is also critical to vulvar and vaginal health and tissue integrity, 100 as evidenced by increases in painful intercourse during breastfeeding 101 and vaginal atrophy in postmenopausal women. 102 Research also suggests that testosterone may play an important role in the maintenance of vulvar tissue health. 103 Painful intercourse can also be caused, or exacerbated, by pelvic floor dysfunction, particularly hypertonicity of the pelvic floor. 104 EDCs may affect pain during sexual activity by influencing physiological processes underlying arousal, as described above. Moreover, any EDC-induced hormonally-mediated effects on the pelvic floor have the potential to influence pain because both pelvic floor dysfunction and hypertonicity, followed by local hypoxia of the pelvis, can contribute to painful intercourse. 104 , 105 Notably, EDC-induced disruptions (i.e., reductions) to vasodilators 72 – 74 and estrogen levels 17 , 18 , 21 , 22 may decrease vaginal lubrication (e.g., by reducing vaginal blood flow) and diminish vaginal tissue integrity, leading to painful intercourse. 90 , 106 99 , 100 In addition, because of their interference with hormonal systems, EDCs have been previously associated with several hormonally-dependent reproductive diseases, such as endometriosis, uterine leiomyomata, and polycystic ovary syndrome, which have concurrently been associated with sexual pain. 20 , 107 – 116 EDCs may therefore influence sexual pain indirectly by increasing the risk for reproductive diseases.