Associations Between Repeated Measures of Urinary Phthalate Metabolites With Hormones and Timing of Natural Menopause

Abstract

Phthalates, ubiquitous endocrine-disrupting chemicals, may impact ovarian folliculogenesis and steroidogenesis. We examined the associations of urinary phthalate metabolites with hormones including estradiol, testosterone, follicle-stimulating hormone (FSH), sex hormone-binding globulin (SHBG), and anti-Müllerian hormone (AMH), and timing of natural menopause in midlife women. Data were from 1,189 multi-racial/ethnic women aged 45-56 years without hormone therapy from the Study of Women’s Health Across the Nation (SWAN). Urinary concentrations of 12 phthalate metabolites and hormones were repeatedly measured in 1999-2000 and 2002-2003, resulting in a total of 2,111 observations. Linear mixed-effect models were used to calculate percent differences (%D) and 95% confidence intervals (95% CIs) in serum concentrations of estradiol, testosterone, FSH, SHBG, and AMH. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% CIs of natural menopause. We observed significant associations of phthalate metabolites with lower testosterone concentrations: MCOP with testosterone (%D: -2.08%, 95% CI: -3.66, -0.47), and MnBP with testosterone (%D: -1.99%, 95% CI: -3.82, -0.13), after adjusting for multiple comparisons with false discovery rates<5%. Lower AMH concentrations were also found with higher MECPP (%D: -14.26%, 95% CI: -24.10, -3.14), MEHHP (%D: -15.58%, 95% CI: -24.59, -5.50), and MEOHP (%D: -13.50%, 95% CI: -22.93, -2.90). No associations were observed for other hormones or timing of natural menopause. These results suggest that exposure to phthalates may affect circulating levels of testosterone and diminish the ovarian reserve in midlife women. Given the widespread exposure, reduced exposure to phthalates may be a key step to prevent reproductive effects of phthalates.

Association of Di(2-ethylhexyl) Phthalate Exposure with Reproductive Hormones in the General Population and the Susceptible Population: A Systematic Review and Meta-Analysis

“…The details of the scores for each article are shown in Table S2. Ultimately, this systematic review comprised 37 studies, of which 28 were included in the meta-analysis. − ,,,,,,− Five articles ,,,, included exposure as a categorical variable, two studies , had data that could not be transformed, and two studies , had a unique hormone that was not included in the meta-analysis.…”

“…Although several studies have revealed this phenomenon, it still has not been addressed why and how postmenopausal women become particularly susceptible to plasticizers. 54,67 It seems not to be the result of exposure levels. Long et al found that postmenopausal women had lower DEHP exposure than premenopausal women.…”

“…67 However, the study by Ding et al showed no appreciable variations in the concentrations of DEHP metabolites across menopausal stages. 54 Alternatively, postmenopausal women have lower TT with reproductive aging and declining ovarian functions compared with premenopausal women. The reproductive hormones of postmenopausal women tend to stabilize independently of the menstrual cycle, 97 which may explain their greater sensitivity to DEHP.…”

“…Age subgroup analysis revealed that postmenopausal women (>45 years old) were more sensitive to DEHP by showing a significant decrease in TT and E 2 concentrations. Although several studies have revealed this phenomenon, it still has not been addressed why and how postmenopausal women become particularly susceptible to plasticizers. , It seems not to be the result of exposure levels. Long et al found that postmenopausal women had lower DEHP exposure than premenopausal women .…”

Phthalate metabolites and sex steroid hormones in relation to obesity in US adults: NHANES 2013-2016

“…A study focusing on midlife women revealed a negative correlation between MCOP and TT levels. (D%: -2.08%; 95% CI, -3.66 to -0.47) (60). Further, a study involving 1179 children aged 6-19 years demonstrated that MiBP, MCOP and MBzP were generally negatively associated with estrodial and TT, while positively associated with SHBG (61).…”