Is presence of a premenstrual disorder associated with higher risk of early menopause and menopause-related vasomotor symptoms?

By Dr. Liji Thomas, MDSep 21 2023Reviewed by Danielle Ellis, B.Sc.

Premenstrual disorders (PMDs) comprise physical and mood-related symptoms that occur repeatedly in association with the premenstrual phase of the female reproductive cycle. Though they are known to reduce the quality of life of affected women and are linked to a higher risk of suicidal thoughts and intentions and hypertension, not much else is known about their impact on women’s lives long-term.

A new paper in JAMA Network Open seeks to fill this gap by exploring how PMDs affect the time of menopause and the severity of vasomotor menopausal symptoms (VMS) like hot flashes.

Introduction

Premenstrual disorders end with menopause. However, it is unclear if and how they predict difficulties during the transition.

Earlier research shows a connection between childhood abuse, early puberty, smoking, early menopause, PMDs, and VMS. This could be via the changes in the neuroendocrine system, with interactions between the hypothalamo-pituitary-adrenal (HPA) axis and the hypothalamo-pituitary-gonadal axis. Such factors could lead to early menopause and more severe VMS.

The current study attempts to identify such an association. The study drew data from the Nurses’ Health Study II, collected from June 1991 to June 2017. The participants were premenopausal at entry to the study, and VMS analysis was of necessity confined to those who provided such data.

Women were asked if they suffered from PMDs, and if so, symptoms were asked for using questionnaires to confirm the condition. A control cohort was identified without PMD symptoms or diagnoses. The researchers followed up with the women to identify the onset of natural menopause and the occurrence and severity of VMS.

What did the study show?

The study included over 1,200 women with PMDs, the median age being 41 years. The control cohort of over 2,400 women had a median age of one year older. The follow-up duration in this study was a median of 20 years.

Women with PMD had higher rates of overweight or obesity, less education, smoking, oral contraceptive use, and depression, anxiety, or childhood abuse. The mean age at natural menopause did not differ significantly in either cohort.

The risk of early menopause (excluding surgical or cancer-associated) was more than 2.5-fold increased in women with PMDs, at an incidence of 7 per 1,000 women-years, vs. 2.7 in women without PMDs. This might be due to depression or anxiety, which also shows such an association. However, women who reported PMD but were not depressed or anxious were likelier to have early menopause.

It is more likely that PMD causes the HPA and HPG axes to become relatively insensitive. The resulting lower feedback from the pituitary to the ovaries results in early menopause, enhanced by the higher levels of inflammation associated with PMD. Inflammatory cytokines cause the ovarian follicles to degenerate faster and speed up the onset of menopause.

This is only a theory at present, though it is supported by some evidence. Future research is essential to confirm this mechanism.  

The odds of moderate to severe VMS were 70% higher in women with PMD, 68% of whom reported this vs. 55% of women without PMDs. This translates into a 20% higher risk of moderate to severe VMS in women with PMD. Women with PMD were 43% more likely to have VMS for five or more years.

The risk of moderate to severe VMS did not, however, differ among women with PMD whether or not they were depressed or anxious. Mild VMS did not show any association with PMD.

The highest risk of moderate to severe VMS was among those with a history of premenstrual dysphoric disorder (PMDD) or premenstrual syndrome (PMS), with an increase in risk by 90% and 70%, respectively. Moreover, hot flashes were three-fold more likely in women with PMD.

Such associations with VMS could reflect the underlying increased sensitivity to hormonal changes, perhaps due to greater arterial stiffness that interferes with the proper cooling down of the body. If so, the presence of PMD and VMS could indicate a higher risk of future cardiometabolic disease.

What are the implications?

This pioneering study shows for the first time a positive association between clinical PMD and early menopause as well as moderate-to-severe VMS, independent of smoking, early puberty, childhood abuse, and other confounders.

It is possible that the presence of PMDs signals disordered reproductive physiology that leads to early menopause and more severe VMS. If so, this suggests “a phenotype observable during the reproductive years that may allow clinicians to target women at risk of earlier menopause and subsequent health risks later in the life course.”