Oestradiol withdrawal in the pathophysiology of VMS

Traditional concept of VMS pathophysiology

The traditional pathophysiological concept of vasomotor symptoms (VMS) is that VMS are associated with low oestrogen levels.¹ However:

• Oestrogen levels may not differ between women with or without VMS^2,3
• Stressors can cause VMS, increase stress-related hormone levels, and increase negative mood^4,5
• VMS are evident in midlife women with regular menstrual cycles⁶

Oestrogen withdrawal, rather than low levels of oestrogen alone, could be a driver of VMS (Figure 1)⁷

An expanded hypothetical concept of VMS pathophysiology

Figure 1. A simplified and expanded hypothesis of VMS pathophysiology based on interdependent oestrogen withdrawal and psychosocial stress.⁷ E2, oestradiol; P4, progesterone; VMS, vasomotor symptoms.

Oestradiol withdrawal and VMS

Declining oestradiol (E2) levels (‘oestradiol withdrawal’) rather than low oestrogen alone is hypothesised to be part of the pathogenesis of VMS (Figure 1).⁷ E2 withdrawal stimulates release of cytokines (e.g., interleukin-6), hormones (e.g., adrenocorticotropic hormone) and neurotransmitters (e.g., noradrenaline), many of which increase and interact during a hot flush.^7,8 As neurotransmitter levels decline, rising levels of noradrenaline (norepinephrine) disrupt function of the hypothalamic thermostat.^3,9 In symptomatic menopausal women, the core thermoneutral zone narrows from the usual 0.4°C to approximately 0.0°C, consistent with the traditional concept.^9,10 Beyond normal temperature homeostasis, a hot flush can be triggered.⁹

“[W]e’ve learned through great basic science research that it is in fact more complicated than oestrogen… there is more to the story.” – Dr Lisa Larkin (President, The Menopause Society). View transcript.

Oestradiol withdrawal and depressive symptoms

Women “who during their earlier years of life have had mood disturbances” can be more susceptible to develop depression – Dr Larkin. View transcript.

VMS negatively impact quality of life in younger and older women, contributing to physical and psychosocial impairment.¹¹ VMS and depression are co-related: VMS increase the risk of depression; women with depressive symptoms are more likely to develop VMS.¹²

Read: Adverse effects of VMS on the mental health of women 

A subset of women appears to be sensitive to rapid declines in E2 and consequent depressive symptoms. In one study, euthymic postmenopausal women with a history of perimenopausal depression (PMD) who were crossed over from E2 to placebo had a significant increase in depression symptom severity. Women with prior PMD who continued E2 therapy, and women in the control group, were asymptomatic.¹³

Further evidence links E2 withdrawal and PMD in a subset of women:

• In the late menopause transition, symptoms of depression can remain high when most menstrual cycles are anovulatory, and periods of hyperestrogenism are infrequent^14,15 
• Increased risk of depressive mood remains in the early postmenopausal phase when ovulatory cycles are absent^16,15

These claims are consistent with the finding that low-E2 menstrual phase can increase suicide risk in women.^15,17 Negative mood changes in VMS, and the sleep disturbances associated with them, could elevate noradrenaline levels.⁷ This could explain why VMS persists for years after swinging E2 levels during perimenopause become low, and E2 levels stabilise during menopause.⁷

Combination oestradiol/progesterone for treating VMS

Dr Larkin outlines oestradiol and progesterone treatment options for the perimenopause and menopause transition. View transcript.

The 1 mg E2/100 mg progesterone (P4) capsule was approved by the US Food and Drug Administration (FDA) in 2021 for the treatment of moderate-to-severe VMS in women with a uterus.¹⁸ Although the full mechanism of action is unknown, E2 and P4 appear to counterbalance and complement each other in the female reproductive system.^19,20 

• E2 stimulates cell growth and proliferation; P4 enhances cellular differentiation and inhibits oestrogens by lowering oestrogen receptor levels^19,20 
• Modern lifestyles could increase E2 levels in the brain and decrease P4 exposure through subclinical ovulatory disturbances (Figure 1)⁷
• Reproductive life E2/P4 balance could prevent age-related diseases²⁰

REPLENISH was a phase 3 clinical trial that investigated four doses of 17β-oestradiol and progesterone (E2/P4) combination capsules for the treatment of menopausal, moderate-to-severe VMS in women with a uterus.²¹ Improvements in the frequency and severity of moderate-to-severe VMS were found with the two highest E2/P4 doses (1.00 mg/100 mg; 0.5 mg/100 mg), satisfying the co-primary endpoints.²¹ Women with moderate-to-severe VMS treated with most E2/P4 doses showed improved quality of life from baseline to 12 weeks, compared with placebo, which was maintained up to 12 months.²²

In another study, transdermal E2 (TE2; 0.1 mg/d) or transdermal placebo was administered to euthymic perimenopausal and early postmenopausal women (aged 45–60 years) for 12 months. Oral micronised P4 (200 mg/d for 12 days) was also administered every 3 months to women taking TE2. Identical placebo pills were given to women receiving placebo. Twelve months of TE2 with intermittent P4 were more effective than placebo in preventing depressive symptoms in the participants.²³

Combination E2/P4 can improve cardiac autonomic control and prevent age-related changes in endothelial function in healthy perimenopausal and early postmenopausal women.²⁴

Conclusion

Oestradiol withdrawal is hypothesised as part of VMS pathogenesis. Stressful lifestyles could increase E2 levels in the brain and decrease P4 exposure. This lays the stage for E2 withdrawal and rising noradrenaline, which cause narrowing of the thermoneutral zone and hot flushes and night sweats. Although the full mechanism of action is unknown, combined E2/P4 can improve depressive symptoms in women with VMS.

Read how unmet needs in VMS can be addressed