The window of opportunity for treating vulvovaginal atrophy in menopause: Insights from oestrogen receptor distribution and age-related changes

OBJECTIVE: To review the biological basis of the "window of opportunity" hypothesis for the treatment of vulvovaginal atrophy (VVA), focusing on the distribution of oestrogen receptors (ERs) in vulvovaginal tissues, the impact of sustained oestrogen deficiency over time, and the rationale for a preventive or very early sequential therapeutic approach. METHODS: Narrative review of experimental and clinical studies evaluating ER expression in vaginal and vulvar tissues, its modulation by age and menopause, and clinical response to local and systemic hormonal therapy, with emphasis on timing of initiation and management strategies. MAIN RESULTS: ER distribution and expression vary with age and menopausal status, with ER-α predominating after menopause. Experimental models show that immediate hormonal intervention after oestrogen deprivation restores tissue trophism and ER expression, whereas delayed treatment is associated with attenuated responses and irreversible histological changes. Loss of collagen, reduced angiogenesis, altered innervation, and inflammatory infiltration contribute to VVA progression. Clinical data suggest that early initiation of vaginal oestrogens enhances therapeutic efficacy. No consistent differences have been observed among local formulations, although ER subtype profile and time since menopause may influence outcomes. CONCLUSIONS: Early initiation of ER-directed therapies may optimise tissue responses and prevent irreversible changes. A sequential treatment framework is useful for long-term management-particularly in women who did not start therapy early-yet further studies incorporating time since menopause and evaluating the long-term safety of hormonal therapy for VVA are warranted.