Background: Why do women have menopause? The evolution of menopause has long been the puzzle and interest of sociologists regarding Darwinian fitness. However, in a biological/medical perspective, the underling drive force of menopause has never been provided in a satisfactory form.
Hypothesis and rationale: It has been well established that the overall reproductive lifespan is reflected in the speed of ovarian primordial follicles depletion. And, every ovarian cycle involves disruption and regeneration of the ovarian epithelium, which is potentially mutagenic. In this regard, menopause could be evolved to protect reproductive organs from over-disruption-reconstruction cycling, as to preclude mutagenic tissue changes. Recent discoveries by tissue/cell specific deletion of one single gene (Pten) within different compartment of ovary have revealed strikingly distinct ovarian phenotypes, ranging from advanced primordial follicle depletion to neoplastic ovarian lesions. To explain the onset of menopause, here we propose a model that the relative amount/activity of Pten between different ovarian compartments (follicular, granulosa and epithelial cells) is spatiotemporally programmed, creating a "menopause tone" fine tuning the speed of follicle depletion and therefore the normal timing of menopause. While imbalanced expression of Pten within the ovary cause either pre-arrived menopause (premature ovarian failure) or over-menstrual cycles which are well recognized as a risk factor for ovarian (and other reproductive) cancer. This hypothesis, if validated, could help us understand ovarian aging and related diseases in a more integrated manner; they are just different nodes on the same string. And Pten could just be the tip of the iceberg involved in the regulation of "menopause tone".