Study question: Is there a critical period of progesterone (P4) withdrawal in a mouse menstrual-like model, and at what time after P4 withdrawal endometrial breakdown become irreversible?
Study answer: Our results showed that a 12-16 h critical period of P4 withdrawal exists in the mouse menstrual-like model.
What is known already: P4 withdrawal is the trigger for endometrial breakdown and shedding during menstruation. To date, the molecular mechanisms responsible for endometrial breakdown have not been fully elucidated. In an ovariectomized macaque model, P4 replacement could reduce or block menses during a period of 36-48 h after P4 withdrawal, but after this, P4 supplementation did not reduce or block menses. Thus, in the macaque, a critical period of P4 withdrawal lasting 36-48 h exists before menses.
Study design, size, duration: We created a mouse menstrual-like model and restored P4 at four time points. The total number of mice was 120 and the duration of treatment was 26 days.
Participants, setting, methods: A mouse menstrual model was characterized by endometrial morphology and plasma P4 levels. P4 was then replaced at 8, 12, 16 and 20 h after the removal of P4 implants. Vaginal smears, endometrial morphology, plasma P4 levels and expression patterns of matrix metalloproteinases (MMP-2, MMP-3, MMP-9, MMP-10, MMP-11 and MMP-13) were investigated.
Main results and the role of change: Replacement of P4 at 8 and 12 h blocked menstrual-like bleeding and endometrial shedding; however, replacement at 16 and 20 h did not suppress bleeding or shedding. Furthermore, P4 replacement at 12 h inhibited the expression of all latent or active MMPs; however, replacement at 16 h inhibited only pMMP-13.
Limitations, reasons for caution: Although determination of the critical period in vivo using a mouse model was successfully demonstrated, the mechanisms of P4 regulation need to be further explored.
Wider implications of the findings: The experimental opportunities provided by the mouse model will facilitate understanding the role of P4 in the regulation of menstruation and help to identify new targets for the clinical intervention of menstrual disorders.
Keywords: critical period; matrix metalloproteinase; mouse menstrual-like model; progesterone replacement; progesterone withdrawal.