Reproductive aging and menopause-like transition in the menstruating spiny mouse (Acomys cahirinus)

STUDY QUESTION: Does the naturally menstruating spiny mouse go through menopause? SUMMARY ANSWER: Our study is the first to show a natural and gradual menopausal transition in a rodent. WHAT IS KNOWN ALREADY: Age-related depletion of the human ovarian reserve (OvR) leads to menopause, the permanent cessation of menstruation and reproduction. Current rodent models of menopause are inappropriate for inferences of the human condition, as reproductive senescence is abrupt or induced through ovariectomy. The spiny mouse is the only confirmed rodent with a naturally occurring menstrual cycle. STUDY DESIGN, SIZE, DURATION: Histological assessment of virgin spiny mice occurred in females aged 6 months (n = 14), 1 year (n = 7), 2years (n = 13), 3 years (n=9) and 4 years (n=9). Endocrinology was assessed in a further 9 females per age group. Five animals per group were used for ovarian stereology with additional ovaries collected at prenatal Day 35 (n = 3), day of birth (n = 5), postnatal Days 35 (n = 5) and 100 (n = 5) and 15 months (n = 5). PARTICIPANTS/MATERIALS, SETTING, METHODS: Morphological changes in the reproductive system were examined using hematoxylin and eosin stains. Proliferating cell nuclear antigen immunohistochemistry assessed endometrial proliferation and sex steroids estradiol and testosterone were assayed using commercial ELISA kits. MAIN RESULTS AND THE ROLE OF CHANCE: The proportion of females actively cycling was 86% at 6 months, 71% at 1 year, 69% at 2 years, 56% at 3 years and 44% at 4 years. Uterine and ovarian weights declined steadily from 1 year in all groups and corresponded with loss of uterine proliferation (P<0.01). Estradiol was significantly decreased at 1 and 2 years compared to 6-month-old females, before becoming erratic at 3 and 4 years, with no changes in testosterone across any age. Fully formed primordial follicles were observed in prenatal ovaries. Aging impacted on both OvR and growing follicle numbers (P<0.001-0.0001). After the age of 3years, the follicle decline rate increased more than 5-fold. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: This is a descriptive study in a novel research rodent whereby reagents validated for use in the spiny mouse were limited. WIDER IMPLICATIONS OF THE FINDINGS: The gradual, rather than sudden, menopausal transition suggests that the spiny mouse is a more appropriate perimenopausal model than the current rodent models in which to examine the neuroendocrine pathways that encompass all hormonal interactions in the hypothalamic-pituitary-gonadal axis. The logistic, ethical and economic advantages of such a model may reduce our reliance on primates in menopause research and enable more thorough and invasive investigation than is possible in humans.

Automated summary

This study is the first to demonstrate a natural and gradual menopausal transition in rodents. The findings suggest that spiny mice may be a more suitable perimenopausal model than current rodent models for studying the pathways involved in menopause.