Modeling menopause: The utility of rodents in translational behavioral endocrinology research

Abstract

The human menopause transition and aging are each associated with an increase in a variety of health risk factors including, but not limited to, cardiovascular disease, osteoporosis, cancer, diabetes, stroke, sexual dysfunction, affective disorders, sleep disturbances, and cognitive decline. It is challenging to systematically evaluate the biological underpinnings associated with the menopause transition in the human population. For this reason, rodent models have been invaluable tools for studying the impact of gonadal hormone fluctuations and eventual decline on a variety of body systems. While it is essential to keep in mind that some of the mechanisms associated with aging and the transition into a reproductively senescent state can differ when translating from one species to another, animal models provide researchers with opportunities to gain a fundamental understanding of the key elements underlying reproduction and aging processes, paving the way to explore novel pathways for intervention associated with known health risks. Here, we discuss the utility of several rodent models used in the laboratory for translational menopause research, examining the benefits and drawbacks in helping us to better understand aging and the menopause transition in women. The rodent models discussed are ovary-intact, ovariectomy, and 4-vinylcylohexene diepoxide for the menopause transition. We then describe how these models may be implemented in the laboratory, particularly in the context of cognition. Ultimately, we aim to use these animal models to elucidate novel perspectives and interventions for maintaining a high quality of life in women, and to potentially prevent or postpone the onset of negative health consequences associated with these significant life changes during aging.

Keywords: Aging; Female; Hormones; Menopause; Model; Rodent.

Figure 1

Stages of Ovarian Follicle Development Stages of ovarian follicle development, beginning at the primordial resting stage and growing in size and shape through the antral (pre-ovulatory) mature follicle. Once the ovum is ovulated, the remaining follicle forms the corpus luteum, a temporary endocrine structure that produces high amounts of progesterone and some estradiol. The corpus luteum degenerates into the corpus albicans if no egg fertilization occurs.

Figure 2

The Ovarian Hormone Cycle During the Reproductive Stage A) The rodent estrous cycle is characterized by four phases. Proestrus is the shortest phase, lasting less than a day, wherein a critical level of increasing 17β-estradiol is thought to trigger the LH surge, inducing ovulation. FSH and progesterone also peak during proestrus. The proestrus phase is followed by the estrus phase. In estrus, LH, FSH, and progesterone decline to baseline levels, while 17β-estradiol levels are moderately low. In metestrus, 17β-estradiol is low, and a transient increase in FSH occurs. Some 17β-estradiol and high amounts of progesterone are released from the corpora lutea following ovulation, increasing circulating progesterone levels between the metestrus and diestrus phases. Gonadal hormones return to baseline as the estrous cycle begins again. B) The human menstrual cycle has three distinct phases. The follicular phase is characterized by steadily increasing 17β-estradiol levels. At a critical level of 17β-estradiol, LH surges, with the trigger for ovulation occurring in the periovulatory phase. Ovulation is followed by the luteal phase, wherein progesterone levels increase and 17β-estradiol is present at a moderate level.

Figure 3

Ovarian Hormone Levels in Reproductive SenescenceA) Rodents commonly enter a persistent estrus state during reproductive senescence (estropause), characterized by moderate to high 17β-estradiol levels and moderate progesterone, LH, and FSH levels as a result of disrupted feedback between the ovaries and hypothalamus/pituitary. b) Human reproductive senescence (menopause) is characterized by low, sometimes undetectable, levels of 17β-estradiol and progesterone, but increased levels of the gonadotropins, FSH and LH.

Figure 4

The Estrous Cycle Representative images of the rat estrous cycle with vaginal cytology. Animals in estrus exhibit cornified cells in their vaginal smears. Metestrus smears contain a combination of cornified cells, leukocytes, needle-like, and round epithelial cells. Diestrus smears are characterized by a large number of leukocytes, and proestrus smears contain round epithelial cells and some cornified cells, sometimes presenting in clustered groups.

Figure 5

Human and Rodent Reproductive Tracts A comparison of the human and rodent reproductive tracts, with analogous structures labeled.

Figure 6

Commonly utilized mazes to study menopause and hormone therapy effects on learning and memory in the rat and mouse model A comparison of common maze paradigms utilized with rodent models of menopause, and examples of representative results using the mazes.

Figure 7

Rodent Models of Menopause An illustration and comparison of three validated rodent models of menopause.