Background

Perimenopause, the transition period from reproductive to non-reproductive life, is defined as the period immediately before menopause. This period is marked by the onset of endocrine and biological changes, as well as clinical symptoms suggestive of the approach of menopause and can extend up to twelve months after the final menstruation, with an average duration of five years (WHO, 1996; Soules et al., 2001; Bacon, 2017; Wang et al., 2019). In addition to menopause or definitive cessation of menstrual cycling, perimenopause is a uniquely human process, but it can be mimicked by experimental models, especially in rodents. According to Prior and Hitchcock, perimenopause, previously seen as a period of hypoestrogenism, can be characterized by three main hormonal changes in women whose menstrual cycle remains regular: 1) normal or erratically high concentrations of estradiol; 2) decline in plasma progesterone concentrations and 3) changes at all levels of the reproductive axis (Prior and Hitchcock, 2011). During perimenopause a high percentage of women manifest typical symptoms of this period, which include: vasomotor changes, variations in menstrual cycle duration, sleep disorders, worsening cognitive functions, behavioral and mood changes (irritability, nervousness, anxiety and depression), in addition to metabolic and physiological changes (Mitchell and Woods, 1996; Brinton et al., 2015; Chalouhi, 2017). Considering the brain changes during this period, Brinton et al. (2015) defined perimenopause as a “state of neurological transition”.

The process of reproductive senescence in mammal species is complex and poorly understood, especially in humans (Brinton et al., 2009; Brinton, 2010). Consequently, animal models of menopause and perimenopause function as windows into the complex mechanisms involved in reproductive biology senescence at different levels (systemic, cellular, molecular, and genomic), which are not possible to perform in humans (Brinton, 2012). Nonetheless, current animal models of menopause do not successfully replicate human perimenopause and the gradual changes that occur in this phase. While the traditional rat model of menopause, ovariectomy or surgical menopause that consist of the rapid and definitive removal of the ovaries resulting in a complete loss of all ovarian hormones, natural or transitional menopause is achieved by the selective loss of ovarian follicle (perimenopause period). However, natural aging models fail to reach very low estrogen concentrations and overlapping changes related to somatic aging and those of reproductive aging (Kermath and Gore, 2012; Frye et al., 2012; Kirshner et al., 2020). Additionally, these models do not reproduce what occurs in women, since the primary causes of reproductive aging between species diverge significantly. In women, loss of fertility appears to be primarily associated with exhaustion of ovarian follicles (Faddy et al., 1992; Rubin, 2000), while in female rodents, reproductive aging seems to begin as a neuroendocrine process, with the changes in hypothalamic/pituitary function appearing independently of the follicular atresia (Gore et al., 2000).

A well-established experimental model in the literature for studying perimenopause and menopause is exposure of rodents to the chemical 4-vinylcyclohexene diepoxide (VCD), which leads a gradual failure of ovarian function by progressive depletion of primordial and primary follicles, but retains residual ovarian tissue similar to women in perimenopause (Springer et al., 1996; Kao et al., 1999; Hoyer et al., 2001). Importantly, the VCD model or model of Accelerated Ovarian Failure (AOF, Brooks et al., 2016) mimic both hormonal (Reis et al., 2014; Pestana-Oliveira et al., 2018; Carolino et al., 2019) and behavioral changes such as anxiety (Reis et al., 2014), impaired memory (Koebele et al., 2016), depression (Kalil et al., 2020) and aggressiveness (Dalpogeto et al., 2016; Scafuto et al., 2017) typically manifested by women in perimenopause. Low doses of VCD specifically cause selective destruction of ovarian small pre-antral follicles without affecting other peripheral tissues. Furthermore this occupational chemical doesn’t cross the blood-brain barrier (Lukefahr et al., 2012).

Therefore, the VCD-induced follicular depletion model, followed by ovarian failure has been widely used in experimental research on perimenopause and menopause (Reis et al., 2014; Liu et al., 2015; Brooks et al., 2016; Koebele et al., 2016; Pestana-Oliveira et al., 2018; Wang et al., 2019; Carolino et al., 2019; Kirshner et al., 2020) and is the experimental model that most closely matches the natural human progression to menopause, since the majority of women enter menopause through a gradual and irreversible process of reduction in ovarian function, while retaining the residual tissue of the ovary (Brooks et al., 2016). Thus, considering that it is a critical number of ovarian follicles and not the woman's age that determines the onset of menopause (Faddy et al., 1992), VCD-induced perimenopause is a translational model that presents analogy, predictability and homology, and allows plausible inferences to be made about the dynamics of follicular loss and its effects on the neurochemistry of women in perimenopause and menopause, periods in which affective disorders, vasomotor alterations and several other symptoms compromise the quality of life of middle-aged women.

Recently (2015-2017) the AOF model was applied to the streets and subways of large North American cities such as Chicago, New York, San Francisco, and Los Angeles with the aim of reducing the population of rats that has infested those cities (https://www.chicagomag.com/Chicago-Magazine/March-2015/birth-control-for-rats/).