Can animal models resemble a premenstrual dysphoric condition?

He said…Premenstrual Syndrome is a condition of women that men -and family- suffer…

The term Premenstrual Disorders (PMD) has been proposed to encompass Premenstrual syndrome (PMS) and Premenstrual dysphoric disorder (PMDD) without considering the complexity of the symptomatology of each one and their variants. For the present review, we use PMD to describe literature findings that include PMS and PMDD.

PMD symptoms are experienced by healthy women and women with pre-existing medical or psychological conditions. According to the literature, 80% of women suffer mild forms of PMD during their reproductive life, while up to a quarter may be affected by moderate to severe symptoms. Between 3% to 8% of women experience a severe form of PMD (Kadian and O’Brien, 2012; Reid and Soares, 2018). The latter is enforced on women who experience most psychiatric symptoms, which leads to periodic interference with day-to-day activities and interpersonal relationships (Appleton, 2018, Reid and Soares, 2018). In 2014, Direkvand-Moghadam et al. described a PMD prevalence of 47.8% worldwide in a metanalysis (n= 18803). These authors also showed that social and cultural factors contribute to its development (Direkvand-Moghadam et al., 2014).

Concerning impairments in the quality of life of women with PMD, literature provides evidence of its relevance. For example, a study that explored PMDD symptoms and their connection with work showed an association with poorer work-life balance, lower levels of psychological resilience, and higher perceived work demands. While, higher symptomatology was associated with work absenteeism, poor ability to be present at work, and intention to reduce working hours (Hardy and Hunter, 2021). Also, women with PMDD perceived a general decrease in health, higher alcohol consumption, poorer sleep quality, anxiety, depression, and other symptoms (Hardy and Hunter, 2021). Therefore, this clinical entity requires investigation to create strategies to relieve symptoms and generate a healthy state.

Physical and psychological symptoms that affect women’s quality of life and day-to-day functioning are included in the criteria for diagnosis (Table 1). According to the DSM-5, five of eleven symptoms must be present during two consecutive menstrual cycles to diagnose PMDD. In the severe form, one of the symptoms should be irritability, depression, anxiety, or lability (Hantsoo and Epperson, 2015, Reid and Soares, 2018) (Table 2). In psychopharmacology, these symptoms are targets to model the pathology. Other symptoms include loss of interest or concentration, lethargy, appetite changes, sleep disturbance, feeling overwhelmed, and physical symptoms. They should occur during the reproductive age and not be exacerbated by other psychiatric disorders (APA, 2013). Because some of the PMDD symptoms (irritability, anxiety, anger, depression, and labile mood) are the same as those experienced by women with other psychiatric disorders, the onset and cessation of the symptoms during the luteal phase of the menstrual cycle is a sine qua non to the diagnosis (Reid and Soares, 2018). However, some reports also show that some symptoms of PMD variants do not meet the endocrine diagnostic criteria.

The etiology of PMDD is complex because several internal and external issues have been postulated as factors that trigger the pathology. From this point of view, factors such as hormonal changes, genetic predisposition, nutritional deficiencies, diet preferences, environment, social aspects of life from early periods, neurotransmitters, and immune system alterations have been considered (Alwafa et al., 2021, Hantsoo and Epperson, 2015). The factors most studied are the hypothalamus-pituitary ovarian (HPO) and the adrenal (HPA) axis. Recently, a new proposal based on genetic approximations provides evidence about the contributions of these factors to the etiology of PMDD. In the following sections, we present evidence of the role of the HPO and HPA axis in the generation of PMDD symptoms as well as the impact on the GABAergic system function to provide a framework that allows us to analyze current animal models, their contributions, and limitations.

The menstrual cycle starts on the first day of menses and ends the day before subsequent bleeding onset. The mean length of the cycle is 29.3 days (Bull et al., 2019), and it repeats during women’s reproductive life from menarche to menopause, except for the gestation period (Schmalenberger et al., 2021). The menstrual cycle is divided into two phases (Figure 1): 1) the follicular phase starts with menses onset and finishes one day after ovulation. It is characterized by low and constant progesterone levels with the increase of estradiol towards the mild-follicular phase reaching the maximum increase at ovulation day. 2) The luteal phase starts one day after ovulation and finishes one day before the menses. In this phase, estradiol drops down initially, but several days after, it shows a slight increase that falls again before the menses. Progesterone, in contrast, rises at the beginning reaching the peak in the middle of the luteal phase and shows an abrupt drop down at the end of the cycle (Schmalenberger et al., 2021). In rodents, instead of ovarian cycles of 29.3 days, there are cycles of 4-5 days with similar hormonal fluctuations (see below); thus, monitoring the estrous cycle makes it possible to make inferences about the hormonal status of females.

The most explored factor associated with PMD symptoms is the ovarian hormone fluctuations due to the cyclic nature of on/off symptomatology (figure 1). Roomruangwong et al. (2019) found a stronger association with progesterone as a predictor of PMD symptoms of depression and anxiety domains of “Daily Record Severity Problems” (DRSP) (Roomruangwong et al., 2019). In addition, a positive relationship between high progesterone levels and mood improvement (lower aggression, irritability, and fatigue), while an inverse association was observed when progesterone falls (Epperson et al., 2007, Rapkin et al., 1997, Wang et al., 1996, Ziomkiewicz et al., 2012). Furthermore, in vulnerable women, the gradual reduction of progesterone appears to protect them from the onset of PMD symptoms, while the abrupt fall induces symptoms (Contreras et al., 2006, Lovick et al., 2017, Schmidt et al., 2017). The later evidence provides an important framework for the progesterone withdrawal model in rodents discussed below.

Regarding estradiol, other authors using pharmacological ovarian suppression detected that the administration of this hormone (high or low doses) did not promote the generation of PMD symptoms (Segebladh et al., 2009); however, low levels could exacerbate some effects of progesterone on PMD symptoms (Roomruangwong et al., 2019). Therefore, low estradiol levels in the luteal phase might contribute to the vulnerability of women to emotional symptoms rather than PMD symptoms generation (Amiel Castro et al., 2021, Roomruangwong et al., 2019, Segebladh et al., 2009, Yen et al., 2019).

Some authors reported that women with PMDD who received the first Estradiol/progesterone (E/P) cycle after a long-term hormonal suppression increased their “Rating Premenstrual Tension” score, mainly sadness and irritability (Schmidt et al., 2017). Also, they found that the PMDD symptoms did not appear during the second and third months of EP administration when steady levels of ovarian hormones were reached. These data reinforce the idea that abrupt changes in ovarian hormones (low to high) are more likely to trigger PMDD symptoms than constant levels (Contreras et al., 2006, Lovick et al., 2017). The results also showed that only one portion of the women with PMDD showed symptom remission after the pharmacological suppression of ovulation. Of those, 58% showed symptom provocation when receiving the first episode of EP add-back (Schmidt et al., 2017), emphasizing the complexity of the etiology of PMDD.

Fluctuations in progesterone and its metabolite allopregnanolone (ALLO) occur naturally along the menstrual cycle, showing an increase from the follicular to the luteal phase. In healthy cycling women, a low ratio of ALLO/Progesterone is detected during the mid and late luteal phase of the menstrual cycle (Kimball et al., 2020, Schmalenberger et al., 2021). It has been reported that a previous depressive condition could modify this pattern in women with PMDD (Klatzkin et al., 2006a, b). This finding suggests that a previous condition of stress could influence the conversion process of progesterone into its metabolites, probably targeting specific enzymes. In line with this idea, evidence postulates that the conversion of progesterone to ALLO could be involved in the generation of PMDD symptoms. For example, Martinez et al. (2016) blocked the conversion of progesterone to ALLO in cycling women with and without PMDD, showing that anxiety, irritability, and sadness were prevented when avoiding the increase of ALLO from the follicular to the luteal phase. Also, the authors showed that elevation of ALLO during the cycle may generate PMDD symptoms and postulated that changes in the 5 α-reductase expression in the brain of women with PMDD could be a contributing factor to these effects (Martinez et al., 2016). These findings contribute to delineating other endocrine characteristics of women with PMDD. The increase of ALLO promotes the symptom onset more than an alleviation and, at the same time, describes the role of possible enzymatic alterations in the etiology of PMDD.

In line with these findings, a subpopulation of women who exhibit an exacerbation of PMDD symptoms in response to ALLO showed a reduction of symptoms with the blockage of ALLO’s actions. Thus, Bixo et al. (2017) tested an isomer of ALLO, isoallopregnanolone (UC1010), which acted as an antagonist of ALLO at the binding site of the gamma-aminobutyric acid receptor type A (GABAAR) and detected the relief of symptoms on women with PMDD (Bixo et al., 2017). Exacerbation of symptoms has been described in women with high progesterone levels, suggesting a paradoxical effect of progesterone and its metabolites (Bäckström et al., 2011; Bäckström et al., 1983; Girdler et al., 2001; Hammarback et al., 1989). Bäckström et al. (2011) propose three hypotheses to explain the paradoxical effect of progesterone and ALLO on mood modulation based 1) on the expression of GABAAR subunits, particularly of α4β1δ composition (see below), 2) on the inhibition of inhibitory neurons in specific brain areas like amygdala; and 3) altered Cl- influx that conducts to excitation. Evidence favoring the three proposals exists; however, it requires further exploration.

Altogether, this evidence led several authors to propose that in women with PMDD, symptoms severity and relief are more related to changes in the sensitivity of target receptors than hormone levels (Backstrom et al., 2011; 2015; Bixo et al., 2017). It is important to note that the GABAAR composition is modified by stress exposition, which is a factor that contributes to the severity of PMDD.

Consistent evidence derived from animal models suggests that deoxycorticosterone, and dehydroepiandrosterone, progesterone’s 3α,5α - and 3α,5β- reduced metabolites are positive modulators of GABAAR (Barbaccia et al., 1997, Barbaccia et al., 2001, Sze et al., 2018). These compounds suppress HPA axis activation in response to stress (Barbaccia et al., 1996, Barbaccia et al., 1997, Barbaccia et al., 2001, Caruso et al., 2013, Girdler et al., 2012); which need an appropriate activation of GABAAR in the hippocampus, amygdala, and prefrontal cortex (Gingnell et al., 2014, Gingnell et al., 2012, Liu et al., 2015, Toffoletto et al., 2014), among other brain structures.

Girdler et al. provide relevant information about neuroactive steroids’ contribution to the HPA axis in women with PMDD. She found high levels of ALLO and progesterone at basal conditions, a blunted response of cortisol, and no response of ALLO to the stress challenge in women with PMDD (Girdler et al., 2001, Segebladh et al., 2013). The authors point out that albeit the high levels of ALLO detected in PMDD women, also they were unresponsive to the stressor, indicating dysregulation of the HPA axis negative feedback. Results were in line with other studies in which low cortisol levels were detected in women with PMDD with an inefficient manner of coping with the stress (Beddig et al., 2019, Girdler et al., 1998, Rabin et al., 1990, Roca et al., 2003).

Furthermore, evidence shows that physical, emotional, or sexual abuse was more significant in women with PMDD than in control women. PMDD women showed an aggravation of psychiatric symptoms and a blunted HPA axis response to stress (Bertone-Johnson et al., 2014, Pilver et al., 2011). Also, a meta-analysis found that women victims of some abuse in early periods of life have twice the risk of showing PMD (Islas-Preciado et al., 2021). These data suggest that the HPA axis activation could predispose to PMDD development because of insults in early life.

GABAAR is a complex composed of five subunits, two α, two β, and one γ or δ, that delimit a central chloride-permeable ion channel (Fogaca and Duman, 2019, Locci and Pinna, 2017, Lovick, 2006) that is opened when GABA acts at two binding sites located between α and β subunits (Locci and Pinna, 2017). The GABAAR also has two different recognition sites for ALLO and other neuroactive steroids; the first is between α and β subunits, and the second is formed by a cavity exclusively on α subunits (Hosie et al., 2006). The subunit composition confers important pharmacological properties to GABAARs (Belelli and Lambert, 2005) and is sensitive to stress and hormonal milieu manipulations (Fogaca and Duman, 2019, Lovick, 2006). The most common combination expressed in the brain under basal conditions is the α/β/γ which is highly sensitive to benzodiazepines and has lower sensitivity to ALLO and GABA (Nusser and Mody, 2002, reviewed in Locci and Pinna 2017). On the other hand, the α/β/δ GABAAR subtype is not sensitive to benzodiazepines and is highly sensitive to ALLO (Belelli et al., 2009, Lovick, 2006); furthermore, this composition shows low efficacy for GABA, and neurosteroids increase its agonist efficacy (Shu et al., 2012, Stell et al., 2003).

The expression of specific subunits of GABAARs suffers changes after prolonged stress. For instance, the α4, α5, and δ subunit expression is markedly increased, and the α1, α2, and γ2 is significantly decreased in the frontal cortex and hippocampus in response to forced swim, chronic mild stress, prolonged social stress, or social isolation in male mice (Locci and Pinna, 2017). These characteristics may confer low sensitivity to benzodiazepines and affect the sensitivity to neuroactive steroids. For example, the altered GABAAR subunit composition, which results from chronic stress, favors high sensitivity for neurosteroids, neurosteroids-like molecules, or alcohol (Pinna et al., 2006, Serra et al., 2006). Interestingly one clinical feature of PMDD is the lack of response to benzodiazepines (Bolea-Alamanac et al., 2018, Evans et al., 1998). Moreover, a population of women with PMDD also showed high sensitivity to ALLO and PMDD symptoms (Backstrom et al., 2011, Bixo et al., 2017, Timby et al., 2016, Timby et al., 2006), suggesting that an altered composition of GABAAR subunits in response to prolonged stress could be participating in the generation of anxiety and depressive symptoms observed in PMDD (Gingnell et al., 2014, Toffoletto et al., 2014). Furthermore, attenuated HPA axis response after prolonged stress is also observed in women with PMDD (Bertone-Johnson et al., 2014, Girdler et al., 2001, Islas-Preciado et al., 2021, Pilver et al., 2011).

An imbalance between excitatory and inhibitory action due to GABA deficiencies and increased glutamatergic function promoting depression and anxiety behavior has been reported (Fogaca and Duman, 2019). Using the proton magnetic resonance spectroscopy, researchers reported that women with PMDD showed lower GABA levels in the anterior cingulate cortex and medial prefrontal cortex than healthy controls; in contrast, high levels of glutamate-glutamine in the same areas were detected. These data support the hypothesis that an imbalance in the amino acid neurotransmitter system could be participating in the pathogenesis of PMDD (Liu et al., 2015). Interestingly, the imbalance reported between excitatory and inhibitory activity in the brain in women with PMDD (Liu et al., 2015) is also a target of neuroactive steroids.

Genetic makers of PMDD candidates are the polymorphism for the serotonin transporter (5HTTLPR) and BDNF (Valine66Methionine). No associations were reported between 5-HTTLPR, hormones, scores for anxiety and depression, and PMDD (Comasco et al., 2014, Magnay et al., 2010). However, women with PMDD diagnostic who were carriers of the Met allele of Val66Met polymorphism showed lower fronto-cingulate cortex activation in the luteal phase of the menstrual cycle compared with controls carrier of the Met allele (Comasco et al., 2014). Interestingly, neuroticism, a personality trait linked to PMDD (Gingnell et al., 2010), has been associated with the BDNF Met allele, with low serum BDNF levels (Lang et al., 2004).

Dubey et al. (2017) explored the cell sensitivity of women with PMDD under hormone suppression and E/P add-back. Women with a diagnosis of PMDD who behaviorally respond to hormone-ovarian suppression treatment and show symptoms of aggravation after E/P add-back showed a different gene and protein regulation than healthy women (Dubey et al., 2017). In lymphoblastoid cell line cultures (LCLs) of women with and without PMDD, authors found differences in untreated and ovarian steroid-stimulated mRNA and protein expression of ESC/E(Z) complex genes which involved in steroids actions. Interestingly the identified genes are like those found in mice that express the polymorphism of human BDNF (Val66Met; rs6265) named Het-Met mice (Marrocco et al., 2020). Also, estradiol treatment exerts neuroticism traits in these mice, which occurs similarly in women after estradiol treatment (Schmidt et al., 2017, Schmidt et al., 1998). Importantly, Het-Met mice show alterations in genes that codify the response of GABA and glutamate, regulating the balance between excitatory and inhibitory responses (Marrocco et al., 2020). These data suggest that the BDNF polymorphism could represent a biomarker of PMDD.

The present data shows that PMDD etiology is complex and implies several factors that require consideration when this condition is modeled in animals.

From clinical data, it is possible to draw some core signs in animal models:

For example, the increase of anxiety, depression, or aggression/ irritability observed in women during the luteal phase of the menstrual cycle or after the hormonal add-back after a period of hormonal suppression fluctuations are symptoms that could be observed in animal models (Table 1). Ideally, these changes in the behavior should be associated with changes in the expression of GABAAR subunits particularly those that showed altered sensitivity of ALLO and benzodiazepines, enzymes involved in the synthesis of progesterone’s 5-α reduced metabolites, changes in glutamatergic activity, and hypothalamus-pituitary-adrenal axis function. Moreover, according to recent findings of BDNF polymorphism, the Het-Met mice would be expected to be responsive to hormone challenges. In the next section, these points are discussed.

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