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. Author manuscript; available in PMC: 2022 Apr 1.
Published in final edited form as: Neuropharmacology. 2021 Feb 16;187:108499. doi: 10.1016/j.neuropharm.2021.108499

Sex differences in progestogen- and androgen-derived neurosteroids in vulnerability to alcohol and stress-related disorders

MacKenzie R Peltier a,b, Terril L Verplaetse a, Yann S Mineur a, Ralitza Geuorguieva a,c, Ismene Petrakis a,b, Kelly P Cosgrove a, Marina R Picciotto a, Sherry A McKee a
PMCID: PMC7992136  NIHMSID: NIHMS1678358  PMID: 33600842

Abstract

Stress and trauma exposure disturbs stress regulation systems and thus increases the vulnerability for stress-related disorders which are characterized by negative affect, including major depressive disorder, anxiety disorders and posttraumatic stress disorder. Similarly, stress trauma exposure results in increased vulnerability to problematic alcohol use and alcohol use disorder, especially among women, who are more likely to drink to cope with negative affect than their male counterparts. Given these associations, the relationship between stress-related disorders and alcohol use is generally stronger among women leading to complex comorbidities across these disorders and alcohol misuse. This review highlights the therapeutic potential for progestogen- and androgen-derived neurosteroids, which affect both stress- and alcohol-related disorders, to target the overlapping symptoms related to negative affect.

1. Introduction

It has been well-documented that early exposure to acute and chronic stressors disrupts stress regulatory systems, including the hypothalamic-pituitary-adrenal (HPA) axis (Harrison & Baune, 2014; Juruena, Eror, Cleare, & Young, 2020). Such disruptions oftentimes are related to an increase in negative affect and stress-related disorders, in which increased activity in the HPA axis can result in reduced inhibitory feedback, which may continue through adulthood, making individuals vulnerable to developing stress-related psychopathologies (Juruena, Eror, Cleare, & Young, 2020). Stress-related disorders include major depressive disorders, a range of anxiety disorders (e.g., generalized anxiety disorder, social anxiety disorder, and panic disorder) and posttraumatic stress disorder (PTSD). While these disorders each have specific diagnostic criteria defined by the Diagnostic and Statistical Manual of Mental Disorders- 5th edition (DSM-5), they are all characterized by central symptoms of negative affect dysregulation, including low mood and excessive worry. Similarly, exposure to early life stress, including childhood maltreatment, is observed in the initiation and maintenance of alcohol use, and the relationship between negative affect regulation and alcohol abuse continues into adulthood (Peltier et al., 2019).

While disruption in stress-systems contributes to stress-related disorders across both sexes, the association is particularly stronger among women. Women experience a 25% lifetime prevalence of major depressive disorder—twice the lifetime rate of depression observed in men—and a 23% past year prevalence for any anxiety disorder, while men had a past year prevalence of 14% for any anxiety disorder (National Institute of Mental Health, 2017; Altemus et al., 2014; Hasin et al., 2018). Additionally, women exhibit twice the lifetime prevalence rate of PTSD as men (8.0% 4.1%; Goldstein et al., 2016), and this sex difference remains when accounting for differences in trauma type and number of traumas (Lehavot et al., 2018).

Across their lifespan, women are also more likely than men to consume alcohol in response to negative emotional states, including stress (Peltier et al., 2019). Beginning in adolescence, onset and frequency of drinking is associated with depression among both boys and girls ranging from 15–18 years old; however, this association is significantly stronger for adolescent girls (Johannessen et al., 2017). The relationship between sex, negative affect regulation, and alcohol continues into adulthood. For example, women who endorsed at least two stressful life events within the past year were four times more likely to have a new diagnosis of alcohol use disorder (AUD) in comparison to men with similar stress exposure, who were only 2.5 times more likely to have a new AUD diagnosis (Verplaetse et al., 2018). Additionally, when compared to men, women report more drinking in response to high-stress situations, such as negative emotions and conflicts with others (Lau-Barraco et al., 2009).

Given the strong associations between altered stress regulation systems and vulnerabilities for psychopathologies, as well as stress-related alcohol use among women, it is not surprising that stress-related psychiatric disorders are disproportionally associated with hazardous drinking among women compared to men. For instance, 22% of individuals with major depressive disorder also meet criteria for an AUD; however, when separated by sex, women have a higher rate of comorbidity than men (24% vs. 13%; Hasin et al., 2018; Peltier et al., 2019). Women also have higher rates of diagnosis with co-occurring PTSD/AUD when compared to men (14% to 6%) and it is more likely for women to meet criteria for PTSD prior to the onset of AUD (Sonne et al., 2003).

Such comorbidities are often complex, with multiple biological and psychosocial factors that contribute to ongoing symptomatology and potentially interfere with treatment. The high rates of comorbidity among disorders related to negative affect place women at increased vulnerability for consuming alcohol for negative reinforcement; these women also experience overall poorer treatment outcomes, as women are more likely to relapse due to stressful situations (Becker & Koob, 2016; Peltier et al. 2019).

Neurosteroids, including progestogen- and androgen- derived neurosteroids, have been implicated in both stress-related disorders and problematic alcohol use (Altemus et al., 2014; Peltier et al., 2019), suggesting that there are likely parallel, underlying mechanisms related to shared vulnerabilities between these disorders. Evidence for such mechanisms will be examined within this review, with respect to what is known in the human literature. However, it is important to note that such work in the clinical field builds upon parallel pre-clinical research.

Similar to clinical observations, male nonhuman primates have been shown to drink more than females; however, female rodents drink in greater quantities than males (Becker & Koob, 2016; Finn, 2020). Additionally, stress plays an important role in alcohol self-administration across preclinical species; for instance, rodent models of PTSD (e.g., predator odor stress) increase alcohol self-administration, especially among female rodents (Finn, 2020). Pre-clinical findings suggest an association between progestogen- and androgen-derived neurosteroids, alcohol and stress, as female rodents (with intact gonads) consume more alcohol than their male counterparts and this may be attributed to the effects of androgens (e.g., estradiol and testosterone; Finn, 2020). Furthermore, in a recent study of nonhuman primates, greater alcohol consumption was positively correlated to distress during the late luteal phase, when progesterone levels are lower (Dozier et al. 2019).

Targeting these progestogen- and androgen-derived neurosteroids has shown initial signals in alcohol administration models in pre-clinical samples (for review see Finn, 2020). For instance, gonadectomized females receiving estradiol replacement increase self-administration of alcohol, while testosterone replacement decreases alcohol consumption in male rodents following gonadectomies (Bertholomey & Torregrossa, 2019). Additionally, allopregnanolone (ALLO), a metabolite of progesterone, has been shown to impact alcohol consumption in male mice but not female mice and demonstrates alcohol-like effects in non-human primates, especially in females during periods of the menstrual cycle with high allopregnanolone levels (Finn, 2020). However, ganaxolone, a synthetic derivative of allopregnanolone, reduces alcohol seeking and drinking in female rodents in higher doses (Finn, 2020). In summary, preclinical evidence clearly suggests shared mechanisms between alcohol administration and models of stress, with emerging sex differences. Translation of such findings to humans in future studies is needed in order to address stress-induced psychiatric disorders and alcohol consumption in clinical populations.

This review will explore the effects of progestogen- and androgen-derived neurosteroids in alcohol and stress-related psychiatric disorders reported in human subjects. The following sections will review the current clinical literature regarding how neurosteroids affect symptomatology and treatment of alcohol and stress-related psychiatric disorders. We also discuss potential clinical treatments and future directions for clinical research on the impact of neurosteroids in alcohol and stress-related psychiatric disorders, particularly with regard to sex differences.

2. Progestogen-derived Neurosteroids

Progesterone and its metabolites, including allopregnanolone, and pregnanolone neurosteroids are primarily responsible for reproductive functions in women, but are also implicated in the regulation of mood and cognition (Peltier & Sofuoglu, 2018). These progestogen-derived neurosteroids are synthesized in the gonads and adrenal glands from cholesterol and thus easily cross the blood-brain barrier (Guennoun, et al., 2015). It has been proposed that progesterone and its metabolites interact with multiple neurotransmitter receptors, including sigma, glutamate, GABAA, and nicotinic acetylcholine receptors (α4β2-containing,α5-containing), which are implicated in both stress-related disorders and alcohol use disorders (Lynch & Sofuoglu et al., 2010; Girdler & Klatzkin, 2007; Finn, 2020). The following sections will review the clinical literature regarding the effects of progesterone, allopregnanolone, and pregnanolone on stress-related disorders and alcohol use (See Table 1 for summary of findings).

Table 1:

Summary of clinical findings

PROG ALLO PREG* TEST E2 DHEA**
Male Female Male Female Male Female Male Female Male Female Male Female
Stress-related dx
Depression N/A ↓ N/A ↓ ↓ ↓ ↓ ↑ N/A ↓ ↑ ↓
PTSD N/A ↓/↑ ↓ ↓ N/A ↓ ↑ N/A N/A ↓/↑ ↑ ↑
Anxiety ↓/↑ ↑ --- ↓/↑ ↓ ↓/↑ ↑ ↓ ↓ ↓/↑ ↑ N/A
Alcohol
AUD N/A N/A N/A N/A N/A N/A ↑ N/A N/A N/A ↓ ↓
Administration/Consumption ↓/↑ ↓/↑ ↓/↑ ↓/↑ N/A ↑ ↓/↑ N/A ↓/↑ ↓/↑ N/A ↑
Withdrawal N/A N/A N/A N/A N/A N/A ↓ ↑ N/A N/A N/A ↓
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Note. PROG= Progesterone; ALLO= Allopregnanolone; PREG= pregnenolone; TEST= Testosterone; E2= Estradiol; DHEA= Dehydroepiandrosterone

*

PREG and PREG-S

**

DHEA and DHEA-S

dx=diagnosis; PTSD= posttraumatic stress disorder; AUD= alcohol use disorder; N/A= no evidence; ↓/↑= mixed evidence; --- = no change

2.1. Progesterone

2.1.1. Stress-related disorders.

Alterations in progesterone have been shown to contribute to stress-related disorders and likely to the observed sex differences among these disorders. Sex differences in depression, anxiety and PTSD begin to emerge in adolescence, and continue at high rates in women as compared to men until postmenopause (Altemus et al., 2014; Marcus et al., 2005). Given the strong association with rates of stress-related disorders and developmental milestones related to sex hormones (e.g., puberty in adolescence and the menopausal transition), it is important to explore such associations.

Women with a history of depression have overall lower serum concentrations of progesterone when compared to healthy controls (Girdler et al., 2012). Similarly, symptoms of PTSD, depression and panic symptoms are reduced in women during the midluteal phase (Nillni et al., 2015), a time when levels of progesterone are elevated [days 21–23 of the menstrual cycle; peak progesterone 2–30 ng/mL (Allen et al., 2016)]. However, there is discordance in this literature as another study demonstrated that women with panic disorder have higher levels of progesterone when compared to controls (Brambilla et al., 2003). High levels of progesterone are also associated with increased levels of anxiety symptoms in men (Brambilla et al., 2005). This indicates that while lower levels of progesterone may be present in individuals with depressive disorders and symptomatology, progesterone may act as a buffer to mitigate heighted arousal symptoms, given the higher levels observed in individuals with panic disorder.

Furthermore, recent evidence suggests that progesterone levels increase in relation to decreasing HPA-axis hormones (Stephens et al., 2016). This demonstrates progesterone’s potential to utility in improving emotion regulation. For example, panic and anxiety symptoms were reduced following pretreatment of synthetic progestin (medroxyprogesterone; Le Melledo et al., 2001). Additionally, pre-treatment with 200mg of oral progesterone decreased state anxiety in conjunction with amphetamine (Reed et al., 2010); however, it should be noted that there is limited evidence to suggests that progesterone attenuates depressive- or anxiety-related symptoms among substance users, as multiple studies among cocaine and tobacco users have failed to demonstrate that progesterone administration changes negative affect symptomatology (Sofuoglu et al., 2009; Sofuoglu et al, 2004; Yonkers et al., 2014; Allen et al., 2016a).

Overall, it appears that higher levels of progesterone may have utility in decreasing depressive symptoms and may also mitigate hyperarousal in the HPA-axis observed in stress-related disorder; however, such findings do not seem to be applicable to substance-related mood and stress disorders.

2.1.2. Alcohol use.

Endogenous progesterone levels have also been related to alcohol use. For example, alcohol consumption increases across the menstrual cycle, in conjunction with fluctuations of progesterone (Becker and Koob, 2016). For instance, naturally-cycling women in the follicular phase of the menstrual cycle [days 1–12; characterized by stable levels of progesterone below 2ng/mL (Allen et al, 2016b)] demonstrate an increased risk of binge drinking on weekends (Martel et al., 2017). Furthermore, reported motivation to drink related to negative affect is associated with the quantity of alcohol consumed during the early follicular phase of the menstrual cycle, when progesterone and estradiol are both at their nadir (Joyce et al., 2017).

Intravenous alcohol administration (0.7 g/kg) increased plasma levels of progesterone in women in the luteal phase [days 16–28 of the menstrual cycle (Allen et al., 2016b)], when progesterone levels are naturally elevated, but not the follicular phase. Additionally, there was no change in progesterone levels in men following intravenous ethanol (0.8g/kg) administration (Holdstock et al., 2006); however, when consuming standard drinks, men’s levels of progesterone decreased (Pierucci-Lagha et al., 2006). Similarly, among premenopausal women progesterone levels decreased following consumption of a standardized alcoholic drink. This suppression of progesterone was observed in women both taking oral contraceptives [which indicated lower baseline progesterone levels] and those not taking oral contraceptives (Sarkola et al., 1999).

This suggests that progesterone levels decrease in both sexes following administration of alcohol in naturalistic settings and administration of exogenous progesterone may decrease alcohol craving or consumption.

2.2. Allopregnanolone

2.2.1. Stress-related disorders.

Low levels of allopregnanolone have been implicated in depression across both sexes (Romeo et al., 1998; Uzunova et al., 1998; Hellgren et al., 2014; Morgan et al., 2009). Allopregnanolone has shown initial promise as a treatment for depression via modulation of GABAA receptor function (Girdler & Klatzkin, 2007). Intravenous allopregnanolone administration improves postpartum depression symptoms and a higher level of allopregnanolone is generally associated with lower concentrations of cortisol at baseline (Kanes et al., 2017; Milivojevic et al., 2014). Further, higher concentrations of allopregnanolone are correlated with positive emotion among individuals with co-morbid cocaine dependence (Milivojevic et al., 2016).

Girdler and Klatzkin (2007) discuss the important role of decreased sensitivity of GABAA receptors in the effects of allopregnanolone on stress-related disorders. These authors suggest that a decrease in GABAA receptor sensitivity blunts allopregnanolone generation in response to stress and results in more severe mood symptoms. Women with premenstrual dysphoric disorder have a blunted allopregnanolone response to stress and experience more severe mood symptoms than those without a history of depression (Girdler & Klatzkin, 2007). Additionally, women with PTSD have lower overall levels of allopregnanolone, as well as blunted increases in allopregnanolone in response to laboratory-induced stressors, compared to healthy controls (Pineles et al., 2018). Similarly, women with PTSD had decreased allopregnanolone concentrations in cerebrospinal fluid (Rasmusson et al., 2016), whereas males with PTSD also had lower levels of allopregnanolone compared to controls in a postmortem study of gray matter tissue (Cruz et al., 2019). In contrast, higher levels of allopregnanolone have been observed in men and women with panic disorder (Bramilla et al., 2003; Eser et al., 2005), with lower concentrations of allopregnanolone following a panic attack (Strohel et al., 2003). This suggests a decrease in allopregnanolone blunting; however, no association between allopregnanolone and other anxiety disorders have been observed among men (Brambilla et al., 2004; Heydari & Le Melledo, 2002).

These studies provide evidence that allopregnanolone may protect against the consequences of stress-related behavioral dysfunction, as higher levels of allopregnanolone are associated with decreased responses to stress and mood-related symptoms across both sexes.

2.2.2. Alcohol use.

There is mixed evidence regarding the effect of alcohol on allopregnanolone. In a sample of a women with severe premenstrual dysphoric disorder (PMDD) and healthy controls, alcohol reduced levels of plasma allopregnanolone following a low dose alcohol infusion (0.2 g/kg) in both groups (Nyberg, 2005). Conversely in another study, there was no observed change in plasma levels of allopregnanolone in women across both the luteal and follicular phases following a moderate dose of intravenous alcohol (0.7g/kg) and no change in allopregnanolone was observed in men (Holdstock et al., 2006). However, other studies suggest that allopregnanolone levels decrease following consumption of alcohol in both sexes (Pierucci-Lagha et al., 2006; Ray et al., 2010) and among women in the luteal phase (Nyberg et al., 2005). This reduction is correlated with alcohol liking and craving in men (Pierucci-Lagha et al., 2006), indicating that not only may alcohol impact allopregnanolone levels, but such changes may be related to subjective effects of alcohol. These discordant findings should be viewed with caution, as studies using phases of the menstrual cycle to infer hormonal levels are not equivalent to studies in which direct hormonal measurements are performed (See Allen et al., 2016b).

2.3. Pregnenolone

2.3.1. Stress-related disorders.

Similar to other progestogen-derived neurosteroids, low levels of pregnenolone generally indicate psychological distress. For example, pregnenolone levels are lower in individuals of both sexes with depression (George et al., 1993; Osuji et al., 2010) and administration of oral pregnanolone may improve symptoms in bipolar depression (Brown et al., 2014). Males with GAD have lower levels of pregnenolone sulfate than controls (Semeniuk et al., 2001; Heydari et al., 2002) and females with PTSD have decreased pregnenolone when compared to those without PTSD (Cruz et al., 2019). Conversely in panic disorder, pregnanolone levels are generally heightened in women (Brambilla et al., 2004). Overall, pregnenolone levels are inversely correlated with depressive and stress-related symptoms.

2.3.2. Alcohol use.

Few studies have explored the effects of progesterone-derived neurosteroids, including pregnenolone, on alcohol consumption and abuse. A study of men (53%) and women (47%) with no history of substance use disorders demonstrated that pregnenolone increased following consumption of alcohol. Additionally, higher levels of baseline pregnenolone were significantly correlated with liking alcohol (Pierucci-Lagha et al., 2006).

Among the limited available clinical studies, higher levels of pregnenolone are generally related to increased alcohol consumption and liking. This may be consistent with the higher levels of pregnenolone observed in individuals with panic disorders (Brambilla et al., 2004), as pregnenolone may be heightened in response to state anxiety and thus be associated with increased alcohol consumption.

2.4. Progesterone-derived neurosteroids summary

Overall, there is a clear relationship between levels of progesterone, allopregnanolone and pregnenolone, stress-related disorders and alcohol use. Progesterone and allopregnanolone generally mitigate negative affect, including low mood, anxiety and trauma-related symptoms across a range of psychological disorders and both sexes. Additionally, progesterone and allopregnanolone could have utility in reducing alcohol consumption through reduction of stress-related symptomatology.

3. Androgen-derived neurosteroids

Androgen-derived neurosteroids encompass testosterone, estradiol (a common form of estrogen) and dehydroepiandrosterone (DHEA). These neurosteroids are primarily derived from cholesterol in the testes or ovaries (to a lesser extent), as well as smaller amounts produced in other parts of the body, such as the adrenal glands or brain (Peltier & Sofuoglu, 2018; Prough, Clark and Klinge, 2016; Rubinow & Schmidt, 1996). Testosterone modulates multiple neurotransmitter systems implicated in psychiatric diagnoses and addiction, including serotonin, dopamine and acetylcholine (Rubinow & Schmidt, 1996). Additionally, estradiol has been related to an increase in serotonergic and dopaminergic receptor density, which mediate addictive and reward responses (Peltier & Sofuoglu, 2018). In contrast, DHEA/DHEA-Sulfate (DHEA-S) are allosteric modulators of NMDA, GABAA and sigma-1 receptors, which have been implicated in mood disorders, cognitive processes and substance use disorders (Prough, Clark and Klinge, 2016). The following sections will review the clinical literature regarding the impact of testosterone, estradiol and DHEA/DHEA-S on stress-related disorders and alcohol use (See Table 1 for summary of findings).

3.1. Testosterone

3.1.1. Stress-related disorders.

There appears to be a sex-specific relationship with testosterone and stress-related disorders. Lower testosterone concentrations are observed in men with depression, who were hospitalized for depressive symptoms (Schweiger et al., 1999) and administration of testosterone decreases depressive symptoms among older men (Perry et al., 2002). Conversely, testosterone levels increase in response to a stressor among men with generalized and social anxiety (Gerra et al., 2000). Testosterone levels prior to a combat deployment predict PTSD symptoms 1–2 years following deployment in men (Reijnen et al., 2015) and there are higher overall levels of testosterone in individuals with “pure” PTSD in comparison to PTSD with co-morbid conditions (e.g., depression or alcohol use; Karlovic et al., 2012). This demonstrates that low testosterone levels in men can be correlated with depressive symptoms, while increased testosterone in response to a stressor is associated with anxiety-related disorders.

However, higher levels of testosterone are observed in depressed premenopausal women (Baischer et al., 1995). The relationship between anxiety and testosterone levels in women differs from that of depression, as increased testosterone in women is associated with decreased avoidance gaze and avoidance tendencies (indicators of increased anxiety; Enter et al., 2016; Enter 2014), whereas females receiving sublingual testosterone (0.5 mg) have reduced stress response to aversive stimuli (Hermans et al., 2007; van Honk et al., 2005). Furthermore, testosterone levels that were highly reactive to treatment were associated with improved symptoms among women with Seasonal Affective Disorder (Hutschemaekers et al., 2020). Thus, in contrast to what has been observed in men, the limited research available illustrates that higher levels of testosterone are associated with depressive symptoms among reproductive aged women, whereas testosterone administration can downregulate stress responses in women.

3.1.2. Alcohol use.

Alcohol consumption has been associated with transient increases in testosterone levels beginning in adolescence, when sex differences in testosterone levels become apparent (Emmanuel et al., 2003; Erol et al., 2017). In one study, higher levels of saliva testosterone were related to onset of alcohol use among adolescent boys, but not girls, after controlling for age (de Water et al., 2013). Similarly, increased levels of testosterone were related to risk of alcohol use in adolescent boys (Costello et al., 2007). The relationship between high testosterone and alcohol use continues into adulthood. Studies have associated higher testosterone levels in males with AUD among forensic samples (Stalenheim et al., 1998) and higher levels of testosterone are related to problematic drinking in both men and women, although the effect is stronger among men (La Granger et al., 1995). It is important to note that the relationship between alcohol and testosterone is a function of age, with testosterone levels decreasing in males as they age, and there is no association between testosterone and alcohol use in older men (Lenz et al., 2017).

Interestingly, acute alcohol administration results in decreased levels of testosterone among men (Vatsalya et al., 2011; Heikkonen, 1996). Decreased levels of testosterone have also been related to psychological symptoms during alcohol withdrawal in males, including increased worrying, fatigue and indecisiveness (Ruusa & Bergman, 1996). However, among females in the luteal phase [days 16–28 of the menstrual cycle (Allen et al., 2016b)], testosterone was higher among women in withdrawal when compared to healthy controls (Valimaki et al., 1995). This demonstrates a unique sex-specific relationship, such that higher levels of testosterone are related to increased vulnerability for alcohol consumption among men but may be related to increased withdrawal symptoms in women; additionally, in men higher levels of testosterone being related to lower symptoms of stress-related disorders. This relationship between alcohol and testosterone in males indicates that it may be beneficial to target alternative mechanisms outside of negative affect (e.g., positive reinforcement of alcohol consumption) to improve treatment of alcohol use in men.

3.2. Estradiol

3.2.1. Stress-related disorders.

Throughout a women’s lifespan, fluctuating levels of estrogen are associated with depressive symptoms. The onset of the menstrual cycle, characterized by fluctuating estrogen levels also coincides with an increase in MDD among girls (Angold et al., 1998). Declining estrogen levels during postpartum periods and during the menopausal transition are associated with depressive symptoms (Shors & Leuner, 2012). Furthermore, in women with PTSD, lower estradiol levels are associated with avoidant responses, while higher levels are associated with hypervigilance [avoidance to memories, thoughts and feelings relevant to the traumatic event is a core diagnostic criterion for PTSD, as is experience of arousal symptoms, including hypervigilance] (Graham & Shin, 2018). Conversely, women with PTSD show increased levels of anxiety during the early follicular phase [days 4–5 in the menstrual cycle, Allen et al., 2016b)], when levels of estradiol are high (Nillni et al., 2015). However, other studies report that women with PTSD and low estrogen levels have a heightened startle response compared with those with higher estrogen levels (Glover et al., 2012). Similarly, pharmacologically induced panic symptoms were attenuated among males with panic disorder administered estradiol (Le Melledo et al., 2011). Such discordant results are likely to be attributed to different methodologies for inferring or measuring levels of sex-specific neurosteroids, as has been reported in other areas of psychiatry and addiction (Allen et al., 2016b).

Despite discordant results regarding stress-response, in general it appears that lower levels of estradiol are related to depressive symptoms across a woman’s lifespan. However, there is limited evidence that stabilizing estrogen levels can treat depression. For example, oral estrogen-based hormonal replacement has not been shown to improve mood among postmenopausal women (Gleason et al., 2015).

3.2.2. Alcohol use.

Alcohol consumption has also been associated with altered estradiol levels among women; however, results are mixed. In some studies, there was no difference in estradiol levels in men or women following administration of intravenous alcohol administration (Holdstock et al., 2005) or during alcohol withdrawal (Valimaki et al.,1995). Conversely, other studies observed increased estradiol levels in women following an alcohol infusion (Vatsalya et al., 2011), as well as an increase in estrone (another metabolite of estrogen; Dorgan et al., 2001). However, among women using oral contraceptives, which lowers baseline levels of estradiol, estradiol increased following alcohol intake (Sarkola et al., 1999).

In line with the clinical literature related to estradiol and stress-related disorders, administering exogenous estradiol did not appear to decrease alcohol consumption. In fact, increases in levels of estradiol among postmenopausal women receiving hormone therapies were associated with acute alcohol consumption (Emmanuel et al., 2003; Purohit, 1998; Longnecker & Tseng, 1998). Furthermore, the amount of alcohol consumed may affect this relationship, as in some studies high levels of alcohol consumption were related with decreased levels of estradiol (Emmanuel et al., 2003; Johannes et al., 1997).

3.3. Dehydroepiandrosterone (DHEA)

3.3.1. Stress-related disorders.

Overall, it appears that DHEA levels increase in response to stressors in both sexes. Among males, DHEA is increased among those with panic disorder (Brambilla et al., 2004), as well as in males following a pentagastrin challenge that can induce panic (Tait et al., 2002). Plasma DHEA and DHEA-sulfate levels are also elevated in individuals with PTSD (Spivak, 2000; Sondergaard et al., 2002; Pico-Alfonso et al., 2004; Butterfield et al., 2005) and this is associated with inhibition of GABAA receptors (Spivak, 2000). Additionally, among women with PTSD, DHEA responses were increased following adrenocorticotropic hormone (ACTH) stimulation compared to trauma-exposed controls, and the change in DHEA was negatively correlated with cognitive symptoms of PTSD (Rasmusson et al., 2004). However, lower levels of DHEA have been observed among depressed women (Girdler et al., 2012; Morgan et al., 2009).

Based upon this limited literature, high levels of DHEA appear to be related to increased stress-related symptoms and disorders (e.g., panic, PTSD) in both sexes, but lower levels of DHEA are related to depressed mood, at least in women.

3.3.2. Alcohol use.

Alcohol intake is associated with increased DHEA concentrations among both sexes with minimal or no substance use history (Field et al., 1994; Pierucci-Lagha et al., 2006). For instance, postmenopausal women not taking hormonal therapies had an increase in DHEA-sulfate levels following alcohol consumption. However, those with chronic alcohol use demonstrate lower overall levels of DHEA/DHEA-sulfate (Dorgan et al., 2001). Women in the follicular phase [days 1–12 of the menstrual cycle (Allen et al., 2016b)] undergoing alcohol withdrawal had DHEA-sulfate levels that were 39% lower than healthy controls (Valimaki et al., 1995). However, such alterations do not appear to be related to exposure to stressors. One study demonstrated that alcohol consumption following a laboratory-induced stressor, did not alter DHEA response (Schrieks et al., 2016) indicating that there may be an important distinction between DHEA response among those with AUD and participants administered alcohol acutely.

3.4. Androgen-derived neurosteroids summary

In general, lower levels of testosterone are correlated with depressive symptoms in men while there is an understudied relationship between mood and testosterone in women across the lifespan; however, higher levels of testosterone are related to increased drinking in both men and women. Additionally, lower levels of estradiol are related to low mood and increased alcohol use among women. Despite this relationship, the available literature does not demonstrate the utility of increasing endogenous estradiol levels to improve mood, and such low levels may in fact, increase alcohol use. Finally, the limited literature regarding DHEA demonstrates that levels are increased following alcohol use, but not among those with chronic alcoholism.

4. Potential clinical treatments

The relationship between neurosteroids, alcohol use and stress-related disorders has been the topic of several treatment studies aiming to investigate the utility of augmenting hormone levels with exogenous hormones; however, many of such trials have resulted in mixed data that is difficult to generalize. For instance, hormone replacement therapy (HRT) is typically prescribed to women to augment and stabilize decreasing estrogen levels during the onset of the menopausal transition. Evidence suggests that transdermal, estrogen-based HRT may have utility in the treatment of peri-menopausal and early postmenopausal-related depression among women; however, there is little evidence that HRT improves depression or anxiety in women who have transitioned into postmenopause or report low mood without depression (Gordon & Gridler, 2014; Navas Demetrio et al., 2011). There is little research exploring the impact of HRT on mood among premenopausal women as well as their male counterparts and thus it is difficult to draw conclusions related to its utility among these populations. Additionally, there is evidence that estrogen may intensify the effects of alcohol (Epstein, Fischer-Elber, & Al-Otaiba, 2007), potentially limiting its utility in the treatment of stress-induced alcohol use.

Similarly, there is emerging evidence that testosterone replacement therapies have antidepressant effects among men with depression, especially when using higher doses (Walther, Breidenstein & Miller, 2019); however, many of the clinical trials exploring testosterone replacement therapy have been in hypogonadal men and depression is not the primary outcome of such studies. Thus, results are difficult to generalize and warrant further investigation using a larger study sample to directly examine the impact of exogenous testosterone on mood among hypogonadal and eugonadal men (Walther et al., 2019). Additionally, it should be noted that such findings do not generalize to women. While small studies have shown that augmenting endogenous testosterone levels with testosterone replacement therapies may improve depression among women without clinical depression; a recent clinical trial demonstrated that transdermal testosterone did not improve mood among women with major depression (Dichtel et al., 2020). There is scant literature exploring the impact of testosterone replacement therapy on alcohol use; however, one study was halted prematurely as testosterone replacement was associated with higher mortality among men with alcoholic cirrhosis of the liver (Gluud, 1986), suggesting it may not be a viable treatment option to target stress-induced alcohol use.

The most promising treatment targets to date have been progestin-based, including progesterone’s metabolite, ALLO. Brexanolone, a synthetic formulation of allopregnanolone available via infusion reduces depressive symptoms among women experiencing postpartum depression (Meltzer-Brody et al., 2018; Scott, 2019). As a GABA-A receptor positive allosteric modulator, brexanolone has shown promise as a novel therapeutic for postpartum depression; however, its effects on reducing negative affect/low mood outside of this specific population remains unknown. Ongoing research is being conducted to explore an oral form of synthetic neurosteroid and positive allosteric modulator of GABAA receptor (e.g., SAGE-217; Zuranolone; Gunduz-Bruce et al., 2019), which may increase the utility of this treatment target. However, there is much work to be done regarding the treatment applications of neurosteriods across multiple populations.

5. Future research directions

This review illustrates the dearth of clinical literature exploring the relationship between progestogen- and androgen-derived neurosteroids in both alcohol and stress-related disorders. Preclinical evidence to date shows strong associations between neurosteroids and alcohol and stress-related disorders, but there is a lack of translational research. This represents a significant discrepancy given the high rates of comorbidities among alcohol and stress-related disorders and a lack of efficacious treatments, especially in women. There are sex-specific parallels in the underlying neurosteroid-based mechanisms of alcohol use and stress-related psychiatric disorders; however, the limited literature to date makes it difficult to draw conclusions across studies. Further research is needed to measure endogenous levels of progestogen- and androgen-derived neurosteroids in both laboratory settings of acute alcohol administration, as well as in mood/stress-induced alcohol consumption paradigms, to discern the role of these hormones in alcohol and stress interactions. Future studies need to be prospectively designed to incorporate sex as a biological variable and to be powered to examine sex differences. There are likely sex-specific differences that may offer unique treatment opportunities for women with comorbid disorders and such studies would begin to elucidate mechanisms to target. Finally, studies among women should measure hormone levels directly at baseline as well as dynamic change across the menstrual cycle, as recommended by experts in the field (Allen et al., 2016b), as opposed to dichotomized menstrual cycle observations.

It is imperative that future research continues to investigate the role of stress-related alcohol use among both men and women, especially given the increased vulnerability for women to experience such disorders (Peltier et al., 2018). There is evidence that levels of progestogen- and androgen-derived neurosteroids are related to increased negative affect which has important implications for their role in stress-related disorders and stress-induced alcohol use. Progestogen- and androgen-derived neurosteroids interact with a number of neurotransmitter systems that underlie negative affect and stress-induced alcohol use, including those within HPA axis (Finn, 2020). Stress responses are partly mediated through the HPA axis; and, progestogen- and androgen-derived neurosteroids such as progesterone, estradiol and testosterone influence HPA axis function. Furthermore, glucocorticoids signaling from the HPA axis can alter levels of these neurosteroids, demonstrating a reciprocal interaction between the two systems (Finn, 2020). Additional research is needed to clarify whether progestogen- and androgen-derived neurosteroids are a point of vulnerability for stress-induced alcohol use and potentially represent a treatment target to address comorbidities and overlapping symptomatologies between stress and alcohol disorders.

To date, the most robust findings among these limited clinical data demonstrate that progestogen and its metabolite, allopregnanolone may mitigate the symptoms related to comorbidities between low mood, anxiety and stress-induced alcohol consumption, especially among women. While there is no clear evidence of a direct effect of allopregnanolone on alcohol consumption, there is some evidence to suggest allopregnanolone may alter alcohol use via modulation of stress-related symptomatology. In addition to several studies suggesting that administration of allopregnanolone is associated with decreases in depressive symptoms (Kanes et al., 2017; Hellgren et al., 2014), one study of men and women admitted for alcohol withdrawal treatment demonstrated lower levels of allopregnanolone while reporting heightened ratings on the Hamilton Anxiety and Depression scales (Romeo et al., 1996). It appears that allopregnanolone may target negative affect and stress reactivity and could be used to augment established alcohol use treatment. Additional research is needed to clarify the impact of alcohol on endogenous allopregnanolone plasma levels and explore the role of allopregnanolone in the relationship between alcohol and stress-related symptoms.

5. Summary

Research has established that exposure to acute and chronic stress, as well as trauma results in stress-related symptoms, which increase vulnerability for stress-related psychiatric disorders, including depression, anxiety and PTSD, as well as an increase in alcohol misuse and alcohol use disorder. Notably, the relationship between stress-related disorders and alcohol use is stronger among women, who generally drink alcohol to cope with negative affect and stress. These comorbidities are complex and difficult to treat. However, progestogen- and androgen-derived neurosteroids affect both stress- and alcohol-related comorbidities and thus understanding such mechanisms may help target overlapping symptoms. While there is limited clinical literature to date, there are promising studies suggesting that targeting overarching vulnerabilities attributed to both stress- and alcohol-related disorders may improve symptomatology and treatment outcome. Particularly, the current literature highlights, the potential utility of allopregnanolone to target these vulnerabilities, including negative affect and stress-reactivity.

Highlights.

  • The relationship between stress-related disorders and alcohol use is stronger among women

  • Progestogen/androgen-derived neurosteroids underlie both alcohol/stress-related disorders

  • Allopregnanolone may reduce alcohol consumption through the reduction of negative affect

Acknowledgments

Funding: National Institute of Alcohol Abuse and Alcoholism U54AA027989 (SAM), P01AA027473 07 (SAM); K01AA025670 (TLV); National Institute of Mental Health R01MH110674 (KPC)

Footnotes

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