Depression is a serious medical condition that causes persistent feelings of sadness and loss of interest ^[1][19]. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), it is classified into five distinct disorders. 

During childhood, there is no notable disparity in the prevalence of depression between boys and girls. However, around the age of 15, following the onset of menarche, there is a rapid increase in estrogen levels, which establishes the female predominance of depression incidence ^[2][3][20,21]. Furthermore, the disparity in depression rates between men and women is only evident during the reproductive period, and it returns to equal following menopause ^[4][22].

One of the factors contributing to the behavioral and emotional changes that occur during puberty are hormonal changes. Estradiol and testosterone levels have been established by Angold et al. as predictors of depression. Researchers have suggested that, during puberty, there is a point at which the increase in testosterone and estrogens reaches a threshold, making girls more susceptible to developing depression. However, they acknowledge that other factors, such as life events and cognitive style, play a crucial role in determining individual episodes of depression ^[5][23].

The impact of hormones during the reproductive period was examined in a Harvard study on moods and cycles. The study encompassed a sample of 976 women between the ages of 36 and 45. The findings reveal that the participating women who exhibited lower levels of estradiol and higher levels of FSH and LH had a documented history of episodes of depression ^[6][24].

Pregnancy is another time in women’s lives with significant changes in hormone regulation. Rates of depression are higher among pregnant individuals compared with non-pregnant women. Gestational age correlates with the onset of depressive and anxiety symptoms, wherein the first trimester the prevalence is 7.5%, then increases to 12.8% in the second and 12.0% in the third trimester ^[7][25]. Following birth, women with a history of depressive symptoms during pregnancy are at higher risk of postpartum depression (PPD). The rapid changes in endogenous estrogen and progesterone levels at delivery are a contributing factor of PPD in susceptible women ^[8][26].

The literature also supports the existence of an association between reproductive hormones before and during the menopausal transition and depressive symptoms. In a systematic review with a meta-analysis, Georgakis et al. demonstrated that women who experience menopause at an older age and have a longer reproductive period have a reduced risk of developing depression in their later years ^[9][27]. In the Penn Ovarian Aging Study conducted by Freeman et al., women with a previous history of depression underwent six assessments of blood hormone levels over a four-year period. Samples were collected 12 times during a period of 2–6 days in the follicular phase. Depression scores correlated with the fluctuations (standard deviation) between results. This study demonstrated that years with greater variability in E2 levels were associated with an increased risk of developing depressive symptoms ^[10][28].

New studies, which measured hormones more frequently, confirmed that studying E2 variability using four blood samples over a span of 14 months showed positive associations between the frequency of fluctuations and depressive symptoms ^[11][12][29,30]. Similar results were found when measuring E2 in saliva and E3G in urine over a four-week period. These fluctuations were positively associated with depressive symptoms and predicted a higher level of weekly negative affect ^[11][29]. This suggests that fluctuations in E2 increase sensitivity to psychosocial stressors during the perimenopause transition and could potentially be utilized to predict periods of heightened sensitivity. In a separate study involving 436 women aged 35 to 47, which examined depression during the follicular phase, blood samples were collected and depression scale scores were evaluated. Individuals who experienced a rapid increase in FSH were less likely to exhibit depressive symptoms (p ≤ 0.001). Symptoms also decreased with age following the menopausal transition (p = 0.02). In bivariate analysis, participant profiles with increasing E2 levels, which are associated with the early phase of transition to menopause, were found to be linked to depressive symptoms (p = 0.053), although the association was not statistically significant. These findings suggest that the hormonal changes that occur during the transition to menopause contribute to dysphoric mood. This is indicated by the increase in depressive symptoms during this period and the subsequent decrease in such symptoms in postmenopausal women ^[10][28].

In postmenopause, a study conducted on 265 older postmenopausal women examined the relationship between absolute physiological levels of estrogen and mood/cognitive functioning. The findings revealed that higher physiological serum concentrations of estradiol and estrone are linked to lower levels of depression and anxiety ^[13][31]. Conversely, another study involving 138 postmenopausal women examined the association between endogenous hormones and depressive symptoms. The results indicate that there was no significant correlation between depressive symptoms and the absolute levels of sex-hormone binding globulin, testosterone, free androgen index, estradiol, free estradiol, or FSH. This suggests that monitoring fluctuations in hormone levels may be more effective than measuring absolute values ^[14][32].

Premenstrual syndrome (PMS) is a disorder characterized by affective symptoms and clinically significant psychological and somatic manifestations during the luteal phase of the menstrual cycle ^[15][33]. A small study of 41 women aged 18–45 years, using blood samples, examined the associations between levels of progesterone and estradiol during menstruation and PMS symptoms ^[16][34]. Lower levels of progesterone and, to a lesser extent, estrogen during the luteal phase are predictive of the severity of peri-menstrual symptoms, as measured by the Daily Record of Severity of Problems (DRSP) scale. Though hormone levels in large studies fail to demonstrate clinical usefulness in diagnosis or treatment, they could potentially be used for predicting symptoms ^[17][35]. A similar study has demonstrated that the daily concentration of saliva progesterone decreased sharply 3 days before menstruation only in women with PMS symptoms, whereas in healthy women, a very gradual decrease was observed over 8 days ^[18][36].

Premenstrual dysphoric disorder (PMDD) is a psychiatric disorder characterized by the onset of negative mood and physical symptoms during the week before menstruation. It is a more severe presentation than PMS. In the luteal phases of their menstrual cycle, women with PMDD experience a combination of symptoms, such as irritability, in comparison with healthy women. This has been demonstrated by higher startle responses to noxious acoustic stimuli in the luteal phase, indicating that women with PMDD are more sensitive to negative stimuli during specific phases of the menstrual cycle ^[19][37]. Similarly to PMS, models have indicated that rapid progesterone withdrawal contributes to the symptoms associated with PMDD. This includes the significant role of one of the main metabolites, allopregnanolone ^[20][38]. Studies have also shown that the premenstrual change in progesterone is negatively correlated with fun-seeking behavior among women with PMDD. This means that women are less likely to engage in outgoing activities before menstruation ^[21][39]. Furthermore, the role of estrogen has been investigated in relation to the severity of PMDD symptoms. It has been revealed that low levels of estrogen during the early luteal phase are associated with worse psychological outcomes ^[22][40]. In general, individuals with PMDD are more sensitive to hormonal changes due to a decrease in the expression of serotonin transporters before the menstrual cycle, as observed in positron emission tomography imaging ^[23][41].

DSM-5 identifies several anxiety disorders, including panic disorder (PD) and generalized anxiety disorder (GAD). In women with PD, there are reports of an increase in the incidence and severity of panic episodes during the luteal phase, which occurs 5–8 days before menstruation ^[24][42]. Women with GAD also report experiencing more anxiety symptoms during the premenstrual phase compared with the follicular phase ^[25][43]

There is a well-established link in the literature that shows women with anxiety disorders are more vulnerable to the influence of gonadal hormones ^[26][44]. In a recent review by Kundakovic et al., it is suggested that the withdrawal of estrogen increases the likelihood of developing anxiety-related disorders ^[27][45]. This phenomenon is often known as premenstrual exacerbation (PME) and can be observed in both depression and anxiety. During this time, women may experience a worsening of mental health symptoms ^[28][46].

The vulnerability of women to reproductive hormones has been proposed through two mechanisms: one that facilitates the maintenance of anxiety symptoms after they appear, and another that alters certain vulnerability factors related to the development of anxiety. Low levels of estradiol and progesterone during menstruation lead to a decrease in serotonin and allopregnanolone. This reduces GABAergic inhibition and causes problems with the regulation of the HPA axis, which increases vulnerability to anxiety disorders ^[29][47].

Furthermore, in a study on the formation of non-associative emotional memory, women were exposed to aversive film clips or images, and their responses were recorded. It was found that during the luteal phase, women reported significantly more spontaneous intrusive recollections (SIRs) compared with the follicular phase. Salivary levels of progesterone were positively correlated with SIR frequency (r2 = 0.23, r = 0.48, p = 0.001). However, no such association was found for estrogen (p > 0.7). This suggests a possible role of progesterone in mediating anxiety symptoms ^[30][48].

Fear extinction studies suggest that fluctuations in estrogen, specifically decreases in estrogen, can lead to an increased likelihood of developing anxiety disorders. This is because these fluctuations impair the natural processes involved in emotional responses to traumatic events, thereby increasing the propensity for anxiety disorders to develop. In a study on 37 healthy women, a significant linear relationship between estradiol levels and conditioned responses during extinction was demonstrated (p = 0.026) by Wegerer et al. This is particularly significant when considering potential treatment options, such as cognitive behavioral therapy (CBT) or exposure therapy, as reduced responses in certain phases of the cycle could result in ineffective treatment outcomes. Sex-specific differences in CBT interventions are currently rarely researched, with no investigations into the potential impact of hormones ^[31][49].

Post-traumatic stress disorder (PTSD) is an example of an anxiety disorder that can develop after experiencing distressing or traumatic events. It is often characterized by intrusive thoughts, memories, nightmares, anxiety and negative mood patterns. It is yet another mental health condition that has a prevalence twice as high in women compared with men ^[32][50]. Studies also demonstrate that women with low estrogen levels and with fear-potentiated startle responses were higher for women with PTSD, when compared with normal and high estrogen groups. This suggests that estrogen levels might have the potential to be used to determine women’s vulnerability to fear conditioning and possibly identify at-risk groups ^[32][50].

A notable limitation of these studies is the fact that women are often excluded from trials in order to reduce the source of variability. The body of evidence specific to women is more limited for this reason.

This is a mental health condition that causes extreme shifts in mood, energy, activity and concentration ^[33][52]. Three types are identified: Type I, Type II and Cyclothymic disorder. The onset of the condition often coincides with puberty, which suggests a role of reproductive hormones. Similarly, some women also experience the onset of symptoms before menstruation, as is the case with certain other mental health conditions. Pregnancy seems to have a protective effect; however, the postpartum period is associated with a worsening of symptoms and the onset of postpartum psychosis ^[34][53].

A review by Meinhard et al. found two studies that explored the link between serum estrogen levels and bipolar disorder in women, as well as four studies that investigated the effectiveness of tamoxifen in producing antimanic effects. The results of the estrogen studies show that women with postpartum psychosis had low levels of estrogen and experienced significant symptom improvement after receiving estrogen treatment. The tamoxifen studies demonstrate that the drug was effective in producing antimanic effects ^[35][54].

Estradiol has also been demonstrated to play a role in the treatment of psychosis and manic episodes. In a study of 10 women with postpartum psychosis, their serum estradiol levels were measured at baseline and throughout a 6 week treatment period using only sublingual estradiol. In all patients, the symptoms diminished significantly (p < 0.001) when the estrogen concentrations reached the normal range ^[36][55].

Schizophrenia is a serious mental illness that is still poorly understood. Although individuals with schizophrenia exhibit a range of symptoms, treatment responses, and long-term outcomes, primary treatment involves antipsychotic drugs and psychosocial support. There is strong evidence of resistance to antipsychotic medications and new approaches have become more demanding. This indicates a potential in biological subtyping that affects the underlying neurobiology and may account for differences in treatment effectiveness ^[37][56].

There is a growing body of literature suggesting that estradiol and progesterone play a role in cellular processes and can influence both positive and negative psychological symptoms ^[38][57]. Deficiency in both males and females has been associated with the onset of psychotic symptoms. Because of their drug modulating abilities, premenopausal women require lower doses of antipsychotics ^[39][58]. Similarly to bipolar disorder, the worsening of symptoms is observed during estrogen withdrawal, such as during the postpartum period. Additionally, periods of high estrogen throughout a woman’s life are associated with less frequent relapses ^[40][59]. The link with progesterone has been documented in the literature as being less clear. Some studies have suggested the neuroprotective roles of hormones, while others have shown a detrimental effect ^[41][60].

Hormone levels have shown potential for predicting the outcomes of hormonal treatments in schizophrenia. Endogenous estradiol levels have been measured as a biomarker for treatment response. According to the findings of these studies, there appear to be two distinct subgroups within the 200 μg estradiol treated group being studied. One subgroup, identified as treatment responders, exhibited a decrease in Positive and Negative Syndrome Scale (PANSS) scores over time, while the other subgroup, identified as treatment non-responders, demonstrated stable PANSS scores over the same period. These measurements demonstrate that it is possible to accurately predict groups of treatment responders, indicating heterogeneity in treatment response and sensitivity to hormonal changes. Moreover, FSH blood serum levels were shown to be able to predict the non-responder group ^[37][56]. In the treatment arm around 80% of participants showed improvement, the baseline PANSS scores of the remaining treatment non-responders were significantly higher. Thus, increasing E2 levels are associated with a decrease in total PANSS symptom scores, providing support for the hypothesis that estrogen treatment directly improves the health of patients with schizophrenia ^[37][56].

Another study investigated FSH/LH ratios, as measured by chemiluminescent immunoassays, and demonstrated that they are not positively correlated with changes in mood scores and overall well-being in women with schizophrenia ^[42][61].

Recent literature has also pointed at the role of raloxifene, a class of selective estrogen receptor modulators, which has shown potential in reducing the incidence of manic episodes in patients with schizophrenia when added alongside normal doses of antipsychotic drugs ^[43][62]. In a clinical trial of 110 people, it was demonstrated that adding raloxifene reduces psychotic symptoms and improves cognition, social functioning and quality of life as compared with a placebo ^[44][63]. 

Obsessive–compulsive disorder (OCD) is a mental health condition characterized by unwanted thoughts and compulsive or repetitive behaviors. Karpinski et al. in their critical review suggest that hormone levels in this condition are similarly associated with the negative onset of symptoms, as previously discussed. Women report symptom exacerbation before menstruation, as well as during the first and second trimesters of pregnancy when estrogen levels are relatively lower. Overall, both estrogen and progesterone have demonstrated regulatory effects on serotonin signaling, which is involved in the modulation of OCD symptoms ^[45][64]. Stein et al. further suggest that changes in the serotonergic system during pregnancy are implicated in the onset of OCD, with an increased incidence during pregnancy and increased depressive symptoms in the postpartum period ^[46][65]. In addition, Weiss et al. have concluded that there is a tentative association between gonadal hormones and the onset and exacerbations of OCD ^[47][66]. Women with elevated levels of estrogen and progesterone, such as those who utilize oral contraceptives, may encounter comparable symptoms to those observed during pregnancy. This similarity in symptomatology could potentially be attributed to a shared mechanism of action that precipitates the onset of these symptoms.