The effectiveness of COCPs in managing mood symptoms has mixed results. Some studies indicate that specific COCPs may exacerbate mood symptoms (Kulkarni, 2007; Skovlund et al., 2016), while others report neutral or positive effects on mood, suggesting that results may vary based on factors such as the population studied, COCP formulation, and dosing regimen (continuous versus intermittent use) (Mu and Kulkarni, 2022).

Recent research into COCPs containing antimineralocorticoid and antiandrogenic progestins, such as drospirenone, shows promising outcomes for managing PMDD (Kelly et al., 2010) (Table 1). COCPs containing antiandrogenic progestins may improve irritability—a key symptom of PMDD (Kelderhouse and Taylor, 2013). Early studies by Freeman et al. (2001) and Pearlstein et al. (2005) demonstrated that drospirenone (3 mg) combined with ethinylestradiol (30mcg), as in Yasmin™ (Bayer Healthcare) effectively reduced PMDD symptoms compared to placebo. A subsequent Cochrane review (Lopez et al., 2012) also suggested that COCPs with drospirenone (3 mg) may benefit PMDD symptom management, although a notable placebo effect was noted. Recent reviews affirm the positive outcomes of drospirenone (3 mg) combined with ethinylestradiol (30mcg) in treating PMDD, but emphasise the need for further research (De Berardis et al., 2022). In contrast, COCPs with levonorgestrel (90 mcg) and ethinylestradiol (20mcg) have not alleviated PMDD symptoms (Freeman et al., 2012).

A newer COCP, nomegestrol acetate (2.5 mg) and 17β-estradiol (1.5 mg) (Zoely™, Merck Sharp & Dohme), has shown promise for off-label treatment of PMDD-related mood symptoms (Table 1). This monophasic formulation includes 24 active pills followed by four placebo pills (2014). It contains a synthetic estrogen (17β-estradiol) that is structurally identical to endogenous estrogen, whereas most other COCPs contain ethinylestradiol. 17β-estradiol can cross the blood brain barrier, interact with serotonin receptors, regulate cerebral blood flow to the amygdala and dorsolateral prefrontal cortex, and many other areas of the brain, including important mood-control brainstem centres, all involved in depression (Rubinow and Girdler, 2011).

Nomegestrol, structurally similar to progesterone, provides strong antigonadotrophic and moderate antiandrogenic activity, with no effects on estrogenic, glucocorticoid or mineralocorticoid pathways. A pooled analysis by Witjes et al. (2015), incorporating studies by Mansour et al. (2011) and Westhoff et al. (2012), evaluated the effects of nomegestrol acetate/17β-estradiol versus drospirenone/ethinylestradiol on premenstrual and menstrual symptoms using the Menstrual Distress Questionnaire Form C (Moos R, 1968). Women taking nomegestrol acetate/17β-estradiol (Zoely ™) experienced significant improvements in dysmenorrhoea, fluid retention, sadness, concentration difficulties and behavioural changes during the premenstrual phase compared to those taking drospirenone/ethinylestradiol (Yasmin ™) (Witjes et al., 2015). Our recent pilot study supports the acceptability and effectiveness of nomegestrol acetate/17β-estradiol (Zoely ™) treatment for PMDD symptoms, with 74.5% of women tested, reporting a positive mood response (Robertson et al., 2021). Significant reductions in scores on the Depression, Anxiety, Stress Scales – 21, a widely used self-report instrument for assessing the severity of symptoms across these three domains (Henry and Crawford, 2005), were observed after treatment initiation. These findings suggest the potential efficacy of nomegestrol acetate/17β-estradiol in managing mood symptoms associated with PMDD. Further research is needed to validate the efficacy of this COCP and understand its mechanism of action.

Transdermal estradiol, delivered via a patch or gel, in combination with cyclical progestogen, has been shown to effectively manage both the physical and psychological symptoms of PMDD (Table 1). These percutaneous formulations provide sufficient estradiol to suppress ovarian function. Clinical trials indicate that 17β-estradiol, when paired with cyclical progestogens, is effective in reducing severe premenstrual syndrome symptoms (Panay et al., 2001; Studd, 2012). However, recent systematic reviews have rated the quality of this evidence as low (Naheed et al., 2017). The tested dose of the transdermal patch has ranged from 100 to 200 µg twice weekly during the luteal phase, with lower doses generally being better tolerated (Naheed et al., 2017). However, the long-term adverse effects of these treatments remain insufficiently studied. When administering percutaneous estradiol, oral or vaginal progesterone is also prescribed to prevent endometrial hyperplasia.

Micronised oral progesterone presents a potential treatment option for PMDD (Table 1), offering a lower risk of androgenic and other unwanted side effects compared to progestogens such as norethisterone and levonorgestrel (Memi et al., 2024). Progesterone might help alleviate premenstrual syndrome symptoms through its diuretic and anxiolytic effects within the central nervous system, though current evidence is limited (Panay and Studd, 1997; Ford et al., 2012). Micronised progesterone can be administered orally (100 or 200 mg) or vaginally, with the latter route sometimes preferred for its ability to bypass first-pass metabolism in the liver, potentially enhancing tolerance.

Selective progesterone receptor modulators offer another treatment option for PMDD due to its antagonistic effects on progesterone receptors (Table 1). Mifepristone (RU 486), the first selective progesterone receptor modulators investigated, did not significantly improve symptoms of severe premenstrual syndrome (Chan et al., 1994). However, a second-generation selective progesterone receptor modulators, ulipristal acetate, is promising. Although primarily used as an over-the-counter emergency contraceptive, ulipristal acetate has been explored in PMDD treatment. In a proof-of-concept randomised controlled trial involving 95 women with PMDD, daily doses of 5 mg ulipristal acetate produced significant symptom improvement over 3 months compared to placebo, with a favourable safety profile (Comasco et al., 2021).

Stabilising the progesterone metabolite ALLO by inhibiting its conversion from progesterone via 5-alpha reductase may offer a promising approach to improving PMDD symptoms (Martinez et al., 2016) (Table 1). Modifying the formation of ALLO, which modulates the GABA system, represents an important avenue for developing a new treatment for PMDD (Schule et al., 2014; Szpunar and Freeman, 2021). Given the similarities in the hormonal underpinnings of both PND and PMDD, brexanolone–a synthetic form of ALLO treatment for PND (see Section 5 below) – may also serve as a novel therapeutic option for PMDD. Brexanolone enhances GABA-A receptor activity, stabilises dysfunctional GABA-A channels, and mimics ALLO, whose fluctuating levels during hormonal changes contribute to mood destabilisation (Edinoff et al., 2021). By restoring GABAergic function, brexanolone stabilises inhibitory neurotransmission, providing therapeutic relief from mood disturbances associated with hormonal fluctuations. Sepranolone, a negative modulator of the GABA-A receptor, offers another approach to PMDD treatment by inhibiting the effects of ALLO on the GABA-A system. Studies have shown that sepranolone significantly reduces PMDD symptoms (Bixo et al., 2017; Backstrom et al., 2021), providing an important contrast on how positive (brexanolone) and negative (sepranolone) GABA-A modulators can be effective in stabilising mood during hormonal fluctuations. However, Asarina Pharma has announced that it will no longer produce sepranolone due to financial difficulties (International Association for Premenstrual Disorder, 2024).

Another potential treatment avenue for PMDD involves targeting ALLO modulation. Dutasteride, a 5-alpha reductase inhibitor that prevents the conversion of progesterone into ALLO. While not yet widely studied or approved for PMDD, preliminary evidence suggests its promise. High-dose dutasteride (2.5 mg/day) has been shown to significantly reduce core PMDD symptoms such as irritability, sadness, anxiety, food cravings, and bloating compared to placebo (Martinez et al., 2016). However, low-dose dutasteride (0.5 mg/day) did not demonstrate a significant effect on PMDD symptoms when compared to placebo.

Progesterone, however, can exacerbate mood symptoms in susceptible women, as seen in those using progesterone-only contraceptives, such as progesterone-only pill and the levonorgestrel intrauterine device (Skovlund et al., 2016). Therefore, careful monitoring is essential. Additionally, a Cochrane review and meta-analysis on the use of progesterone for premenstrual syndrome found limited evidence supporting its effectiveness when used alone (Ford et al., 2012).

Gonadotropin-releasing hormone (GnRH) analogues are highly effective in treating severe PMDD (Wagner-Schuman et al., 2023) (Table 1). GnRH is a releasing hormone responsible for the release of follicle-stimulating hormone and luteinising hormone from the anterior pituitary. GnRH analogues are designed to ‘switch off’ the ovaries temporarily and chemically induce menopause. A meta-analysis of five clinical trials of GnRH for premenstrual syndrome concluded that GnRH are effective for reducing both physical and emotional premenstrual symptoms (Wyatt et al., 2004). Since then, further studies have shown that GnRH treatments are effective for PMDD (Pincus et al., 2011; Nguyen et al., 2017), with response rates reaching up to 75% compared to placebo (Nevatte et al., 2013).

Given that GnRH analogues fully suppress both progesterone and estrogen, the resulting estrogen deficiency often leads to significant side effects, particularly vasomotor symptoms and bone demineralisation (Nevatte et al., 2013). Consequently, GnRH analogues are typically reserved for severe cases of PMDD and limited to 6 months of use (Surrey, 1999). For extended treatment, add-back therapy with combination of estradiol and progestogen, or tibolone—an agent with estrogenic, androgenic and progestogenic effects—is required to mitigate the adverse effects of estrogen deficiency (Wyatt et al., 2004).

Menopause hormone therapy (MHT), previously known asHRT, has long been a key treatment for managing physical menopausal issues, such as vasomotor symptoms. However, MHT has not been recommended in menopause guidelines for the treatment of menopausal depression.

There are many types of MHT, which include different types of estrogens and progestogens in differing doses (Table 3). A 4-year study reported that conjugated equine estrogen (0.45 mg/day, with cyclic progesterone) improved some depressive symptoms compared to placebo (Gleason et al., 2015). However, a large 4-month trial investigating the effects of conjugated equine estrogen (0.625 mg/day, with continuous medroxyprogesterone acetate) found no significant impact on mood or emotional wellbeing, suggesting that the formulation and dosing regimen may influence the therapeutic efficacy of MHT for affective symptoms (Maki et al., 2007).

One small study showed that perimenopausal women with minor and major depression treated with transdermal estradiol (0.5 mg/day) improved significantly after 3 weeks, compared to women receiving placebo (Schmidt et al., 2000). In a secondary analysis, both groups received an additional 3 weeks of transdermal estradiol 0.5 mg/day. By the end of the full 6 weeks, the treatment group sustained their reduced depression scores relative to baseline, while the placebo patients also showed significantly improved scores following the active treatment phase (Schmidt et al., 2000).

In a double-blind clinical trial by Soares et al. (2001), transdermal estradiol (100 μg/day) was administered to perimenopausal women with endocrinologically confirmed diagnoses. The study demonstrated a significant reduction in depressive symptoms in the estrogen group compared with placebo, over a 12-week treatment period, with most participants achieving complete remission and experiencing similar side effects to the placebo group (Soares et al., 2001).

Additionally, other studies indicate that combined therapy with estrogen and traditional antidepressants is more effective in treating menopausal depression than either treatment alone (Schneider et al., 1997; Nagata et al., 2005). This synergistic effect may result from estrogen’s ability to modulate serotonergic and dopaminergic systems, enhancing the efficiency of antidepressants.

Extended use of estrogen and progestins raises potential concerns regarding the impact on breast and uterine tissue, prompting interest in selective estrogen receptor modulators (SERMs) as an alternative. SERMs offer many of estrogen’s therapeutic benefits–supporting bone health, improving lipid levels, and potentially benefiting cognitive function–while minimising risks to the breast and uterus (Dutertre and Smith, 2000; Littleton-Kearney et al., 2002). Initially developed to treat breast cancer and osteoporosis (Komm and Mirkin, 2014), SERMs may have potential as additional treatment for menopause depression (Table 3).

Raloxifene, a second-generation SERM, has been established as a safe and effective treatment for postmenopausal women, particularly in supporting bone health (Komm and Mirkin, 2014). It may also affect neuronal tissue by modulating serotonin receptors, blocking estrogen activation of estrogen response elements on DNA, and promoting brain-derived neurotrophic factor (Littleton-Kearney et al., 2002; Bourque et al., 2014; Ishihara et al., 2015). Research by Kulkarni et al. found that high doses of raloxifene (120 mg/day) improved clinical outcomes in treatment-resistant schizophrenia (Kulkarni et al., 2016). However, evidence for raloxifene’s effects on depression remains limited (Yang et al., 2013). In a recent 8-week randomised controlled trial, Schmidt et al. found no significant benefit of raloxifene over placebo in treating menopausal depression (Schmidt et al., 2021), and similar studies have reported minimal impact on depressive symptoms (Khorsand et al., 2018).

Bazedoxifene, a third-generation SERM, has a unique pharmacological profile that may be particularly well-suited for managing menopausal symptoms, with a potentially safer breast tissue profile favourable for long-term use (Pickar and Komm, 2015). When combined with conjugated estrogens, bazedoxifene effectively reduces vasomotor symptoms, prevents bone loss, improves sleep quality, and enhances the quality of life for menopausal women (Taylor and Ohleth, 2012; Mirkin et al., 2014; Lello et al., 2017). These benefits have been shown in five Phase III randomised controlled trials (Pickar et al., 2009; Pinkerton et al., 2009; Kagan et al., 2010; Skouby et al., 2015; Umland et al., 2016). However, its potential role in addressing mental health concerns related to menopause is still being explored. There is an ongoing double-blind randomised controlled trials of bazedoxifene plus conjugated estrogen evaluating its efficacy in menopausal depression (ACTRN12620001015932).

Tibolone, is a synthetic steroid that is classified as a selective tissue estrogenic activity regulator. Tibolone is also emerging as a promising treatment for menopausal depression due to its potential neuroprotective effects, which stem from antioxidant activity at the cellular level (Cardona-Gomez et al., 2001; Genazzani et al., 2006; Pinto-Almazán et al., 2017; Del Rio et al., 2020). In a 6-month study involving women following surgical menopause, tibolone and transdermal estradiol significantly improved menopausal, depression, and anxiety scores compared to placebo (Baksu et al., 2005). A recent 12-week randomised controlled trials further showed tibolone’s effectiveness in reducing depressive symptoms in menopausal women without significant side effects (Kulkarni et al., 2018b). However, findings in postmenopausal women are mixed, with some studies indicating that tibolone may not consistently outperform placebo in treating depression (Lam et al., 2004; Karşıdağ et al., 2012; Kim et al., 2019), and may not enhance the antidepressant effects of SSRIs (Schneider et al., 1997; Berlanga et al., 2004). Unlike tamoxifen and raloxifene, tibolone effectively reduces vasomotor symptoms and vaginal dryness, with fewer bleeding irregularities than traditional MHT (Hammar et al., 1998), due to estrogen, progesterone, and androgen metabolites, which support endometrial and mammary tissue health, maintain bone density, and provide relief from vaginal dryness (Kloosterboer, 2004).

Testosterone therapy is gaining attention as a potential treatment for cognitive impairment and mood disturbances in menopausal women (Table 3). Although often viewed as a ‘male’ hormone, testosterone plays a key role in women’s physiology, including mood regulation, energy levels, libido, and cognitive function (Scott and Newson, 2020). In women, testosterone levels decline with age and can be as much as 50% lower in menopausal women compared with younger women (Davis, 2023), which may contribute to symptoms like brain fog and depression (Glynne et al., 2024). However, studies have indicated that during the menopause transition, phases where there is a higher testosterone-to-estradiol ratio may be linked to increased depressive symptoms (Sander et al., 2021).

The current evidence for testosterone therapy treating menopausal depression is still emerging. An early randomised controlled trials found that testosterone, whether used alone or added to MHT, enhanced mood, energy, and libido in women with surgical menopause beyond what estrogen therapy alone provided (Sherwin and Gelfand, 1985). In a study of 978 perimenopausal and postmenopausal women, Riesel et al. reported that MHT, with or without testosterone, led to significant improvement in menopause-related symptoms over 3 months, with ‘profound low mood’ showing the greatest improvement (Reisel et al., 2024). For women already using standard MHT, the addition of transdermal testosterone improved concentration, memory, mood and motivation, with the most notable improvements seen in mood and motivation (Kamal et al., 2023). Similarly, a recent pilot study found that 4 months of transdermal testosterone treatment significantly improved mood and cognition, with mood improving more than cognition (47% vs 39%) (Glynne et al., 2024). However, a meta-analysis concluded that randomised controlled trials evidence supporting testosterone therapy for menopausal symptoms other than low libido is insufficient (Islam et al., 2019). Concerns about testosterone treatment in postmenopausal women primarily focus on adverse reactions such as hirsutism and acne (Braunstein, 2007; Islam et al., 2019). These side effects are generally dose- and time-dependent and typically reversible upon discontinuation of testosterone therapy. Nonetheless, more research is needed to determine the efficacy of testosterone, specifically for depressive symptoms during menopause. Furthermore, long-term prospective studies are essential to gather comprehensive data on the safety profile of testosterone use in women, as the majority of current evidence is limited to a maximum duration of 2 years (Braunstein, 2007).