Sex & gender bias in medicine

Medicine from inception has been male dominated and there remains a majority of male doctors, particularly in senior positions (Irish Medical Council, 2022; Lombarts & Verghese Reference Lombarts and Verghese2022). There is a long history of attributing blame for so called ‘mental illness’ on female reproductive organs (Maldonado et al. Reference Maldonado, Marsella, Higgins and Richardson2024; Ussher, Reference Ussher2013), which originated in classical times as the ‘wandering womb’ (Scull, Reference Scull2009). Hysteria as a diagnosis emerged in the latter 1600s and was thought to be a nervous disease of gynaecological origin which primarily affected females due to their ‘delicate’ nerves and ‘brains more susceptible to breakdown’ (Scull, Reference Scull2009). Though the diagnosis of hysteria has now fallen out of fashion, the ‘hysterical patient’ trope remains, such as in the treatment by many medical professionals of sufferers of functional neurological disorders (McLoughlin et al. Reference McLoughlin, Hoeritzauer, Cabreira, Aybek, Adams and Alty2023) and chronic pain conditions (Hoffmann & Tarzian Reference Hoffmann and Tarzian2001), most of whom are women. Women are more likely to have their physical symptoms attributed to psychological processes (Clareus & Renstrom Reference Clareus and Renstrom2019), receive less thorough medical work-up (Ballering et al. Reference Ballering, Muijres, Uijen, Rosmalen and Olde Hartman2021) and even have their pain underestimated and undertreated compared to male counterparts (Zhang et al. Reference Zhang, Losin, Ashar, Koban and Wager2021). Mental health professionals have a major role in advocating for our patients with our medical colleagues to ensure biases do not prevent appropriate diagnosis and treatment. Andronormativity, where the male presentation is considered the norm and female is considered atypical (Verdonk et al. Reference Verdonk, Benschop, de Haes and Lagro-Janssen2009b) is exemplified in psychiatry where women experience what are referred to as ‘atypical’ depressive symptoms (Kuehner, Reference Kuehner2017) which mirrors the male biased description of female presentations in other conditions such as acute coronary syndrome (Al Hamid et al. Reference Al Hamid, Beckett, Wilson, Jalal, Cheema, Al-Jumeily Obe, Coombs, Ralebitso-Senior and Assi2024).

Implicit biases are automatic ‘habit(s) of mind’ that we are all subject to that bypass our conscious thinking (Chapman et al. Reference Chapman, Kaatz and Carnes2013). Gender bias can occur by either assuming differences when there are none or by assuming sameness when there are differences, (Risberg et al. Reference Risberg, Johansson and Hamberg2009), that is being ‘gender blind’ (Verdonk et al. Reference Verdonk, Benschop, de Haes and Lagro-Janssen2009b). Many health professionals have an andronormative bias taught to them throughout their undergraduate and postgraduate training. This can equally affect male and female clinicians, and many are unaware of this bias. Clinicians are subject to the same cultural gender norms and biases as the rest of the population, which may unconsciously affect their clinical practice and patient outcomes (Chapman et al. Reference Chapman, Kaatz and Carnes2013; FitzGerald & Hurst Reference FitzGerald and Hurst2017), recognition of which is essential to counteract the gender health gap (The National Women’s Council of Ireland 2023). For example, diagnostic biases exist for autism, which has been traditionally viewed as the ‘extreme male brain’ (Baron-Cohen, Reference Baron-Cohen2002). Earlier epidemiological studies relied on referred populations to determine sex ratios, though as females have less externalising symptoms than males, they come to less attention and are less likely to be referred for assessment (Cruz et al. Reference Cruz, Zubizarreta, Costa, Araujo, Martinho, Tubio-Fungueirino, Sampaio, Cruz, Carracedo and Fernandez-Prieto2024). In addition to this, females employ masking more than males to present themselves in a neurotypical manner in social situations, and their repetitive and restricted interests may seem more socially normalised, for example in fashion or celebrities (Brickhill et al. Reference Brickhill, Atherton, Piovesan and Cross2023). As assessment tools were developed in predominantly male populations, they are also inherently less likely to detect this female phenotype (Brickhill et al. Reference Brickhill, Atherton, Piovesan and Cross2023). A similar pattern occurs in attention deficit hyperactivity disorder, where externalising symptoms are predictive of receiving a diagnosis with females displaying less hyperactivity and more inattentive symptoms compared to males (Loyer Carbonneau et al. Reference Loyer Carbonneau, Demers, Bigras and Guay2021). Delivering gender sensitive care requires a careful balance, with the need to avoid normalisation of suffering, and avoid inadvertent or intentional pathologisation of normal experiences and physiological processes. It is also important to beware the nuanced transition from epidemiological evidence to stereotyping (Zelek et al. Reference Zelek, Phillips and Lefebvre1997). Observed associations that may be a product of inequality, discrimination or the intersection of vulnerability, can easily be causally attributed to a population, creating a stereotype.

Sex & gender bias in research

Much of the information we know about human health and disease originates from research on male subjects by male researchers (Verdonk et al. Reference Verdonk, Benschop, de Haes and Lagro-Janssen2009b; Zelek et al. Reference Zelek, Phillips and Lefebvre1997) and is applied to female patients on the assumption that the only difference between male and female bodies is the reproductive function (Dijkstra et al. Reference Dijkstra, Verdonk and Lagro-Janssen2008). Until the 1990s, women were excluded from clinical trials due to concerns about teratogenicity and fluctuating hormone levels with results being extrapolated from male only studies (Hamberg, Reference Hamberg2008; Howard et al. Reference Howard, Ehrlich, Gamlen and Oram2017; Mazure & Jones Reference Mazure and Jones2015; McGregor et al. Reference McGregor, Templeton, Kleinman and Jenkins2013). Balanced use of male and female cell lines and animals in preclinical research was only mandated in the United States in 2016 with primarily male cells and animals used prior to this (Mazure & Jones Reference Mazure and Jones2015; Zakiniaeiz et al. Reference Zakiniaeiz, Cosgrove, Potenza and Mazure2016) though more work is needed now to ensure that results are analysed by sex (Howard et al. Reference Howard, Ehrlich, Gamlen and Oram2017; Mazure & Jones Reference Mazure and Jones2015). Research funding for female dominated conditions still lags behind that of conditions primarily affecting men (Mirin, Reference Mirin2021). There is therefore an extraordinary disparity in what is known about mental disorders and their treatments in females, particularly about what is known about medical treatments in pregnancy (Kim et al. Reference Kim, Tingen and Woodruff2010). Considering that the reproductive years coincide with the onset of most major mental illness, this has serious implications for our patients. The Sex and Gender Equity in Research (SAGER) guidelines were developed to counteract historical biases and encourage comprehensive reporting of gender and sex in academic research (Heidari et al. Reference Heidari, Babor, De Castro, Tort and Curno2016). It has been demonstrated that inclusion of women in clinical trials is correlated with female authorship (Chhaya et al. Reference Chhaya, Binion, Mulles, Tannhauser, Aziz, Greenwood, Barlek, Rouan, Wyatt and Kibbe2023). Many health research funding bodies have adopted gender policies to ensure balanced representation in research grants, including the Irish Health Research Board (Health Research Board, 2022).

Gender considerations in prescribing

It is important to be aware of historical biased research practices when prescribing. There are important sex differences in response to medications through differing pharmacokinetics (absorption, distribution, metabolism and elimination) and pharmacodynamics (the effects of the drug on the body) and this changes across the reproductive life cycle (Brand et al. Reference Brand, Haveman, de Beer, de Boer, Dazzan and Sommer2022). Combined with the underrepresentation of females in clinical trials, this means that women are more vulnerable to side effects, adverse reactions and poor treatment response (Kim et al. Reference Kim, Tingen and Woodruff2010; Marazziti et al. Reference Marazziti, Baroni, Picchetti, Piccinni, Carlini, Vatteroni, Falaschi, Lombardi and Dell’Osso2013).

Reproductive hormones have important interactions with commonly used psychotropic medications. There are limited sex disaggregated analyses of antipsychotic medications and available evidence arises from largely male research participants resulting in female patients being more prone to side effects, partly due to being overdosed (Brand et al. Reference Brand, de Boer, Dazzan and Sommer2022; Brand et al. Reference Brand, Haveman, de Beer, de Boer, Dazzan and Sommer2022). As oestrogen increases bioavailability and sensitivity to dopamine, dosing decisions of antipsychotics should consider menstrual and menopausal status – with higher doses needed in low oestrogen states such as the late luteal and perimenstrual phases of the menstrual cycle and postmenopause (Brand et al. Reference Brand, de Boer, Dazzan and Sommer2022; Brand et al. Reference Brand, de Boer and Sommer2021; Brand et al. Reference Brand, Haveman, de Beer, de Boer, Dazzan and Sommer2022; Seeman, Reference Seeman2020). In reproductive years, women require lower doses of antipsychotics compared to men and postmenopausal women (Brand et al. Reference Brand, Haveman, de Beer, de Boer, Dazzan and Sommer2022; Seeman, Reference Seeman2020) and have lower relapse and admission rates, though around the time of menopause, antipsychotic response deteriorates (Sommer et al. Reference Sommer, Brand, Gangadin, Tanskanen, Tiihonen and Taipale2023). Prolactin-sparing antipsychotics should be favoured for women both from a physical perspective – to avoid suppression of the gonadal endocrine axis with resultant hypo-oestrogenic side effects of subfertility, bone mineral loss, and increased cardiovascular risk etc – and the treatment effect of the medication itself (Brand et al. Reference Brand, de Boer, Dazzan and Sommer2022; Brand et al. Reference Brand, de Boer and Sommer2021; Riecher-Rossler, Reference Riecher-Rossler2017). Similar to antipsychotic response, women in reproductive years also respond better than men to serotonergic antidepressants with this advantage also subsiding after menopause (Marazziti et al. Reference Marazziti, Baroni, Picchetti, Piccinni, Carlini, Vatteroni, Falaschi, Lombardi and Dell’Osso2013; Sramek et al. Reference Sramek, Murphy and Cutler2016).

With regard to perinatal prescribing, there is increasing awareness of hormonally mediated alterations in metabolism of medications in pregnancy and the impact of genetics on treatment response (Betcher & George Reference Betcher and George2020). This can lead to the under treatment of some conditions or increased side effects. For example, SSRIs, quetiapine, aripiprazole and lamotrigine metabolism can increase though conversely, metabolism of antipsychotics such as olanzapine and clozapine can decrease (Betcher et al. Reference Betcher, Montiel and Clark2019). A limited awareness of this can heighten the risk of relapse at a formative period in a women’s life, compromising her health and early bonding with her baby, not to mention the longer-term impact on the infant’s psychological and cognitive development.

Menstrual cycle effects on mental disorders

Premenstrual dysphoric disorder (PMDD) is a menstrual related mood disorder affecting 3–5% of women of reproductive age (Epperson et al. Reference Epperson, Steiner, Hartlage, Eriksson, Schmidt, Jones and Yonkers2012) with comparable disability adjusted life years lost as major depression (Halbreich et al. Reference Halbreich, Borenstein, Pearlstein and Kahn2003). Symptoms last for 1–2 weeks of every menstrual cycle and considering the prevalence, this is an enormous burden of illness on women in a critical time of their life. It is poorly recognised and managed by healthcare professionals (Funnell et al. Reference Funnell, Martin-Key, Spadaro and Bahn2024) and can often be misdiagnosed as depressive or personality disorders which precludes appropriate treatment (Matthews & Riddell Reference Matthews and Riddell2023). An appreciation of the temporal pattern of symptoms with the menstrual cycle through prospective symptom tracking is crucial to the diagnosis.

Perimenstrual exacerbation of underlying mental disorders is also common and occurs in psychosis, depression, eating disorders, ADHD and borderline personality disorder (Nolan & Hughes Reference Nolan and Hughes2022). A thorough understanding of a patient’s cyclical symptoms facilitates tailored supports, treatments and medication doses for when their symptoms are most severe. The menstrual cycle may play a role in predicting suicide risk as higher rates of completed suicide, attempted suicide and psychiatric admission are observed in the luteal and perimenstrual phases (Jang & Elfenbein Reference Jang and Elfenbein2019). Those with PMDD have high rates of suicidality, even in the absence of mental health co-morbidities, and are over-represented in those who present with suicidal thoughts and behaviours (Eisenlohr-Moul et al. Reference Eisenlohr-Moul, Divine, Schmalenberger, Murphy, Buchert, Wagner-Schuman, Kania, Raja, Miller, Barone and Ross2022; Prasad et al. Reference Prasad, Wollenhaupt-Aguiar, Kidd, de Azevedo Cardoso and Frey2021). Given the low specificity of suicide risk assessment, this presents a potentially predictable and modifiable risk factor for preventing suicide.

The menopausal transition is a further window of vulnerability for relapse or new onset of mental disorder. As previously discussed, oestrogen is protective against psychosis, and there is a second midlife peak of incidence only observed in female patients coinciding with reducing oestrogen levels (Sommer et al. Reference Sommer, Tiihonen, van Mourik, Tanskanen and Taipale2020). Perimenopause is also associated with heightened risk for major depressive disorder, though usually in those who have experienced prior episodes (de Kruif et al. Reference de Kruif, Spijker and Molendijk2016) but also a new onset of mania (Shitomi-Jones et al. Reference Shitomi-Jones, Dolman, Jones, Kirov, Escott-Price, Legge and Di Florio2024). The reasons for this are likely multifactorial and not simply hormone related. Stressful life events are common in this time period, and physical symptoms of menopause, particularly sleep disturbance, are prone to trigger mental health symptoms. Ensuring our patients with major mental illness are informed about the benefits and risks of hormone replacement and facilitated to access it, should be a high priority for all psychiatrists.

Delivering gender sensitive mental health care

Gender neutral approaches do not consider the specific needs of female patients (Judd et al. Reference Judd, Armstrong and Kulkarni2009) and there is a need for mental health professionals and services to ensure they are responsive to the needs of women. More women attending mental health services are victims of domestic violence than the general population and so it is essential for services and professionals to recognise and respond to this (Oram et al. Reference Oram, Khalifeh and Howard2017; Trevillion et al. Reference Trevillion, Oram, Feder and Howard2012). Being the victim of intimate partner violence infers nearly three times the risk of developing a subsequent mental illness in women (Chandan et al. Reference Chandan, Thomas, Bradbury-Jones, Russell, Bandyopadhyay, Nirantharakumar and Taylor2020) and also a heightened risk of suicide (MacIsaac et al. Reference MacIsaac, Bugeja and Jelinek2017). Women with psychosis have higher rates of childhood physical and sexual abuse than their counterparts without psychosis; this association is not seen in men (Fisher et al. Reference Fisher, Morgan, Dazzan, Craig, Morgan, Hutchinson, Jones, Doody, Pariante, McGuffin, Murray, Leff and Fearon2009).

Psychiatric care, particularly in services with high levels of restrictive practices, has the potential to retraumatise survivors of abuse (Judd et al. Reference Judd, Armstrong and Kulkarni2009; Sweeney et al. Reference Sweeney, Filson, Kennedy, Collinson and Gillard2018). Feeling powerless or unheard is an important predictor of being traumatised by an experience (Sweeney et al. Reference Sweeney, Filson, Kennedy, Collinson and Gillard2018). Trauma informed care (TIC) has been demonstrated to reduce the need for such restrictive practices but needs to be meaningfully adopted (Saunders et al. Reference Saunders, McGuinness, Barnett, Foye, Sears and Carlisle2023). Clinical leadership, organisational change, staff training, time for staff reflective practice and most importantly sufficient resourcing and investment are all required to achieve this (Huo et al. Reference Huo, Couzner, Windsor, Laver, Dissanayaka and Cations2023; Saunders et al. Reference Saunders, McGuinness, Barnett, Foye, Sears and Carlisle2023). TIC should not be restricted to mental health settings but adopted across all healthcare settings, particularly maternity hospitals (Sperlich et al. Reference Sperlich, Seng, Li, Taylor and Bradbury-Jones2017), emergency departments (Molloy et al. Reference Molloy, Fields, Trostian and Kinghorn2020) and women’s health clinics.

Consideration of women in mental health policy

In care on psychiatric wards and in wider mental health services, there needs to be a consideration for sexual and reproductive health of all patients. Women and people who menstruate feel inadequately supported around their period with difficulty accessing menstrual products, pain relief or privacy (Porter, Reference Porter2024). Pregnancy and breastfeeding are not sufficiently addressed in mental health ward policy (McGuire et al. Reference McGuire, Curtis and Duffy2023a) despite there being several key aspects of inpatient psychiatric care that can affect the physical health of a mother and her baby, and risk causing undue psychological distress (McGuire et al. Reference McGuire, Murray and Duffy2023). This is particularly crucial given the lack of a mother and baby unit in Ireland which results in mothers with severe mental illness in the perinatal period being treated in general psychiatric units. Separation from their babies is inevitable in this circumstance which has repercussions for maternal mental health, bonding and feeding. Consideration of gender, pregnancy, sexual health and reproductive health should therefore not be siloed in isolated polices but rather integrated into all general policy where appropriate.

Gender is rarely considered in mental health legislation (Hoare et al. Reference Hoare, Murphy, O’Donoghue, Allen and Duffy2024) and the opportunity to address this lacuna should not be missed with the upcoming revision of the Mental Health Act. Gender sensitive provisions have been included in legislation across the world, however there is massive heterogeneity in what is included. Some of the provisions have worsened the care that women receive, such as by reducing access to specialised treatment through ward gender separation, and further ingraining gender-based discrimination and stereotypes, through removing sexual autonomy from women on the basis of having a mental illness. However, Hoare et al. Reference Hoare, Murphy, O’Donoghue, Allen and Duffy(2024) also identify legislative previsions that can improve the mental healthcare women receive. These include giving consideration to gender balance on the mental health commission and tribunals, the need for seclusion, restraint and searches to be carried out in a way that protects women, the need for trauma informed principles to be imbedded in practice, and gender disaggregated data to be collected on all routine data. Where this is not included in legislation it should be present in policy.

Integration with physical healthcare

Gender also influences the interaction between physical and mental health, and this interaction is bidirectional. Physiological states and medical conditions specific to women can influence mental health. Women with major mental illness have changing needs as they enter perimenopause and beyond, when their metabolic and cardiovascular risk factors elevate (Seeman, Reference Seeman2012). Despite similar rates of cardiovascular disease to men, cardiac events in women are less well identified by both healthcare professionals and patients due to gender biases and differing symptom profiles (Al Hamid et al. Reference Al Hamid, Beckett, Wilson, Jalal, Cheema, Al-Jumeily Obe, Coombs, Ralebitso-Senior and Assi2024). Physical health monitoring of psychotropic medications needs to be sensitive to reproductive status and a proactive approach needs to be taken to ensuring women are informed of their individualised balance of benefits and risks for hormone replacement at time of menopause. Assessment, management and psychoeducation of menopause needs to be integrated into general psychiatric care to improve both somatic and psychiatric outcomes (Brand et al. Reference Brand, de Boer, Dazzan and Sommer2022).

Being affected by a reproductive system disorder such as endometriosis or polycystic ovary syndrome is associated with 2-3 times the risk of a psychiatric disorder and chronic pelvic pain is associated with nearly four times the risk (Zaks et al. Reference Zaks, Batuure, Lin, Rommel, Reichenberg, Grice, Bergink, Fox, Mahjani and Janecka2023). But conversely, psychological ill health can impact physical health in women. Women with serious mental illness are more likely to have gynaecological diseases, experience recurrent miscarriage and are less likely to attend for cervical screening than the general population (Hope et al. Reference Hope, Pierce, Johnstone, Myers and Abel2022). Women with schizophrenia have a higher incidence of a number of cancers (as do their male counterparts), but specifically have higher rates of breast and cervical cancer (Wootten et al. Reference Wootten, Wiener, Blanchette and Anderson2022; Xiping et al. Reference Xiping, Shuai, Feijiang, Bo, Shifeng and Qihui2019), and are more likely to be diagnosed with metastases already present (Wootten et al. Reference Wootten, Wiener, Blanchette and Anderson2022). Ensuring this population attend cancer screening is crucial and close working relationships with primary care and other medical specialties are key to delivering integrated mental and physical healthcare (Kulkarni et al. Reference Kulkarni, Butler and Riecher-Rossler2019).

Medical education and training

It is essential to begin to introduce teaching on the impact of sex and gender on health and healthcare delivery (i.e. gender medicine) early into medical training (McGregor et al. Reference McGregor, Templeton, Kleinman and Jenkins2013) to counteract gender biases (Sen & Ostlin Reference Sen and Ostlin2008) and increase gender awareness among healthcare professionals. The GSMH report recommends undergraduate and postgraduate training for mental health professionals which echoes the WHO’s earlier call for this in 2006 (The National Women’s Council of Ireland 2023; World Health Organization (WHO) 2006). However, systemic organisational change will be required to truly achieve gender equity in our health services (Celik et al. Reference Celik, Lagro-Janssen, Widdershoven and Abma2011). Integrating this solely into undergraduate psychiatry curricula may prove difficult given the restricted time allotted to the subject in Irish medical schools, in some universities as low as four weeks (Byrne et al. Reference Byrne, Murphy, O’Rourke, Cotter, Murphy, Guerandel, Meagher, Sweeney, Gill, Campbell, McDonald and Hallahan2020). While the responsibility for implementing these changes should not be placed solely on the shoulders of mental health educators, psychiatrists should take an active role in light of their expertise relative to other medical specialties in the biopsychosocial model and in reflective practice. Sex and gender medicine should be incorporated throughout the medical curriculum, ideally in a longitudinal format over multiple academic years (Khamisy-Farah & Bragazzi, Reference Khamisy-Farah and Bragazzi2022; Ludwig et al. Reference Ludwig, Oertelt-Prigione, Kurmeyer, Gross, Gruters-Kieslich, Regitz-Zagrosek and Peters2015; McGregor et al. Reference McGregor, Templeton, Kleinman and Jenkins2013). It has been introduced into medical curricula in Europe and North America (Ludwig et al. Reference Ludwig, Oertelt-Prigione, Kurmeyer, Gross, Gruters-Kieslich, Regitz-Zagrosek and Peters2015), with much of the academic literature on the subject arising from the Netherlands where a national programme in gender medicine commenced in 2002 (Verdonk et al. Reference Verdonk, Benschop, de Haes, Mans and Lagro-Janssen2009a). It has been reported to be difficult to incorporate non-biological topics like gender based violence into curricula though support from other disciplines within universities could be beneficial in this regard (Verdonk et al. Reference Verdonk, Benschop, de Haes, Mans and Lagro-Janssen2009a). Aligning the project with medical professional values of providing excellent care (Miller et al. Reference Miller, Rice, Schiebinger, Jenkins, Werbinski, Nunez, Wood, Viggiano and Shuster2013) and gaining institutional and senior academic support facilitates the integration of gender awareness into core medical curricula (Celik et al. Reference Celik, Lagro-Janssen, Widdershoven and Abma2011).