The Importance of Sex in Clinical Trials

Stress is also considerably interwoven with depression, and the literature on sex differences in depression and its treatment is extensive. The incidence of depression is almost double in women than men- in the US, the lifetime risk of major depression is 21% vs 13%, respectively. This increased susceptibility may be due to increases in sex hormones during adolescence, as this is normally when sex differences arise before returning to similar levels of vulnerability after menopause. The difference may also be attributable to differential monoamine action (i.e. dopamine, serotonin, and norepinephrine) between sexes. In addition to increased vulnerability, symptom presentation is generally worse in women, and they typically experience prolonged or recurrent depression more often than men. Women are also more likely to experience greater weight gain and more physical manifestations of the illness. Despite this, there is hope that women may respond preferentially to some treatments. A review paper notes that females respond better to serotonergic SSRI antidepressants than males, however, this is only true for those premenopausal, as postmenopausal women have a diminished response. (Sramek et al., 2016, p449). This implies that female sex hormones play a significant role in the observed response. Alternatively, no sex differences were reported for the serotonergic SNRI antidepressants, although a significantly higher therapeutic response has been shown by men to TCAs than females. Additionally, higher plasma levels and lower clearance of TCAs have been found in women, suggesting that the drug lingers in a woman’s body longer despite having minimal therapeutic benefit. (Sramek et al., 2016, p452). As a plus, monoamine oxidase inhibitors (MAOIs) demonstrate superiority over TCAs in females but are less effective than TCAs in men. As indicated, the therapeutic response to antidepressants is varied across sex and by type of drug administered. Also, antidepressants are known to cause weight gain in women but not men, and these differences in weight and distribution of fat can significantly affect the pharmacokinetics of the drug, suggesting they may have variable effects in women depending on the duration of treatment. As will be shown, similar sex-related differences have been identified for a variety of other drugs, as well as general and neurological health conditions. 

Relapse remitting multiple sclerosis (MS) is up to three times more likely in women of childbearing age. There are also sex differences in disease expression: women present with symptoms up to 5 years before men and are therefore diagnosed sooner, and women recover faster from flare ups and have slower disease progression. These protective differences are typically attributed to the effects of oestrogen as menopause typically increases severity and frequency of flare-ups and relapse rates decrease in late pregnancy when estriol levels are high. (Wisdom et al., 2013, p908). The MS animal model, rodent experimental autoimmune encephalomyelitis (EAE) has also shown that sex differences are related to both reproductive and non-reproductive factors. Accordingly, oestrogenic ligands as candidate neuroprotective agents are being explored as a therapy for MS. Interestingly, until the 1920s, men were diagnosed more frequently than women, as men were more likely to be diagnosed with an organic disease. Women presenting with the same symptoms were often diagnosed with hysteria. It is now also believed testosterone may protect men (in a different way to oestrogen in women), leading to protection from the disease or later onset. 

In the same way, ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome) is up to four times more likely in women than men. It was frequently labelled as hysteria even into the 1970s, and despite the original literature surrounding the Royal Free Epidemic of 1955 quickly disregarding hysteria as a cause, two psychiatrists revisited the literature in 1970 and refuted the original conclusions.  They stated that in regards to ME "there is little evidence of organic disease affecting the central nervous system and epidemic hysteria is a much more likely explanation. The data which support this hypothesis are the high attack rate in females compared with male" and “the presence of subjective features similar to those seen in a previous epidemic of hysterical overbreathing.” (McEvedy and Beard, 1970, p7). They also described the initial manifestations of the disease as ‘subjective complaints’ and went on the compare these to the frequency of similar complaints in 154 schoolgirls during an ‘epidemic of overbreathing’ (otherwise known as hyperventilation). They attributed almost all symptoms to overwhelming anxiety. The paper had devastating effects on the research that was ongoing at the time, with those focused on biological causes finding their funding depleted and more prioritisation on psychiatric remedies, as well as the perception of the disease for the past 50 years. 

In Parkinson’s disease, men are only 1.5 times more likely to be affected but women are routinely mis- and under-diagnosed due to ‘atypical’ disease expression. Women are likely to display cognitive changes, depression, fatigue, and stiffness rather than the characteristic tremors. This links back to the concept that illnesses and their accompanying symptoms are studied with respect to the male anatomy and what is typical for male disease expression may not be typical in women. The difference in expression may be due to differential dopamine transporter activity between men and women. Measuring dopamine transporter activity (DAT) reveals that there is up to 21% more DAT activity/binding in women than men in the caudate nucleus in both normal and degenerated dopaminergic systems (healthy individuals and Parkinson’s sufferers). A similar near significant difference was also seen in the right posterior putamen. This increase in activity seen in women could be neuroprotective, suggesting why more men suffer from Parkinson’s disease than women. (Kaasinen et al., 2015, p1761). It is again proposed that oestrogen protects dopaminergic neurons as women are more likely to develop Parkinson’s during or shortly after menopause. In fact, oestrogens are known to reduce microglial inflammation and turn on microglia repair process, which could contribute to protecting neurons. (Villa et al., 2016, p384). The paradox here is that while these cellular mechanisms should be protective in women, Alzheimer’s disease affects more women. 

Two thirds of patients diagnosed with Alzheimer’s disease are women. This is suggested to be because functional decline is more noticeable in women as they typically stay more active in age. Alternatively, it has also been attributed to the longevity of women, but this has been discredited by age-matched groups where the finding still stands. Therefore, while oestrogen may protect the body from the effects of Alzheimer’s disease, as women tend to develop the disease when oestrogen levels drop after menopause, oestrogen therapy has failed to yield reliable results. There are also other sex differences to explain this observation. A study in mice suggests that male and female brains exhibit significantly distinctive pathways through aging: the brains of female mice experience the largest changes in gene expression with aging, and this starts earlier than in males. (Zhao et al., 2016, p71). The group measured the expression levels of 182 genes involved in producing energy and amyloid (a protein associated with normal aging and Alzheimer’s disease) and found that, in females 44.2% genes showed significant changes between 6-9 months of age. These changes were indicative of decreased bioenergetic function and increased amyloid dyshomeostasis. Alternatively, in males changes in gene expression primarily occurred between 12-15 months of age and were upregulated, suggesting an adaptive response to aging. (Zhao et al., 2016, p77). A running hypothesis is that the overall changes reduce the utilisation of energy in neurons and slow down removal of amyloid, making females more susceptible to Alzheimer’s disease. However, whether these findings are translatable to human disease is questionable. Other research has shown that the observed sex differences are most pronounced in individuals with less than 16 years of education (a known risk factor for Alzheimer’s disease). (Koran et al., 2017, p208-9). The risk factor may not apply to everyone though, as the group found less education to be associated with increased risk for Alzheimer’s disease in women but not men, with no known molecular mechanism behind the disparity. Furthermore, in longitudinal analyses, Koran et al. found female sex to be associated with worsening outcomes and executive function and increased hippocampal atrophy in the presence of enhanced Alzheimer’s disease biomarkers. Altogether, this suggests women may be more susceptible to the effects of Alzheimer’s neuropathology, irrespective of their longevity and more noticeable functional decline.

Women’s affliction doesn’t end here, however. In fact, a literature review surrounding somatic symptom reporting between 1966 and 1999 found that women report more frequent and intense somatic symptoms than men. This finding was consistent across time and age, as well as if psychiatric disorders, medical comorbidity, and gynaecological and reproductive symptoms were adjusted for. (Barsky et al., 2001, p266-7). As previously mentioned, the group also reported that women may have a lower pain threshold and tolerance than men and that female animals show more pronounced responses to experimental pain. (Barksy et al., 2001, p267). So, not only do women suffer more frequently than men, but they also likely feel pain more intensely. This has applications in pain treatment, for example, whether women should be offered more analgesia than men. Even so, this may not be useful. Preclinical studies in rats suggest that female sex hormones desensitise the cannabinoid receptors to THC (tetrahydrocannabinol), making females less sensitive to the drug over repeat exposure. (Cooper and Haney, 2016, p117-8). On the same hand, smoking marijuana, releasing cannabinoids, was found to decrease pain sensitivity and increase pain tolerance in men but not women, as measured by a Cold Pressor Test. Instead, women experienced a small increase in pain tolerance shortly after smoking but this rapidly decreased to below control levels, suggesting women are more susceptible to hyperanalgesic effects of the drug. (Cooper and Haney, 2016, p15-6). This research relates to using pharmacotherapies, such as cannabis, for neurodegenerative disorders and chronic pain conditions, where medical marijuana is prescribed, and especially the prescription of analgesia to women. These differential effects cannot solely be attributable to sex hormones as sex differences have been found in the endocannabinoid system of gonadectomised rats (to reduce impact of circulating sex hormones). For example, FAAH (fatty acid amide hydrolase) inhibition (to increase levels of endocannabinoids) significantly suppressed responses at inhibitory synapses in over half of the experimental female hippocampal slices but had little effect on the male specimens. (Tabatadze et al., 2015, p11264). This suggests that the sex differences in response to THC may not be solely due to the effects of sex hormones and more clinical studies should investigate sex as a variable in the endocannabinoid system, as well as other pain systems. This is not to say that sex hormones are unimportant. It is well established that pain perception and inhibition is influenced by GABA activity and this in turn is hormonally dependent. The endogenous opioid systems are also modulated by oestrogen and other sex hormones, highlighting the importance of exploring sex as a variable in pain treatment and in the development of analgesia.