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The interplay between sex hormones and immune system: an undiscovered path in the affective disorder

The interplay between sex hormones and immune system: an undiscovered path in the affective disorder maze?


For generations (until the ‘90s), males were considered as the ideal target population in clinical drug trials, triggering biased research and incomplete knowledge not only on the biological and psychological differences between males and females, but also on the treatment response of female patients. As a young contemporary PhD student in psychiatry, I feel I have a duty to study these differences, in order to help create multidisciplinary, sex-tailored precision medicine.

In my previous blogs on Inspire the Mind, I published an initial reflection on sex differences in mental health with a particular focus on sex hormones, and a blog about mindfulness as a promising tool to handle stressful situations and to help improve mental wellbeing; but this time I want to talk about differences between male and female patients in the affective disorder population, focussing on sex hormones and inflammation, which is the main topic of my PhD.


Sex differences in mental health are important, in particular in affective disorders


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Affective disorders (also known as “mood disorders”) are a set of psychiatric conditions such as for example major depressive disorder (MDD) and bipolar disorder (BD). There are important differences between male and female patients with these disorders. For example, as I wrote in my recently published paper, the risk of developing depression is higher in women than in men. But sex differences do not stop here, they spread out to other areas, such as the type of experienced symptoms and the response to medications.


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In fact, female patients tend to show a higher prevalence of atypical depression (an example of an atypical symptom is hypersomnia — that is, sleeping too much) and have a better response to selective serotonin reuptake inhibitors (SSRI), the newer and safer class of antidepressants that

increases the amount of available serotonin in the brain and the serotonin activity. In comparison, male patients respond better to tricyclic antidepressants, which also act on the serotonin and norepinephrine reuptake, but they are older compounds and have more side effects and more risk of toxicity than SSRIs.

Sex also plays a role in bipolar disorder, a condition characterised by mood swings (pathologically high and low mood, also called mania/hypomania episodes alternating with depressive episodes); female patients show later age of onset, more history of suicide attempts, and more frequent depressive episodes, mixed mania and rapid cycling (that is experiencing at least 4 mood episodes — depression, mania, hypomania — in a 12-month period) in comparison with male patients.


What are the biological mechanisms that may explain the sex differences in affective disorders?

Inflammation is one of the most studied biological mechanisms in depression. The immune system (that is the system that fights infections in your body) is, as previously discussed in this blog, hyperactivated in depressed patients. In fact, one of the signs telling us this system is activated is the increased levels of peripheral inflammation.

Depressed patients present an over-activation of the immune system even though there is no ongoing infection in the body; moreover, we also see that those who do not respond to antidepressant treatments have even higher levels of inflammation in comparison with responders. This could truly be a turning point in helping those depressed individuals who cannot see the light at the end of the tunnel, going from one antidepressant treatment to another without significant improvement.

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Like in “Alice in Wonderland”, down the rabbit hole, one question leads to another.

Why is this happening?

Does the same mechanism affect the activation of the immune system in depression, in both males and females?

Is out there a new possible sex-specific therapeutic approach for those patients who do not respond to antidepressant treatments?

Answering these questions may give us the basis for the multidisciplinary sex-tailored precision medicine I mentioned earlier, with different treatments for male and female patients.

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Having seen the predominant role of inflammation in major depressive disorder, one of the possible answers may be a yet unexplored mechanism: the interaction between sex hormones and inflammation in affective disorders.

It may seem strange that sex hormones, something that is commonly known as the regulator of processes such as our sexual development and reproduction, is also linked to a system that regulates stress response and that fights infections in our body.

But let me take a little step back: what are sex hormones doing?

Sex hormones (also known as gonadal hormones) can be divided into different classes such as androgens (for example testosterone), estrogens (for example estradiol), and progestogens (for example progesterone). They are known as the main actors of reproduction and development of secondary sex characteristics.

To give you an overview, testosterone is involved, for instance, in the development of male reproductive organs in the fetal stage, the physical changes during puberty, and the production of sperm in adulthood.

Estradiol is produced primarily by the ovaries in females and levels vary during the menstrual cycle, reaching the peak with ovulation (egg maturation and release), and the lowest levels during menstruation (also called “menses”). During pregnancy, the levels of estradiol increase exponentially, (also thanks to the cooperation of the placenta that produces estrogens and progesterone), with a drastic drop after the delivery and the expulsion of the placenta.

Progesterone is also produced primarily by the ovaries in females and mainly in the luteal phase (second half of the menstrual cycle); furthermore, it maintains the early stages of pregnancy, inhibits gonadotrophin-releasing hormone (GnRH) and luteinising hormone (LH) liberation (with gonadotropins being essential for reproduction). If the egg is fertilised, this hormone also plays a significant role in pregnancy, by contributing for example to implanting the egg in the womb (uterus), to avoid contractions (which may cause miscarriages) and prevent milk production (through prolactin inhibition).

However, sex hormones are also involved in a broader spectrum of functions throughout the whole life of an individual, with the ability also to affect mood and behaviour, as I described in my previous blog, and with potentially neuroprotective abilities.

For example, testosterone is also implicated in the production of blood cells, in supporting the strength of the musculoskeletal system (specifically muscles and bones); and it shows anxiolytic and anti-depressant actions and the ability to improve cognitive functions, such as spatial memory (that is the memory which helps you to recover the locations of places and objects, and which is vital for survival).

Moreover, estradiol improves the density of bones and cartilage (that is, the tissue that protects for example the extremities of long bones and is also a body component in your ears and nose) and improves cognitive functions (such as verbal fluency).

But the story continues…

Sex hormones also have immunoregulator proprieties. Inflammatory levels also vary accordingly to the hormonal environment, with testosterone showing anti-inflammatory effects and estrogen showing both, pro- and anti-inflammatory proprieties. Interestingly, pregnancy is generally characterised by a change towards an anti-inflammatory profile, whereas depressed pregnant women show increased inflammatory profiles in early pregnancy. Moreover, hormonal fluctuations and changes in physiology across the lifetime (for example puberty, pregnancy and menopause) can affect our mood and can be linked to sex differences in affective disorders. In fact, the risk of depression soars in puberty, and for females, it increases in particular after menarche (that is the first occurrence of menstruation), with testosterone being also linked to increased risk of suicide attempts in female patients with bipolar disorder.

All these differences and links between mood, sex hormones and inflammation pushed me to explore this mechanism in affective disorders, by doing a systematic review.

A systematic scientific review is a method used to understand what is already known about a topic, and what the key points are.

This process allows us to select published articles that talk about the data of interest and thus understand the state of the art in your research question. It may bring new insights and/or an understanding of what is needed to be done in future research, and connects the dots between apparently disjointed pieces of evidence.

However, when doing this review, the answer to the question was not so immediate, and I noticed that this interaction between inflammation, sex hormones, and affective disorders is quite understudied.

In the published literature, we found only 20 articles that investigated our triad of factors — sex hormones, inflammation and depressive symptoms — in the same subjects; nevertheless, my systematic review finds some new insights that can be used for future research (and in the end, for potentially improving clinical practice). I have described this evidence in my paper “Sex hormones and immune system: a possible interplay in affective disorders? A systematic review”. Trying to put together these 20 articles was like walking through a maze! But I was able to find my way, at least a little.

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Testosterone may be protective in bipolar depression in men through anti-inflammatory effects.

Bipolar disorder exhibits different mood states associated with different levels of sex hormones, such as higher testosterone levels in manic mood states than in depressive mood. Remarkably, a study found that male patients with bipolar disorder show decreased testosterone levels. Moreover, the lower the testosterone, the higher the inflammation, as measured by a protein in the blood called interleukin-17 (a pro-inflammatory biomarker). This suggests a possible protective role of testosterone as an anti-inflammatory agent in male patients.

Basically, male patients with bipolar disorder tend to have increased inflammatory levels and decreased testosterone levels: perhaps increasing testosterone could have an anti-inflammatory effect in these patients, and help stabilise the mood? A study to be conducted in the future. Interestingly, this is relevant for male patients only, as testosterone is increased in female patients with bipolar disorder.

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Hormonal therapy may be protective in peri/postmenopausal women through anti-inflammatory effects.

Menopause is an actual dilemma, requesting a balance of hormonal therapies to counteract the symptoms of hormonal deprivation and the increased risk of depression. Even though hormonal replacement therapy has some major benefits, such as improving mood and libido, it is associated with moderate side effects like headaches or feeling sick, and an increased risk of breast cancer.

Studying the side effects of hormonal variations may help us to better understand the role of sex hormones in the interaction with the immune system. The studies focussing on menopause highlight a possible key role for hormonal therapies as protective factors in peri- and postmenopausal women, possibly through an effect on the immune system. For example, one study found that in women who are not taking hormonal therapy, higher inflammation is associated with more depressive symptoms. Another study showed that hormonal therapy improves depressive symptoms with a parallel decrease in pro-inflammatory biomarkers and increase of sex hormone levels. Thus, hormonal replacement therapy in peri-/postmenopausal women may be protective against depression through an anti-inflammatory action.

The questions for the future

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One of the major findings of my systematic review is that… basically, we do not know much about the interaction between inflammation and sex hormones in affective disorders. We aim to study, and better understand, which patients with affective disorders would benefit from add-on hormonal therapies, with a view of targeting the immune system.

In fact, if we can understand the underlying mechanisms associated with increased inflammatory levels or new ways to address these, we could reach a better understanding of new treatments or of the use of already existing compounds.

For example, minocycline has been seen to be effective in those patients who do not respond to antidepressant treatment (defined as treatment-resistant depressed (TRD) patients) and who have higher inflammation in comparison with other TRD patients. We do not know if these effects are different in male and female TRD patients.

Moreover, most of the studies did not analyse “female” sex hormones (such as estradiol) in male patients and “male” sex hormones (such as testosterone) in female patients. It would have been interesting to see the sex-crossed role of gonadal hormones and how they affect inflammatory response and depressive symptoms. We all have both sets of hormones, of course at different levels and with various effects, and it is another source of insufficient knowledge if we only measure female hormones in women and male hormones in men.

All of these issues highlight the need to overcome the conceptual dualism of mind/body that has derailed the medical practice in the past decades, with the need to dig deep into the biological differences between males and females in order to detect new, tailored, therapeutic strategies that tap into these biological mechanisms.

In conclusion, a better understanding of the modulating effect of sex hormones on the immune system will be a key point in prescribing hormonal add-on treatment for a sub-group of depressed patients with the aim of improving mood by regulating the immune system, with different interventions for men and women.

If this will lead to an improvement in the mental health of people with affective disorders, then we will be finally out of the maze!

 

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