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ScienceSocietySpiegeloog 412: Happiness

SSRIs & oestrogen – Happiness hormones for the menstruating

By June 4, 2021June 9th, 2021No Comments

In a research article from 1961, 386 convicted women were interviewed, and it was shown that 49% of them committed their crime during menstruation or in the days preceding it, whereas only 29% of all crimes would be expected to take place in this period (Dalton, 1961).

How reasonable is the presence of a menstrual cycle to explain this outcome? And do we know what causes large changes in behaviour in those who menstruate? This article takes a closer look at the effect of the menstrual cycle on the mental health of those who menstruate, and possible treatments.

Women vs men

Although we’d like to consider women and men as equal, there does seem to be a difference in gender when it comes to developing mental health disorders. Worldwide, fear and depression are more prevalent in women than in men (4.6% vs 3%) (Denys, 2020). Halbreich & Kahn (2001) mention that women are 1.5 to 3 times more likely to suffer from depression than men. However, two times as many women than men visit a general practitioner for their mental health in the Netherlands, so it is important to keep in mind that women tend to seek help faster than men (Denys, 2020).

Some research has found a clear pattern of mood changes in those who menstruate (Gonda et al., 2008), while others finding a less clear pattern (Romans et al., 2013) or even fail to find one at all (Romans et al., 2012). Seney and Sibille (2014) argue that the way people perceive stress influences the prevalence of depression, with women reporting to feel more stressed than men in stressful situations. Other research shows that even when the physiological response in both men and women is the same, women still feel more irritable and anxious, but also happy, compared to men (Kelly et al., 2008).

Research is still ongoing as to what causes the difference, with studies showing that social environment and culture also play a role in pain sensitivities caused by menstrual cycles (Vigil, 2014). There seems to be strong evidence for the neurobiological mechanisms being responsible (Seney & Sibille, 2014). Both men and women have the same hormones, but the way they interact in male and female bodies are different. According to LaBarbera (2010), the hypothalamic–pituitary unit, which is controlling our gonadal hormone system, changes in sensitivity to the positive and negative feedback effects of the hormones oestrogen and progesterone. This makes the female hormonal rhythm cyclic. Oestrogen and progesterone are two of these gonadal hormones. They are essential for reproduction and have large control over our emotional states. It is mostly oestrogen that is thought to contribute to the increased occurrence of psychiatric illness in those who menstruate (Toufexis, 2007).

PMS and PMDD

Those who have a menstrual cycle can be dealing with some intense hormonal fluctuations during their lives. PMS (Premenstrual Syndrome) is attributed to a fluctuation in hormones, starting in the luteal phase of the menstrual cycle, right after ovulation. The chapter on the luteal phase (see graph 1) in Maisie Hill’s book Period Power is called Highway to Hell, and with good reason. Symptoms can be mood swings, feelings of worthlessness, irritability, lack of concentration, increased tiredness, and physical symptoms like headaches, breast swelling and bloating. PMDD (Premenstrual Dysphoric Disorder) is a severe form of PMS, with symptoms occurring in the week before menstruating and disappearing soon after (Hill, 2019).

According to Hill, 90% of menstruators suffer from PMS, while 3 to 8 percent of menstruators suffer from PMDD. A change in mood is caused by the fluctuation of hormones in the luteal phase of the menstrual cycle: progesterone goes up while oestrogen drops (see graph 1; Hill, 2019). Especially the drop of oestrogen has been associated with depression among women sensitive to these fluctuations (Halbreich & Kahn, 2011).

It is hard to say what ‘sensitive’ means, since the absolute levels of the hormones were on equal levels across women with PMDD who participated in research (Hill, 2019). An important indication to the sensitivity is the absence of symptoms in the follicular phase, and when suppressing ovulation by the use of estradiol, for instance (Halbreich & Kahn, 2011). Hill explains the difference in sensitivity by means of the OSR1 gene: ‘Individuals with PMDD have a variation in their oestrogen receptor alpha gene, which make them more sensitive to the effects of oestrogen and progesterone across the menstrual cycle.’

The function of our hormone system is very complex, so without getting too carried away by it, let’s talk about the treatment of PMDD.

Treating PMDD

There are many effective treatments for PMDD, including psychotherapy and medications such as SSRIs (selective serotonin reuptake inhibitors). SSRIs are currently the most effective medication for treating PMDD, according to Mohamed, Gharib & Dawood (2017), with serotonin being the most commonly used SSRI (Morishita & Kinoshita, 2008). Prescription drugs don’t have to be taken throughout the entire cycle (Hill, 2019), since symptoms only occur during its luteal phase. Symptom relief can often be felt within 1 to 2 days (Hill, 2019) and Halbreich and Kahn (2001) mention a success rate of up to 70% with continuous, as well as intermittent, SSRI treatment.

However, the root cause is not just serotonin deficiency. As Scott Alexander puts it: ‘Playing with puppies makes depressed people feel better, therefore depression is, at root, a puppy deficiency.’ The effects of oestrogen on our mood and behaviour are very complicated, and not yet fully understood by scientists. What we know thus far is that oestrogen has an inhibitory effect, positively contributing to our mental well-being (Halbreich & Kahn, 2001).

Serotonin can be found in our gastrointestinal tract, blood platelets and the central nervous system (Mohamed, Gharib, Dawood, 2017), and as the level of oestrogen drops, so does the level of serotonin (Halbreich & Kahn, 2001). Oestrogen seems to have a strong effect on the serotonin levels in female bodies (Joffe & Cohen, 1998), since it modulates multiple neurotransmitter systems and brain regions including the serotonergic system (Keating, Tolbrook & Kulkarni, 2001).

Treatment with oestrogen has also been shown effective in some research (Keating et al., 2011). Halbreich and Kahn (2001) clarify that patients need to receive a high enough dosage to suppress ovulation, and taken in a cyclic fashion to imitate the menstrual cycle, similar to the use of contraceptives. However, Hill (2019) is quite sceptical about this form of medication, since it can cause significant health issues, such as an increased risk of breast, cervical and liver cancer, and is linked to inflammatory bowel disease. In fact, research in Denmark which sampled 1 million women showed that taking contraceptives led to a higher use of antidepressants (Skovlund et al., 2016).

Keating et al. (2011) propose a combination of oestrogen and SSRIs. In menopausal patients with major depression, oestrogen treatment may improve the response to SSRIs, by reducing the activation of the HPA axis. However, the effect has not been trialled in non-menopausal women yet.

To conclude

It is clear that the menstrual cycle in women has a large effect on their well-being, but the causes are still being researched. It might explain the increase in crime rates from the research in the introduction, and perhaps PMS or PMDD are not sufficient as an explanation, but it does seem to play a major role in the behaviour of these women.

PMS and PMDD are not solely mood issues, and if anyone is experiencing these symptoms, there are effective treatments, such as the (intermittent) use of SSRIs, and the use of contraceptives. Symptoms of PMS and PMDD do not simply have to be accepted as inconvenient. Once the cause is known, it can be a relieve to be able to connect the changes in mood to the nature of the cycle. This doesn’t mean any criminal act will be justified, but it can improve understanding of the symptoms, also for the environment.

Emma Kemp

References

-Alexander, S. (2014). SSRIs: much more than you wanted to know. Slate Star Codex.
https://slatestarcodex.com/2014/07/07/SSRIs-much-more-than-you-wanted-to-know/
-Dalton, K. (1961). Menstruation and Crime. Br Med J, 2, 1752.
https://www-bmj-com.vu-nl.idm.oclc.org/content/2/5269/1752?resolvedby=highwire.org
-Denys, D. (2020). Het tekort van het teveel. De paradox van de mentale zorg. Nijgh & Van Ditmar.
-Gonda X., Telek. T., Lazary, J., Vargha, A. & Bagdy. G (2008). Patterns of mood changes throughout the reproductive cycle in healthy women without premenstrual dysphoric disorders. Prog Neuropsychopharmacol Biol Psychiatry. 32(8). 1782-8.
https://pubmed.ncbi.nlm.nih.gov/18721843/
-Halbreich, U., Kahn, L.S. (2001). Role of estrogen in the ethiology and treatment of mood disorders. CNS Drugs, 15, 797–817. 
https://pubmed.ncbi.nlm.nih.gov/11602005/
-Hill, M. (2019). Period Power. Green Tree.
-Joffe, H. & Cohen, L.S. (1998). Estrogen, serotonin, and mood disturbance: where is the therapeutic bridge? Biological Psychiatry, 44(9), 798-811.
https://www-sciencedirect-com.vu-nl.idm.oclc.org/science/article/pii/S0006322398001693 
-Keating, C., Tilbrook, A. & Kulkarni, J. (2001). Oestrogen: an overlooked mediator in the neuropsychopharmacology of treatment response? International Journal of Neuropsychopharmacology, 14, 553–566.
https://academic.oup.com/ijnp/article/14/4/553/729861
-LaBarbera, A.R. (2010). Reproductive and Endocrine Toxicology. Comprehensive Toxicology, 11. 347-366.
https://www.sciencedirect.com/science/article/pii/B9780080468846011210
-Mohamed, M.K., Gharib, M.N. & Dawood, A.S. (2018). The Effects of Sertraline on Premenstrual Tension Syndrome. J.Obstetrics Gynecology and Reproductive Sciences, 10.
https://www.jbcrs.org/articles/the-effects-of-sertraline-on-premenstrual-tension-syndrome-4082.html 
-Morishita, S. & Kinoshita, T. (2008). Predictors of response to sertraline in patients with major depression. Human Psychopharmacology, 23(8), 647-651.
https://onlinelibrary.wiley.com/doi/abs/10.1002/hup.969
-Romans, S.E., Clarkson, R., Einstein, G., Petrovic, M., Stewart, D. (2012). Mood and the Menstrual Cycle: A Review of Prospective Data Studies. Gender Medicine, 9 (5). 361-384.
https://doi.org/10.1016/j.genm.2012.07.003.
-Romans, S. E., Kreindler, D., Asllani, E., Einstein, G., Laredo, S, Levitt, A., Morgan, K., Petrovic, M., Toner, B., Stewart, D.E. (2013). Mood and the Menstrual Cycle. Psychother Psychosom 82(1). 53-60.
https://www.karger.com/Article/Abstract/339370#
-Seney, M.L. & Sibille, E. (2014). Sex Differences in Mood Disorders: Perspectives from Humans and Rodent Models. Biology of Sex Differences 5(17).
https://bsd.biomedcentral.com/articles/10.1186/s13293-014-0017-3
-Skovlund, C., Mørch, L.S., Kessing, L.V. & Lidegaard, Ø. (2016). Association of Hormonal Contraception With Depression. JAMA Psychiatry, 73(11), 1154-1162.
https://pubmed.ncbi.nlm.nih.gov/27680324/
-Toufexis, D. (2007). Region‐ and Sex‐Specific Modulation of Anxiety Behaviours in the Rat. Journal of Neuroendocrinology, 19(6), 461-473.
https://onlinelibrary-wiley-com.vu-nl.idm.oclc.org/doi/10.1111/j.1365-2826.2007.01552.x
-Vigil, J.M., Strenth, C., Trujillo, T. & Gangestad S.W. (2014). Fluctuating Experimental Pain Sensitivities across the Menstrual Cycle Are Contingent on Women’s Romantic Relationship Status. PLoS ONE 9(3): e91993.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0091993

In a research article from 1961, 386 convicted women were interviewed, and it was shown that 49% of them committed their crime during menstruation or in the days preceding it, whereas only 29% of all crimes would be expected to take place in this period (Dalton, 1961).

How reasonable is the presence of a menstrual cycle to explain this outcome? And do we know what causes large changes in behaviour in those who menstruate? This article takes a closer look at the effect of the menstrual cycle on the mental health of those who menstruate, and possible treatments.

Women vs men

Although we’d like to consider women and men as equal, there does seem to be a difference in gender when it comes to developing mental health disorders. Worldwide, fear and depression are more prevalent in women than in men (4.6% vs 3%) (Denys, 2020). Halbreich & Kahn (2001) mention that women are 1.5 to 3 times more likely to suffer from depression than men. However, two times as many women than men visit a general practitioner for their mental health in the Netherlands, so it is important to keep in mind that women tend to seek help faster than men (Denys, 2020).

Some research has found a clear pattern of mood changes in those who menstruate (Gonda et al., 2008), while others finding a less clear pattern (Romans et al., 2013) or even fail to find one at all (Romans et al., 2012). Seney and Sibille (2014) argue that the way people perceive stress influences the prevalence of depression, with women reporting to feel more stressed than men in stressful situations. Other research shows that even when the physiological response in both men and women is the same, women still feel more irritable and anxious, but also happy, compared to men (Kelly et al., 2008).

Research is still ongoing as to what causes the difference, with studies showing that social environment and culture also play a role in pain sensitivities caused by menstrual cycles (Vigil, 2014). There seems to be strong evidence for the neurobiological mechanisms being responsible (Seney & Sibille, 2014). Both men and women have the same hormones, but the way they interact in male and female bodies are different. According to LaBarbera (2010), the hypothalamic–pituitary unit, which is controlling our gonadal hormone system, changes in sensitivity to the positive and negative feedback effects of the hormones oestrogen and progesterone. This makes the female hormonal rhythm cyclic. Oestrogen and progesterone are two of these gonadal hormones. They are essential for reproduction and have large control over our emotional states. It is mostly oestrogen that is thought to contribute to the increased occurrence of psychiatric illness in those who menstruate (Toufexis, 2007).

PMS and PMDD

Those who have a menstrual cycle can be dealing with some intense hormonal fluctuations during their lives. PMS (Premenstrual Syndrome) is attributed to a fluctuation in hormones, starting in the luteal phase of the menstrual cycle, right after ovulation. The chapter on the luteal phase (see graph 1) in Maisie Hill’s book Period Power is called Highway to Hell, and with good reason. Symptoms can be mood swings, feelings of worthlessness, irritability, lack of concentration, increased tiredness, and physical symptoms like headaches, breast swelling and bloating. PMDD (Premenstrual Dysphoric Disorder) is a severe form of PMS, with symptoms occurring in the week before menstruating and disappearing soon after (Hill, 2019).

According to Hill, 90% of menstruators suffer from PMS, while 3 to 8 percent of menstruators suffer from PMDD. A change in mood is caused by the fluctuation of hormones in the luteal phase of the menstrual cycle: progesterone goes up while oestrogen drops (see graph 1; Hill, 2019). Especially the drop of oestrogen has been associated with depression among women sensitive to these fluctuations (Halbreich & Kahn, 2011).

It is hard to say what ‘sensitive’ means, since the absolute levels of the hormones were on equal levels across women with PMDD who participated in research (Hill, 2019). An important indication to the sensitivity is the absence of symptoms in the follicular phase, and when suppressing ovulation by the use of estradiol, for instance (Halbreich & Kahn, 2011). Hill explains the difference in sensitivity by means of the OSR1 gene: ‘Individuals with PMDD have a variation in their oestrogen receptor alpha gene, which make them more sensitive to the effects of oestrogen and progesterone across the menstrual cycle.’

The function of our hormone system is very complex, so without getting too carried away by it, let’s talk about the treatment of PMDD.

Treating PMDD

There are many effective treatments for PMDD, including psychotherapy and medications such as SSRIs (selective serotonin reuptake inhibitors). SSRIs are currently the most effective medication for treating PMDD, according to Mohamed, Gharib & Dawood (2017), with serotonin being the most commonly used SSRI (Morishita & Kinoshita, 2008). Prescription drugs don’t have to be taken throughout the entire cycle (Hill, 2019), since symptoms only occur during its luteal phase. Symptom relief can often be felt within 1 to 2 days (Hill, 2019) and Halbreich and Kahn (2001) mention a success rate of up to 70% with continuous, as well as intermittent, SSRI treatment.

However, the root cause is not just serotonin deficiency. As Scott Alexander puts it: ‘Playing with puppies makes depressed people feel better, therefore depression is, at root, a puppy deficiency.’ The effects of oestrogen on our mood and behaviour are very complicated, and not yet fully understood by scientists. What we know thus far is that oestrogen has an inhibitory effect, positively contributing to our mental well-being (Halbreich & Kahn, 2001).

Serotonin can be found in our gastrointestinal tract, blood platelets and the central nervous system (Mohamed, Gharib, Dawood, 2017), and as the level of oestrogen drops, so does the level of serotonin (Halbreich & Kahn, 2001). Oestrogen seems to have a strong effect on the serotonin levels in female bodies (Joffe & Cohen, 1998), since it modulates multiple neurotransmitter systems and brain regions including the serotonergic system (Keating, Tolbrook & Kulkarni, 2001).

Treatment with oestrogen has also been shown effective in some research (Keating et al., 2011). Halbreich and Kahn (2001) clarify that patients need to receive a high enough dosage to suppress ovulation, and taken in a cyclic fashion to imitate the menstrual cycle, similar to the use of contraceptives. However, Hill (2019) is quite sceptical about this form of medication, since it can cause significant health issues, such as an increased risk of breast, cervical and liver cancer, and is linked to inflammatory bowel disease. In fact, research in Denmark which sampled 1 million women showed that taking contraceptives led to a higher use of antidepressants (Skovlund et al., 2016).

Keating et al. (2011) propose a combination of oestrogen and SSRIs. In menopausal patients with major depression, oestrogen treatment may improve the response to SSRIs, by reducing the activation of the HPA axis. However, the effect has not been trialled in non-menopausal women yet.

To conclude

It is clear that the menstrual cycle in women has a large effect on their well-being, but the causes are still being researched. It might explain the increase in crime rates from the research in the introduction, and perhaps PMS or PMDD are not sufficient as an explanation, but it does seem to play a major role in the behaviour of these women.

PMS and PMDD are not solely mood issues, and if anyone is experiencing these symptoms, there are effective treatments, such as the (intermittent) use of SSRIs, and the use of contraceptives. Symptoms of PMS and PMDD do not simply have to be accepted as inconvenient. Once the cause is known, it can be a relieve to be able to connect the changes in mood to the nature of the cycle. This doesn’t mean any criminal act will be justified, but it can improve understanding of the symptoms, also for the environment.

Emma Kemp

References

-Alexander, S. (2014). SSRIs: much more than you wanted to know. Slate Star Codex.
https://slatestarcodex.com/2014/07/07/SSRIs-much-more-than-you-wanted-to-know/
-Dalton, K. (1961). Menstruation and Crime. Br Med J, 2, 1752.
https://www-bmj-com.vu-nl.idm.oclc.org/content/2/5269/1752?resolvedby=highwire.org
-Denys, D. (2020). Het tekort van het teveel. De paradox van de mentale zorg. Nijgh & Van Ditmar.
-Gonda X., Telek. T., Lazary, J., Vargha, A. & Bagdy. G (2008). Patterns of mood changes throughout the reproductive cycle in healthy women without premenstrual dysphoric disorders. Prog Neuropsychopharmacol Biol Psychiatry. 32(8). 1782-8.
https://pubmed.ncbi.nlm.nih.gov/18721843/
-Halbreich, U., Kahn, L.S. (2001). Role of estrogen in the ethiology and treatment of mood disorders. CNS Drugs, 15, 797–817. 
https://pubmed.ncbi.nlm.nih.gov/11602005/
-Hill, M. (2019). Period Power. Green Tree.
-Joffe, H. & Cohen, L.S. (1998). Estrogen, serotonin, and mood disturbance: where is the therapeutic bridge? Biological Psychiatry, 44(9), 798-811.
https://www-sciencedirect-com.vu-nl.idm.oclc.org/science/article/pii/S0006322398001693 
-Keating, C., Tilbrook, A. & Kulkarni, J. (2001). Oestrogen: an overlooked mediator in the neuropsychopharmacology of treatment response? International Journal of Neuropsychopharmacology, 14, 553–566.
https://academic.oup.com/ijnp/article/14/4/553/729861
-LaBarbera, A.R. (2010). Reproductive and Endocrine Toxicology. Comprehensive Toxicology, 11. 347-366.
https://www.sciencedirect.com/science/article/pii/B9780080468846011210
-Mohamed, M.K., Gharib, M.N. & Dawood, A.S. (2018). The Effects of Sertraline on Premenstrual Tension Syndrome. J.Obstetrics Gynecology and Reproductive Sciences, 10.
https://www.jbcrs.org/articles/the-effects-of-sertraline-on-premenstrual-tension-syndrome-4082.html 
-Morishita, S. & Kinoshita, T. (2008). Predictors of response to sertraline in patients with major depression. Human Psychopharmacology, 23(8), 647-651.
https://onlinelibrary.wiley.com/doi/abs/10.1002/hup.969
-Romans, S.E., Clarkson, R., Einstein, G., Petrovic, M., Stewart, D. (2012). Mood and the Menstrual Cycle: A Review of Prospective Data Studies. Gender Medicine, 9 (5). 361-384.
https://doi.org/10.1016/j.genm.2012.07.003.
-Romans, S. E., Kreindler, D., Asllani, E., Einstein, G., Laredo, S, Levitt, A., Morgan, K., Petrovic, M., Toner, B., Stewart, D.E. (2013). Mood and the Menstrual Cycle. Psychother Psychosom 82(1). 53-60.
https://www.karger.com/Article/Abstract/339370#
-Seney, M.L. & Sibille, E. (2014). Sex Differences in Mood Disorders: Perspectives from Humans and Rodent Models. Biology of Sex Differences 5(17).
https://bsd.biomedcentral.com/articles/10.1186/s13293-014-0017-3
-Skovlund, C., Mørch, L.S., Kessing, L.V. & Lidegaard, Ø. (2016). Association of Hormonal Contraception With Depression. JAMA Psychiatry, 73(11), 1154-1162.
https://pubmed.ncbi.nlm.nih.gov/27680324/
-Toufexis, D. (2007). Region‐ and Sex‐Specific Modulation of Anxiety Behaviours in the Rat. Journal of Neuroendocrinology, 19(6), 461-473.
https://onlinelibrary-wiley-com.vu-nl.idm.oclc.org/doi/10.1111/j.1365-2826.2007.01552.x
-Vigil, J.M., Strenth, C., Trujillo, T. & Gangestad S.W. (2014). Fluctuating Experimental Pain Sensitivities across the Menstrual Cycle Are Contingent on Women’s Romantic Relationship Status. PLoS ONE 9(3): e91993.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0091993
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