Gender differences in ADHD
ADHD is diagnosed in children significantly more often in boys than in girls. This difference levels out in adults.
While boys are 5 to 9 times more likely to be diagnosed with ADHD outside of clinics than girls, only 3 times as many boys are diagnosed as girls in inpatient clinical settings (probably due to the more detailed examination there).
In adults, the ADHD ratio is then balanced 1:1 in all environments.1
Whether the likelihood of occurrence of individual symptoms is gender-specific, such that females are more likely to develop the ADHD-I subtype and males are more likely to develop the ADHD-HI subtype, is now questioned. One study found that boys and girls do not differ in symptomatology of inattention and hyperactivity.4 Moreover, even in adults, the distribution of symptoms appears to be independent of gender.5
- 1. Estrogen reduces dopamine degradation in the PFC
- 2. Estrogen increases oxytocin levels
- 3. COMT gene variant influences stress perception in a gender-specific manner
- 4. Thyroid hormones in women as a masking factor of ADHD?
- 5. Creatine, choline, glutamate/glutamine in anterior cingulate and cerebellum
- 6. Anxiety symptoms more common in girls with ADHD than in boys
- 7. Temporal symptom development by gender
- 8. Higher symptom intensity in diagnosed girls and women?
- 9. Higher divorce rate of women with ADHD
- 10. More comorbidities in women with ADHD
- 11. No gender differences in ADHD and ASD social behavior
1. Estrogen reduces dopamine degradation in the PFC
The increased dopamine depletion in the PFC due to estrogen causes (mild) stress to have sex-specific differential effects.
Estrogen levels in women are low after menstruation (day 1-9), then rise steadily to their maximum by ovulation (day 10 - 15), fall to 1/3 of maximum with ovulation (day 16 / 17), then rise to 2/3 of maximum by day 24, and then fall by menstrual bleeding (day 27).6
In male humans and animals, the slight increase in dopamine levels in the PFC due to mild stress increases mental performance compared with the resting state. In female humans and animals, on the other hand, the slight increase in dopamine in the PFC due to mild stress (on the overall average) leads to impaired mental performance. This difference is apparently caused by estrogen. The deterioration of mental performance by mild stress occurs only in the estrogen-rich phase around menstruation. In the estrogen-depleted phase, mild stress raises mental performance in women just as it does in men.78910111213
Estrogen reduces the activity of the dopamine-degrading enzyme COMT.141516 Dopamine degradation in the PFC is therefore significantly increased before ovulation and noticeably reduced before menstruation.
COMT is therefore 30% less active in women than in men.1718
Because COMT causes at least 60% of dopamine breakdown in the PFC (and a maximum of 15% of dopamine breakdown in the striatum,19 women in the estrogen-rich menstrual phase have nearly 20% less dopamine breakdown in the PFC.
It could follow that, with respect to PFC-mediated ADHD symptoms such as inattention, women require lower doses of drugs (such as stimulants or atomoxetine) that act in the PFC dopaminergically during periods of high estrogen levels (3-4 days before ovulation as well as approximately one week after ovulation) than during periods of low estrogen levels.7
This could further explain increased sensitivity in women compared to men, as slightly elevated dopamine levels increase perceptual intensity.
Since the COMT Met-158-Met variant is also common in borderline, causing five times slower dopamine degradation in the PFC, and estrogen further slows COMT dopamine degradation by COMT, this association could potentially provide a clue to explain the clustering of borderline in women.20
2. Estrogen increases oxytocin levels
Since estrogen increases oxytocin levels, all effects of oxytocin are likely to be enhanced in women.
- Decreases ACTH
- Probably reduces CRH
- Likely reduces stress symptoms mediated by the HPA axis
- Increases the “tend and befriend” stress response
More on this at ⇒ Oxytocin
3. COMT gene variant influences stress perception in a gender-specific manner
COMT is controlled by the COMT gene. COMT polymorphisms therefore primarily affect dopamine levels in the PFC and hardly affect DA levels in other brain regions. Similarly, norepinephrine levels in the PFC are not affected by COMT.23
To be distinguished are:24
- COMT-Val-158-Met (mixed Val/Met)
- COMT-Val-158-Val (homozygous Val)
- COMT-Met-158-Met (homozygous Met)
The COMT-Val-158-Val polymorphism causes dopamine degradation 4 times faster than the COMT-Met-158-Met variant.
COMT-Met-158-Met carriers are compared to COMT-Val-158-Val carriers25
- Mentally more powerful (more efficient, not more intelligent)
- Better executive functions of the PFC
- More sensitive to stress (high dopamine levels (only) in the PFC already at rest, significant dopamine increase (only) in the PFC already at mild stress)26
- Consequently, probably worse effect of amphetamine drugs (deterioration of working memory by AMP at high stress)27. We suspect that the result is likely to be transferable to MPH.
- More anxious and
- More sensitive to pain.
In females, the COMT-Val-158-Val polymorphism leads to better executive function and mental performance than that of the COMT-Met-158-Met polymorphism during periods of high estrogen levels.28
4. Thyroid hormones in women as a masking factor of ADHD?
The updated 2018 European Consensus on the Treatment and Diagnosis of ADHD in Adults1 notes the special role of thyroid hormones in the etiology of ADHD in women and girls.
Healthy 4-year-old children with thyroid-stimulating hormone levels in the upper normal range have a higher risk of ADHD than children with low free thyroxine levels. Thyroid disorders are more common in females than in males. Since ADHD further has a possible association with thyroid hormone receptor insensitivity, a role of thyroid hormones in the development and manifestation of ADHD in women and girls should be further investigated.29
5. Creatine, choline, glutamate/glutamine in anterior cingulate and cerebellum
One study found significant sex- and age-specific differences in creatine, choline, and glutamate/glutamine in the anterior cingulate and significant age-specific differences in choline and glutamate/glutamine in the cerebellum.30
6. Anxiety symptoms more common in girls with ADHD than in boys
ADHD-affected girls are far more likely to have anxiety symptoms than ADHD-affected boys.31
7. Temporal symptom development by gender
While girls typically develop a large spurt of increased symptoms in early adolescence, boys have increased symptom expression from childhood onward. For both sexes, early adolescence is associated with the risk of significant symptom increase.32
8. Higher symptom intensity in diagnosed girls and women?
Girls with autism who also had ADHD showed significantly more severe symptoms of ADHD, learning disabilities, and ODD than boys with ASD and ADHD in a large study.33
This is reminiscent of the increased symptom intensity of women diagnosed with ADHD as adults.
9. Higher divorce rate of women with ADHD
Women (in Japan) with ADHD appear to have even higher divorce rates than men with ADHD.34
10. More comorbidities in women with ADHD
Females (in Japan) with ADHD appear to have a higher rate of comorbidity than males with ADHD.34
11. No gender differences in ADHD and ASD social behavior
A meta-study failed to find gender differences in social behavior and communication behaviors in ADHD and ASD.35
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Slobodin, Davidovitch (2019): Gender Differences in Objective and Subjective Measures of ADHD Among Clinic-Referred Children. Front Hum Neurosci. 2019 Dec 13;13:441. doi: 10.3389/fnhum.2019.00441. eCollection 2019. ↥
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Wood, Beylin, Shors (2001): The contribution of adrenal and reproductive hormones to the opposing effects of stress on trace conditioning in males versus females. Behav Neurosci. 2001 Feb;115(1):175-87. ↥
Shansky, Glavis-Bloom, Lerman, McRae, Benson, Miller, Cosand, Horvath, Arnsten (2004): Estrogen mediates sex differences in stress-induced prefrontal cortex dysfunction. Mol Psychiatry. 2004 May;9(5):531-8. ↥
Wood, Shors (1998): Stress facilitates classical conditioning in males, but impairs classical conditioning in females through activational effects of ovarian hormones; Proc Natl Acad Sci U S A. 1998 Mar 31; 95(7): 4066–4071. PMCID: PMC19964 ↥
Ho, P., Garner, Ho, J., Leung, Chu, Kwok, Kung, Burka, Ramsden, Ho, S. (2008): Estrogenic Phenol and Catechol Metabolites of PCBs Modulate Catechol-Omethyltransferase Expression Via the Estrogen Receptor: Potential Contribution to Cancer Risk; Current Drug Metabolism, Volume 9, Number 4, May 2008, pp. 304-309(6); DOI: https://doi.org/10.2174/138920008784220600 ↥
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Chen, Lipska, Halim, Ma, Matsumoto, Melhem, Kolachana, Hyde, Herman, Apud, Egan, Kleinman, Weinberger (2004): Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet. 2004 Nov;75(5):807-21. ↥
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Klein, Corwin (2002): Seeing the unexpected: how sex differences in stress responses may provide a new perspective on the manifestation of psychiatric disorders. Curr Psychiatry Rep. 2002 Dec;4(6):441-8. ↥
Papaleo, Crawley, Song, Lipska, Pickel, Weinberger, Chen (2008): Genetic dissection of the role of catechol-O-methyltransferase in cognition and stress reactivity in mice. J Neurosci. 2008 Aug 27;28(35):8709-23. doi: 10.1523/JNEUROSCI.2077-08.2008. ↥
Nackley, Shabalina, Tchivileva, Satterfield, Korchynskyi, Makarov, Maixner, Diatchenko (2006): Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure. Science. 2006 Dec 22;314(5807):1930-3. ↥
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Egan, Goldberg, Kolachana, Callicott, Mazzanti, Straub, Goldman, Weinberger (20019): Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6917-22. ↥
Mattay, Goldberg, Fera, Hariri, Tessitore, Egan, Kolachana, Callicott, Weinberger (2003): Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci U S A. 2003 May 13;100(10):6186-91. ↥
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Mahendiran, Brian, Dupuis, Muhe, Wong, Iaboni, Anagnostou (2019): Meta-Analysis of Sex Differences in Social and Communication Function in Children With Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder. Front Psychiatry. 2019 Nov 4;10:804. doi: 10.3389/fpsyt.2019.00804. eCollection 2019. ↥