Sex differences in ADHD

ADHD is diagnosed 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 (likely due to the more detailed screening there).
In adults, the ADHD ratio is then balanced 1:1 in all environments.¹

One large study found a sex ratio of 1.6 : 1 (boys to girls) in children with ADHD.² While impulsivity was more common in boys and inattention in girls, hyperactivity was equally common.³

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. Sex hormones as drivers of gender-specific mental disorders
  • 1.1. Genetic sex, gonadal sex, hormonal sex
  • 1.2. Sex-specific differentiation of neural circuitry and behavior
    • 1.2.1. Theories
      • 1.2.1.1. Classical theory
      • 1.2.1.2. Active feminization
      • 1.2.1.3. Gradient model
    • 1.2.2. Sex hormones and dopamine
    • 1.2.3. Sex hormones and sexually dimorphic brain structures, brain functions and behavior
• 2. Theories about hormonal mechanisms of depression
  • 2.1. Probability of depression increases in girls with puberty
  • 2.2. Likelihood of depression and hormonal fluctuations in the menstrual cycle
  • 2.3. Depression likelihood and hormonal fluctuations after childbirth/at menopause
  • 2.4. Estrogen appears to affect transcription and activity of serotonin genes
  • 2.5. Estrogens influence HPA activity
    • 2.5.1. Estradiol influences HPA stress response
    • 2.5.2. Progesterone enhances HPA stress response
• 3. Hormonal mechanisms of ADHD development and modulation
  • 3.1. Sex hormones indirectly modulate development of dopaminergic circuits
  • 3.2. Sex hormones directly modulate development of dopaminergic circuits
  • 3.3. ADHD and externalizing symptoms correlate positively with prenatal testosterone exposure
  • 3.4. ADHD and decreased prenatal/postnatal estrogen
    • 3.4.1. Estrogen reduces dopamine degradation in the PFC
    • 3.4.2. Estrogen increases oxytocin levels
• 4. COMT gene variant influences stress perception in a gender-specific manner
• 5. Thyroid hormones in women as a masking factor of ADHD?
• 6. Creatine, choline, glutamate/glutamine in ACC and cerebellum
• 7. Anxiety symptoms more common in girls with ADHD than in boys
• 8. Temporal symptom development by gender
• 9. Higher symptom intensity in diagnosed girls and women?
• 10. Higher divorce rate among women with ADHD
• 11. More comorbidities in women with ADHD
• 12. No gender differences in ADHD and ASD social behavior

1. Sex hormones as drivers of gender-specific mental disorders¶

Sex hormones (gonadal hormones, sex hormones, gonadal hormones) are:

• Androgens (C19 steroid hormones), including:
  • Testosterone
  • Androstenedione (biochemically reduced testosterone)
  • 5α- and 5β-dihyrotestosterone (DHT)
  • Dehydroepiandrosterone (DHEA).
• Estrogens (C18 steroid hormones)
  Estrogens, like progestins, are female sex hormones. Estrogens are C-18 steroid hormones. They are synthesized in a cycle-dependent manner in the cells of the ovarian follicle.
  There are four natural estrogens:
  • Estradiol (17β-estradiol, estradiol; most bioactive estrogen)
  • Estrone (3/10 of the bioactivity of estradiol)
  • Estriol (1/10 of the bioactivity of estradiol)
  • Östetrol

Oral intake of natural estrogens is ineffective due to inactivation in the liver. Synthetic estrogens are therefore used as drugs and are primarily used to inhibit ovulation in hormonal contraception.

In addition, other hormones may also have a psychopathological influence (e.g., progestins (pregnancy hormones)).

Males are more prone to (externalizing) behavioral disorders in childhood (ADHD, ODD, CD, autism, learning disorders), whereas females are more prone to emotional (internalizing) disorders in adolescence (depression, anxiety disorders, dysthymia, eating disorders, PTSD). This could also be due to sex hormones.⁶⁷⁸⁹

In 2013, Martel et al discussed the contribution of sex hormones to this in more depth¹⁰
The following discussion is largely based on the work of Martel et al.

• Testosterone might prenatally (“organizationally”) modulate dopaminergic circuits in the striatum, putting boys at greater risk for early development of inattention and disruptive behavior disorders.
  • An “extreme male brain” theory of autism views autism symptoms as exaggerations of typical sex differences and sees exposure to high prenatal testosterone levels as a risk factor for autism¹¹
  • Testosterone appears to reduce pain responses in men⁶
  • Androstenedione correlated with behavioral problems only in boys¹²
  • Testosterone-estradiol-binding globulin correlated negatively with sad affect and acting out behavior.¹²
• Estradiol might modulate circuits in puberty (“activating”), including in the amygdala (especially affecting serotonergic signaling pathways), such that girls are at higher risk for internalizing and affective disorders
  • In eating disorders, lower prenatal testosterone is considered a risk factor¹³¹⁴ , while rising estradiol levels during and after puberty reduce risk¹⁵¹⁶

Sex hormones have an important role in the organization and plasticity of the brain and behavioral systems.¹⁷¹⁸

• “Organizational” effects
  • Exposure to androgens
    • Androgens
    • Between pregnancy and 4 months of life
    • permanent masculinizing effects on nervous system and behavior
  • “Activating” effect
    • Predominantly estrogens
    • During adolescence
      • Puberty as a phenotypic activating event
        • Testosterone level increases during puberty¹²
          • For men by a factor of 18
          • For women by 8 times
        • Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) stimulate the production of androgens, estrogen and progesterone¹⁹
        • Estradiol and testosterone can regulate gene expression and neurotransmission , e.g. GABA²⁰ and Serotonin²¹
        • Estradiol affects in puberty²²
          • Orbital cortex
          • MPFC
          • Amygdala²³
          • Hippocampus²³
        • Estradiol interacts with the HPA axis²⁴
        • Estradiol enhances stress response in the PFC in a sex-specific manner by means of serotonin, norepinephrine, and dopamine levels²⁴
        • Estrogen might interact with the HPA axis
          • Increase in stress sensitivity of the HPA axis
          • Modulation of the HPA axis during puberty
            • Altered HPA activity may increase stress sensitivity and thereby susceptibility to depression²⁴
          • Estrogen is a strong regulator of several serotonergic systems (e.g., the 5HT2a receptor)²⁵²⁶
          • Rapidly changing estrogen levels during puberty can directly affect transcription of serotonin genes. Consequence:
            • Abnormalities in the amygdala
            • Low serotonin levels
    • Transient effect on neuronal structure and behavior
    • Alteration and activation of previously organized neural circuits
    • Possibly also some organizational effects⁹

1.1. Genetic sex, gonadal sex, hormonal sex¶

Genetic sex leads to gonadal sex, which in turn is linked to hormonal sex.¹⁰
The genetic (i.e. chromosomal) sex is determined at conception. Subsequently, a gene on the Y chromosome causes the gonads to develop into testes. The testes release several androgenic steroid hormones (e.g., testosterone) that masculinize the body and brain during pregnancy development.
Ovaries release little or no hormone prenatally. The relative absence of androgens causes the development of a female body and brain .
Hormonal sex is the circulating estrogen to androgen ratio, which is higher in most females than in males. Sexual differentiation (this refers to the development of humans (and animals) into males and females) is closely linked to the organizational effects of sex hormones.

1.2. Sex-specific differentiation of neural circuitry and behavior¶

1.2.1. Theories¶

The following 3 theories are not mutually exclusive ²⁷¹⁰

1.2.1.1. Classical theory¶

• Androgens cause male development
• lack of androgens causes female development
• high testosterone levels (men) cause
  • “Upstream” effects
    • Increased cell proliferation
    • increased cell death in the right hemisphere of the brain
    • Slower prenatal development / slower brain development
      • thereby altered cerebral lateralization²⁸
      • possible consequences in men:
        • more susceptible to environmental stresses
        • more variable behavioral results¹⁷
        • increased risk for learning disorders
        • increased risk for hyperactivity
        • prone to injury and structural abnormalities in the left hemisphere for prolonged periods of time
    • increased neuronal lateralization (= specialization of the brain hemispheres)
      • Consequence, among others: after a focal stroke, women regain speech more frequently than men²⁹
    • Modulation of neurotransmission
    • Interaction with the genotype
  • “Downstream” effects
    • Influence on the selection of the environmental niche
    • Influence on the triggering of environmental reactions

1.2.1.2. Active feminization¶

Ovarian hormones actively promote feminization of neural circuitry and behavior

1.2.1.3. Gradient model¶

Influence hormones:

• Behavioral differences between the sexes (e.g., in cognition, childhood play, and aggression)
• Behavioral variations within the sexes
  • Females prenatally exposed to higher levels of androgens might exhibit more masculine characteristics (e.g., increased spatial abilities)

1.2.2. Sex hormones and dopamine¶

Pregnant rats placed under constraint stress had male offspring with decreased testosterone levels and with increased dopamine levels in the striatum.³⁰ Further, testosterone levels may indirectly influence neuronal development through so-called “downstream” effects: via the organism’s selection of experiential niches and the triggering of environmental responses¹⁷

1.2.3. Sex hormones and sexually dimorphic brain structures, brain functions and behavior¶

Sex hormones influence the formation of brain structures and brain functions. This in turn influences behavior¹⁰

Larger for men:³¹

• Total brain volume
• White substance
• CSF
• Cerebellum
• Pons
• Amygdala
  • medial amygdala nucleus¹⁰
• Hypothalamus
• Frontomedial cortex
• Corpus callosum (unclear)³²

Larger for women:³¹

• Gray substance
  • in posterior, temporal and inferior parietal brain regions
    • greater proportion
    • greater cortical thickness
• Hippocampus
• Frontoorbital cortex
• Superior frontal and lingual gyrus
• front commissure¹⁰
• Caudate (unclear)
• Corpus callosum (unclear)

Other differences:

• lower lateralization (i.e., specialization) of cortical functions in females
  • lower prevalence of left-handedness
• greater variation in extracellular striatal dopamine across the estrous cycle in women³³
• Estrogen and progesterone modulate dopamine in striatum and nucleus accumbens only in women³⁴
• significantly higher juvenile increases in dopamine receptor density in the striatum, nucleus accumbens, and prefrontal cortex in male rats (Andersen & Teicher, 2000).
• global cerebral blood flow is higher in women³¹
• Serotonin whole blood level is higher in women³¹
• Men synthesize serotonin faster³¹
• higher availability of dopamine transporters in women³¹
• higher presynaptic dopamine synthesis in the striatum in women³¹
• IQ correlates with gray matter volume³⁵
  • in men in the frontal and parietal lobes
  • in women in the frontal lobe and Broca’s area

2. Theories about hormonal mechanisms of depression¶

2.1. Probability of depression increases in girls with puberty¶

Girls were twice as likely to be depressed as boys only from the age of 10 to 15 years. This 2:1 ratio was caused by altered estradiol and testosterone levels, but not by FSH and LH, was independent of Tanner stage, and persisted at later ages.³⁶³⁷
Higher levels of negative affect correlated with higher testosterone levels, higher cortisol, and lower adrenal hormones, but not with altered estradiol levels.³⁸

2.2. Likelihood of depression and hormonal fluctuations in the menstrual cycle¶

Estradiol and progesterone levels are relatively low during menstrual bleeding. Estradiol levels increase during the follicular phase until the LH surge, at which time ovulation occurs. After ovulation, estradiol levels decrease while progesterone levels steadily increase. In the middle of the luteal phase, estradiol levels reach a second peak, but then both progesterone and estradiol decline throughout the premenstrual phase. At this time, menstrual bleeding begins and completes the cycle.³⁹

Symptoms of depressed mood vary systematically across fluctuations in the menstrual cycle. In women, the likelihood of mood problems (i.e., depressed mood, apathy) is greatest during the mid-to-late luteal phase of the menstrual cycle. During this period, progesterone levels peak while estradiol levels decline. Negative affect is also cycle-dependent, occurring most strongly before or during the menstrual phase and less so during ovulatory or premenstrual phases¹⁰

Oral contraceptives altered the variability of mood over the course of the day. Triphasic preparations (oral contraceptives with three hormonal phases) caused increased affect variability.⁴⁰ Depressed mood typically occurs during the premenstrual period when estradiol and progesterone decrease.⁴¹
In PMS, suppression of ovarian function with leuprolide improved symptoms. However, in a subset, these recurred after replacement with estradiol or progesterone, suggesting an abnormal response to hormonal changes as a cause of PMS mood problems.⁴² Indeed, women with premenstrual dysphoric mood showed an abnormal gonadotropin response to estradiol loading compared with other women:⁴³

• stronger negative feedback response to the nadir LH level
• higher LH levels at the nadir
• more LH surge-like reactions
• 50 % higher LH-AUC
• LH response was associated with VAS-rated symptoms
• the negative increment (AOC) correlated with bloating in the luteal phase
• AUC of LH correlated with irritability
• Depressed mood correlated with
  • FSH base mirrors
  • AUC of FSH during the negative feedback phase

2.3. Depression likelihood and hormonal fluctuations after childbirth/at menopause¶

15% of women develop depression symptoms in the first six months postpartum, when sex hormones decline rapidly and dramatically.¹⁰ A sharp decline in estradiol and progesterone after childbirth correlated with depression in women with a history of postpartum depression⁴⁴

The onset of menopause is associated with a decrease in estrogen levels and a 2-fold to 4.3-fold risk of irritability and depression,^{4546 47} while postmenopausal depression risk is decreased.
The risk of depression in women was⁴⁸⁴⁹

• increased 2.5-fold during menopause
• reduced after menopause
• with a rapidly increasing profile of FSH reduces
• with high level and increased variability of FSH increased
• with high level and increased variability of LH increased
• increased with rising estradiol levels and increased variability of estradiol increased

Estrogen administration during menopause significantly reduced depressed mood.³⁹⁵⁰
Low estrogen levels or dramatic changes in estrogen levels appear to increase depression risk.

Whether estradiol administration after childbirth / during perimenopause / during menopause correlates with a decrease in depression is inconsistent. There are quite a few studies for and against this.¹⁰
Estradiol administration may accelerate effect of antidepressants in menopausal nonresponders.⁵¹
Withdrawal of estradiol in rats exposed to high levels of estradiol and progesterone (to mimic levels during pregnancy) resulted in increased depressive symptoms.⁵² Estradiol administration increased mobility in rats, suggesting an antidepressant effect of estradiol administration.⁵³⁵⁴
It is possible that an inverted-U curve is at work here as well: optimal estradiol levels are protective, decreased as well as increased estradiol levels exacerbate depressive symptoms.
To examine the relationships between estradiol levels and affect over a 30- or 60-day period, daily measurements throughout the menstrual cycle are required.¹⁰

2.4. Estrogen appears to affect transcription and activity of serotonin genes¶

Estrogen modulates the central neurotransmitter systems involved in depression, particularly that of serotonin ^{55 46 5657}

2.5. Estrogens influence HPA activity¶

2.5.1. Estradiol influences HPA stress response¶

Estrogens, particularly estradiol, appear to enhance the stress response (i.e., release of catecholamines) in the PFC.⁵⁸ Estradiol does not appear to have antidepressant effects under stress conditions.⁵⁹

Estrogen lowers the threshold for prefrontal cortical dysfunction resulting from stressful experiences.⁵⁸
Estrogen, particularly estradiol, thus increases depression risk by altering thresholds for prefrontal activation in response to stress.

According to another view, estradiol should have moderating effects on depression via interaction with stressful life events and HPA axis. Estradiol moderates the function of the limbic-OPFC circuit and the HPA axis, which reduces the risk of depression.⁶⁰ Estrogen significantly decreased the stress response of the HPA axis in postmenopausal women. Responses to ACTH, cortisol, and norepinephrine were attenuated.⁶¹

The antidepressant effects of estradiol may also depend on optimal corticoid levels, suggesting an interaction between estradiol effects and HPA axis tone⁶²

2.5.2. Progesterone enhances HPA stress response¶

The progestin progesterone appears to enhance the stress response of the HPA axis in postmenopausal women. Responses to ACTH and cortisol were attenuated, and responses to norepinephrine were increased.⁶¹ Women with PMS did not show the normal increased HPA axis response to exercise during the luteal phase. Progesterone produced an increased HPA axis response to treadmill exercise testing in healthy controls. Estradiol did not cause an increased HPA response.⁶³

3. Hormonal mechanisms of ADHD development and modulation¶

3.1. Sex hormones indirectly modulate development of dopaminergic circuits¶

Sex hormones may modulate the processes that control the development of dopaminergic circuits and influence corresponding deficits in cognitive control and reward processes in ADHD.

High testosterone levels may affect dopaminergic neuronal circuits by slowing overall neuronal development and rendering brain dopaminergic components vulnerable for a prolonged period during prenatal development. Thus, prenatal testosterone levels could moderate the relationship between prenatal risk factors (including genes, pollutants, low birth weight, maternal smoking) and developing ADHD-related neurobiology.¹⁷

Polycystic ovary syndrome (PCOS) is associated with hyperandrogenemia, i.e. greatly increased androgen levels. PCOS in pregnancy increases the risk of ADHD by 95% in boys only.^64
65
Women with PCOS were themselves at increased risk of ADHD, although no association was found between their testosterone levels and their ADHD symptoms⁶⁶
See more at Prenatal stressors as ADHD environmental causes In the chapter Emergence,

Maternal smoking increases fetal testosterone levels.⁶⁷ Prenatal smoking causes a 1.9-fold⁶⁸ to 2.7-fold ADHD risk⁶⁹ for the offspring. Other studies also found significantly increased risk scores.^70717273
See more at Prenatal stressors as ADHD environmental causes In the chapter Emergence,

3.2. Sex hormones directly modulate development of dopaminergic circuits¶

Masculinizing effects of sex hormones directly affect prenatal development of dopaminergic neuronal circuits and dopamine function in

• Nucleus accumbens
• Striatum
• PFC

thereby causing deficits in cognitive control and reward processes.
Androgen effects act on the striatum, including caudate nucleus and associated dopamine circuits.³⁰

Animal studies based on prenatal hormone manipulation in relation to ADHD are not known so far. There are only experiments with early childhood hormone manipulation. The transferability of the ADHD animal model of SHR with respect to sex differences in ADHD is questionable because the animals do not show the sex differences in behavioral symptoms that are known in humans. Female SHR appear more impulsive than males, especially during diestrus.⁷⁴
SHR (spontaneously hypertensive rat) and Wistar (WKY) control animals were exposed to testosterone during early development (postnatal day 10). At postnatal day 45, SHR animals showed:⁷⁵

• additional deficits in spatial memory in the water maze (but not WKY)
• Evidence of a dysfunctional HPA axis:
  • high basal ACTH levels
  • low corticosterone levels
• Suppression of tyrosine hydroxylase immunoreactivity in frontal cortex
  The authors see this as support for the hypothesis that in cases of genetic ADHD predisposition, early androgen exposure may contribute to increased expression of ADHD symptoms.

High testosterone levels may increase the risk for ADHD symptoms through a maturational delay in the development of dopaminergic innervation and metabolism, as well as through increased lateralization of underlying dopaminergic neuronal circuits and increased reuptake of dopamine neurotransmission.⁷⁶
Pavlovian conditioning of a visual stimulus paired with food was:⁷⁷

• weaker in female SHR than in male SHR
• Wistar rats equal in both sexes
  Gonadectomy altered Pavlovian conditioning:⁷⁸
• in male and female SHR: enhanced conditioning
• for female Wistar rats: unchanged
• in male Wistar rats: reduced conditioning

SHR showed increased motor activity with early androgen administration. In contrast, Wistar showed no change.⁷⁹

In male castrated SHR, testosterone increased the density of tyrosine hydroxylase immunoreactive fibers (an indicator of innervation by catecholamines) in the frontal cortex more than in WKY. The authors see this as a possible explanation for the fact that high testosterone levels in adulthood do not increase ADHD symptoms in either SHR or males .⁸⁰

These results suggest that dopaminergic neuronal circuitry and cognition are hormonally affected in SHR¹⁰
This also seems to affect ADHD symptoms.

In contrast, girls and boys with ADHD showed equally weak cognitive control.⁸¹⁸²⁸³ Boys with ADHD-I showed lower cognitive impairment than boys with ADHD-C and girls with ADHD-I or ADHD-C.⁸⁴
To date, however, studies have always examined sex as a proxy, without examining the direct effect of hormones themselves on cognitive control and reinforcement learning.

3.3. ADHD and externalizing symptoms correlate positively with prenatal testosterone exposure¶

Overall, the research findings on finger length ratios suggest that prenatal testosterone exposure is positively associated with ADHD symptoms and possibly also with related traits such as externalizing problems and sensation seeking. However, contrary to the conclusion of Martel et al¹⁰, we cannot infer from the body of studies that this would be predominantly the case in boys.

Several studies investigated the finger length ratio (and thus indirectly prenatal testosterone exposure) in clinically diagnosed samples of children with ADHD. These studies thus indirectly addressed the hypothesis that higher prenatal testosterone exposure is associated with increased ADHD symptoms. The results are indifferent-at least with respect to sex.

Increased prenatal testosterone exposure is (indirectly) indexed by a decreased index finger to ring finger length ratio (index finger length divided by ring finger length, 2D:4D). A low 2D:4D ratio (i.e., high prenatal testosterone exposure) correlated with in several studies:

• Hyperactivity
  • girls only (preschool age)⁸⁵
  • only in girls (preschool age), also impulsivity⁸⁶
  • only in women (student age) on the left hand (also impulsivity)⁸⁷
  • only in boys (school enrollment age), also behavioral problems⁸⁸
  • gender-independent⁸⁹
• social problems
  • only for boys (school enrollment age)⁸⁸
• Sensation seeking (at the same time high testosterone levels)⁹⁰
  • Sensation seeking exhibits sex differences in favor of boys and is associated with externalizing disorders.⁹¹⁹²¹⁰
• ADHD
  • only in boys, most markedly in ADHD-I.⁹³
  • in boys and girls (from 7 to 15 years) with ADHD-I (smaller CEOAEs and smaller 2D:4D) than ADHD-C or controls⁹⁴
  • in German men, but not in German women or Chinese men or women⁹⁵
  • one study found no correlation between 2D:4D and ADHD symptoms or ADHD subtypes in children with ADHD.⁹⁶
• Inattention
  • gender-independent⁸⁹
  • only in women, on the left hand (student age).⁸⁷
  • Correlation low right 2D:4D / increased ADHD inattention symptomatology could be mediated by decreased conscientiousness.⁹⁷

A high 2D:4D ratio (i.e., low prenatal testosterone exposure) correlated with

• prosocial behavior
  • only for girls of school enrollment age⁸⁸

Boys with autism/Asperger syndrome and ADHD/oppositional defiant disorder had lower finger length ratios than boys with anxiety disorders. Boys with autism spectrum disorders had lower finger length ratios than healthy controls⁹⁸

A study using sibling sex distribution found circumstantial evidence of increased intrauterine testosterone exposure in ADHD and ASD and reading disability, which was significant only in reading disability.⁹⁹

3.4. ADHD and decreased prenatal/postnatal estrogen¶

Decreased prenatal and postnatal estrogen levels also appear to correlate with ADHD symptoms.
Women with Turner syndrome or a single X chromosome have ovaries that produce decreased prenatal and postnatal estrogen levels.¹⁰⁰ These women have at the same time a characteristic cognitive profile with well ADHD-like deficits in:

• visual-motor integration
• Pattern recognition
• Face recognition
• motor speed
• Coordination
• Attention
• Planning (Test of Attention Variables, Familiar Figures Test, Tower of Hanoi)
• for legal-lateral, spatially demanding executive tasks¹⁰¹

A study of the menstrual cycle of regularly cycling young women found that decreased estradiol levels associated with increased progesterone or testosterone levels correlated with higher ADHD symptoms the next day, particularly in women with high impulsivity. Phase analyses indicated an increase in ADHD symptoms in both the early follicular phase and the early luteal phase, or after ovulation.¹⁰²

3.4.1. Estrogen reduces dopamine degradation in the PFC¶

The increased dopamine breakdown in the PFC caused by estrogen via COMT means that (mild) stress can 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).¹⁰³

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 contrast, in female humans and animals, the slight increase in dopamine in the PFC due to mild stress (on the overall average) leads to a deteriorated mental performance. This difference appears to be 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.^{10410558106107108109}

Estrogen reduces the activity of the dopamine-degrading enzyme COMT.^110111112 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.¹¹³¹¹⁴
Because COMT causes at least 60% of dopamine degradation in the PFC (and a maximum of 15% of dopamine degradation in the striatum¹¹⁵ ), women in the estrogen-rich menstrual phase have nearly 20% less dopamine degradation in the PFC.

It may follow that, with respect to PFC-mediated ADHD symptoms such as inattention, women may require lower doses of drugs (such as stimulants or atomoxetine) that act dopaminergically in the PFC 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.¹⁰⁴
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.¹¹⁶

3.4.2. Estrogen increases oxytocin levels¶

Since estrogen increases oxytocin levels, all effects of oxytocin are likely to be enhanced in women.

Oxytocin

• Decreases ACTH
• Probably reduces CRH
• Likely reduces stress symptoms mediated by the HPA axis
• Increases the “tend and befriend” stress response
  • The combination of oxytocin and certain attachment patterns may be related to the female “tend and be friend” stress response¹¹⁷¹¹⁸

See more at ⇒ Oxytocin

4. COMT gene variant influences stress perception in a gender-specific manner¶

Polymorphisms of the COMT gene primarily affect dopamine levels in the PFC and hardly affect dopamine levels in other brain regions. Similarly, norepinephrine levels in the PFC are not affected by COMT¹¹⁹

To be distinguished are:¹²⁰

• COMT-Val-158-Met (mixed Val/Met)
• COMT-Val-158-Val (homozygous Val)
• COMT-Met-158-Met (homozygous Met)

The COMT-Met-158-Met polymorphism causes dopamine degradation 4 times slower than the COMT-Val-158-Val variant.
COMT-Met-158-Met carriers are compared to COMT-Val-158-Val carriers¹²¹

• 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)¹²²
  • Consequently, probably worse effect of amphetamine drugs (deterioration of working memory by AMP at high stress)¹²³. We suspect that the result is likely to be transferable to MPH.
• More anxious and
• More sensitive to pain.

COMT is influenced by estrogen. In females, the COMT-Val-158-Val polymorphism leads to better executive functions and mental performance during periods of high estrogen levels compared to the COMT-Met-158-Met polymorphism.¹²⁴

5. 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 males. Since ADHD is further associated 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.¹²⁵

6. Creatine, choline, glutamate/glutamine in ACC and cerebellum¶

One study found significant sex- and age-specific differences in creatine, choline, and glutamate/glutamine in the ACC, and significant age-specific differences in choline and glutamate/glutamine in the cerebellum.¹²⁶

7. 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.¹²⁷

8. 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.¹²⁸

9. 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.¹²⁹

This is reminiscent of the increased symptom intensity of women diagnosed with ADHD as adults.

10. Higher divorce rate among women with ADHD¶

Women (in Japan) with ADHD appear to have even higher divorce rates than men with ADHD.¹³⁰

11. More comorbidities in women with ADHD¶

Females (in Japan) with ADHD appear to have a higher rate of comorbidity than males with ADHD.¹³⁰

12. 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.¹³¹