Gender differences in ADHD

ADHD in children is diagnosed significantly more frequently in boys than in girls.¹ This difference levels out in adults.

While boys are diagnosed with ADHD in medical practice 5 to 9 times more often than girls, only 3 times as many boys as girls are diagnosed in epidemiological studies (possibly due to the more detailed examination there).
In adults, the ADHD ratio is then balanced 1:1 in all environments.²

A large study found a gender ratio of 1.6:1 (boys to girls) in children with ADHD.³ While impulsivity was more common in boys and inattention in girls, hyperactivity was equally common.⁴

Whether the likelihood of individual symptoms occurring is gender-specific, so that women develop the ADHD-I subtype more frequently and the ADHD-HI subtype is more common in men, is now being questioned. One study found that boys and girls do not differ in the symptoms of inattention and hyperactivity.⁵ The distribution of symptoms also appears to be gender-independent in adults.⁶

• 1. Sex hormones as drivers of gender-specific mental disorders
  • 1.1. Genetic sex, gonadal sex, hormonal sex
  • 1.2. Gender-specific differentiation of neuronal circuits 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
  • 1.3. Gender-specific susceptibility to neurotoxins
• 2. Theories about hormonal mechanisms of depression
  • 2.1. Probability of depression increases in girls with puberty
  • 2.2. Probability of depression and hormonal fluctuations in the menstrual cycle
  • 2.3. Probability of depression and hormone fluctuations after childbirth / during menopause
  • 2.4. Estrogens appear to influence 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 the development and modulation of ADHD
  • 3.1. Sex hormones modulate the development of dopaminergic circuits
    • 3.1.1. Indirect modulation of the development of dopaminergic circuits by sex hormones
    • 3.1.2. Direct modulation of the development of dopaminergic circuits by sex hormones
  • 3.2. ADHD and externalizing symptoms correlate positively with prenatal testosterone exposure
  • 3.3. ADHD and reduced prenatal / postnatal estrogens
    • 3.3.1. Estrogens reduce COMT-mediated dopamine degradation in the PFC
    • 3.3.2. Oestrogens increase oxytocin levels
    • 3.3.3. Oestrogens reduce learning and memory problems
    • 3.3.4. Symptoms of ADHD and other mental health problems fluctuate with the cycle
    • 3.3.5. Symptom fluctuations during pregnancy
• 4. Sex hormones in ADHD
• 5. Chromosome-X
• 6. Different ADHD symptoms in boys and girls
• 7. Oestrogens as a resilience factor against stress
• 8. Development of symptoms over time by gender
• 9. Higher symptom intensity in diagnosed girls and women?
• 10. Higher divorce rate for women with ADHD
• 11. More comorbidities in women with ADHD
• 12. No gender-specific differences in the social behavior of ADHD and ASD
• 13. COMT gene variant influences gender-specific perception of stress
• 14. Thyroid hormones in women as a masking factor of ADHD?
• 15. Creatine, choline, glutamate/glutamine in ACC and cerebellum
• 16. Differences in ADHD medication effects by gender

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

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

• Androgens (C19 steroid hormones), among others:
  • Testosterone
  • Androstenedione (biochemically reduced testosterone)
  • 5α- and 5β-dihyrotestosterone (DHT)
  • Dehydroepiandrosterone (DHEA).
• Oestrogens (C18 steroid hormones)
  Like gestagens, oestrogens are female sex hormones. Oestrogens are C-18 steroid hormones. They are synthesized in the cells of the ovarian follicles in a cycle-dependent manner.
  There are four natural estrogens:
  • Estradiol (17β-estradiol, oestradiol; most bioactive oestrogen)
  • Estrone (3/10 of the bioactivity of estradiol)
  • Oestriol (1/10 of the bioactivity of estradiol)
  • Östetrol

Taking natural oestrogens orally is ineffective due to inactivation in the liver. Synthetic oestrogens are therefore used as medication and are primarily used to inhibit ovulation in hormonal contraception.

Other hormones can also have a psychopathological influence (e.g. gestagens (pregnancy hormones)).

Males are more prone to (externalizing) behavioural 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.⁷⁸⁹¹⁰

The following explanations are largely based on the work of Martel et al (2013), who discussed the differentiating contribution of sex hormones in greater depth¹¹

• Testosterone may prenatally (“organizationally”) modulate dopaminergic circuits in the striatum, placing 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 autism¹²
  • Testosterone appears to reduce men’s pain responses⁷
  • Androstenedione correlated with behavioral problems only in boys¹³
  • Testosterone-estradiol-binding globulin correlated negatively with sad affect and conspicuous behavior.¹³
• Estradiol could modulate (“activating”) circuits in puberty, including in the amygdala (especially with effects on serotonergic signaling pathways), such that girls have a higher risk of internalizing and affective disorders
  • Lower prenatal testosterone levels are considered a risk factor for eating disorders¹⁴¹⁵ , while increasing estradiol levels during and after puberty reduce the risk¹⁶¹⁷

Sex hormones play an important role in the organization and plasticity of the brain and behavioral systems.¹⁸¹⁹

• “Organizational” effects
  • Exposure to androgens
    • Androgens
    • Between pregnancy and 4 months of age
    • Permanent masculinizing effects on the nervous system and behaviour
  • “Activating” effect
    • Predominantly estrogens
    • During adolescence
      • Puberty as a phenotypic activating event
        • Testosterone levels rise during puberty¹³
          • For men by a factor of 18
          • For women by a factor of 8
        • Luteinizing hormone (LH) and follicle stimulating hormone (FSH) stimulate the production of androgens, estrogens and progesterone²⁰
        • Estradiol and testosterone can regulate gene expression and neurotransmission, e.g. GABA²¹ and serotonin²²
        • Estradiol influences puberty²³
          • Orbital cortex
          • MPFC
          • Amygdala²⁴
          • Hippocampus²⁴
        • Estradiol interacts with the HPA axis²⁵
        • Estradiol enhances the stress response in the PFC in a sex-specific manner via serotonin, noradrenaline and dopamine²⁵
        • Estrogens could interact with the HPA axis
          • Increase in the stress sensitivity of the HPA axis
          • Modulation of the HPA axis during puberty
            • Altered HPA activity can increase sensitivity to stress and thus susceptibility to depression²⁵
          • Oestrogens are strong regulators of several serotonergic systems (e.g. the 5HT2a receptor)²⁶²⁷
          • Rapidly changing oestrogen levels during puberty can directly influence the transcription of serotonin genes. Consequences:
            • Abnormalities in the amygdala
            • Low serotonin levels
    • Transient effect on neuronal structure and behavior
    • Change and activation of previously organized neuronal circuits
    • Possibly also some organizational effects¹⁰

1.1. Genetic sex, gonadal sex, hormonal sex¶

The genetic sex leads to a gonadal sex, which in turn is linked to the hormonal sex.¹¹
The genetic (i.e. chromosomal) sex is determined at conception. Consequences are that a gene on the Y chromosome causes the gonads to develop into testes. The testes release several androgenic steroid hormones (e.g. testosterone), which 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 women than in men. 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. Gender-specific differentiation of neuronal circuits and behavior¶

1.2.1. Theories¶

The following 3 theories are not mutually exclusive ²⁸¹¹

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
      • resulting altered cerebral lateralization²⁹
      • possible Consequences for Men:
        • more susceptible to environmental pollution
        • more variable behavioral results¹⁸
        • increased risk of learning disorders
        • increased risk of hyperactivity
        • prone to injuries and structural abnormalities in the left hemisphere for a prolonged period of time
    • increased neuronal lateralization (= specialization of the brain hemispheres)
      • Consequences include: after a focal stroke, women are more likely to regain speech than men³⁰
    • 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 neuronal circuits and behaviour

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
  • Women who are prenatally exposed to higher androgen levels may exhibit more masculine traits (e.g. increased spatial abilities)

1.2.2. Sex hormones and dopamine¶

Pregnant rats subjected to forced stress had male offspring with reduced testosterone levels and increased dopamine levels in the striatum.³¹ Furthermore, testosterone levels can indirectly influence neuronal development through so-called “downstream” effects: via the selection of experiential niches by the organism and the triggering of environmental responses¹⁸

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 behavior¹¹

Larger for men:³²

• Total brain volume
• White substance
• Liquor
• Cerebellum
• Pons
• Amygdala
  • medial amygdala nucleus¹¹
• Hypothalamus
• Frontomedial cortex
• Corpus callosum (unclear)³³

Larger for women:³²

• Gray matter
  • in posterior, temporal and inferior parietal brain regions
    • larger share
    • greater cortical thickness
• Hippocampus
• Frontoorbital cortex
• Upper frontal and lingual gyrus
• front commissure¹¹
• Caudat (unclear)
• Corpus callosum (unclear)

Other differences:

• lower lateralization (i.e. specialization) of cortical functions in women
  • lower prevalence of left-handedness
• greater variation in extracellular striatal dopamine across the estrous cycle in women³⁴
• Oestrogen and progesterone modulate dopamine in the striatum and nucleus accumbens only in women³⁵
• significantly higher juvenile increase 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 women³²
• Whole blood serotonin levels are higher in women³²
• Men synthesize serotonin faster³²
• higher availability of dopamine transporters in women³²
• higher presynaptic dopamine synthesis in the striatum in women³²
• IQ correlates with gray matter volume³⁶
  • in men in the frontal and parietal lobe
  • in women in the frontal lobe and Broca’s area
• emotional events are processed differently in the amygdala:³⁷
  • Women: primarily in the left amygdala
  • Men: primarily in the right amygdala
  • This lateralization could be the reason why men tend to react physically to emotional stimuli, whereas women tend to think rather than act

1.3. Gender-specific susceptibility to neurotoxins¶

As described in the chapter Development (of ADHD) neurotoxins - especially prenatally and in childhood - are a significant risk factor for the development of ADHD.

The reasons given for the greater susceptibility of the male brain to neurotoxins are³⁸

• lower glutathione availability than in women
• lower sulphate-based detoxification capacity than in women
• Neurotoxins and testosterone show potentiating effects
• stronger neuroinflammatory response in men
• higher susceptibility to oxidative stress than women
• lack of neuroprotective effects of female hormones (estrogens and progesterone), particularly with regard to the reduction of inflammation and oxidative stress

2. Theories about hormonal mechanisms of depression¶

2.1. Probability of depression increases in girls with puberty¶

Girls were only twice as likely to be depressed as boys from the age of 10 to 15. 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 later in life.³⁹⁴⁰
A higher degree of negative affect correlated with higher testosterone levels, higher cortisol and lower adrenal hormones, but not with altered estradiol levels.⁴¹

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

Estradiol and progesterone levels are relatively low during menstruation. Estradiol levels rise during the follicular phase until the LH surge, when ovulation takes place. After ovulation, the estradiol level drops, while the progesterone level rises steadily. 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 point, menstrual bleeding begins and completes the cycle.⁴²

The symptoms of depressive mood vary systematically with fluctuations in the menstrual cycle. In women, the likelihood of mood problems (i.e. depressed mood, apathy) is greatest in the mid to late luteal phase of the menstrual cycle. During this period, progesterone levels peak while estradiol levels drop. Negative affect is also cycle-dependent and occurs most strongly before or during the menstrual phase and less so in ovulatory or premenstrual phases¹¹

Oral contraceptives changed the variability of mood over the course of the day. Triphasic preparations (oral contraceptives with three hormonal phases) caused increased affect variability.⁴³ Depressed mood typically occurs during the premenstrual period when estradiol and progesterone decrease.⁴⁴
In PMS, suppression of ovarian function by leuprolide improved the symptoms. However, in a subset, these recurred after replacement of estradiol or progesterone, suggesting an abnormal response to hormonal changes as a cause of PMS mood problems.⁴⁵ In fact, women with premenstrual dysphoric disorder showed an abnormal gonadotropin response to estradiol exposure compared to other women:⁴⁶

• stronger negative feedback reaction up 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 flatulence in the luteal phase
• AUC of LH correlated with irritability
• Depressed mood correlated with
  • FSH basic mirrors
  • AUC of FSH during the negative feedback phase

2.3. Probability of depression and hormone fluctuations after childbirth / during menopause¶

15% of women develop symptoms of depression in the first six months after giving birth, when sex hormones drop rapidly and dramatically.¹¹ A sharp drop in estradiol and progesterone after childbirth correlated with depression in women with a history of postpartum depression⁴⁷

The onset of menopause is associated with a decrease in oestrogen levels and a 2-fold to 4.3-fold risk of irritability and depression,^{4849 50} while the risk of depression is reduced after menopause.
The risk of depression in women was⁵¹⁵⁰

• increased 2.5-fold during the menopause
• decreased after the menopause
• with a rapidly increasing profile of FSH decreases
• with high levels and increased variability of FSH increased
• with high levels and increased variability of LH increases
• increases with rising estradiol levels and increased variability of estradiol

Estrogen administration during the menopause significantly reduced depressive mood.⁴²⁵²
Low estrogen levels or dramatic changes in estrogen levels appear to increase the risk of depression.

Whether estradiol administration after childbirth / during perimenopause / during menopause correlates with a reduction in depression is inconsistent. There are several studies for and against.¹¹
Estradiol administration can accelerate the effect of antidepressants in non-responders in the menopause.⁵³
Withdrawal of estradiol from rats exposed to high levels of estradiol and progesterone (to mimic levels during pregnancy) resulted in increased depressive symptoms.⁵⁴ Estradiol administration increased mobility in rats, suggesting an antidepressant effect of estradiol administration.⁵⁵⁵⁶
An inverted-U curve may also be at work here: optimal estradiol levels are protective, reduced and increased estradiol levels increase depressive symptoms.
To investigate the relationship between estradiol levels and affect over a period of 30 or 60 days, daily measurements over the entire menstrual cycle are required.¹¹

2.4. Estrogens appear to influence transcription and activity of serotonin genes¶

Oestrogens modulate the central neurotransmitter systems that play a role in depression, particularly that of serotonin ^{57 49 5859}

It is possible that the increased symptoms of ADHD before menstruation are due to reduced serotonin levels.⁶⁰ The lowest oestrogen levels are not found before, but during menstruation (1st to 4th day of the cycle) and in the first days of the proliferation phase (5th to 14th day of the cycle). There are no reports of a cycle-related increased need for ADHD medication during these periods.

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. the release of catecholamines) in the PFC.⁶¹ Estradiol does not appear to have antidepressant effects under stress conditions.⁶²

Estrogens lower the threshold for prefrontal cortical dysfunction resulting from stressful experiences.⁶¹
Estrogens, especially estradiol, thus increase the risk of depression by altering the thresholds for prefrontal activation in response to stress.

According to another view, estradiol is said to have a moderating effect on depression via interaction with stressful life events and the HPA axis. Estradiol moderates the function of the limbic-OPFC circuit and the HPA axis, which reduces the risk of depression.⁶³ Estrogen significantly reduced the stress response of the HPA axis in postmenopausal women. The responses to ACTH, cortisol and noradrenaline were attenuated.⁶⁴

The antidepressant effect of estradiol may also depend on optimal corticoid levels, suggesting an interaction between estradiol effects and HPA axis tone⁶⁵

2.5.2. Progesterone enhances HPA stress response¶

The progestin progesterone appears to increase the stress response of the HPA axis in postmenopausal women. The responses to ACTH and cortisol were attenuated, while the response to noradrenaline was increased.⁶⁴ Women with PMS did not show the normal increased response of the HPA axis to exercise during the luteal phase. Progesterone caused an increased HPA axis response to treadmill exercise testing in healthy controls. Estradiol did not cause an increased HPA response.⁶⁶

3. Hormonal mechanisms of the development and modulation of ADHD¶

3.1. Sex hormones modulate the development of dopaminergic circuits¶

3.1.1. Indirect modulation of the development of dopaminergic circuits by sex hormones¶

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 circuitry by slowing overall neuronal development and leaving the dopaminergic components of the brain 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.¹⁸

Polycystic ovary syndrome (PCOS) is associated with hyperandrogenemia, i.e. greatly increased androgen levels. PCOS during pregnancy increases the risk of ADHD by 95% in boys only.^67
68
Women with PCOS had an increased risk of ADHD themselves, although no link was found between their testosterone levels and their ADHD symptoms⁶⁹
More on this at Prenatal stressors as ADHD environmental causes In the chapter Development,

Maternal smoking increases the fetal testosterone level.⁷⁰ Prenatal smoking causes a 1.9-fold⁷¹ to 2.7-fold risk of ADHD⁷² for the offspring. Other studies also found significantly increased risk values.^73747576
More on this at Prenatal stressors as ADHD environmental causes In the chapter Development,

3.1.2. Direct modulation of the development of dopaminergic circuits by sex hormones¶

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

• Nucleus accumbens
• Striatum
• PFC

and thus cause deficits in cognitive control and reward processes.
Androgen effects act on the striatum, including the caudate nucleus and the associated dopamine circuits.³¹

Animal studies using prenatal hormone manipulation in relation to ADHD are not yet known. There are only experiments with hormone manipulation in early childhood. The transferability of the ADHD animal model of SHR with regard to gender differences in ADHD is questionable, as the animals do not show the gender differences in behavioral symptoms known in humans. Female SHR appear to be more impulsive than males, especially during estrus.⁷⁷
SHR (spontaneously hypertensive rat) and Wistar (WKY) control animals were exposed to testosterone early in development (postnatal day 10). On postnatal day 45, SHR animals showed:⁷⁸

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

High testosterone levels may increase the risk of ADHD symptoms through a maturational delay in the development of dopaminergic innervation and metabolism, as well as increased lateralization of underlying dopaminergic neuronal circuits and increased reuptake of dopamine neurotransmission.⁷⁹
The Pavlovian conditioning of a visual stimulus paired with food was:⁸⁰

• weaker in female SHR than in male SHR
• Wistar rats equal in both sexes

A gonadectomy (castration) changed the Pavlovian conditioning:⁸¹

• for male and female SHR: increased conditioning
• for female Wistar rats: unchanged
• in male Wistar rats: reduced conditioning

SHR showed increased motor activity when given androgens in early childhood. Wistar, on the other hand, showed no change.⁸²

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 men .⁸³

These results suggest that dopaminergic neuronal circuits and cognition are hormonally influenced in SHR¹¹
This also seems to affect ADHD symptoms.

Girls and boys with ADHD, on the other hand, show equally weak cognitive control.⁸⁴⁸⁵⁸⁶ Boys with ADHD-I showed lower cognitive impairments than boys with ADHD-C and girls with ADHD-I or ADHD-C.⁸⁷
So far, however, studies have always examined sex as a proxy, without investigating the direct effect of hormones themselves on cognitive control and reinforcement learning.

3.2. 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 al¹¹, we cannot conclude from the study that this is primarily the case for 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 regard to gender.

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

• Hyperactivity
  • only for girls (preschool age)⁸⁸
  • only in girls (preschool age), also impulsivity⁸⁹
  • only in women (student age) on the left hand (also impulsivity)⁹⁰
  • only in boys (school age), also behavioral problems⁹¹
  • independent of gender⁹²
• Impulsiveness⁹³
• Aggression
  • for adult men⁹³
• social problems
  • only for boys (school age)⁹¹
• Sensation seeking (high testosterone levels at the same time)⁹⁴
  • Sensation seeking shows gender differences in favor of boys and is associated with externalizing disorders.⁹⁵⁹⁶¹¹
• ADHD
  • for adult men⁹³
  • only in boys, most clearly in ADHD-I.⁹⁷
  • in boys and girls (from 7 to 15 years) with ADHD-I (smaller CEOAEs and smaller 2D:4D) than in ADHD-C or controls⁹⁸
  • for German men, but not for German women or Chinese men or women⁹⁹
  • one study found no correlation between 2D:4D and ADHD symptoms or ADHD subtypes in children with ADHD.¹⁰⁰
• Inattention
  • independent of gender⁹²
  • only in women, on the left hand (student age).⁹⁰
  • Correlation low right 2D:4D / increased ADHD inattention symptomatology could be mediated by decreased conscientiousness.¹⁰¹
• Alexithymia
  • for adult men⁹³
• Addiction
  • for adult men⁹³

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

• prosocial behavior
  • only for girls of school age⁹¹

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 controls¹⁰²

A study using sibling sex distribution found evidence of increased intrauterine testosterone exposure in ADHD and ASD and reading impairment, which was significant only in reading impairment.¹⁰³

3.3. ADHD and reduced prenatal / postnatal estrogens¶

Reduced 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 reduced prenatal and postnatal estrogen levels.¹⁰⁴ These women also have a characteristic cognitive profile with largely 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 tasks¹⁰⁵

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, especially in women with high impulsivity. Phase analyses indicated an increase in ADHD symptoms both in the early follicular phase and in the early luteal phase or post-ovulation.¹⁰⁶

3.3.1. Estrogens reduce COMT-mediated dopamine degradation in the PFC¶

Estrogens genetically reduce the activity of the dopamine-degrading enzyme COMT^{107108 109} in the PFC, while COMT was increased in the prostate¹¹⁰

The estrogen level in women is low after menstruation (day 1 - 9), then rises steadily to its maximum until ovulation (day 10 - 15), falls to 1/3 of its maximum with ovulation (day 16 / 17), then rises to 2/3 of its maximum by day 24 and then falls until menstruation (day 27).¹¹¹

Shortly before ovulation and (slightly weaker) approx. 1 week after ovulation), dopamine degradation in the PFC is therefore significantly reduced (dopamine is increased, possibly reduced need for ADHD medication). Before menstruation, dopamine degradation is noticeably increased (dopamine is reduced, possibly increased need for ADHD medication)
COMT is therefore on average 30% less active in women than in men.¹¹²¹¹³
As COMT causes at least 60 % of dopamine degradation in the PFC (and a maximum of 15 % of dopamine degradation in the striatum¹¹⁴ ), women in the oestrogen-rich phase shortly before ovulation have almost 20 % less dopamine degradation in the PFC.

Consequences of this are that some women require a lower dosage of drugs with a dopaminergic effect in the PFC (such as stimulants or atomoxetine) during periods with high oestrogen levels (3 - 4 days before ovulation and approx. one week after ovulation) than during periods with low oestrogen levels (days before menstruation) with regard to PFC-mediated ADHD symptoms such as inattention.¹¹⁵ In individual cases, this depends on the COMT gene variant, among other things.
This could further explain the increased sensitivity of women compared to men, as a slightly higher dopamine level increases the intensity of perception.

Since the COMT Met-158-Met variant is also common in borderline, which causes five times slower dopamine degradation in the PFC, and estrogen further slows down COMT dopamine degradation, this connection could possibly provide a clue to explain the prevalence of borderline in women (75% of people with ADHD are women).¹¹⁶

The reduction in dopamine degradation in the PFC caused by estrogens via COMT means that (mild) stress can have different effects depending on gender.
In male humans and animals, the slightly increased dopamine level in the PFC during mild stress increases mental performance compared to 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 average) leads to a deterioration in mental performance. This difference appears to be caused by estrogens. The deterioration in mental performance due to mild stress only occurs in the estrogen-rich phase shortly before ovulation. In the estrogen-poor phase before or during the menstrual phase, mild stress increases mental performance in women just as much as in men.^{11511761118119120121}

3.3.2. Oestrogens increase oxytocin levels¶

As oestrogens increase oxytocin levels, all the effects of oxytocin are likely to be enhanced in women.

Oxytocin

• Reduces ACTH
• Probably reduces CRH
• Probably reduces stress symptoms mediated by the HPA axis
• Increases the “tend and befriend” stress response
  • The combination of oxytocin and certain attachment patterns could be linked to the female “Tend and be Friend” stress response¹²²¹²³

Find out more at ⇒ Oxytocin

Oxytocin also influences the dopamine balance. More on this at Oxytocin In the article What regulates dopamine

3.3.3. Oestrogens reduce learning and memory problems¶

High estrogen levels alleviate deficits in learning and memory.¹²⁴
This could possibly explain why ADHD symptoms are often not yet detectable in girls during their school years and only become more apparent in women from the age of 35 (see “late onset ADHD” in women).

3.3.4. Symptoms of ADHD and other mental health problems fluctuate with the cycle¶

The symptoms of a number of psychological problems vary systematically with fluctuations in the menstrual cycle.

• during the highest progesterone level (mid to late luteal phase) are often elevated:
  • Mood problems (i.e. depressed mood, apathy)¹¹
• are often elevated during the drop in estrogen levels (before the menstrual phase):
  • Negative affect¹¹, depression¹²⁵
  • ADHD¹²⁵
  • Schizophrenia¹²⁵
  • Bipolar Disorder¹²⁵
  • ASS¹²⁵¹²⁵
  • Anxiety disorder, generalized¹²⁵
  • PTSD¹²⁵
  • Eating disorders¹²⁵

The intensification of PMS symptoms towards the end of the luteal phase (before and in the first days of menstruation) could be due to a drop in oestrogen levels and not a consequence of their lowest levels. Since estrogens increase serotonin, the drop in estrogen causes a drop in serotonin.⁶⁰ Although oestrogen levels fall in the days before menstruation, the lowest oestrogen levels are found during menstruation (1st to 4th day of the cycle) and in the first days of the proliferation phase (5th to 14th day of the cycle). There are no reports of a cycle-related increased need for ADHD medication during these periods.
Oestrogens also influence dopamine. More on this under Oestrogens promote dopamine in the striatum and PFC In the article What regulates dopamine

3.3.5. Symptom fluctuations during pregnancy¶

One review reports diminishing symptoms during pregnancy due to the increased estrogen levels at this time in¹²⁵

• ADHD
• Schizophrenia

4. Sex hormones in ADHD¶

Decreased estradiol levels in conjunction with increased progesterone or testosterone levels during the menstrual cycle correlated with higher ADHD symptoms the next day, especially in women with high impulsivity. ADHD symptoms increased in the early follicular phase as well as in the early luteal phase or after ovulation.¹⁰⁶

Steroid sulfatase (STS, arylsulfatase C) catalyzes the conversion of sulfated steroid precursors into the respective free steroids in the endoplasmic reticulum. This concerns, among other things

• DHEA sulphate to DHEA
• Estrone sulfate to estrone
• Pregnenolone sulphate to pregnenolone
• Cholesterol sulphate to cholesterol

STS also causes the sulphation of dopamine sulphate to dopamine in the blood. More on this under Sulfation by sulfotransferases In the article Dopamine degradation.

Sulphated and non-sulphated steroids can affect GABA-A and NMDA receptors in the brain.¹²⁶ Both DHEAS and its non-sulphated form DHEA inhibit the GABA-A receptor and activate the NMDA receptor.¹²⁷
More about DHEA at DHEA in the chapter Neurological aspects / Hormones in ADHD.

• A steroid sulfatase deficiency therefore leads to a deficiency of these steroid hormones. Mice with a deficiency of the STS enzyme show clear ADHD symptoms¹²⁸¹²⁹ This appears to be accompanied by an increased serotonin level in the hippocampus and increased motivation.¹³⁰
• The STS gene defect X-linked ichthyosis (steroid sulfatase deficiency) correlates with increased risk of ADHD, ASD and social communication disorders.¹³¹
• DHEAS and STS influence attention.¹³² DHEAS administration improved performance in the five-choice serial-reaction time task under attention-demanding conditions, while STS inhibition impaired accuracy. There were no influences on basic motor activity.

STS (other names: Aryl sulfatase C, steroid sulfatase, sterol sulfatase, dehydroepiandrosterone sulfate sulfatase, steroid 3-sulfatase, steroid sulfate sulfohydrolase, dehydroepiandrosterone sulfatase, pregnenolone sulfatase, Phenol steroid sulfatase, 3-beta-hydroxysteroid sulfate sulfatase or steryl sulfate sulfohydrolase) Is associated with inattention, cognitive problems and other ADHD symptoms.^{133134132128135}

One study found in both boys and girls with ADHD¹³⁶

• DHEA-S reduced
  • low DHEA-S correlated with higher impulsivity
• SHBG unchanged
  • low SHGB correlated with increased ADHD symptoms
• free testosterone unchanged
  • no correlation of free testosterone to ADHD symptoms

In SHR (Spontaneously hypertensive rats), serum levels were compared to WKR (Wistar-Kyoto rats):¹³⁷

• Testosterone and free estriol increased in 10-week-old SHR and WKR compared to 5-week-old SHR and WKR
• Progesterone, corticosterone and cortisol increased in 10-week-old SHR compared to 5-week-old SHR and 5- or 10-week-old WKR

See also under

• DHEA for ADHD
• Testosterone for ADHD

5. Chromosome-X¶

Rare X-linked gene variants put boys and men in particular at risk of ADHD, ASD and Tourette’s syndrome.¹³⁸

6. Different ADHD symptoms in boys and girls¶

Boys with ADHD have higher scores at¹³⁹

• Hyperactivity
• Inattention
• Impulsiveness
• externalizing problems

Girls with ADHD showed higher scores at¹³⁹

• intellectual impairments
• internalizing problems
  • e.g. far more frequent anxiety symptoms¹⁴⁰

7. Oestrogens as a resilience factor against stress¶

Oestrogens could increase cognitive resistance to stress in women.¹⁴¹

Seen from a distance, an increased capacity for suffering (in other words: a reduced perception of suffering) would be a possible explanation as to why women with ADHD are diagnosed so much later on average than men.

8. Development of symptoms over time by gender¶

While girls typically develop a large surge of increased symptoms in early adolescence, boys have an increased symptom manifestation from childhood onwards. For both sexes, early adolescence is associated with the risk of a significant increase in symptoms.¹⁴²

9. Higher symptom intensity in diagnosed girls and women?¶

Girls with autism who also had ADHD showed significantly stronger symptoms of ADHD, learning disabilities and ODD than boys with ASD and ADHD in a large study.¹⁴³

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

10. Higher divorce rate for women with ADHD¶

Women (in Japan) with ADHD seem to have even higher divorce rates than men with ADHD.¹⁴⁴

11. More comorbidities in women with ADHD¶

Females (in Japan) with ADHD appear to have a higher rate of comorbidity than males with ADHD.¹⁴⁴

12. No gender-specific differences in the social behavior of ADHD and ASD¶

A meta-analysis found no gender-specific differences in social and communication behavior in ADHD and ASD.¹⁴⁵

13. COMT gene variant influences gender-specific perception of stress¶

Polymorphisms of the COMT gene primarily affect dopamine levels in the PFC and barely affect dopamine levels in other brain regions. Similarly, the noradrenaline level in the PFC is not influenced by COMT¹⁴⁶

A distinction must be made:¹⁴⁷

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

The COMT-Met-158-Met polymorphism causes 4 times slower dopamine degradation than the COMT-Val-158-Val variant.
COMT-Met-158-Met carriers are more suitable than COMT-Val-158-Val carriers¹⁴⁸

• Mentally more powerful (more efficient, not more intelligent)
• Better executive functions of the PFC
• More sensitive to stress (high dopamine level (only) in the PFC even at rest, significant increase in dopamine (only) in the PFC even under mild stress)¹⁴⁹
  • As a result, the effect of amphetamine medication was probably worse (deterioration of working memory due to AMP under high stress)¹⁵⁰. We suspect that the result may be transferable to MPH.
• More anxious and
• More sensitive to pain.

COMT is influenced by oestrogen. In women, the COMT-Val-158-Val polymorphism leads to better executive functions and better mental performance than the COMT-Met-158-Met polymorphism during periods of high oestrogen levels.¹⁵¹

14. Thyroid hormones in women as a masking factor of ADHD?¶

The updated European consensus on the treatment and diagnosis of ADHD in adults from 2018² points out 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 women than in men. Since ADHD is further associated with thyroid hormone receptor insensitivity, the role of thyroid hormones in the development and manifestation of ADHD in women and girls should be investigated in more detail.¹⁵²

In relation to autism, the first evidence of female masking behavior was found in mice.¹⁵³

15. 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.¹⁵⁴

16. Differences in ADHD medication effects by gender¶

ADHD medication seems to work slightly differently for women than for men.¹⁵⁵
MPH showed

• for girls:
  • reduced symptom severity and greater symptom improvement in the long term
  • a stronger effect of MPH at the beginning of the day, with an earlier decrease in effect
    • a single daily dose of MPH does not appear to be optimal for girls
• for women:
  • less improvement in inattention, hyperactivity and impulsivity

Non-stimulants showed

• for girls and women
  • greater improvement in symptoms, hyperactivity, impulsivity and emotional dysregulation/emotional factors
  • ATX could be more helpful for girls and women with ADHD than for boys and men