Gender Differences in ADHD

ADHD is diagnosed significantly more often in boys than in girls.¹ This difference evens out in adults.

While boys are diagnosed with ADHD 5 to 9 times more often than girls in medical practices, epidemiological studies (possibly due to the more thorough examinations conducted in those settings) show that only 3 times as many boys as girls are diagnosed. Among 5-year-olds, the ratio was 3.16 times as many boys as girls.²
Among adults, the ADHD ratio is then balanced at 1:1 across all settings.³
This is comparable to autism, where the gender ratio of those diagnosed in childhood (10 boys to 1 girl) changes significantly by adulthood (2 men to 1 woman).Vogeley (2023): Presentation at the LVR Autism Conference 2023

A large study found a gender ratio of 1.6:1 (boys to girls) among children with ADHD.⁴ While impulsivity was more common in boys and inattention was more common in girls, hyperactivity occurred with equal frequency.⁵

1. Sex Hormones as Drivers of Gender-Specific Mental Disorders¶

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

• Androgens (C19 steroid hormones), including:
  • Testosterone
  • Androstenedione (biochemically reduced testosterone)
  • 5α- and 5β-dihydrotestosterone (DHT)
  • Dehydroepiandrosterone (DHEA).
• Estrogens (C18 steroid hormones)
  Like progestins, estrogens are female sex hormones. Estrogens 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; the most bioactive estrogen)
  • Estrone (3/10 the bioactivity of estradiol)
  • Estriol (1/10 the bioactivity of estradiol)
  • Östetrol

Oral administration of natural estrogens is ineffective because they are inactivated in the liver. Therefore, synthetic estrogens are used as medications and serve primarily to inhibit ovulation in hormonal contraception.

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

Men are more prone to (externalizing) behavioral disorders in childhood (ADHD, ODD, CD, autism, learning disabilities), while women are more prone to emotional (internalizing) disorders in adolescence (depression, anxiety disorders, dysthymia, eating disorders, PTSD). This could also be attributed to sex hormones.⁶⁷⁸⁹

The following discussion is based largely on the work of Martel et al. (2013), who have provided an in-depth analysis of the differential roles of sex hormones.¹⁰

• Testosterone may modulate dopaminergic circuits in the striatum prenatally (“organizationally”), such that boys are at greater risk for the early development of inattention and disruptive behavioral disorders.
  • A theory of the “extremely masculine brain” in autism views autism symptoms as exaggerations of typical gender differences and identifies exposure to high prenatal testosterone levels as a risk factor for autism¹¹
  • Testosterone appears to reduce pain responses in men⁶
  • Androstenedione was correlated only with behavioral problems in boys¹²
  • Testosterone-estradiol-binding globulin was negatively correlated with sad mood and behavioral problems.¹²
• During puberty, estradiol may “activate” and modulate neural circuits—including those in the amygdala (particularly affecting serotonergic signaling pathways)—in such a way that girls are at higher risk for internalizing and affective disorders
  • In eating disorders, lower prenatal testosterone levels are considered a risk factor¹³¹⁴ , while rising estradiol levels during and after puberty reduce the risk¹⁵¹⁶

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

• “Organizational” implications
  • Exposure to androgens
    • Androgens
    • from pregnancy through the 4th month of life
    • permanent masculinizing effects on the nervous system and behavior
  • “Stimulating” effect
    • primarily estrogens
    • during adolescence
      • Puberty as a phenotypic triggering event
        • Testosterone levels rise during puberty¹²
          • about 18 times higher in men
          • about 8 times higher in women
        • Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) stimulate the production of androgens, estrogens, and progesterone¹⁹
        • Estradiol and testosterone can regulate gene expression and neurotransmission, e.g., GABA²⁰, and serotonin²¹
        • Estradiol affects puberty:²²
          • orbital cortex
          • mPFC
          • Amygdala²³
          • Hippocampus²³
        • Estradiol interacts with the HPA axis²⁴
        • Estradiol enhances the stress response in the PFC in a sex-specific manner via serotonin, norepinephrine, and dopamine²⁴
        • Estrogens may interact with the HPA axis
          • Increased stress sensitivity of the HPA axis
          • Modulation of the HPA axis during puberty
            • Changes in HPA activity can increase sensitivity to stress and, as a result, susceptibility to depression²⁴
          • Estrogens are powerful regulators of several serotonergic systems (e.g., the 5HT2a receptor)²⁵²⁶
          • Rapid fluctuations in estrogen levels during puberty can directly influence the transcription of serotonin genes. Consequences:
            • Abnormalities in the amygdala
            • low serotonin levels
    • temporary effects on neural structure and behavior
    • Modification and activation of previously organized neural circuits
    • possibly also some organizational implications⁹

1.1. Genetic sex, gonadal sex, hormonal sex¶

Genetic sex leads to gonadal sex, which in turn is linked to hormonal sex.¹⁰
Genetic (i.e., chromosomal) sex is determined at conception. As a consequence, a gene on the Y chromosome triggers the development of the gonads into testes. The testes release several androgenic steroid hormones (e.g., testosterone), which cause the body and brain to develop male characteristics during fetal development.
Before birth, the ovaries release little or no hormones. The relative absence of androgens leads to the development of a female body and brain.
Biological sex is defined by the ratio of circulating estrogen to androgen, which is higher in most women than in men. Sexual differentiation (which 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 Neural Circuits and Behavior¶

1.2.1. Theories¶

The following three theories are not mutually exclusive:²⁷¹⁰

1.2.1.1. Classical Theory¶

• Androgens cause male development
• A lack of androgens leads to female development
• High testosterone levels (in men) cause
  • “Upstream” effects
    • Increased cell proliferation
    • increased cell death in the right hemisphere of the brain
    • Slowed prenatal development / slower brain development
      • resulting in altered cerebral lateralization²⁸
      • Possible consequences for men:
        • more susceptible to environmental stress
        • more variable behavioral outcomes¹⁷
        • increased risk of learning disabilities
        • increased risk of hyperactivity
        • prone to injuries and structural abnormalities in the left hemisphere over a longer period of time
    • increased neural lateralization (= specialization of the brain hemispheres)
      • Consequences: After a focal stroke, women are more likely than men to regain their ability to speak²⁹
    • Modulation of neurotransmission
    • Interaction with the genotype
  • “Downstream” effects
    • Influence on the choice of ecological niche
    • Impact on the triggering of environmental responses

1.2.1.2. Active Feminization¶

Ovarian hormones actively promote the feminization of neural circuits and behavior

1.2.1.3. Gradient Model¶

Hormones affect:

• Gender differences in behavior (e.g., in cognition, childhood play, and aggression)
• Variations in behavior within each sex
  • Women exposed to higher levels of androgens during prenatal development may exhibit more masculine traits (e.g., enhanced spatial abilities)

1.2.2. Sex Hormones and Dopamine¶

Pregnant rats subjected to enforced stress gave birth to male offspring with reduced testosterone levels and elevated dopamine levels in the striatum.³⁰ Furthermore, testosterone levels can indirectly influence neural development through so-called “downstream” effects: via the organism’s selection of experiential niches and the triggering of environmental responses.¹⁷

1.2.3. Sex Hormones and Sex-Dimorphic Brain Structures, Brain Functions, and Behavior¶

Sex hormones influence the development of brain structures and brain functions. This, in turn, influences behavior.¹⁰

For men who are taller:³¹

• Total brain volume
• White matter
• Cerebrospinal fluid
• Cerebellum
• Pons
• Amygdala
  • medial amygdala nucleus¹⁰
• Hypothalamus
• Anteromedial cortex
• Corpus callosum (unclear)³²

For women who are taller:³¹

• Gray matter
  • in the posterior, temporal, and inferior parietal regions of the brain
    • larger share
    • greater cortical thickness
• Hippocampus
• Frontal-orbital cortex
• Superior frontal and lingual gyri
• anterior commissure¹⁰
• Caudat (unclear)
• Corpus callosum (unclear)

Other differences:

• less lateralization (i.e., specialization) of cortical functions in women
  • lower prevalence of left-handedness
• Greater variation in extracellular striatal dopamine levels throughout the estrogen cycle in women³³
• Estrogens and progesterone modulate dopamine in the striatum and nucleus accumbens only in women³⁴
• A significantly greater increase in dopamine receptor density during the juvenile period in the striatum, nucleus accumbens, and prefrontal cortex of male rats (Andersen & Teicher, 2000).
• Total cerebral blood flow is higher in women³¹
• Full-blood serotonin levels are higher in women³¹
• Men synthesize serotonin more quickly³¹
• higher levels 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
• Emotional events are processed differently in the amygdala:³⁶
  • Women: primarily in the left amygdala
  • Men: primarily in the right amygdala
  • This lateralization could explain why men tend to react physically to emotional stimuli, while women tend to think things through rather than act on impulse

1.3. Gender-Specific Susceptibility to Neurotoxins¶

As discussed in the chapter “Etiology (of ADHD)“ , neurotoxins—especially during the prenatal period and childhood—are a significant risk factor for the development of ADHD.

The following reasons are cited for the male brain’s greater susceptibility to neurotoxins:³⁷

• lower levels of available glutathione than in women
• lower sulfate-based detoxification capacity than in women
• Neurotoxins and testosterone have synergistic effects
• a more pronounced neuroinflammatory response in men
• greater susceptibility to oxidative stress than women
• the lack of neuroprotective effects of female hormones (estrogens and progesterone), particularly with regard to reducing inflammation and oxidative stress

2. Theories on the Hormonal Mechanisms of Depression¶

2.1. The Risk of Depression Increases in Girls During Puberty¶

Girls were twice as likely as boys to be depressed only between the ages of 10 and 15. This 2:1 ratio was caused by changes in estradiol and testosterone levels—but not by FSH and LH—was independent of Tanner stage, and persisted as the children grew older.³⁸³⁹
A higher level of negative affect correlated with higher testosterone levels, higher cortisol levels, and lower levels of adrenal hormones, but not with changes in estradiol levels.⁴⁰

2.2. Probability of Depression and Hormonal Fluctuations During the Menstrual Cycle¶

Estradiol and progesterone levels are relatively low during menstrual bleeding. Estradiol levels rise during the follicular phase until the LH surge, at which point ovulation occurs. After ovulation, estradiol levels drop, while progesterone levels rise 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, marking the end of the cycle.⁴¹

The symptoms of depressive mood systematically vary with fluctuations in the menstrual cycle. In women, the likelihood of mood problems (i.e., depressive mood, apathy) is highest 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 and occurs most frequently before or during menstruation and less frequently during the ovulatory or premenstrual phases.¹⁰

Oral contraceptives altered mood variability throughout the day. Triphasic formulations (oral contraceptives with three hormonal phases) resulted in increased affective variability.⁴² Depressive mood typically occurs during the premenstrual period, when estradiol and progesterone levels decline.⁴³
In cases of PMS, suppression of ovarian function with leuprolide improved symptoms. However, in a subgroup of patients, these symptoms recurred after estradiol or progesterone replacement, suggesting that an abnormal response to hormonal changes is the cause of PMS mood problems.⁴⁴ In fact, women with premenstrual dysphoria showed an abnormal gonadotropin response to an estradiol challenge compared to other women:⁴⁵

• a stronger negative feedback response until the LH level reaches its nadir
• higher LH levels at the nadir
• more LH surge-like responses
• 50% higher LH AUC
• LH response was associated with VAS-rated symptoms
• the negative increment (AOC) correlated with bloating during the luteal phase
• The AUC of LH correlated with irritability
• Depressed mood was correlated with
  • Basal FSH levels
  • AUC of FSH during the negative feedback phase

2.3. Risk of Depression and Hormonal Fluctuations After Childbirth / During Menopause¶

15% of women develop symptoms of depression in the first six months after childbirth, when sex hormones decline rapidly and dramatically.¹⁰ A sharp drop in estradiol and progesterone levels after childbirth was associated with depression in women with a history of postpartum depression.⁴⁶

The onset of menopause is associated with a decrease in estrogen levels and a 2- to 4.3-fold increased risk of irritability and depression,^{4748 49} while the risk of depression is reduced after menopause.
The risk of depression was higher among women⁵⁰⁴⁹

• 2.5 times higher during menopause
• decreases after menopause
• reduced by a rapidly rising FSH curve
• elevated with high levels and increased variability of FSH
• elevated levels of LH with high concentrations and increased variability
• increases as estradiol levels rise and estradiol variability increases

Estrogen therapy during menopause significantly reduced depressive mood.⁴¹⁵¹
Low estrogen levels or dramatic changes in estrogen levels appear to increase the risk of depression.

The evidence on whether estradiol administration after childbirth, during perimenopause, or during menopause correlates with a reduction in depression is inconsistent. There are numerous studies supporting this as well as studies refuting it.¹⁰
Estradiol administration may accelerate the effects of antidepressants in menopausal non-responders.⁵²
Withdrawal of estradiol in rats exposed to high levels of estradiol and progesterone (to mimic levels during pregnancy) led to increased depressive symptoms.⁵³ Estradiol administration increased mobility in rats, suggesting an antidepressant effect of estradiol administration.⁵⁴⁵⁵
An inverted U-curve may also be at play here: optimal estradiol levels have a protective effect, while both low and high estradiol levels exacerbate depressive symptoms.
To investigate the relationship between estradiol levels and mood over a period of 30 or 60 days, daily measurements are required throughout the entire menstrual cycle.¹⁰

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

Estrogens modulate the central neurotransmitter systems involved in depression, particularly the serotonin system.^56485758

It is possible that the increased symptoms of ADHD before menstruation are due to reduced serotonin levels.⁵⁹ The lowest estrogen levels are not found before, but rather during menstruation (days 1 through 4 of the cycle) and in the first few days of the proliferative phase (days 5 through 14 of the cycle). There are no reports of a cycle-related increase in the need for ADHD medication during these periods.

2.5. Estrogens influence HPA activity¶

2.5.1. Estradiol Influences the HPA Stress Response¶

Estrogens, particularly estradiol, appear to enhance the stress response (i.e., the release of catecholamines) in the PFC.⁶⁰ Estradiol does not appear to have antidepressant effects under stressful conditions.⁶¹

Estrogens lower the threshold for prefrontal cortical dysfunction resulting from stressful experiences.⁶⁰
Estrogens, particularly estradiol, thus increase the risk of depression by altering the thresholds for prefrontal activation in response to stress.

According to another view, estradiol is thought to have a moderating effect on depression through its 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.⁶² Estrogen significantly reduced the HPA axis stress response in postmenopausal women. Responses to ACTH, cortisol, and norepinephrine were attenuated.⁶³

The antidepressant effect of estradiol may also depend on optimal corticosteroid levels, suggesting an interaction between the effects of estradiol and the tone of the HPA axis.⁶⁴

2.5.2. Progesterone enhances the HPA stress response¶

The progestin progesterone appears to amplify the stress response of the HPA axis in postmenopausal women. Responses to ACTH and cortisol were attenuated, while the response to norepinephrine was increased.⁶³ Women with PMS did not exhibit the normal increased HPA axis response to physical exertion during the luteal phase. In healthy controls, progesterone caused an increased HPA axis response to treadmill exercise tests. Estradiol did not cause an increased HPA response.⁶⁵

3. Hormonal Mechanisms Underlying 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 can modulate the processes that govern the development of dopaminergic circuits and influence associated deficits in cognitive control and reward processing in ADHD.

High testosterone levels can affect dopaminergic neural circuits by slowing overall neural development and leaving the dopaminergic components of the brain vulnerable for a longer period during prenatal development. Thus, prenatal testosterone levels could moderate the relationship between prenatal risk factors (including genes, environmental toxins, low birth weight, and maternal smoking) and the developing neurobiology relevant to ADHD.¹⁷

Polycystic ovary syndrome (PCOS) is associated with hyperandrogenism, or significantly elevated androgen levels. PCOS during pregnancy increases the risk of ADHD by 95% only in boys.^66
67
Women with PCOS themselves had an increased risk of ADHD, although no association was found between their testosterone levels and their ADHD symptoms.⁶⁸
For more information, see Prenatal Stressors as Environmental Causes of ADHD in the chapter “Development,”

Maternal smoking increases fetal testosterone levels.⁶⁹ Prenatal smoking increases the risk of ADHD in children by 1.9 times⁷⁰ to 2.7 times⁷¹. Other studies have also found significantly elevated risk levels.^72737475
For more information, see Prenatal Stressors as Environmental Causes of ADHD in the chapter on Development,

3.1.2. Direct Modulation of Dopaminergic Circuit Development by Sex Hormones¶

The masculinizing effects of sex hormones directly influence the prenatal development of dopaminergic neural circuits and dopamine function in

• Nucleus accumbens
• Striatum
• PFC

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

To date, there are no known animal studies involving prenatal hormonal manipulation in relation to ADHD. There are only studies involving hormonal manipulation during early childhood. The applicability of the SHR animal model of ADHD with regard to sex differences in ADHD is questionable, as the animals do not exhibit the sex differences in behavioral symptoms observed in humans. Female SHRs appear to be more impulsive than males, particularly during diestrus.⁷⁶
SHR (spontaneously hypertensive rat) and Wistar (WKY) control animals were exposed to testosterone during the early developmental phase (10th postnatal day). On the 45th postnatal day, SHR animals exhibited:⁷⁷

• additional deficits in spatial memory in the water maze (but not in the WKY)
• Signs of a dysfunctional HPA axis:
  • high basal ACTH levels
  • low corticosterone levels
• Suppression of tyrosine hydroxylase immunoreactivity in the frontal cortex
  The authors view this as supporting the hypothesis that, in the presence of a genetic predisposition to ADHD, early exposure to androgens may contribute to more severe ADHD symptoms.

High testosterone levels may increase the risk of ADHDby causing a delay in the maturation of dopaminergic innervation and metabolism, as well as by increasing the lateralization of the underlying dopaminergic neural circuits and enhancing the reuptake of dopamine neurotransmission.⁷⁸
Pavlovian conditioning of a visual stimulus paired with food was:⁷⁹

• weaker in female SHRs than in male SHRs
• Wistar rats of both sexes are the same

A gonadectomy (castration) altered Pavlovian conditioning:⁸⁰

• in male and female SHRs: enhanced conditioning
• in female Wistar rats: unchanged
• in male Wistar rats: reduced conditioning

SHR mice exhibited increased motor activity following androgen administration during early childhood. Wistar mice, on the other hand, showed no change.⁸¹

In male castrated SHR rats, testosterone increased the density of tyrosine hydroxylase-immunoreactive fibers (an indicator of catecholamine innervation) in the frontal cortex to a greater extent than in WKY rats. The authors see this as a possible explanation for why high testosterone levels in adulthood do not increase ADHD symptoms in either SHR or men.⁸²

These results suggest that dopaminergic neural circuits and cognition in SHR are influenced by hormones.¹⁰
This also appears to affect ADHD symptoms.

In contrast, girls and boys with ADHD alike exhibit weak cognitive control.^{8384 85} Boys with ADHD-I showed fewer cognitive impairments than boys with ADHD-C and girls with ADHD-I or ADHD-C.⁸⁶
However, studies conducted to date have consistently used gender as a proxy, without examining the direct effect of hormones themselves on cognitive control and reinforcement learning.

3.2. ADHD and externalizing symptoms are positively correlated 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 characteristics such as externalizing problems and sensation seeking. Contrary to the conclusion reached by Martel et al.¹⁰, however, the available studies do not suggest a tendency for this to be primarily the case among boys.

Several studies examined finger length ratios (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 more severe ADHD symptoms. The results are inconclusive—at least with regard to gender differences.

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

• Hyperactivity

  • only for girls (preschool age)⁸⁷
  • only in girls (preschool age), including impulsivity⁸⁸
  • only in women (of college age) on the left hand (as well as impulsivity)⁸⁹
  • only in boys (school-age), as well as behavioral problems⁹⁰
  • gender-neutral⁹¹

• Impulsivity⁹²

• Aggression

  • in adult men⁹²

• social problems

  • only for boys (school-age)⁹⁰

• Sensation seeking (along with high testosterone levels)⁹³

  • Sensation seeking shows gender differences in favor of boys and is associated with externalizing disorders.⁹⁴⁹⁵¹⁰

• ADHD

  • in adult men⁹²
  • Only in boys, most clearly in ADHD-I.⁹⁶
  • in boys and girls (ages 7 to 15) with ADHD-I (lower CEOAEs and lower 2D:4D ratios) than in those with ADHD-C or in the control group⁹⁷
  • among German men, but not among German women or Chinese men or women.⁹⁸
  • One study found no correlation between the 2D:4D ratio and ADHD symptoms or ADHD subtypes in children with ADHD.⁹⁹

• Inattention

  • gender-neutral⁹¹

  • Only in women, on the left hand (during college years).⁸⁹

  • A low right-to-left 2D:4D ratio / increased ADHD inattentiveness symptoms could be mediated by reduced conscientiousness.¹⁰⁰

• Alexithymia

  • in adult men⁹²

• Addiction

  • in adult men⁹²

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

• prosocial behavior
  • only for girls of school age⁹⁰

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 controls.¹⁰¹

A study based on the gender distribution of siblings found evidence of increased intrauterine testosterone exposure in ADHD, ASD, and reading difficulties, although this was significant only for reading difficulties.¹⁰²

3.3. ADHD and Reduced Prenatal/Postnatal Estrogen Levels¶

Lower prenatal and postnatal estrogen levels also appear to be correlated with ADHD symptoms.
Women with Turner syndrome or a single X chromosome have ovaries that produce reduced prenatal and postnatal estrogen levels.¹⁰³ These women also have a characteristic cognitive profile with deficits—some of which are similar to those seen in ADHD—in:

• visual-motor integration
• Pattern recognition
• Face recognition
• motor speed
• Coordination
• Attention
• Planning (attention variable test, Familiar Figures Test, Tower of Hanoi)
• in right-lateral, spatially demanding executive functions¹⁰⁴

A study of the menstrual cycle in young women with regular cycles found that reduced estradiol levels, in conjunction with elevated progesterone or testosterone levels, correlated with more severe ADHD symptoms the following day, particularly among women with high impulsivity. Phase analyses suggested an increase in ADHD symptoms both in the early follicular phase and in the early luteal phase, or after ovulation.¹⁰⁵

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

Estrogens genetically reduce the activity of COMT, the enzyme that breaks down dopamine,^{106107 108} in the PFC, while COMT levels were increased in the prostate¹⁰⁹

Estrogen levels in women are low after menstruation (days 1–9), then rise steadily until ovulation, reaching their peak (days 10–15), drop to one-third of the peak level at ovulation (days 16–17), rise to two-thirds of the peak level by day 24, and then decline until menstrual bleeding begins (day 27).¹¹⁰

Shortly before ovulation, as well as (to a slightly lesser extent) about 1 week after ovulation, dopamine breakdown in the PFC is therefore significantly reduced (dopamine levels are elevated, possibly resulting in a reduced need for ADHD medication). Before menstruation, dopamine breakdown is noticeably increased (dopamine levels are reduced, potentially leading to an increased need for ADHD medication).
As a result, COMT is, on average, 30% less active in women than in men.¹¹¹¹¹²
Since COMT accounts for at least 60% of dopamine breakdown in the PFC (and a maximum of 15% of dopamine breakdown in the striatum¹¹³ ), women in the estrogen-rich phase just before ovulation experience a nearly 20% reduction in dopamine breakdown in the PFC.

The consequences are that some women may require a lower dose of PFC-acting dopaminergic medications (such as stimulants or atomoxetine) for PFC-mediated ADHD symptoms—such as inattention—during periods of high estrogen levels (3 –4 days before ovulation and approximately one week after ovulation) a lower dose of medications that act on the dopaminergic system in the PFC (such as stimulants or atomoxetine) than during periods of low estrogen levels (days before menstruation).¹¹⁴ This depends, among other factors, on the COMT gene variant in each individual case.
The effect of estrogen depends on the baseline condition and follows an inverted U-shaped curve. In healthy young women, the influence of fluctuating estradiol levels on working memory depended on the COMT Val158Met genotype and the measured COMT enzyme activity. Val/Val carriers have higher COMT activity and thus lower baseline prefrontal dopamine levels. In these women, high estradiol improved working memory performance because dopamine levels rose to the optimal range. In Met/Met carriers, however, high estradiol levels drove dopamine levels beyond the optimal range and impaired performance. For cycle-dependent dose adjustment, this means that the direction of the necessary adjustment does not have to be the same for all women, and that a blanket premenstrual dose increase is not always appropriate.¹¹⁵
This could further explain why women are more sensitive than men, since a slightly elevated dopamine level increases the intensity of perception.

Since the COMT Met-158-Met variant—which causes dopamine degradation in the PFC to be five times slower—is also common in borderline personality disorder, and estrogen further slows COMT-mediated dopamine breakdown, this association could potentially provide a clue to explaining the higher prevalence of borderline personality disorder among women (75% of people with borderline personality disorder are women).¹¹⁶

According to a study, the COMT Val158Met variant (also known as rs4680) is associated with an increased perception of the placebo effect in various treatments.¹¹⁷¹¹⁸

The reduction in dopamine breakdown in the PFC caused by estrogens via COMT means that (mild) stress can have different effects depending on gender.
In males and male animals, the slight increase in dopamine levels in the PFC caused by mild stress enhances mental performance compared to the resting state. In females, however, the slight increase in dopamine in the PFC caused by mild stress (on average) leads to a decline in cognitive performance. This difference appears to be caused by estrogen. The decline in cognitive performance due to mild stress occurs only during the estrogen-rich phase shortly before ovulation. During the estrogen-poor phase before or during menstruation, mild stress enhances cognitive performance in women just as it does in men.^{11411960120121122123}

The COMT promoter contains two estrogen response elements. At physiological concentrations, estrogen inhibits COMT mRNA expression in cells with estrogen receptors, and the reduced mRNA levels are associated with decreased COMT activity. Consistent with this, women have 20 to 30% lower COMT activity than men.¹²⁴On the one hand, the study describes how estrogen inhibits COMT activity. On the other hand, it refers to an older finding indicating that women with high estrogen levels exhibit higher COMT activity than women with low levels. The authors cite the inhibition as the established regulatory mechanism without resolving the contradiction.

Although the claim that estrogen inhibits COMT is well-documented at the cellular level, it is not clear whether this translates into measurable differences among women with different hormonal profiles.

3.3.2. Estrogens increase dopaminergic activity in the striatum and nucleus accumbens¶

17β-estradiol (E2):¹²⁵

• increases the activity of dopamine neurons and the release of dopamine from dopamine terminals in the striatum by directly inhibiting GABAergic neurons, which reduces GABA levels and thereby decreases GABA-mediated inhibition of dopaminergic terminals
• increases dopamine release in the nucleus accumbens by
  • acts directly on GABA or DA neurons there
  • acts on GABAergic neurons in the medial preoptic area (MPOA), which increases their inhibitory transmission to GABA interneurons in the VTA. This increased inhibition of GABAergic interneurons in the VTA leads to reduced inhibitory tone in the VTA and increased DA transmission.

3.3.3. Estrogens increase oxytocin levels¶

Since estrogens increase oxytocin levels, all of oxytocin’s effects are likely to be amplified in women.

Oxytocin

• reduces ACTH
• likely 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 styles may be linked to the female “Tend and Be Friend” stress response¹²⁶¹²⁷

For more information, visit ⇒ Oxytocin

Oxytocin also affects dopamine levels. For more on this, see Oxytocin in the article What Regulates Dopamine

3.3.4. Estrogens reduce learning and memory problems¶

High estrogen levels help alleviate deficits in learning and memory.¹²⁸
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 starting at age 35 (see “late-onset ADHD” in women).

3.3.5. Symptoms of ADHD and other mental health issues fluctuate with the menstrual cycle¶

The symptoms of many mental health conditions systematically vary in response to fluctuations in the menstrual cycle.

• During the period of peak progesterone levels (mid- to late luteal phase), the following are often elevated:
  • Mood problems (i.e., depressed mood, apathy)¹⁰
• As estrogen levels drop (before menstruation), the following are often elevated:
  • Negative affect¹⁰, depression¹²⁹
  • ADHD¹²⁹
  • Schizophrenia¹²⁹
  • Bipolar Disorder¹²⁹
  • ASS¹²⁹¹²⁹
  • Generalized anxiety disorder¹²⁹
  • PTSD¹²⁹
  • Eating Disorders¹²⁹

A study reports increased hyperactivity and inattention during the first third of the cycle, normal levels during the first third, decreased hyperactivity and inattention during the first part of the second third of the cycle, and decreased hyperactivity toward the end of the third third of the cycle.¹³⁰

The intensification of PMS symptoms toward the end of the luteal phase (before and during the first few days of menstruation) may be a consequence of the decline in estrogen levels rather than a consequence of their lowest levels. Since estrogen increases serotonin levels, a decline in estrogen causes a decline in serotonin.⁵⁹ Although estrogen levels decline in the days leading up to menstruation, the lowest estrogen levels are found during menstruation (days 1 through 4 of the cycle) and in the first few days of the proliferative phase (days 5 through 14 of the cycle). For these periods, there are no reports of a cycle-related increase in the need for ADHD medication.
Estrogens also influence dopamine. For more on this, see Estrogens promote dopamine in the striatum and PFC in the article How Dopamine Is Regulated

3.3.6. Fluctuations in Symptoms During Pregnancy¶

One review reports that symptoms subside during pregnancy due to elevated estrogen levels at that time in¹²⁹

• ADHD
• Schizophrenia

4. Sex Hormones and ADHD¶

Decreased estradiol levels, in conjunction with elevated progesterone or testosterone levels throughout the menstrual cycle, correlated with more severe ADHD symptoms the following day, particularly among women with high impulsivity. ADHD symptoms increased both during the early follicular phase and the early luteal phase, or after ovulation.¹⁰⁵

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

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

STS also catalyzes the sulfation of dopamine sulfate to dopamine in the blood. For more information, see Sulfation by Sulfotransferases in the article Dopamine Degradation.

Sulfated and unsulfated steroids can affect GABA-A and NMDA receptors in the brain.¹³¹ Both DHEAS and its unsulfated form, DHEA, inhibit the GABA-A receptor and activate the NMDA receptor.¹³²
Learn 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 exhibit clear ADHD symptoms¹³³¹³⁴ This appears to be accompanied by elevated serotonin levels in the hippocampus and increased motivation.¹³⁵
• The STS genetic disorder X-linked ichthyosis (steroid sulfatase deficiency) is associated with an increased risk of ADHD, ASD, and social communication disorders.¹³⁶
• DHEAS and STS influence attention.¹³⁷ Administration of DHEAS improved performance on the five-choice serial reaction time task under conditions requiring high levels of attention, while STS inhibition impaired accuracy. No effects on baseline motor activity were observed.

STS * E (other names: Arylsulfatase C, Steroid Sulfatase, Sterol Sulfatase, dehydroepiandrosterone sulfate sulfatase, steroid 3-sulfatase, steroid sulfate sulfo-hydrolase, 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.^{138139137133140}

A study found that among boys and girls with ADHD:¹⁴¹

• DHEA-S decreases
  • Low DHEA-S levels correlated with higher impulsivity
• SHBG unchanged
  • Low SHGB was correlated with increased ADHD symptoms
• Free testosterone remains unchanged
  • No correlation between free testosterone and ADHD symptoms

In SHR (spontaneously hypertensive rats), a comparison of serum levels with those of WKR (Wistar-Kyoto rats) revealed:¹⁴²

• Testosterone and free estriol levels were elevated in 10-week-old SHR and WKR mice compared to 5-week-old SHR and WKR mice
• Progesterone, corticosterone, and cortisol levels were elevated 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 and ADHD

5. Gender Differences in the Dopamine System¶

In women / female animals, the following was found:¹⁴³

• a “more sensitive” dopamine system, at least during estrus¹⁴⁴
  • Dopamine release is more sensitive to weaker stimuli
  • feedback inhibition is lower
  • which can lead to increased dopamine release in certain situations
• higher levels of DRD2 in the putamen (striatum)¹⁴⁵
• elevated dopamine levels in the caudate nucleus¹⁴⁶

This could affect the efficacy and effectiveness of stimulants.

6. X Chromosome¶

Rare X-linked genetic variants pose a risk of ADHD, ASD, and Tourette syndrome, particularly for boys and men.¹⁴⁷

7. Differences in ADHD Symptoms Between Boys and Girls¶

Some studies cast doubt on the idea that the likelihood of individual symptoms occurring is gender-specific—that is, that women are more likely to develop the ADHD-I subtype and men are more likely to develop the ADHD-HI subtype. One study found that boys and girls do not differ in terms of symptoms of inattention and hyperactivity.¹⁴⁸ Another study found a gender-independent distribution of symptoms among adults.¹⁴⁹

In contrast, several meta-analyses found gender-specific differences:

Boys with ADHD have higher levels of:

• Hyperactivity¹⁵⁰¹⁵¹
• Inattention¹⁵¹
• Impulsivity¹⁵⁰¹⁵¹
• externalizing problems¹⁵¹¹⁵²

Girls with ADHD had higher scores in:

• Inattention¹⁵⁰
• intellectual disabilities¹⁵¹
• internalizing problems¹⁵¹¹⁵²
  • e.g., anxiety symptoms that occur much more frequently¹⁵³

Women with ADHD were particularly likely to

• Organizational problems¹⁵⁰
• Verbiage¹⁵⁰

8. Estrogens as a Resilience Factor Against Stress¶

Estrogens may increase cognitive resilience to stress in women.¹⁵⁴

Viewed from a distance, a higher tolerance for suffering (or, to put it another way, a reduced perception of suffering) could be one possible explanation for why women with ADHD are, on average, diagnosed so much later than men.

9. Changes in Symptoms Over Time by Gender¶

While girls typically experience a significant surge in symptom severity during early adolescence, boys exhibit increased symptom severity as early as childhood. For both genders, early adolescence is associated with a risk of a significant increase in symptoms.¹⁵⁵

10. ADHD Symptom Severity by Gender¶

Data from rating scales and clinical diagnostic interviews found: (meta-analysis, k = 52, n = 18,408)¹⁵⁶
Men exhibited statistically significantly more severe symptoms of hyperactivity and impulsivity than women.
Boys exhibited a statistically significant higher level of hyperactivity/impulsivity than girls.
In adulthood, men exhibited a statistically significant higher level of inattention than women, while there was no longer any difference in the hyperactivity/impulsivity dimension.
All statistically significant differences were of small effect size.
Data from clinical interviews with children or adults show no significant gender-specific differences in symptom severity.

In a large study, girls with autism who also had ADHD showed significantly more severe symptoms of ADHD, learning disabilities, and ODD than boys with ASD and ADHD.¹⁵⁷

A study of n = 900 adults with ADHD found that, compared to men, women¹⁵⁸

• a higher severity of ADHD (p < 0.001)
• higher rates of depression (p = 0.003)
• increased anxiety (p < 0.001)
• lower substance use (p < 0.001)
• reduced functional ability (p = 0.039)
• a greater degree of disability (p = 0.001)
• Unchanged distribution of ADHD subtypes
• Unchanged age at symptom onset
• a later ADHD diagnosis
• ADHD-C correlated with
  • greater clinical severity
  • more severe depression
  • increased anxiety
  • more severe impulsive symptoms
  • increased substance use
  • more severe disability

11. Higher Divorce Rate Among Women with ADHD¶

Women (in Japan) with ADHD appear to have even higher divorce rates than men with ADHD.¹⁵⁹

12. More Comorbidities in Women with ADHD¶

Women (in Japan) with ADHD appear to have a higher rate of comorbid conditions than men with ADHD.¹⁵⁹

13. No Gender-Specific Differences in the Social Behavior of Individuals with ADHD and ASD¶

A meta-analysis found no gender-specific differences in social and communication behaviors among individuals with ADHD and ASD.¹⁶⁰

14. COMT Gene Variant Influences Stress Perception in a Gender-Specific Manner¶

Polymorphisms in the COMT gene primarily affect dopamine levels in the PFC and have barely any effect on dopamine levels in other brain regions. Similarly, norepinephrine levels in the PFC are not influenced by COMT.¹⁶¹

A distinction must be made between:¹⁶²

• 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 results in dopamine breakdown that is four times slower than that of the COMT Val-158-Val variant.
COMT-Met-158-Met carriers differ from COMT-Val-158-Val carriers¹⁶³

• more mentally capable (more efficient, not more intelligent)
• improved executive functions of the PFC
• more sensitive to stress (high dopamine levels (only) in the PFC even at rest; a significant increase in dopamine (only) in the PFC even in response to mild stress)¹⁶⁴
  • Consequently, amphetamine medications are likely to be less effective (AMP impairs working memory under high stress)¹⁶⁵. We suspect that this finding may also apply to MPH.
• more anxious and
• more sensitive to pain.

COMT is influenced by estrogen. In women, the COMT Val-158-Val polymorphism is associated with better executive function and mental performance during periods of high estrogen levels than the COMT Met-158-Met polymorphism.¹⁶⁶

15. Could Thyroid Hormones in Women Be a Masking Factor for ADHD?¶

The updated 2018 European Consensus on the Diagnosis and Treatment of ADHD in Adults³ highlights the specific 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 may also be 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 more closely.¹⁶⁷

With regard to autism, the first evidence of masking behavior in female mice has been found.¹⁶⁸

16. Creatine, Choline, Glutamate/Glutamine in the ACC and Cerebellum¶

A study found significant gender- and age-specific differences in creatine, choline, and glutamate/glutamine in the ACC, as well as significant age-specific differences in choline and glutamate/glutamine in the cerebellum.¹⁶⁹

17. Gender Differences in the Effects of ADHD Medications¶

ADHD medications appear to work somewhat differently in women than in men.¹⁷⁰
MPH showed

• for girls:
  • less severe symptoms and greater improvement in symptoms over the long term
  • a stronger effect of MPH at the start of the day, with the effect wearing off earlier
    • Taking MPH once a day does not seem 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 may be more helpful for girls and women with ADHD than for boys and men

18. PMS and ADHD Symptoms — Increased Need for Medication Before Menstruation¶

Many women with ADHD report that the severity of their ADHD symptoms fluctuates throughout their menstrual cycle.
It is recognized that in the 2 to 5 days before the onset of menstruation, as progesterone levels drop at the end of the luteal phase—along with the PMS or PMDD that frequently occurs during this time—ADHD symptoms may also increase.¹⁷¹ Experienced physicians recommend increasing ADHD medication by approximately 30% during this time.

19. More Severe Perimenopausal Symptoms in ADHD¶

Among women with ADHD, there were significantly higher overall scores for perimenopausal symptoms, as well as a higher prevalence of severe perimenopausal symptoms (54.2% vs. 30.1%).¹⁷²