Attention Deficit Hyperactivity Disorder (ADHD) in Females – Gender Differences in Neurobiology, Assessment & Management

SEX DIFFERENCES IN NEURODEVELOPMENT

Neurodevelopment is non-linear, with the brain reaching 80% of its adult size by age two. [Gilmore et al., 2018]

After five years, the main processes in neurodevelopment include neuron growth pruning and cortical organisation.  In puberty, the process of synaptic pruning accelerates and reduces synaptic density to 60% of the maximum.  Synaptic pruning is a natural process in which the brain eliminates extra synapses, allowing the neurons to become more efficient at signal transmission. [Hanamsagar, 2015]

Differences in Glial Maturation: 

• It is hypothesised that the sex differences are attributed to glial maturation, which occurs faster in females than in males, with brain cortical volume growth slower in males than in females. [Hanamsagar, 2015]

Female Protective Effect: 

• The female protective effect hypothesises that females may need to reach a higher threshold of genetic and environmental exposures for ADHD to be expressed. 
• The rapid glial maturation in males in the absence of a protective effect (which females have) can lead to widespread inflammation and neuronal cell death.  The innate protective mechanism protects females against this neurodevelopmental insult. [Hanamsagar, 2015]

Differences in the trajectory of brain development: 

• Females reach total cerebral volume at 10.5 years on average and males at 14.5 years. [Lenroot et al., 2007]
• Thus, cross-sectional studies comparing girls to boys at the same age in ADHD may be misleading as girls are at a different neurodevelopmental stage than boys.  This has significant implications in diagnosis.

Differences in white and grey matter development: 

• White matter volume increases linearly in both sexes at a faster pace for females than males. [Koolschijn & Crone 2013]
• Grey matter volume is non-linear, and regionally-specific differences occur in boys and girls.  
• Reduced volumes of ventral anterior cingulate gyrus are found in boys with ADHD compared with normal controls. At the same time, girls with ADHD showed increased volumes of ventral cingulate gyrus compared with typically developing girls. This area is linked to emotional dysregulation symptoms. [Villemonteix et al., 2015]

Role of Hormones: 

Hormonal effects on the brain during development can be divided into two components:

• Organisational effects in perinatal development
• Activational effects at the pubertal transition.

Cerebral Lateralisation Theory: [Geschwind & Galaburda, 1985]

High levels of testosterone lead to increased neural lateralisation (i.e., specialisation of each brain hemisphere) and slower brain development, making the brain vulnerable to neurodevelopmental insults. This theory of cerebral lateralisation postulates that exposure to fetal testosterone slows normal structural development in the left hemisphere of the brain making males more prone to learning difficulties and hyperactivity.

There are three direct developmental mechanisms related to testosterone that appear to increase male vulnerability to subtle insult in the pre-and perinatal period:

• Increased cell proliferation and death
• Slower prenatal brain development
• Increased lateralisation of brain function.

Hormones and Dopamine Systems:

• This cerebral lateralisation through exposure to high levels of testosterone also affects dopamine systems via a maturational delay in the development of dopaminergic innervation and metabolism and increasing dopamine reuptake increasing the risk for ADHD. [Andersen et al.,  2000]
• Estrogen and progesterone appear to modulate dopamine in the striatum and nucleus accumbens in females but not in males. A pubertal increase in oestrogen is known to increase dopamine receptors. With dopamine playing a critical role in the pathogenesis of ADHD, the hormonal influences may affect the development of ADHD, either increasing or decreasing the likelihood of the condition. [Martel et al., 2009]

Neurophysiology and EEG changes: 

Four to eight years:

• Boys with ADHD show a less right lateralised frontal alpha (alpha waves are present during awake state but resting) symmetry.
• Girls show a more right lateralised asymmetry pattern. 

Adolescence:

• Boys show widespread theta activity
• Girls show localised frontal enhancement of theta activity. 

Arousal Model vs Developmental deviation model [Hermens et al., 2005]

• Females show greater involvement of central and autonomic function, which is consistent with the arousal model emphasis. According to the arousal model, hyperactivity and sensation-seeking are autoregulatory reactions to an unstable brain arousal regulation. [Huang. et al., 2019]
• Males show widespread theta activity, which is consistent with a developmental deviation model. the developmental deviation model, also known as maturational deviance, proposes that maturation is not necessarily lagging, but that it is not approaching normality or maturation, and that it is unlikely to do so at any stage during the lifespan. [Barry et al., 2003] 

SEX DIFFERENCES IN NEUROBEHAVIOURAL PROFILE IN GIRLS WITH ADHD - CLINICAL FEATURES

Females present with a specific neurobehavioural profile that may contribute to an under-diagnosis and subsequent under treatment. 

Key differences in females with ADHD:

Nature of Symptoms: 

• Symptoms of ADHD may be more internalised in nature, leading to alternative diagnoses such as personality disorders or mood disorders. 
• Low mood, emotional lability or anxiety may be prevalent in females with ADHD. 
• Externalising behaviours and conditions may present in females with ADHD. However, these are less common than in males with ADHD.   
• Difficulties with emotional lability and emotional dysregulation may be more severe in girls with ADHD, which may attract a personality disorder diagnosis.

Hyperactivity – Impulsivity symptoms:

• Girls show a lower severity of hyperactivity and impulsivity with a greater compensatory behaviour in girls, such as compliance, resilience and coping strategies.  The impact of this is the delayed diagnosis, higher risk of adverse outcomes and increased psychiatric morbidity.  
• Early meta-analysis of gender effects has lower hyperactivity-impulsivity or all ADHD symptoms in girls than boys, although individual studies show mixed results. [Gershon J, 2002]; [Gaub & Carlson, 1997]
• Borderline personality traits in ADHD tend to be associated with women with hyperactive-impulsive symptoms being associated with self-harming behaviours. 

Inattention Symptoms:

• Inattention in girls and women with ADHD may present as being easily distracted, disorganised, overwhelmed and lacking in effort or motivation.
• Girls may have more difficulty with tasks involving independent planning (particularly mental planning).  
• Females may suffer more general impairments in intellectual functioning.

Course of ADHD

• Symptoms are pervasive and impairing rather than transient or fluctuating. 
• ADHD symptoms may become more obvious later in females during periods of social or educational transition. 
• Symptoms may be exacerbated by hormonal changes during the menstrual cycle, pregnancy or menopause. 

Comorbidities: 

• Greater risk of severe mental illness such as schizophrenia and admissions to inpatient psychiatric hospitals in adulthood.  
• Greater risk of all eating disorder syndromes
• Greater risk of fibromyalgia and chronic fatigue syndrome.  
• Greater risk of alcohol and cannabis use when compared to males

The key message is not to disregard females because they do not present with the externalising behavioural problems or the disruptive, hard to manage presentation (eg: engaging in boisterous, loud behaviours) commonly associated in males with ADHD.Females with ADHD may be overlooked and/or their symptoms misinterpreted, particularly for those in highly structured environments, receiving a high level of support and for those who have developed strategies to mask or compensate for their difficulties. [Young et al., 2020]

Clues to diagnosis of ADHD in females across the life-span. [Young et al., 2020]

KEY PRINCIPLES IN ASSESSMENT OF FEMALES WITH ADHD

Many questionnaires used in the diagnosis of ADHD may not be sensitive to female norms.  Ones  that provide female norms with cut-offs more sensitive to female presentation include the following:  

• Conners’ Comprehensive Behavior Rating Scales (CBRS) 6-18
• Strengths and Difficulties Questionnaire (SDQ) [Goodman, 1997]
• Conners’ Adult Rating Scales (CAARS) [Conners et al., 1998]

Clinical interviews:

Three clinical interviews prompt the assessor to consider the presence of co-existing conditions (which may differ between males and females);

1. ADHD Child Evaluation (ACE)
2. ACE+ [Young, 2016]
3. The Development and Well-being Assessment (DAWBA) [Goodman et al., 2000]

The Nadeau & Quinn checklists are also useful to indicate possible ADHD in girls and women, providing structured self-enquiry of ADHD symptoms and associated problems, including a range of difficulties such as learning problems, social/interpersonal and behavioural problems. [Nadeau et al., 2015], [Nadeau et al., 2002]

Recommendations in Diagnosis of ADHD in females: [Young et al., 2020]

• Findings with scales and interviews should be interpreted cautiously. Rigid adherence to cut-offs may lead to a higher proportion of false positives or negatives.
• Small modifications to questions may assist in capturing ADHD in females. e.g. excessive giggling and talking vs excessive talking
• Examine factors that may mask or moderate behaviour in different settings, e.g. compensatory strategies or accommodations at home or school. Coping strategies may be overt, such as substance use or social network by forming damaging relationships (for example, joining a gang, engaging in promiscuous and unsafe sexual practices, or criminal activities) or covert such as avoiding specific events, settings or people, not facing up to problems, spending too much time online or not seeking out help when needed.
• Recognise common co-occurring conditions in females with ADHD (ASD, tics, mood disorders, anxiety, eating disorders, fibromyalgia and chronic fatigue syndrome). 
• Screen for undiagnosed ADHD in treatment-resistant anxiety and/or depression.

Collateral information

• Where female norms are not available, greater emphasis on collateral information is required.
• Objective neuropsychological test results are not specific markers of ADHD but may provide additional information.
• The Qb scales have female-specific normative data and may therefore be more sensitive. QbTest [Ulberstad, 2012]
• Symptoms related to excessive talking, blurting out answers, fidgeting, interrupting and/or intruding on others have been reported more frequently endorsed by women than men with ADHD.  

PHARMACOLOGICAL MANAGEMENT IN FEMALES WITH ADHD

Read a detailed review on the management of ADHD.

Stimulant medications show good efficacy for improving ADHD symptoms in children and adults, and the response is comparable in females and males. However, girls with ADHD are less likely to be prescribed stimulant treatment than boys with ADHD and are likely to start treatment at an older age.

• Medication recommendations do not differ by sex. 
• Consider treating ADHD symptoms first and monitor for improvement when mood symptoms are comorbid but not pervasive.
• Take into account appetite suppression as a side-effect of stimulant medication, particularly if eating disorders (higher rate in females with ADHD) are of concern.
• Consider the risk of substance abuse while on ADHD medication.
• ADHD symptoms can become worse and particularly difficult to manage during pregnancy and post-natal period given additional life pressures.
• Treatment with ADHD medication is not recommended in pregnancy or breastfeeding.
• Medication can be timed around breastfeeding to minimise transfer between mother and child.
• Higher estrogen and lower levels of progesterone are associated with greater subjective stimulation after amphetamine in women, and these hormonal influences contribute to sex differences in response to amphetamine. Thus, dose adjustments may be needed depending on the phases of the menstrual cycle. [White et al., 2002]
• While there is no strong evidence for this approach, a consensus group supported dose adjustments. It noted that dose adjustments might be easier to manage for adult women who can take more control of their dosing than adolescent girls who respond better to routine. [Young et al., 2020]
• A case study showed a positive response to augmentation with an antidepressant (fluoxetine) during the immediate pre-menstrual period to reduce moodiness, irritability and inattention normally well controlled through stimulant medication alone. [Quinn, 2005] Read more on the management of PMDD
• Anecdotal accounts of symptom exacerbation in women during the post-menopausal period have been reported, and the use of hormone replacement therapy may be beneficial. [Young et al., 2020]

My personal experience in treating females with ADHD is that female patients can be sensitive to activating effects of stimulants, particularly dexamphetamine. Dexamphetamine is particularly implicated as it has serotonergic potentiation and a more potent dopaminergic potentiation than methylphenidate. We know that some patients have similar activation phenomenon with SSRIs initially due to the activation of the 5-HT2A receptor in the limbic system. The 5-HT activation plus dopaminergic potentiation can be particularly activating , especially in females with heightened emotional arousal symptoms as part of their ADHD.

This is consistent with the cognitive and arousal model in females as described earlier. I would recommend a start low; go slow approach. Furthermore identifying the patient’s menstrual phase is beneficial as some patients may experience an exaggerated effect of stimulants during the luteal phase due to the enhanced effect of estrogen on dopamine. 

Females may require combination mood stabilisers (e.g Lamotrigine) and/or alpha-2 agonists such as clonidine as a buffer in addition to stimulant treatment to reduce hyperarousal / activation which can then enhance tolerability to stimulants, thus providing maximal benefit for the ADHD symptoms but also reducing the activation/ hyperarousal side effects that can occur in some female patients.  

Estrogen plays an important role in dopaminergic modulation and is of significant importance in the Prefrontal Cortex (PFC) (key region involved in ADHD), a region with high amounts of estrogen compared to other brain areas. Estrogen in the PFC affects dopaminergic signalling and influences working memory, impulsive and emotional behaviours. [Del Rio et al., 2018]

Due to the reduction in estradiol levels, patients during perimenopausal and postmenopausal period may be especially vulnerable to relapse of ADHD symptoms or new onset ADHD diagnoses with associated comorbidities. 

In my experience, female patients with a background of a previously undiagnosed childhood or adult ADHD can present with severe melancholic depression (associated with reduction of dopamine in PFC) during perimenopausal and menopausal periods. In such patients, broad spectrum antidepressants may be required for adequate treatment of depression and in the context of treatment resistance psychostimulants may be indicated in some cases. 

NON-PHARMACOLOGICAL TREATMENT IN FEMALES WITH ADHD

Overall, the non-pharmacological treatment for boys and girls remains the same and differ only moderately by age.  

Primary Age : 

• Parent/carer support interventions, where people can meet and share experiences with others
• Parent/carer mediated interventions sometimes referred to as ‘parent training’.
• Age-appropriate psychoeducation to the child about the difficulties and challenges they will face at home, in school and in social activities and strategies to respond.
• Specific interventions to assist with organisation, time management, planning activities, prioritising and organising tasks
• Coping skills for interpersonal difficulties, social anxiety, conflict management, emotional lability, anxiety and feelings of distress

Secondary Age: 

• Cognitive behavioural therapy (CBT) and psychoeducation (which can be provided to both patients and parent/carers together or independently).
• Psychoeducation to parents about the elevated risk of deliberate self-harming behaviour (e.g. cutting), eating disorders, substance abuse, risk-taking behaviours, and vulnerability to exploitation in teenage girls with ADHD.
• Assistance with enhancing adherence to medication
• Enhance self-esteem and promotion of a healthy sense of self
• Coping strategies for comorbidities, e.g. emotional dysregulation, low mood and anxiety, self-harm behaviour, impulsive eating for pleasure or restricting food.
• Interventions to address impulsivity and associated risk-taking behaviour

Adulthood: 

• Psychoeducation and CBT to address core ADHD symptoms, executive dysfunction, comorbid conditions and dysfunctional coping strategies (e.g. substance use, deliberate self-harm)
• Due to the significant demands during motherhood, there may be an increase in anxiety and low self-esteem (e.g. thoughts of being a poor parent). Parent training may reinforce these beliefs and is therefore not recommended.
• Mothers with ADHD may benefit from life skills coaching, guidance and support in parenting, including ancillary support around parenting strategies.
• Women with ADHD may experience problems in the workplace, such as disorganisation, forgetfulness, inattention, accepting constructive criticism and appraisal, and difficulties managing interpersonal relationships with colleagues. Specific interventions to address these domains may be beneficial.

CONCLUSION

Females with ADHD constitute a silent minority with a propensity towards underdiagnosis and undertreatment. The table below is a summary of the key gender differences.

Females with ADHD present with greater internalised symptoms which may contribute to the gender-differential in referral patterns and misdiagnosis.

Females have a greater risk of specific comorbidities such as eating disorders, substance use, chronic fatigue syndrome and fibromyalgia.

Current diagnostic systems and services are tailored towards the diagnosis of ADHD in males due to the greater focus on externalising symptoms.

Clinicians should recognise the subtle and more internalised presentation of ADHD in females and incorporate a life span approach to ADHD assessment in females.

Treatment options should take into account the specific gender differences e.g hormonal changes, comorbidities for optimal outcomes in females.