Edited by: Yael Leitner, Tel Aviv Sourasky Medical Center and Tel Aviv University, Israel
Reviewed by: Yael Leitner, Tel Aviv Sourasky Medical Center and Tel Aviv University, Israel; Miki Bloch, Tel Aviv Sourasky Medical Center, Israel
*Correspondence: Ronit Haimov-Kochman, Unit of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Hadassah Hebrew University Medical Center, Churchill Boulevard, P.O. Box 24035, Mount Scopus, Jerusalem 91240, Israel e-mail:
This article was submitted to the journal Frontiers in Human Neuroscience.
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Attention Deficit/Hyperactivity Disorder (ADHD) is considered as a model of neuro-developmental cognitive function. ADHD research previously studied mainly males. A major biological distinction between the genders is the presence of a menstrual cycle, which is associated with variations in sex steroid hormone levels. There is a growing body of literature showing that sex hormones have the ability to regulate intracellular signaling systems that are thought to be abnormal in ADHD. Thus, it is conceivable to believe that this functional interaction between sex hormones and molecules involved with synaptic plasticity and neurotransmitter systems may be associated with some of the clinical characteristics of women with ADHD. In spite of the impact of sex hormones on major neurotransmitter systems of the brain in a variety of clinical settings, the menstrual cycle is usually entered to statistical analyses as a nuisance or controlled for by only testing male samples. Evaluation of brain structure, function and chemistry over the course of the menstrual cycle as well as across the lifespan of women (premenarche, puberty, cycling period, premenopause, postmenopause) is critical to understanding sex differences in both normal and aberrant mental function and behavior. The studies of ADHD in females suggest confusing and non-consistent conclusions. None of these studies examined the possible relationship between phase of the menstrual cycle, sex hormones levels and ADHD symptoms. The menstrual cycle should therefore be taken into consideration in future studies in the neurocognitive field since it offers a unique opportunity to understand whether and how subtle fluctuations of sex hormones and specific combinations of sex hormones influence neuronal circuits implicated in the cognitive regulation of emotional processing. The investigation of biological models involving the role of estrogen, progesterone, and other sex steroids has the potential to generate new and improved diagnostic and treatment strategies that could change the course of cognitive-behavioral disorders such as ADHD.
Behavioral, biochemical, and physiological data in animals demonstrate that gonadal steroid hormones estrogen, progesterone and testosterone have an effect on behavior and modulate neuronal activity (McEwen and Alves,
Most women (80%) experience regular menstrual cycle from menarche to menopause, whereas the rest have irregular cycles (Münster et al.,
Before menarche and after menopause estrogen and progesterone levels are usually un-measurable. In premenopausal years, and depletion of the follicular reserve of the ovary, the cycle length tends to shorten, and anovulatory cycles are more frequent, until its cessation during menopause.
It has been established that sex hormones act on the central nervous system and influence the organization of neural circuits during the prenatal period (Collaer and Hines,
As it becomes clearer that hormonal transition periods across the life span of women also affect brain organization, some newly neuroimaging studies have started addressing the relevance of subtle hormonal fluctuations across the menstrual cycle on brain architecture, connectivity, metabolism and blood flow. For example, there is some evidence that estrogen in postmenopausal women increases regional cerebral blood flow (Resnick et al.,
Genetic and hormonal differences are the two most obvious possible causes for gender differences in neuro-cognitive-behavioral aspects (Mahone,
5-HT functions to coordinate complex sensory and motor patterns during a variety of behavioral states and is implicated in the pathology of mood disorders, sleep and eating disorders, and schizophrenia. There is an association between estrogen and schizophrenia. A deficiency in estrogen exposure may impact gray matter cortical thickness, which may be reversed by higher levels of estrogen that may induce or activate neuroprotective mechanisms (van der Leeuw et al.,
Interestingly, studies on the effects of exogenous sex steroids in postmenopausal women have demonstrated higher 5HT2A binding throughout the cerebral cortex in women treated with estradiol plus progesterone replacement (Moses et al.,
Although not as well studied, differences between men and women have been reported for other receptor systems. These include the cholinergic system, which is involved in memory and cognition; the GABAergic system, the major inhibitory neurotransmitter system involved in mood and memory; and the opioid system, which is involved in pain and reward processes. Women express higher numbers of cortical muscarinic acetylcholine receptors (Yoshida et al.,
Women are believed to have better verbal skills and inferior spatial abilities than men. In women, IQ correlates with gray matter volume of the frontal lobe and Broca’s area, which is involved in language (Haier et al.,
Both androgens and estrogens have been shown to influence the organization of neural structure and function (Miodovnik et al.,
Previous studies have explored the link between sex hormones and other female-related mood disorders such as premenstrual dysphoric disorder (PMDD), (unipolar) postpartum depression, perimenopausal depression, and bipolar disorder (Schmidt et al.,
Several (not many) studies have investigated the impact of fluctuating sex hormone levels during the menstrual cycle on the interplay between emotion and cognition in healthy regularly cycling women. This lack of knowledge is remarkable, considering the evidence for major emotional disorders occurring specifically during normal hormonal swings in the lifespan of women. A recent review of the literature by
As with many neurodevelopmental disorders, the prevalence of attention deficit/hyperactivity disorder (ADHD) differs in males and females (American Psychiatric Association,
The investigation of biological models involving the role of estrogen, progesterone, and other sex steroids has also the potential to generate new and improved diagnostic and treatment strategies that could change the course of cognitive-behavioral disorders such as ADHD in women.
Sex differences in brain morphology, function and neurochemistry are likely to impact normal and abnormal behavior and function. Until the role of sex hormones in the female human brain is understood, it is important to take into account critical variables, such as menstrual cycle phase, hormonal status (e.g., post partum, perimenopause, menopause), and external hormonal use (e.g., combined oral contraception, hormonal replacement therapy at menopause). In spite of the impact of sex hormones on major neurotransmitter systems of the brain in a variety of clinical settings, the menstrual cycle is usually entered to statistical analyses as a nuisance regressor (Lonsdorf et al.,
We suggest that the menstrual cycle should be considered as a modulating factor when examining cognitive response to emotional information in women. Furthermore, with the introduction of sensitive tests to measure cognitive performance and imaging techniques to visualize brain morphology and study its neurochemistry, it is now becoming possible to carefully analyze cognitive performance in women by their menstrual cycle phase, or current hormonal status. This may lead to better understanding of the sex hormone impact on women’s brain in health as well as in ADHD and may resolve the inconsistency of the findings in women with ADHD.