Archives of Gynecology and Obstetrics

, 278:299

Cognitive, sensory, and emotional changes associated with the menstrual cycle: a review

Authors

    • The Procter & Gamble CompanyWinton Hill Business Center
  • Thomas W. Osborn
    • The Procter & Gamble CompanyWinton Hill Business Center
  • Allan B. MacLean
    • Department of Obstetrics and GynaecologyUniversity College
Review Article

DOI: 10.1007/s00404-008-0708-2

Cite this article as:
Farage, M.A., Osborn, T.W. & MacLean, A.B. Arch Gynecol Obstet (2008) 278: 299. doi:10.1007/s00404-008-0708-2

Abstract

The hormones progesterone and estrogen and, more precisely, their sophisticated interdependent fluctuations over the course of the female human lifespan, have long been known to play a dominant role in the physiological development and homeostasis of the human female. What is only recently coming to light, however, is that the fluctuation of these two hormones also plays a crucial role in neurological and psychological development and function which impacts brain function, cognition, emotional status, sensory processing, appetite, and more. The ability of reproductive hormones to impact psychoneurological processes involves the interplay of several body systems, lending credibility to the view of premenstrual syndrome (PMS) as a disorder founded in real biochemical disturbances. The effects of the menstrual cycle on cognitive, emotional, and sensory function in the female of childbearing age are reviewed. In addition, recent evidence is discussed which confirms the biological basis of PMS as a real disorder of primarily autoimmune origin.

Keywords

Menstrual cyclePMSMoodSensory changesCerebral asymmetryPremenstrual

The menstrual cycle

The menstrual cycle begins, by definition, with the onset of menstrual flow on day 1. The menstrual phase (generally lasting between 4 and 6 days) is defined by the shedding of the thickened endometrium, a process known as menstrual bleeding. The follicular or proliferative phase continues until ovulation, typically days 7 through 14. The luteal, or secretory phase begins at ovulation and continues until the onset of the menstrual flow, typically days 15 through 28 [1].

The menstrual phase and early follicular phase of the menstrual cycle are characterized by low levels of both progesterone and estrogen. Estrogen levels rise rapidly late in the follicular phase, peaking 1 day before ovulation. The luteal phase sees a steady rise in progesterone levels that peaks mid-luteal phase, in parallel with a second estrogen peak. Late luteal phase is characterized by declines in both estrogen and progesterone levels that reach baseline shortly before the onset of menstruation, which begins the cycle again [2], as shown in Fig. 1.
https://static-content.springer.com/image/art%3A10.1007%2Fs00404-008-0708-2/MediaObjects/404_2008_708_Fig1_HTML.gif
Fig. 1

Hormonal fluctuations over the menstrual cycle. This Wikipedia and Wikimedia Commons image is from the user Chris 73 and is freely available at http://commons.wikimedia.org/wiki/Image:MenstrualCycle.png under the creative commons cc-by-sa 2.5 license

The cyclic hormonal changes which regulate the menstrual cycle are an important biological influence on the female body, with numerous physical ramifications [1]. Estrogen initiates or mediates an impressive array of biological functions (Table 1), with receptors in a multitude of tissues and cell types. In fact, fluctuating levels of estrogen have been shown to have physiologically demonstrable effects on virtually every organ system in the body [3]. The influences of progesterone on the body are less studied and more limited, but still an important determinant [3]. Our companion paper reviews the modulation of physiological processes by these hormones as they fluctuate over the menstrual cycle [4].
Table 1

Organs, tissues and cell types with confirmed estrogen receptors

By body system

Reference no.

Cardiovascular system

Cardiovascular system overall

Millikan [81]

Blood vessels

Brincat [77]

Endothelial cells

Sekigawa et al. [76]

Central nervous system

Central nervous system overall

Millikan [81]

Cerebral cortex

Hall and Phillips [2]

Digestive system

Gallbladder

Millikan [81]

Liver

Millikan [81]

Pancreas

Millikan [81]

Endocrine system

Adrenal gland

Millikan [81]

Hypothalamus

Hall and Phillips [2]

Parathyroid

Millikan [81]

Thymus tissue

Tamer et al. [82]

Thyroid

Millikan [81]

Female reproductive system

Breast carcinoma

Brincat [77]

Cervix

Brincat [77]

Fallopian tubes

Brincat [77]

Mammary glands

Millikan [81]

Ovaries

Millikan [81]

Placenta

Millikan [81]

Uterus

Brincat [77], Millikan [81]

Vaginal epithelium

Hall and Phillips [2]

Immune system

B cells

Sekigawa et al. [76]

CD4+ T cells

Sekigawa et al. [76]

CD8+ T cells

Sekigawa et al. [76]

Macrophages

Sekigawa et al. [76]

Thymocytes

Sekigawa et al. [76]

Integumentary system

Corneal epithelia

Suzuki et al. [83]

Cutaneous mucinous carcinoma

Brincat [77]

Cutnaeous vascular tumors

Brincat [77]

Fibroblasts

Brincat [77]

Hair (dermal pappila of hair follicles)

Millikan [81] [84]

Melanocytes

Brincat [77]

Sebaceous glands

Hall and Phillips [2]

Skin (facial much higher than breast or thigh)

Hall and Phillips [2], Millikan [81]

Dermis

Brincat [77]

Epidermis

Brincat [77]

Skeletal system

Bone

Millikan [81]

The effects of the menstrual cycle on emotional state and cognitive function have been long recognized (if only recently systematically studied), a fact easily confirmed by the observation that a significant proportion of internet humor exchanged by modern women deals with the emotional impact of menses, particularly during the premenstrual period [5]. As medical science continues to investigate the complex interplay of the hormones which influence the menstrual cycle and their interdependent influence on the mind and body, it is becoming clear that the fluctuating levels of these hormones affect both physiological and psychological processes (Table 2).
Table 2

Menstrual cycle symptoms

Concentration

Negative effect

Accidents

Anxiety

Confusion

Crying

Difficulty concentrating

Depression

Distractible

Irritability

Forgetfulness

Loneliness

Insomnia

Mood swings

Lowered judgment

Restlessness

Lowered motor coordination

Tension

Pain

Control

Backache

Blind spots, fuzzy vision

Cramps

Chest pains

Fatigue

Feeling of suffocation

General aches and pains

Heart pounding

Headache

Numbness, tingling

Muscle stiffness

Ringing in the ears

Behavioral change

Arousal

Avoid social activities

Affectionate

Decreased efficiency

Bursts of energy, activity

Lowered school or work performance

Excitement

Stay at home

Feelings of well-being

Take aps; stay in bed

Orderliness

Autonomic reactions

Water retention

Cold sweats

Painful breasts

Dizziness, faintness

Skin disorders

Hot flashes

Swelling

Nausea, vomiting

Weight gain

Sources: adapted from Ref. [17, 85]

Effects of menstrual cycle on mood

A widespread belief that negative moods are characteristic of the premenstrual period is replete in the popular culture. This belief has scientific support. In an early landmark study of neurotic women, psychoanalytic analysis of diaries in which women recorded emotional status and dreams was able to correctly identify hormonal status in 94% of patient cycles analyzed. Patients were consistently more restless, irritable, fatigued, fearful, and depressed during the premenstrual period than other phases of the menstrual cycle, as well as being hypersensitive to various stimuli [6].

Benedek was doubtful that her results could be extrapolated to normal women, but ensuing decades of research has shown conclusively that estrogen and progesterone do have substantial effects on mood and mental function. One telling statistic is that until puberty, boys require psychiatric treatment at a rate twice that of girls; after puberty, that statistic is reversed, with women suffering from anxiety and depression at a rate twice that of men [7]. Women with mood disorders evidence definite peaks related temporally to times of substantial hormonal fluctuation: i.e., adolescence, perimenopause, and, in the reproductive years, the week before the onset of menses [811]. Negative premenstrual changes in mood, in studies that evaluated self-reports, range widely [12, 13], but it is believed that about 95% of women have recurrent and noticeable increase in negative emotions [14]. Highest levels of well-being and self esteem are reported during mid-cycle and increasing negative feelings (anxiety, hostility, and depression) occur premenstrually as both estrogen and progesterone levels decline.

Recent research has compiled statistics that lend tragic support to long-standing observation of an increase in negative emotion in the premenstrual period. Baca-Garcia et al. demonstrated that, in a group of 113 Spanish women who had attempted suicide, 36% of attempts had occurred in the first week of the menstrual cycle (i.e., during the menstrual phase), while only 19% had occurred during the second week, and 16% during the third. Interestingly 29% of attempts had occurred during the fourth week, meaning that 65% of all suicide attempts occurred during the premenstrual and menstrual period. In a follow-up study, which compared 134 women who had attempted suicide with 108 female controls, the percentage of suicide attempts during the menstrual phase exceeded that predicted by representation of menstrual phase women in the group by 75% [15, 16]. This work confirmed earlier reports of increased risk of suicides during the premenstrual and menstrual phases [17].

A recent meta-analysis which evaluated 44 studies of suicide in fertile women found that a positive relationship does appear to exist between the fluctuating hormone levels of the menstrual cycle and suicidal behavior. Suicide attempts appear to correlate to the periods of time when estrogen levels are lowest (late luteal and early follicular, i.e., menstrual, phases). The authors suggest that interaction between circulating estrogen and the serotonergic system may contribute to the risk of suicidal behavior associated with this period of the menstrual cycle [18].

The specific pathways by which the neuroendocrine changes that occur over the menstrual cycle affect central nervous system (CNS) control of mood and emotion are currently the focus of much research. The autonomic nervous system may be an important intermediary mechanism in mood cycling that parallels hormonal changes in women, especially with regard to the premenstrual period [19].

Numerous studies have looked at indicators of autonomic nervous system function, including heart rate, blood pressure, respiration rate, cardiovagal response, and body temperature and attempted to correlate these objective assessments with mood and/or hormone fluctuations, with nonconclusive results [11, 19].

Luteal phase connection, however, with an activated sympathetic nervous system (with its connection to heightened emotional state) is supported by the findings of Sigmon et al. (2000) [11]. In a study that evaluated autonomic nervous responses specifically in women with anxiety disorders, women with panic disorders had significantly higher response, both in frequency and degree of reactions, to anxiety-provoking stimuli than controls during the premenstrual phase. Mood disorder subjects, however, did not evidence elevated arousal across the menstrual cycle [11].

Effects of menstrual cycle on mental function

The last few decades have confirmed scientifically that gender resides in the nervous as well as the reproductive systems. Estrogens are critical elements in the imprinting of gender on a developing fetus, creating a synaptic plasticity that becomes abundantly evident during puberty and thereafter during the menstrual cycle [20]. The distinct differences between men and women with regard to information processing is thought to stem from differing exposure to sex hormones in utero, which lays down gender-specific wiring that will be activated by surges in gonadal steroids at puberty [21]. Interestingly, these early hypotheses have been confirmed by studies in unfortunate natural experiments such as Turner Syndrome children [who have only one sex chromosome (an X)] and in another congenital disorder called congenital adrenal hyperplasia, in which congenital disturbances in the levels of sex hormones carry predictable effects on mental processing [22].

Neurocognitive processes

For the last few decades, the confirmation of estrogen receptors spread throughout the brain—hypothalamus, pituitary, hippocampus, cerebral cortex, mid-brain, and brainstem—has suggested a potential for numerous influences of estrogen on neurocognitive processes [21]. Estrogen acts on the central nervous system on a variety of levels (genomic and beyond) directing and modulating neurotransmitter production and action, influencing electrical excitability and synaptic function, and changing the morphological features of neural elements involved in function [20]. Estrogen has been demonstrated to affect numerous neurotransmitter systems, including the dopaminergic [21], catecholaminergic, serotonergic, cholinergic, and gamma-aminobutyric acidergic systems [23].

Information processing in the human brain is complex and multifactorial, involving attention, learning, memory, pattern recognition, problem solving, language processing, abstract intellectual processing, and psychomotor skills [21]. From animal studies, consolidation of memory seems to occur in the hippocampus [24]. Estrogen has been shown to affect cyclic changes in the hippocampus [25] as well as enhancing short-term memory, thereby influencing the acuity of working memory [21]. The largest concentration of estrogen receptors (beta) in the human brain are in the hypothalamus, amygdala, and the hippocampus [26]; and its strongest upregulation of neurotransmitters is associated with acetylcholine [27].

The effects of estrogen on cognitive processing are also seen at menopause; the estrogen withdrawal typical of this period has pronounced influences on mood, behavior, and cognition [20]. Early experiments found that estrogen replacement in postmenopausal women increased verbal IQ scores after 1 year of treatment. Numerous later studies found that estrogen administration after surgical menopause improved memory, abstract reasoning, and reaction times, while those patients who were given placebo had significant deterioration of cognitive function in these areas [21]. Other studies had less consistent results, however, and in a recent nine-year study of more than 2,300 women given estrogen replacement, those on hormone replacement therapy had no significant mental gains over those who were not taking estrogen [28].

A closer look at the data, however, helps to clarify an apparent conflict. Randomized controlled trials in which patients were given estrogen replacement therapy (ERT) either post natural menopause or coincident with surgical menopause have repeatedly shown significant protection of memory associated with the estrogen replacement [21]. However, the 9-year Women’s Health Initiative Memory Study, a randomized controlled trial which evaluated ERT in 2,302 women after surgical or natural menopause, found no protective effect [29]. Careful study of the existing body of literature revealed, that the strongest data showing memory protection from ERT was derived from surgical menopause studies in which ERT was begun immediately after surgery, whereas the Women’s Health Initiative Memory Study provided ERT to women often long after natural menopause had occurred. Sherwin (2007) has proposed the existence of a critical window of opportunity that is at or near the time of natural menopause or surgical ovariectomy in which administration of estrogen protects mental acuity, particularly with regard to retention of memory [30]. This theory is supported by evidence from both basic neuroscience and existing animal studies, as well as providing a plausible explanation for the apparent conflict between the Women’s Health Initiative study and the findings of the bulk of controlled trials that predated it [30].

Cerebral assymetry

The extreme complexity of neurocognition in general makes it very unlikely that one molecule will influence all cognitive functions [21], and not all mental processes seem to be affected by estrogen. Particular mental functions, however, display very strong sexual dimorphism [31]. Women tend to outdo men in verbal facility, memory, fine motor skills, and perception (both speed and accuracy), while men are generally superior on tests of visual memory, mathematical ability, and spatial ability [31].

Brain hemispheres represent a division of labor, with the left hemisphere largely responsible for male-dominance functions like spatial orientation and lexical decision, while the right brain is responsible for more female-dominance tasks like figural comparisons and facial discrimination [32]. The right hemisphere has an advantage in women, while the left hemisphere has the advantage in men [33].

The foundation for these dimorphic differences appears to be a cerebral asymmetry associated with estrogen [32]. Women’s brains are believed to be less lateral, due to an increased number of mid-brain connections in the corpus callosum [34]. These gender differences were long thought to be static [33]. Interestingly, a study of the changes in processing over the menstrual cycle has done much to change that view.

It has been consistently observed that while male performance on cognitive tasks does not vary significantly over time, female performance shows consistent fluctuations.

The most dramatic differences have been observed with regard to tests of mental rotation, a task shown to have a strong male dominance. Women’s scores on mental rotation tests show a strong negative correlation to estrogen levels, with lowest scores during the mid-luteal phase and highest scores during menstruation. Men score significantly higher than women in all points of the menstrual cycle except menses [3537]. Mental rotation scores in cycling women in the luteal phase were lower than scores in women on oral contraceptives [38]. There is a strong positive correlation with circulating testosterone levels in the female subject [35]. Asymmetry in lexical tasks did not change over the cycle, but asymmetry in face perception did [34]. Hampson and Kimura found decreased performance on perceptual/spatial tasks during the mid-luteal phase [39].

Women scored higher in memory tasks in the mid-luteal phase, and lower during menstruation [36]. Concentration (assessed by the Stroop color-word test) in 50 women demonstrated lower scores during the premenstrual period [40]. The same pattern was seen in performance of fine motor-skill tasks [36]. Semantic processing in word-matching tests also increased during the mid-luteal (premenstrual) phase [41]. Hampson and Kimura found increased mid-luteal scores on tests of speed and motor coordination when compared to early follicular performance [39]. Phillips and Sherwin found verbal memory, attention and visual memory enhanced in the mid-luteal phase, which they specifically determined to be correlated to progesterone levels [42], while Maki et al. determined that poorer performance on tests of spatial ability during the mid-luteal phase, as well as increased fine motor dexterity and verbal fluency to be correlated with estrogen (E2) [36].

Hausman and Güntürkün concluded that functional cerebral asymmetries exist in women due to changes in hormone levels. Although function is somewhat bilateral when progesterone levels are highest in mid-luteal phase, strong lateralization appears during menses [32]. This has been interestingly demonstrated in sensory-acuity tests.

Sanders and Wenmoth (1998) evaluated auditory responses and cerebral asymmetry; typically (apart from hormonal fluctuations) the right ear has an advantage on verbal auditory acuity, while the left ear has an advantage with music. In this study, the right-ear advantage during verbal listening increased during mid-luteal phase compared to menses, while the left-ear advantage for music increased during menses compared to the luteal phase. Over the course of the menstrual cycle, left-ear performance decreased substantially on both tasks, while right-ear performance increased steady but less substantially [43]. Olfactory acuity was found to have a similar pattern. The right nostril had higher olfactory acuity during menses, while the left nostril had more acuity around ovulation [33].

Overall effect of hormone levels

Early published studies yielded inconsistent data in terms of meaningful studies which were needed to define cycle phases more clearly, use cognitive tests that have dimorphic variation, correlate findings to hormone levels, and include sufficient sample size for statistical power. However, more recent well-done studies have yielded dimorphic differences that, although small, are consistent [21]. On tasks in which women typically score better than men, women score higher during mid-luteal phase than within menstrual phase (although some results correlate with progesterone levels more than estrogen, both of which have peaks during the mid-luteal phase) [21]. On tasks in which men typically outperform women, women typically do best during menses [21]. In other words, estrogen positively influences performance on sexually dimorphic tasks that favor females and negatively influences performance on tasks that favor males [44].

Effects of menstrual cycle on sensory function

Effect on hearing

In numerous reports of both animal and human studies, estrogen has been suggested to have positive effects on the auditory process. Women have consistently been found to have more acute hearing than men of a similar age [45, 46]. Parlee found the auditory threshold to be lower around the time of ovulation [47]. Swanson and Dengerink found the pure-tone thresholds at 4 kHz were poorer during menses (when plasma levels of estrogen are lowest) than over the rest of the cycle [48].

Effect on smell

Asso found that olfactory acuity reaches a peak at about the time of ovulation [49]. Direct association exists between estrogen levels and olfactory sensitivity, with fertile women more sensitive to the macrocyclic musk exaltolide than premenarchal or postmenopausal women [49]. Parlee found that the olfactory threshold was lower around ovulation [47]. Sommer similarly found increased olfactory sensitivity around the time of ovulation [50]. In a more recent study, Navarrete-Palacios evaluated the olfactory threshold in 332 ovulatory women, using different log-based concentrations of amyl acetate. Olfactory thresholds differed significantly over the cycle, with the lowest thresholds during the ovulatory phase and the highest during the menstrual flow [51].

Effect on vision

Parlee, Asso, and Sommer all demonstrated increased visual sensitivity during the time of ovulation [47, 49, 50]. Friedman and Meares demonstrated, in 21 women with normal menstrual cycles, that visual sensitivity was enhanced during the late follicular phase of the cycle as ovulation approached, while at other points in the cycle visual acuity was constant and comparable to women on oral contraceptives [52]. Barris et al. in a small study in five fertile women found a consistent increase in visual acuity on the day of highest basal body temperature, with no corresponding increase in five controls [53].

Effect on touch/pain

Numerous studies have been performed in women which attempted to evaluate potential differences in pain perception across the menstrual cycle, for both intrinsic and experimentally induced pain [54] but no conclusive findings have been obtained. Studies involving pressure stimulation, cold pressor pain, and ischemic muscle pain have produced a pattern of diminished sensitivity in the follicular phase as compared to the ovulatory, luteal, and premenstrual phases, but not a consensus. Limited studies on pain induced by electrical stimulation have produce conflicting results [55, 56].

The majority of pain studies, however, have relied on subjective self-reports of perceived pain, in addition to being plagued with the same issues of patient population selection and hormone status verification that confound menstrual-cycle research in general. A recent study of pain across the menstrual cycle utilizing nocioceptive flexion reflexes as an objective and easily quantified measure of the pain response compared these objective measures with subjective perceptions in 14 normal fertile women. Tassorelli et al. found that both reflex thresholds and psychophysical pain thresholds were significantly reduced in the luteal phase as compared with the follicular phase. In addition, pain sensitivity as revealed by the reduction in the reflex threshold was significantly correlated to the total mental distress score reported by the patient for that day [57].

Far less work has focused on tactile sensitivity apart from pain sensation. Henkin (1974), studying tactile spatial acuity on the skin and using two-point thresholds as the assessment, found acuity to be higher in the luteal phase than in the follicular or ovulatory phases of the menstrual cycle [58]. A study that evaluated sensitivity to electrical stimulation at various tissue depths in the abdomen and limbs found increased cutaneous sensitivity in the periovulatory period, while subcutaneous tissue and muscle were more sensitive during the menstrual and follicular phases [55]. Bajaj et al. studying tactile threshold sensitivity on the abdomen and lower back, found no differences across the menstrual cycle, although women were significantly more sensitive than males [59]. Gescheider et al. evaluated vibrotactile sensitivity throughout the menstrual cycle (at either 15 or 250 Hz) and observed significant changes in threshold sensitivity over the menstrual cycle, but only at the 250 Hz level of stimulation. The 250 Hz threshold decreased steadily in the premenstrual period; once menstruation had begun, threshold levels increased steadily until approximately the time of ovulation, then began to fall again. Tactile sensation on the breast, specifically, has also been evaluated. Before puberty, no gender differences are present; but after puberty, women’s breasts are considerably more sensitive than men’s. Maximal sensitivity in adult women was observed during the periovulatory period and again during menstruation [60].

Effect on taste and appetite

The predictable hormonal fluctuations characteristic of the menstrual cycle have also been shown to affect appetite and food preferences. Numerous studies have demonstrated a distinct increase in energy consumption in the premenstrual period [6163], with lowest levels of food intake occurring during the periovulatory period [64, 65].

Hormone levels appear to regulate consumption of specific macronutrients as well, although the numerous studies have yielded somewhat conflicting data. Numerous studies have observed significantly increased consumption of carbohydrates during the premenstrual period [6163]; some have demonstrated an increase in fat intake during this period as well [63, 66] Rogers et al. found a 61% increase in energy intake during the premenstrual period, with a strong preference for foods with a high concentration of both fat and sugar, foods with high hedonistic properties [67]. Consumption of these foods, however, was found to be independent of premenstrual changes in mood [68]. These changes in energy intake parallel well-documented changes in basal metabolism that are also dependent on menstrual changes in hormone levels [69]. Some studies, however, have not found these increases [63].

A paper by Cross et al. reveals that part of the reason for the existing inconsistencies in the current body of research may be related to the way that the populations were defined as well as the way that the results were analyzed [62]. Cross et al. looked at both total energy intake as well as intake of specific macronutrients in 154 women by a dietary intake diary and found that the total intake of energy was increased in the premenstrual period, with a specific increase in intake for fat and carbohydrates, especially simple sugars. When the increase in carbohydrate and fat consumption was expressed as the percentage of increase in the total energy intake, however, no preference for these macronutrients was found, at least among normal women. In women with premenstrual syndrome (PMS) (defined by prescreening using the Steiner self-rated questionnaire), however, a distinct preference for sugars and fat during the premenstrual period was documented, with calorie-dense foods like cakes and cookies, high in both fat and sugar, preferentially consumed. A significant increase in binging behaviors was also observed [62].

The mechanism for this preference for sweets has been elucidated. Alberti-Fidanza et al. (1998) in a study of eight fertile women with regard to alterations in taste sensation and food preferences over the menstrual cycle, found a significant increase in sensitivity to sweet tastes which paralleled estrogen concentrations, and an increase in sensitivity to bitter taste which paralleled progesterone concentrations [70]. Than et al. (1994) observed the same preovulatory increase in sensitivity to sugar in 14 ovulatory women [71]. Men had no temporal variations in sucrose sensitivity.

Effect on premenstrual syndrome

Premenstrual syndrome is a disorder characterized by a diverse set of symptoms, primarily mood-oriented and cutaneous but encompassing numerous other systems that recur in concert with the 2 weeks before onset of menses [72]. PMS tendencies are heritable and persistent throughout adult life [73]. PMS is officially diagnosed in 30–40% of the female population, with less than 10% affected severely [74]. Virtually every adult female in the western world, however, experiences some PMS symptoms at some time.

Approximately 70% of women report an increase in acne and other cutaneous eruptions, associated with increased greasiness of the skin and hair [72]. Pruritus vulvae and hyperpigmentation deteriorate in the premenstrual period as well [74]. In atopic patients, predictable exacerbations of atopic dermatitis (AD) occur [74], including increases in pruritis as well as erythematous papules and pustules [75].

Although the specific etiology of AD is not understood, dysregulation of the autonomic nervous system is a prominent feature, with a growing association of AD with stress, anxiety, and depression [75]. Seiffert et al. demonstrated a higher heart rate and lower vagal activity that persisted throughout both resting and stress phases of testing, indicating an increased vegetative excitability in AD patients [75].

There are also indications of allergic hypersensitivity in the premenstrual phase, in some individuals, which may be associated with PMS. Systemic lupus erythematosus is believed to result from an overproduction of autoantibodies during the luteal phase [76]; autoimmune progesterone dermatitis and estrogen dermatitis are abnormal responses to the endogenous hormones themselves [77, 78].

An unusual case of premenstrual eruptions related to sensitization to a copper intrauterine contraceptive device (IUCD) that was in place for 12 years was characterized by cutaneous eruptions appearing 3–7 days before menses and resolving with the beginning of flow. Patch testing confirmed copper sensitization, and symptoms resolved upon removal of the IUCD [79].

Itsekson et al. investigated the connection of hypersensitivity to female hormones, dermatologic manifestations, and PMS. They studied a total of 30 fertile women, 10 who had both PMS and a concomitant skin disease, 10 with PMS but no cutaneous manifestation, and 10 healthy controls [74]. Immediate and delayed hypersensitivity reactions to both estradiol and progesterone were observed in all of the women with PMS, whether or not they displayed cutaneous symptoms, but none of the controls. Even more compelling with regards to an immunologic etiology of PMS, desensitization treatment resulted in substantial amelioration of both emotional and cutaneous PMS symptoms [74].

The authors speculated, on the basis of their results, that both autoimmune estrogen dermatitis and autoimmune progesterone dermatitis may be a dermatologic expression of PMS. In addition, the association of delayed hypersensitivity to female sex hormones in PMS with skin disease as well as a multitude of mental and emotional processes demonstrates a genuine relationship between endocrine, immune, and neural responses [74].

Although the precise hormonal origin for PMS remains elusive, its obligatory correlation with the period shortly before menses suggests a predominant role for progesterone. Itsekson’s demonstration of positive progesterone and estradiol sensitization in PMS patients is compelling support for an immune component to the disorder, as is the response of PMS symptoms to immuno-desensitization treatment. PMS, then, may represent an abnormal immunologic response to normal hormonal changes, with far-reaching consequences to both physical and emotional health [74, 80].

Conclusion

The complex interplay of the central nervous system with the autonomic nervous system, reproductive system, and immune system, an interplay that produces subtle but far-reaching changes in mood, emotion, sensory processing, appetite, and neurocognitive function are just beginning to be elucidated. What is clear is that estrogen and progesterone are central players. As the prevalence of estrogen and progesterone receptors continues to be defined and the roles that these two hormones play are more completely understood, the interactions of these molecules within the exquisitely balanced milieu that is the female body, particularly of child-bearing age, will also continue to be teased out. As women today spend much of their lives beyond menopause, the hope is that by gaining an understanding of the interplay of estrogen and progesterone—hormones that define female biochemistry for much of a woman’s life—in regulating so many physiological and psychological processes, we will be able to more effectively maintain women’s health throughout their lifespan.

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© Springer-Verlag 2008