Gender-Specific Differences in the Central Nervous System’s Response to Anesthesia
- First Online:
- Cite this article as:
- Mawhinney, L.J., Mabourakh, D. & Lewis, M.C. Transl. Stroke Res. (2013) 4: 462. doi:10.1007/s12975-012-0229-y
- 165 Views
Males and females are physiologically distinct in their responses to various anesthetic agents. The brain and central nervous system (CNS), the main target of anesthesia, are sexually dimorphic from birth and continue to differentiate throughout life. Accordingly, gender has a substantial impact on the influence of various anesthetic agents in the brain and CNS. Given the vast differences in the male and female CNS, it is surprising to find that females are often excluded from basic and clinical research studies of anesthesia. In animal research, males are typically studied to avoid the complication of breeding, pregnancy, and hormonal changes in females. In clinical studies, females are also excluded for the variations that occur in the reproductive cycle. Being that approximately half of the surgical population is female, the exclusion of females in anesthesia-related research studies leaves a huge knowledge gap in the literature. In this review, we examine the reported sex-specific differences in the central nervous system’s response to anesthesia. Furthermore, we suggest that anesthesia researchers perform experiments on both sexes to further evaluate such differences. We believe a key goal of research studying the interaction of the brain and anesthesia should include the search for knowledge of sex-specific mechanisms that will improve anesthetic care and management in both sexes.
KeywordsAnesthesiaBrainCentral nervous systemGender differencesReview
The impact of gender differences on outcomes of general anesthesia continues to be poorly understood. Several physiological and pharmacological differences that modulate the effects of anesthesia exist between men and women. The central nervous system (CNS) of males and females differ significantly as a consequence of genetic and hormonal events that start in the womb. Major changes occurring at puberty solidify gender differences through adulthood. Because the brain is the target organ of general anesthetics, it would be fair to ask whether these differences have any relevance to the practice and effects of general anesthesia. Sex-specific physiology may impact drug sensitivities and metabolism related to general anesthetics, playing a key role in induction, maintenance, and recovery from anesthetic agents.
Consequently, gender differences in the brain and CNS would be highly relevant to both the practice and study of anesthesia. Yet, a review of the preclinical literature shows that many studies do not report the sex of the animals tested. A greater proportion of those that report sex typically used only males to test their hypotheses. In laboratory settings, studying males only has been more convenient in that it avoids confounding variables associated with mating, estrous cycle, reproductive consequences, and pregnancy. However, in the past decade, studies on sex-based CNS differences have become increasingly more common due to their importance in medical research. Researchers analyzing the effects of anesthetics have begun to compare gender differences more frequently in their studies, yet still little is known about anesthetics’ effects on the female brain.
In clinical studies, one reason that females are typically excluded from studies on drug development has been due to variability induced by reproductive hormone flux [1, 2]. With 49.2 % of the population as male and 50.8 % as female , it is troublesome that many new drugs are not evaluated for sex differences in bioequivalence. Chen and colleagues  found that the Federal Drug Administration (FDA) only evaluated sex differences in bioequivalence in 26 studies submitted between 1977 and 1993. Overall, most studies of the brain and other organs continue to focus on one sex, usually males, or fail to report the sex of the animals studied . Moreover, a review of FDA-approved cardiovascular devices revealed that a majority of studies declined to offer the gender of their test populations, and of the studies that did report sex distribution, the study populations were, on average, 67 % male . Is the exclusion of females medically valid for studies of anesthesia? In this review, we explore many of the differences in the male and female CNS with respect to the effects of anesthetics on the brain, focusing on gender differences that arise at particular periods during the life cycle. Although some of the rationale for exclusion of a specific gender in research trials may be valid, we suggest that there are gaps in the literature with respect to the sex differences in the interaction between the brain and various anesthetic agents.
The Sexually Dimorphic Brain
It is important to recognize that male and female brains are different from the beginning. Sexual differentiation of the brain begins in the womb, triggered by intrauterine exposure to testosterone [7–9], estrogen, and progesterone [10–13] and the differential representation of sex chromosome genes in males and females [14–18]. These changes in very early development give rise to a lifetime of anatomical, physiological, and behavioral differences between men and women.
Sexual dimorphism is first observed in the neonatal brain , yet adolescence further differentiates the male and female brains. Many sex differences in brain structure occur after the age of 9 [20, 21]. Additional evidence supports the notion that brain maturation is linked to the onset of puberty [22–24]. The male and female brains have completed their sexual dimorphism from one another in early adulthood. In adults, cerebral sex differences are apparent in structural volumes in certain brain areas. Specifically, women have larger structural volumes in the hippocampus, caudate nucleus [21, 25–27], and anterior cingulate gyrus , with greater gray matter volumes in the precentral gyrus, the anterior cingulate, the right inferior parietal, and the orbitofrontal cortex [29–33], whereas typically men have a greater structural volume of the amygdala [21, 27, 34] and more gray matter in the medial temporal lobe, the cerebellum, and the lingual gyrus [30, 35].
Differences in the brain between the sexes do not stop at the anatomical level. Estradiol, a major brain metabolite of testosterone , has a permanent organizational effect in the pre- and postnatal brain. Diverse mechanisms also mediate the estradiol-induced sexual differentiation of synaptic patterning in specific brain regions . Higher levels of estradiol in males during the prenatal period organize the number and density of dendritic spines compared to axosomatic synapses, resulting in two- to threefold differences in males and females, specifically well characterized in preoptic and hypothalamic nuclei, the ventromedial nucleus of the hypothalamus, and the arcuate nucleus . The cellular mechanism responsible for organizing the synaptic pattern is also distinct between males and females, with the estrogen receptor invoking a distinct mechanism depending on gender [39–43].
The adult male and female brains exhibit distinct cerebral anatomy, connectivity, and function, rendering men and women differently susceptible to neuropsychiatric disorders [44, 45] and pathophysiology associated with CNS injury . In CNS injury, there are controversial findings with regard to which sex fares better following brain injury. Pathohistological effects of acute brain injury have been reported to be more severe in males than females [46–50, 55, 56], while often women experience poorer outcomes following CNS injury . Following mild to moderate traumatic brain injury (TBI), women experience higher incidence of postconcussion syndrome, characterized by persistent symptoms in the cognitive, emotional, physical, and sleep domains [52–54]. The neuroprotective effects of estrogen and progesterone have been one hypothesis to explain the sex differences in pathophysiology in TBI [46–50]. However, explanation for poor outcomes in women following TBI is still up for debate. For ischemic insults to the brain, the incidence of stroke is higher in men than in women well beyond menopause, suggesting that ovarian hormones are not the sole contributing factor to the observed sex differences [55, 56]. These differences may be due to divergent mechanisms following injury. Although cell death occurs in both sexes following experimental stroke or ischemic insult, striking sex differences in the cell death pathways are observed [57–63]. Further complicating the debate on the sexually dimorphic brain and its susceptibility to pathological mechanisms, males experience a greater susceptibility to learning disorders with developmental origins [44, 64, 65]. Additionally, the rates of neuropsychiatric disorders are higher in males . In the aged population, a greater number of men are diagnosed with Parkinson’s disease [66–68]. Yet, higher rates of Alzheimer’s disease and associated dementias are found for females [44, 69–74]. Sex differences in susceptibility to mental disease and CNS injury point to the likelihood of similar disparities in the effects of exposure to general anesthesia.
Gender-Specific Physiological Differences in Modulating the Effects of Anesthetics
It has been claimed that sex-specific sensitivities to certain anesthetic agents exist [76–87], and this may be due to sex differences in physiology and body composition that have an effect on the response of the CNS to anesthesia [88, 89]. As a consequence of the various gender differences, anesthetic agents targeting the brain may be interacting in a sex-specific manner that deserves further exploration. Men and women have dissimilar body compositions with regard to fat and fluid, which influences both pharmacokinetics and pharmacodynamics of anesthesia-related drugs. These sex-dependent anesthetic differences are due, in part, to body composition differences, but it is not as simple as a weight measurement. Gender differences in anesthetic requirements could be attributed to several factors, including increased adipose tissue in females [90–94], acute tolerance to anesthetics after initial dose [89, 95, 96], hormonal differences, or different metabolic rates of anesthetic agents [86, 97–103].
Sex differences in physiology can impact how anesthetics interact within the body. Pharmacokinetic gender disparities are prevalent within the respiratory, renal, and endocrine systems. Independent of body size, females shave smaller lungs, smaller expiratory flow rates, and smaller diffusion surfaces than males [104–106]. Females also have lower ventilatory responses to exercise  due to the smaller diameter airways relative to lung size . Female ventilatory responses to elevated carbon dioxide (CO2) levels are also less than males . To examine differences in renal function, Reckelhoff demonstrated that nitric oxide production is higher in the systemic vasculature of female rats than male rats and is stimulated during high estrogen states, such as pregnancy . The data suggested that the renal vasculature of males may be more dependent on nitric oxide than is the renal vasculature in females . Hepatic clearance of drugs is a function of liver blood flow and hepatic enzyme activity. Cytochrome P enzymes have also been shown to vary by sex in both humans and animals, although findings have been inconclusive [110, 111]. These differences are influenced by endogenous sex hormone production, as well as hormonal changes associated with oral contraceptive use, pregnancy, and menopause . The volume of distribution (Vd), defined as the ratio of the plasma concentration to the amount of drug in the body, is affected by individual body mass index, body composition in relation to water and fat content, plasma volume, organ blood flow, and protein binding of a drug. Females have lower relative average body weight, higher average body fat, lower average plasma volume, and lower average organ blood flow than males that can influence Vd. In addition, major protein groups responsible for binding drugs in human plasma are influenced by concentrations of sex hormones; accordingly, plasma drug binding is a process clearly influenced by gender. Protein binding is one of the many factors that affect Vd for a drug that demonstrates disparities in the sexes .
Disparities in body composition, size, and physiology in females often result in higher drug concentrations at the target tissues when given the recommended dosage based on weight measurement. Higher concentrations of anesthetic agents in female patients may also be due to lower clearance rates or smaller Vd . This could lead to inequality in drug efficacy because of differences in the effective drug concentrations within the body, as well as improper concentrations of drugs at the desired sites of action. Excessive concentrations of a drug at the target site may result in adverse effects. Therefore, drug concentrations must remain within a defined therapeutic range  across genders. More than body composition must be taken into account to determine accurate estimation of effective drug concentrations in the body and brain, which is highly influenced by the differences between the genders. Sex-specific differences must be carefully considered during critical care and anesthesia.
Sex Differences in Anesthetics for Each Life Stage
Age is a significant factor affecting the pharmacokinetics of medications. Major changes occur to the body during development, maturation, and aging in humans, including changes in body weight and organ volumes. There is a unique physiological makeup to each life stage with respect to its exposure–tissue dose relationship . Therefore, each life stage has unique sex-specific differences in the way the brain responds to anesthetic agents.
Despite growing evidence of the damaging effects of anesthetics on the developing brain [115–126], very few studies have examined differences in the effects of anesthetics on the brains of neonates and small children across genders. In basic research, the first study of its kind identified gender differences in anatomical and behavioral consequences of anesthetic exposure in young animals . Rothstein and colleagues  examined the differences in response to neonatal anesthesia in male and female Sprague–Dawley rats. Rat pups were administered with either phenobarbital (25 mg/kg) or isoflurane (2 % for 3 min, followed by 1 % for 7 min) or controls and were then tested on a battery of neonatal and adult behavioral tests. Volumetric analysis of the hippocampus revealed significantly lower hippocampal volume in animals exposed to either of the anesthetics. However, males were more greatly affected by exposure to anesthetics, resulting in less hippocampal volume than treated females. Behavioral results revealed significant deficits in both males and females exposed to the anesthetics on the day of birth, with the water maze deficits significantly greater in males than in females. The results of this study suggest that the anatomical and behavioral deficits following neonatal isoflurane and phenobarbital exposure are more pronounced in males compared to females .
Clinically, the pharmacokinetic disparities between male and female children are less prevalent. However, a potential source of sex-dependent differences in the effects of anesthesia on the young brain may involve differences in arterial blood flow. This difference in arterial blood flow in male and female children may account for differences in drug delivery and clearance  that may affect anesthetic exposure duration and effective drug concentration estimates in young boys and girls. Tontisirin and colleagues  studied gender differences in blood flow velocity and autoregulation of the anterior and posterior cerebral circulations in children before the onset of puberty. They found that female children between 4 and 8 years of age had higher middle cerebral and basilar artery flow velocity than males of the same age. This observed difference may reflect inherent gender disparities in cerebral metabolic rate and/or estimated cerebrovascular resistance . While male and female brains are physiologically different due to genetics, prepubescent gender disparities in pharmacokinetics have not been shown in the young clinical population to warrant a significant impact on the practice of anesthesiology. However, more studies are necessary to rule out the possibility of sex-specific differences in the response of the developing brain to various anesthetic agents.
Puberty May Impact Sex Differences in Anesthesia Effects on the Body
The surge of hormones at puberty exerts effects on various organs: the heart, lungs, kidneys, liver, and, most importantly, the brain. Female sex hormones and androgens play a role in gender differences observed in the cardiovascular system, leading to increased cardiac mass in males [129–131], better diastolic function in females [132, 133], and an increase in the average resting heart rate of females 3–5 bpm faster compared to males . Respiratory development is also affected by puberty, in that postpubescent females have smaller lungs, expiratory flow rates, and diffusion surfaces compared to age-matched males [104–106]. Additionally, females’ ventilatory responses to elevated CO2 levels are less than men . The kidneys, responsible for the excretion of drugs, demonstrate sex-related disparities in glomerular filtration rates that may cause differences in processing of drugs in the kidneys . The liver, an important route of anesthesia drug metabolism and elimination, displays variations in hepatic enzyme activity in postpubescent males and females that are largely responsible for differences in drug effects between men and women . The brain, the primary target of anesthetic agents, endures sexually dimorphic changes evident in differences in anatomy, connectivity, and function following the pubescent hormone surge. The maturation of the brain during puberty sets the stage for the gender-specific differences in drug–brain interactions in adulthood.
The leading hypothesis explaining the gender differences in CNS effects of anesthesia in adults involves the variation of hormone levels between men and women resulting in distinct interactions of anesthetic drugs in the brain. Estrogen, progesterone, and androgen receptors have been identified in the mammalian brain and display actions unrelated to reproduction . Progesterone, in particular, is thought to have hypnotic effects . Progesterone, which is produced in the ovaries, the adrenal glands, and during pregnancy in the placenta and stored in adipose tissue, is found at relatively low and stable levels in children, men, and postmenopausal women . However, in adult females, progesterone fluctuates dramatically depending the time during the menstrual cycle . Progesterone and some of its metabolites (3α,5α-tetrahydroprogesterone or allopregnanolone and 3α,5β-tetrahydroprogesterone or pregnenolone) modulate γ-aminobutyric acid type A receptors [136, 140–142]. Progesterone has been shown to produce various behavioral effects, such as anxiolysis , sedation , analgesia , general anesthesia at large dose , and benzodiazepine-like sleep electroencephalogram profiles in rats [147, 148] and humans . The action of ovarian hormones in the brain and CNS may impact the effects of anesthetics, further complicating gender differences in anesthesia.
Basic and clinical studies aimed at investigating progesterone-related effects on anesthesia have reported conflicting results. Some researchers have shown a distinct relationship between high progesterone levels and a reduction in anesthetic requirement [150–152]. Others have reported no relationship . In support of progesterone’s role in modulating anesthetic requirement, an animal study, performed in rabbits, demonstrated that administration of exogenous progesterone reduced the minimum alveolar concentration (MAC) of halothane . Erden and colleagues  investigated the effects of progesterone on anesthetic requirement by measuring serum progesterone levels and bispectral index (BIS) scores for 20 female patients under general anesthesia. Researchers found that high levels of progesterone during the luteal phase of the menstrual cycle decreased anesthetic requirement in women , indicating that not only gender but also the levels of specific ovarian hormones may influence the impact of anesthesia on the brain. Contrary to this finding, the phase of menstrual cycle was determined to be unrelated to MAC in Japanese women . The evidence for gender-specific anesthetic requirement is also heavily debated and seems to depend on the clinical population evaluated. Two studies of Japanese patients found smaller MAC values in women [154, 155], yet two studies of primarily Caucasian patients demonstrated no gender differences for MAC values [156, 157].
Pregnancy is a special case of dramatic hormonal fluctuations that may impact the sensitivity of the body and brain to anesthetic agents. Hormonal effects of pregnancy have been posed as probable components of gender-related differences in drug disposition . Animal studies demonstrate that the requirement for inhaled anesthetics is decreased by up to 40 % during pregnancy , indicating a possible hormonal role in anesthetic drug sensitivity. Reduced MAC has also been demonstrated during early pregnancy [158, 159] and in the immediate postpartum period  in humans. Estrogen, which is elevated during pregnancy, may also play a role in pharmacokinetic processes regulating anesthesia due to its interaction with albumin and various other glycoproteins. Since albumin, alpha-1 acid glycoprotein (AAG), and alpha-globulins are the main binding proteins for various drugs in plasma and are also shown to vary in association with endogenous and exogenous estrogens [161–164], the effects of pregnancy on the binding proteins are complex. As pregnancy progresses, the levels of albumin and other plasma proteins, such as AAG decrease [165–167]. Yet, one study reported no change in AAG levels during pregnancy . Additionally, unresolved questions still exist regarding drug protein binding capacity in the setting of pregnancy. Some researchers report that endogenous ligands, such as free fatty acids, which are excessively produced during pregnancy, are available for drug binding sites on albumin [169, 170]. Furthermore, protein-binding capacity may be reduced secondary to intrinsic alterations in protein structure during pregnancy . Pregnancy has been shown to increase the activity of the hepatic enzyme CYP2D6, which plays a main role in metabolism of drugs . Overall, the hormone flux and increased production of glycoproteins and endogenous binding proteins that may influence anesthetic interactions during pregnancy present a special case for sex differences in general anesthesia that must be considered for patients of obstetric anesthesia. Aside from special cases of hormonal interactions with anesthesia in the brain, sex-specific differences can be further examined by looking at the three phases of general anesthesia: induction, maintenance, and recovery.
Induction of anesthesia involves the initial administration of a drug or combination of drugs at the beginning of general anesthesia. Induction of anesthesia is sex specific in that males may require different doses of a particular anesthetic agent to induce and maintain the plane of anesthesia. Animal studies indicate that males, in general, require larger doses of anesthetic to produce general anesthesia [76, 173, 174]. For example, male rats require twice the amount of pentobarbital compared to females to produce severe loss of muscle tone . Additionally, Suzuki and colleagues  examined the anesthetic effects of pentobarbital on various strains of rats. The researchers found that pentobarbital-induced sleep time was significantly longer in females than males in all four strains tested. Torbati and colleagues  investigated how the breathing pattern and gas-exchange outcome are modified by sustained pentobarbital anesthesia in young age-matched male and female rats. Torbati and colleagues  found that the average anesthetic requirement during a 5–6-h period was approximately 30 % less in females than in males. They also found differences in induction requirement for pentobarbital anesthesia, with males requiring 65 mg/kg and females requiring only 45 mg/kg .
In clinical studies, the type of anesthetic agent used to induce general anesthesia seems to influence the sex differences observed. In clinical studies, it has been observed that women require less anesthetics than men for water-soluble drugs used in anesthesia, such as vecuronium [69, 72], rocuronium , pancuronium , and atracurium . However, cisatracurium has been shown to have no significant gender differences in the onset time and clinical duration of anesthesia  or in diffusion rates between the sexes . For lipid-soluble drugs used in anesthesia, studies show that the Vd is typically higher in females, and females have been found to require higher levels of benzodiazepines, such as diazepam [82–84] and midazolam , as well as hypnotic drugs such as propofol [86, 87, 102, 177–179]. Specifically, in males, diazepam has been shown to have a faster clearance rate, shorter half-life, and lower Vd (when adjusted for body weight) . Additionally, females showed greater impairment in psychomotor skills following diazepam administration . A number of the studies evaluating sex differences in midazolam do not reveal any significant metabolic differences across genders [85, 99, 100], although conflicting results were found demonstrating a greater clearance in females compared to males [111, 180]. Additionally, numerous studies have demonstrated a disparity in systematic clearance of propofol due to patient sex [86, 102, 103]. Pharmacodynamic differences may explain the 30–40 % increase in sensitivity to the effects of propofol in males compared to females [89, 102, 177, 178]. Therefore, the gender-specific requirements of induction of anesthesia are identifiable to each class of anesthetic agents and must be considered on a case-by-case basis.
Maintenance requirements, which sustain a surgical plane of anesthesia, have been shown to be gender dependent. It has been demonstrated in rats that males required a larger dose of pentobarbital to maintain clinical anesthesia compared to female rats [76, 101]. Additionally, when given identical doses of pentobarbital, male rats were found to have significantly lower plasma pentobarbital concentrations than did female rats over 100 min . These data indicate that there are significant differences in the rate at which male and female rats metabolize or otherwise clear sodium pentobarbital from the plasma . Clinically, drugs such as oxazepam, temazapan, and paracetamol are cleared faster in men [181, 182]. However, females metabolize propofol faster through the glucuronidation process [86, 102, 103], indicating that the discussion of maintenance and speed of clearance is not well defined. It seems that the type of anesthetic agent used has a great impact on the sex-dependent effects on the CNS during general anesthesia.
Awareness with recall is a rare but noteworthy complication of general anesthesia that occurs during the maintenance phase due to inadequate anesthesia in some individuals. Female patients have been shown to have more awareness under anesthesia and are less responsive to anesthesia’s hypnotic effect [103, 175, 178, 183–188]. Lower hypnotic effects of such drugs correspond to higher BIS levels in women during general anesthesia, despite having similar amounts of anesthesia [188, 189]. Interestingly, recent evidence suggests that cumulative deep hypnotic time (longer duration of low BIS levels) is associated with increased risk of death [190–192]. Therefore, female insensitivity to the hypnotic effects of anesthetics, although frightening in the face of awareness during anesthesia, suggests that women may have less risk of death following surgery because of higher BIS levels during anesthesia. Although, this question warrants further study in order to draw any conclusions between awareness, BIS levels, and risk of mortality. Furthermore, sex differences in both short- and long-term recovery must also be considered when assessing the outcome of males and females during the recovery phase of anesthesia.
Patient gender may be an important factor influencing recovery from general anesthesia. It has been proposed that men wake slower than women after general anesthesia [1, 103, 178, 179, 187–189, 193, 194]. This could be a result of gender differences in pharmacokinetics and pharmacodynamics, a consequence of greater anesthetic requirements, or possibly a function of the type of surgery . It is also possible that women receive less general anesthesia than males, which could also account for this observation. Furthermore, reports indicate that the levels of drugs that remain present in the system in the immediate postoperative period are higher in females . In an animal study, brain levels of pentobarbital were higher in female rats compared to their male counterparts . The researchers also found that when pentobarbital-admixed food was administered for 47 days, only female rats exhibited moderate to severe motor impairment. After the treatment ended, pentobarbital withdrawal was observed in females only , indicating sex differences in anesthesia effects after cessation of treatment.
Additional clinical evidence has surfaced suggesting that a patient’s sex is a factor in postoperative short-term and long-term recovery from general anesthesia [178, 188, 189, 195–200]. In one study of 918 cases that received neurosurgical intervention at the University of Michigan, 20.3 % of male patients experienced complications versus only 11.3 % for females within 30 days of surgery . However, other clinical studies indicate that females exhibit a greater risk of adverse outcomes following surgery [103, 188], with higher scores in postoperative pain scores, nausea, vomiting, sore throat, headache, and backache [189, 195–198]. Female patients also demonstrate higher morbidity and mortality and increased length of hospital stay following surgery . It is possible that the sexually distinct postoperative outcomes are directly influenced by anesthetic and CNS interactions. Overall, the sex differences are the most pronounced between men and women of premenopausal age, with postmenopausal women displaying similar BIS scores during anesthesia and recovery characteristics to age-matched men , further supporting the role of ovarian hormones’ differences as a source of sex differences in anesthetic effects on the brain in adults.
Advance age may impact the differences between how male and female brains are affected by general anesthetics. Current evidence suggests that inhaled anesthetics are capable of inducing long-term cognitive dysfunction in aged rodents [201–204]. However, in these studies, either only males were examined or the gender information was not disclosed. Therefore, it is currently unknown how these agents may affect the cognitive function of aged female animals.
Given that higher rates of many aging-related neurodegenerative diseases and mental health dysfunction are found for females [40, 69–74], it is possible that the aged female brain may be more vulnerable to the toxic effects of anesthesia. Recent evidence demonstrates that anesthetics may exacerbate neurodegenerative pathways in the brain [205–217]. In studies performed in various cell lines, anesthetics have been shown to enhance protein misfolding and aggregation [205, 212] and may induce neuronal injury in a similar fashion to Alzheimer’s disease (AD) or Parkinson’s disease [205, 210, 216–218]. To compare neuronal damage found in vitro with behavioral correlates, researchers have tested transgenic mice following anesthetic exposure in behavioral paradigms [215–217]. In a study performed on female Alzheimer transgenic (Tg2576) mice at 12 months of age, researchers demonstrated that anesthetic exposure did not enhance cognitive decline in transgenic mice, yet isoflurane exposure impaired cognitive function in nontransgenic mice, implying an alternative path for neurodegeneration in those animals . Conversely, Tang and colleagues  exposed male and female triple-transgenic AD mice to either halothane or isoflurane during the presymptomatic phase of AD, showing that exposure to two different inhalation anesthetics did not accelerate cognitive decline and may cause a stress response, marked by hippocampal phosphorylated tau, found primarily in females . A clinical study performed in 11 patients (three males, eight female) demonstrated that anesthesia may increase neuroinflammatory responses in a pattern consistent with AD . Taken together, these findings suggest the possibility that anesthetics may exacerbate some of the symptoms of pathological neurodegeneration, leaving many questions of gender differences in the effects of anesthesia in the elderly, healthy, or otherwise unanswered.
Cognitive dysfunction is common in adult patients of all ages at hospital discharge after major noncardiac surgery, but only the elderly (aged 60 years or older) are at a significant risk for long-term cognitive problems. Moreover, patients with postoperative cognitive dysfunction (POCD) are at an increased risk of death in the first year after surgery . The majority of studies on postoperative cognitive do not include gender as an independent factor. However, Chan and colleagues  related POCD to BIS levels during surgery in patients over 60. It was concluded that BIS-guided anesthesia (with lower BIS levels) reduced the risk of immediate postoperative delirium and POCD at 3 months after surgery . Several other studies have indicated that lower BIS levels are associated with reduced risk of POCD [223–227]. Given that females have been shown to have higher BIS levels on average , it is possible that elderly women may suffer greater risk of POCD. Because POCD has been associated with increased risk of mortality in the intermediate postsurgical period , it is possible that elderly women may also be at greater risk of mortality following surgery. However, further study of the differences in elderly men and women who undergo general anesthesia is warranted to determine potentially elevated risks of general anesthesia for female patients.
It is evident that the brains of men and women are different from before birth. These differences have a substantial impact on how male and female brains tolerate anesthetic agents. Yet because male-only research dominates the anesthesia field, it is unclear how the female brain, at any age, interacts with various anesthetic agents. Currently, the leading hypothesis to explain gender differences in anesthetic effects involves hormonal differences between men and women, such that the levels of ovarian hormones are a critical factor in determining induction doses, maintenance requirements, BIS scores, and recovery outcomes. Yet, is the sex dependence really just a question of hormone levels? Are there other contributing factors to the way each gender endures an anesthetic exposure? Sex differences seem to be most pronounced in adulthood, with children and the elderly exempt from these differences for the most part. Yet, further studies on sex differences in anesthetic effects on the brain are warranted for the extremes of age to elucidate potential mechanisms associated with gender differences in small children and the elderly. It remains unclear whether the very early changes in the brain during development result in the sex-related differences observed in anesthetic sensitivity and metabolism in the brain, although one report in rats shows that males are more sensitive to anesthetics . While puberty seems to further exacerbate these differences, supporting the role of hormones in gender differences, it is also unclear whether adolescent sex differences may impact sensitivities and metabolism of anesthetic agents in the brain. And, what are the mechanisms associated with these changes in the brain during puberty that influence the effects of general anesthesia? In adults, sex differences are apparent in the induction, maintenance, and recovery phases of general anesthesia. What is the role of critical factors besides hormonal differences, such as body composition and physiology, in influencing how general anesthesia affects the brain? Furthermore, if the gender differences are mainly due to hormone variations in women, then how do normal hormonal variations in women like the menstrual cycle, pregnancy, and menopause influence outcomes of general anesthesia?
Taken together, it is clear that we know little about the sex differences in anesthetic actions and effects on the brain. And because most of what we know about the interaction between anesthetics and the brain are taken from studies of males only, the anesthetic management and care of female patients may be hindered by a lack of knowledge about gender-specific mechanisms. In our view, it is recommended that all researchers consider testing their hypotheses in both sexes or, if restricted by practical considerations, only in females. It is invalid to assume that data obtained in male subjects will generalize to females. If only males are examined in a given study, it is important that a rationale for exclusion of females be provided and that the potential limitation of the findings is addressed in the discussion. In both preclinical and clinical studies, a comparison of both sexes will further our understanding of individual differences in the brains of males and females exposed to anesthesia, thus improving our ability to administer the best anesthesia to all surgical patients.
The authors extend a note of appreciation to Eric Shaw and Dr. Dalton Dietrich for the critical review of this manuscript and helpful discussion. The authors regret space limitations that prevented the citation of many noteworthy and relevant studies. The support for the authors’ work and laboratories was from The Miami Project to Cure Paralysis and Department of Anesthesiology at the University of Miami Miller School of Medicine.
Conflict of Interest
The authors declare that they have no conflict of interest.