Neurologic Disease in Women - part 3 pdf

NEUROLOGIC DISEASE IN WOMEN 82 Progesterone genomically influences the enzymatic activity controlling the synthesis and release of various neurotransmitters and neuromodulators (7). Progesterone decreases the number of dendritic spines and synapses on hippocampal CA1 pyramidal neurons, thus counter- acting the stimulatory effects of E2 (33). It has inhibitory direct membrane effects, described in the next section. Neuroactive Steroids The anticonvulsant effect of progesterone is largely mediated by its 3 ␣-hydroxylated metabolite, 3-␣-hydroxy-5-␣- pregnan-20-one or allopregnanolone (AP) (37,38). Allo- pregnanolone and the 3␣,5␣-hydroxylated natural metabolite of the mineralocorticoid deoxycorticosterone, allotetrahydro-deoxycorticosterone (allo-THDOC), are the two most potent of a number of endogenous neuroactive steroids with a direct membrane effect on neuronal excitability (37,39). Allopregnanolone is devoid of hormonal effects. It may be thought of as an endogenous regulator of brain excitability with anxiolytic, anticonvulsant, and sedative-hypnotic properties (37). Allopreg- nanolone and allo-THDOC hyperpolarize hippocampal and other neurons by potentiating GABA-mediated synaptic inhibition. They act as positive allosteric modulators of the GABA-A receptor, interacting with a steroid-specific site near the receptor to facilitate chloride (Cl) channel opening and prolong the inhibitory action of GABA on neurons (7,37,39). Allopregnanolone is one of the most potent ligands of GABA-A receptors in the CNS, with affinities similar to the potent benzodiazepines and approximately a thousand times higher than pentobarbi- tal (37,39). Progesterone by itself enhances GABA-induced Cl- currents only weakly and only in high concentrations (37). Plasma and brain levels of allopregnanolone parallel those of progesterone, and plasma levels of AP corre- late with progesterone levels during the menstrual cycle and pregnancy (37). Brain activity of progesterone and AP, however, is not dependent solely on ovarian and adrenal production, because they are both synthesized de novo in the brain (40). Their synthesis is region-specific and includes the cortex and the hippocampus. Allopregnanolone and allo-THDOC have potent anticonvulsant effects in animal seizure models and in status epilepticus (37,38,41). Allopregnanolone’s anticonvulsant properties resemble those of clonazepam, but with lower relative toxicity and with little habituation to its anticonvulsant effect (42). The abrupt withdrawal of allopregnanolone induces seizures, possibly by a modulation of the ␣-4 GABA-A receptor subunit that confers GABA- insensitivity on the GABA-A receptor. This may be a mechanism of the perimenstrual seizure exacerbation seen in some women with epilepsy (43). Although the 3- and 5-␣-reduced steroids potentiate GABA-A receptor activity and enhance neuronal inhibition, some of the sulfated neuroactive steroids have neuroexcitatory effects. These include pregnenolone sulfate and DHEAS, the naturally occurring sulfated esters of the progesterone precursor pregnenolone and of the progesterone metabolite DHEA (Figure 6.4; 37,44). These steroids increase neuronal firing when directly applied to neurons by antagonizing GABA action at the GABA-A receptor and by facilitating glutamate-induced excitation at the NMDA receptor (45). In animals, pregnenolone sulfate and DHEAS have a proconvulsant effect that is prevented by chronic pretreatment with progesterone (37,45). These neurosteroids may also affect cognition and memory (46). Pregnenolone sulfate stimulates ACh release as well as glutamatergic activity in adult rat hipp- pocampus. DHEAS and PS improve memory and learning in aging mice. In humans, DHEA has been reported to have mood elevating and memory-enhancing effects in middle-aged healthy men and women and in patients with depression (47,48). Trophic Effects In addition to their neuromodulatory effect on neuronal excitability, gonadal steroids also exert a trophic effect on neurons and glial cells. Estrogen is an important neural trophic factor throughout life, with influences on neuronal differentiation, survival, and plasticity (49–51). The trophic effects of estrogen may ameliorate the degeneration of neurons in diseases such as Alzheimer disease (see also Chapter 30), reduce apoptotic neuronal death in ischemic and traumatic brain injury, and promote neuronal regeneration and growth following such injuries. Trophic Effects and Cholinergic Function in Basal Forebrain and Cortex Estrogen plays an important role in the function of the basal forebrain cholinergic system involved in memory and cognition. In ovariectomized rats, estradiol replacement improves spatial memory and maze learning (52). The basal forebrain cholinergic neurons of the nucleus basalis myenert (NBM) and of the diagonal band of Broca (DBB) innervate the forebrain and the hippocampus, areas important in cognition, learning, and memory. Their degeneration is a key feature of Alzheimer disease. Estradiol protects cholinergic neurons against excitotoxic neuronal damage (53). It does so by potentiating the endogenous trophic effects of the neurotrophins, nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF). These trophins are produced in the target areas of basal forebrain cholinergic projections and exert a trophic effect on cholinergic neurons by binding with specific tyrosine kinase receptors, tyro- EFFECT OF OVARIAN HORMONES ON THE NERVOUS SYSTEM 83 sine kinases A and B (trkA and trkB). TrkA and BDNF mRNA levels in the cholinergic neurons fluctuate across the estrous cycle in parallel with estrogen levels (54). Estradiol and estradiol with progesterone increase trkA and trkB levels in the basal forebrain cholinergic neurons and BDNF in the hippocampus (55). The protective effects of estrogen on cholinergic neurons may underlie the observed protective effect of postmenopausal estrogen replacement therapy against the development of Alzheimer disease (26,56,57). Role in Neuronal Injury and Neuroprotection Estradiol protects neurons against a wide variety of neu- rotoxic stimuli, including ischemic CNS injury, oxidative stress, excitotoxic insults, and b-amyloid-induced toxicity (49,50,58). In the middle cerebral artery (MCA) occlusion animal model of cerebrovascular accident (CVA), low levels of estradiol replacement reduce infarct size by 50%. The treatment must precede ischemia by several days (59). Low-dose estradiol pretreatment has a similar neuroprotective effect on the pyramidal CA1 neurons of the hippocampus in status epilepticus in rats (60) and protects explant cultures of both neurons and astrocytes against cell death. The mechanism of this neuroprotection may include the estrogen receptor–mediated inhibition of the apoptotic signaling pathways (58), regulation of growth factor genes and their receptors, and modulation of neurite outgrowth and plasticity (51). In the neocortex, estrogen ␣ receptor (ER-␣) is expressed at high levels only during development, when neocortical differentiation occurs, thus suggesting a developmental role (10). Neocortical estrogen ␤ receptor (ER-␤), by contrast, is expressed throughout life. In adulthood, ER-␣ is expressed in the cortex only after neuronal injury such as CVA. In ER-␣ knockout rats, estradiol has no protective effect against CVA (58). Thus, ischemia or injury induces the expression of ER- ␣, the activation of which by estradiol protects against ensuing neuronal injury. Recently, another membrane-associated estrogen receptor (ER-X) has been identified; ER-X is also expressed perinatally and is only expressed in adulthood following neuronal injury such as stroke. Its activation may also be involved in injury- related neuroprotection (49–51). Pregnenolone also may be important in neuroprotection. It reduces the degree of the histopathological injury and increases the recovery of motor function in rats after traumatic spinal cord injury (61). The mechanism is unclear. Other poorly understood, potentially neuroprotective effects include a reduction of cerebral edema by progesterone following cortical contusion, first suggested by the observations that males have more edema after similar degrees of cortical contusion than females (61). Myelination Finally, gonadal steroids may play a hitherto little appre- ciated role in myelination. Oligodendrocytes and Schwann cells express estrogen and progesterone receptors. Estradiol increases the proliferation of Schwann cells. This finding may relate to the exacerbation of neurofibromatosis during perimenarche (62). Schwann cell synthesize progesterone from pregnenolone. Progesterone synthesis may be important in myelin formation. Expression of the synthesizing enzyme, 3- ␤-hydroxysteroid dehydrogenase (3␤HSD) and progesterone synthesis increase in Schwann cells during myelin formation. Progesterone, in turn, promotes myelin formation by Schwann cells. Following cryolesion of the sci- atic nerve, progesterone concentrations in the regenerat- ing nerve are about sixfold higher than in plasma. Blocking progesterone synthesis or receptor inhibits the formation of new myelin. Conversely, local application of progesterone or pregnenolone accelerates remyelina- tion (61,63). Oligodendrocytes also express progesterone receptors and 3␤HSD, and progesterone may also promote myelination in the CNS. CLINICAL IMPLICATIONS Genetically Based Disorders Disorders that have a genetic basis may encompass an altered ovarian hormonal production, which may affect neurologic function and may affect those neurologic disorders that have a recognized relationship to fluctuations in cyclical hormones. Most of these disorders are dealt with in a more detailed fashion in other chapters of this book, but a few of these conditions deserve additional comments here. Turner syndrome is an example of a chromosomal deletion. About 1 in every 5,000 live-born females has 45 chromosomes plus a single X chromosome; that is, there is a deletion of one X chromosome. Girls have ovarian dysgenesis, absence of ovarian hormonal secretion, high FSH levels, and delayed adolescence as well as a number of associated somatic developmental anomalies. When sexual maturation is desired, patients must be treated with exogenous hormone replacement. Women with Turner syndrome exhibit male cognitive patterns—they perform better on visuospatial tasks than on verbal tasks. When untreated with estrogen, patients with Turner syndrome have memory, attention, and spatial performance impairment and hippocampal volume loss on magnetic resonance imaging (MRI) (64). Another genetically based disorder is congenital adrenal hyperplasia (CAH). This autosomal recessive dis- NEUROLOGIC DISEASE IN WOMEN 84 order can be caused by a defect in one of six recognized steroid synthesizing enzymes. It affects both men and women. In three forms, only the adrenal gland is affected. In the other three, both the adrenal gland and the ovary are affected. The enzymatic deficiency (e.g., of the CYP450-c21 hydroxylase) results in impaired adrenal synthesis of cortisol, reduced inhibitory feedback of ACTH, and increased adrenal synthesis of the cortisol precursors that can be converted to androgens. Clinically, women with this condition have mild to moderate viril- ization that manifests itself early in life, and that is occa- sionally associated with a delay in the onset of sexual development. Two clinical forms of the disease present neonatally, one in late childhood, adolescence, or adulthood. In the neonatal forms, there is an increased prenatal production of androgens. The classic form of CAH due to 21-hydroxylase deficiency is a rare disorder of adrenal steroid synthesis that affects approximately 1 in 15,000 live births as a result of a gene mutation on the short arm of chromosome 6. Males or females with CAH are exposed to high levels of androgens during gestation, beginning in the third month of fetal life. As the disease is now readily diagnosable and treatable at birth, the hormonal abnormalities are confined to prenatal and early neonatal exposure. CAH has been associated with some behavioral changes that have been attributed to intrauter- ine exposure to increased androgen levels. Women with CAH have an increased risk of gender identity disorder (e.g., of adopting male sexual identity), increased incidence (33%–45%) of homosexual tendencies, and show masculine play behavior in childhood and male-typical cognitive performance in adulthood (65). In addition, women with CAH have a higher incidence of polycystic ovarian syndrome, which may have neurologic conse- quence (2). Physiologic Disorders Changes in the secretion of ovarian hormones associated with menarche, menstrual cycles, pregnancy, and menopause may all affect the clinical manifestation of a number of disorders such as epilepsy, migraines, multiple sclerosis, movement disorders, and pseudotumor cere- bri during a woman’s life. Partial Epilepsy Several researchers have noted that epilepsy commonly starts around the time of menarche (66,67). In one study, seizures began at menarche in 19% of all adult women with epilepsy. In another study, 35% of epilepsy that began between the ages of 0.5 and 18 years began within 2 years of menarche. Epilepsy was much more likely to start within 2 years of menarche (perimenarche) and during the year of menarche than during any other postna- tal childhood period (66). In girls with pre-existing epilepsy, approximately one-third experience seizure exacerbation during puberty (66–68). This is more likely to occur in girls with focal epilepsies, refractory seizures, evidence of CNS damage, and delayed menarche. Changes in reproductive hormones may be responsible for these observations. Sexual maturation begins with adrenarche, which starts between the age of 8 and 10 with a marked increase in the secretion of DHEAS and DHEA (69). This is followed by gonadarche, which starts around the age of 10 with the secretion of estrogen, but without the secretion of progesterone. The ovarian secretion of estrogens gradually rises through menarche (median age 12.8 years) until the onset of ovulation. In the majority of girls, menstrual cycles are initially anovulatory. Ovulation only starts 12 to 18 months after menarche. It is only at this point that the ovarian secretion of progesterone begins, with a parallel increase in serum allopregnanolone levels in late puberty (70). Thus, the secretion of the neuroexcitatory steroids, DHEAS and estrogen, precedes the secretion of progesterone, the neu- roinhibitory steroid, by several years. Continued exposure of the brain during this time to the proconvulsant effects of estrogen and DHEAS without the anticonvulsant effect of progesterone may facilitate the development of epilepsy (epileptogenesis) in susceptible girls. The cyclical pattern of estradiol and progesterone secretion may influence the likelihood of seizures (36). Catamenial seizures broadly refer to an identifiable and predictable occurrence of seizures in relationship to the menstrual cycle (28,71–73). Herzog et al. described three patterns of catamenial seizure exacerbation (74). The two more easily recognized patterns are (i) worsening of seizures during the mid-cycle and (ii) perimenstrually in women with normal ovulation. In the first case, the occurrences of seizures coincide with ovulation, whereas in the second form, the occurrences happen 1 to 2 days before the onset and 1 to 2 days after the onset of menstruation. The third pattern occurs in women who fail to ovulate, when seizures occur throughout the entire late stage of the cycle, which may vary considerably in duration. It is sometimes easier to note that seizures decrease in occurrence from day 2 through days 8 to 10, and then increase until menstruation. As mentioned earlier, estradiol has proconvulsant effects on the brain, whereas progesterone has anticonvulsant effects. In women with ovulatory cycles, the surge of ovarian secretion of estrogen before and during ovulation may be responsible for the periovulatory seizure exacerbation. During the luteal phase, the anticonvulsant effect of progesterone secreted by the corpus luteum may protect against seizures, resulting in lower seizure frequency (71,72,74). Perimenstrual seizure exacerbation may be due to the withdrawal of progesterone and its GABA-mediated anticonvulsant effect, similar to the EFFECT OF OVARIAN HORMONES ON THE NERVOUS SYSTEM 85 withdrawal seizures seen with a discontinuation of bar- biturates, benzodiazepines, or alcohol (42,43). In women with anovulatory cycles, the ovary secretes essentially normal quantities of estrogen during the late follicular and luteal phases (not the periovulatory phase) but does not secrete progesterone. Thus, an elevated estrogen:progesterone ratio occurs from late follicular phase until menstruation. This may explain the unusual pattern of seizure exacerbation, when seizures occur from about menstrual cycle day 8 to 10 until menstruation. In essence, such women are only protected against seizure exacerbation when the ovary secretes very little estrogen during the early and mid-follicular phase of the cycle. Menopause may also affect epilepsy. The term menopause refers to a complex process that encompasses both menopause, cessation of all menstruation, and perimenopause, the preceding decline in reproductive endocrine function. Perimenopause often extends for several years. Early in perimenopause ovulatory cycles change to anovulatory, and progesterone secretion declines (75). By contrast, estrogen secretion remains normal through most of perimenopause and may even increase episodically when, as a result of erratic follicular development, multiple follicles develop during some menstrual cycles. Estrogen levels only drop consistently late in the perimenopause, during the last few months before cessation of menses, as the follicle pool becomes exhausted. Thus, for a period of time that may last for several years, there may be a relative excess ratio of estrogen to progesterone. Based on the pattern of hormonal change, an evolving seizure pattern with seizure exacerbation during the perimenopause might be expected: ini- tial seizure exacerbation when progesterone secretion declines but estrogen secretion continues, followed by sta- bilization or improvement after menopause, as estrogen secretion ceases. This pattern did, in fact, occur in a recent study (76). Sixty-four percent of women experienced seizure exacerbation, and only 13% of women experienced seizure improvement during the perimenopause. By contrast, 43% of women had seizure improvement during the menopause, with only 31% experiencing seizure exacerbation. Partial epilepsy may also begin during the climacteric, sometime without an apparent cause (77). It is possible that the chronic exposure of the brain to estrogen without progesterone during the perimenopausal years could “kindle” an occult nonepileptic CNS lesion into an epileptic one, in a way similar to the suggested epileptogenic effect of perimenarche. Estrogen replacement therapy may also be associated with seizure exacerbation during the perimenopause and menopause (76). We believe that if there is a clinically significant increase in seizure frequency, hormonal replacement should include both estrogen together with natural progesterone. In addition, epilepsy, particularly temporal lobe epilepsy, can influence the menstrual cycle. As mentioned, the amygdala, a mesial temporal lobe structure, has reciprocal relationships with hypothalamic structures that influence gonadotrophin secretion. In our study of 50 women with clinical and electroencephalographic evidence of temporal lobe onset partial epilepsy, 38% had significant reproductive abnormality (78). Approximately 20% had polycystic ovarian syndrome (PCOS), and 12% had hypogonadotrophic hypogonadism (HH). Two of the women had premature menopause, and one had hyper- prolactinemia. An increased risk of premature menopause among women with epilepsy was also observed in another study (79). In humans, it appears that a significant right temporal lobe versus left temporal lobe differential effect occurs in the hypothalamic gonadotrophin response to temporal lobe seizure activity. We first observed that the LH levels in women with temporal lobe epilepsy varied considerably compared to age-matched controls (80). Women with left temporal seizures had more LH surges during an 8-hour period than controls. These women all had PCOS. In women with hypothalamic hypogonadism (HH), there was a marked decrease in the number of LH surges during an 8-hour period compared to controls, and the seizure focus was more often right-sided. A possible explanation for these findings may include a differential effect of altered input from the right and left amygdala on the hypothalamic GnRH neuronal pulsatile activity (80). In addition to the above observations regarding the complex interactions of seizure type and seizure location on hormonal cyclicity and the hormonal effect on seizure frequency, medications play an important and often con- founding role. Similarly, pregnancy may have a major effect on seizures through its effect on endogenous hormone production and its effect on the metabolism of the antiseizure medication. These effects are discussed in more detail in a later chapter. Migraine Migraine is equally prevalent in boys and girls until adolescence, when the ratio changes to 3:1 in favor of women: 17.6% of women suffer from migraines compared with 5.7% of males (81). In approximately 60% of women, migraine attacks are linked to the menses, and in approximately 15% of women with migraines, attacks occur exclusively perimenstrually. The catamenial exacerbation of migraines begins at menarche in approximately 33% of women with menstrual migraines. During pregnancy, migraines may worsen during the first trimester and remit during the last two trimesters, although the pattern of improvement or exacerbation is highly variable and individual; approximately 25% of women with migraines experience no change in their headaches during pregnancy (82). Migraines may worsen transiently, but at times markedly and for a prolonged time, during perimenopause; migraines may improve after NEUROLOGIC DISEASE IN WOMEN 86 completion of menopause when the female:male ratio drops to 2:1 (83). The pathophysiologic underpinnings of these clinical phenomena remain essentially obscure. A popular hypothesis is that estrogen withdrawal perimenstrually alters vascular tone, leading to vascular instability and a greater susceptibility to cerebrovascular dilatation and headache. Estrogen receptors are found on the media of medium-size cerebral vessels. Estrogen stimulates the production of nitric oxide and causes cerebrovascular dilatation (84). Blood flow in the internal carotid artery increases by 15% during the ovulatory phase of the menstrual cycle in normal women (85). However, no difference has been found in the systemic levels of estrogens, progesterone, androgens, LH, or FSH between women with catamenial migraines and controls (86). No blood hormone–blood flow correlation studies have been per- formed in women with migraines. Progesterone has not been thought to be a significant factor in migraine, but it is noteworthy that in an animal model of migraine, pretreatment with both progesterone and the 3,5-a reduced metabolites allopregnanolone and tetrahydrodeoxycorti- costerone ameliorated plasma extravasation within the meninges (87). This would suggest that progesterone— via allopregnanolone—may play an anti-inflammatory role in the CNS. Perimenstrual withdrawal of progesterone could thus theoretically contribute to an increase in the vasogenic inflammation that may be part of the pathophysiology of migraine. Other possible mechanisms that have been suggested include a perimenstrual reduction of hypothalamic opioid secretion, increased prostacyclin activity, and prostacyclin-related vasodilation and modulation of prolactin secretion (83). Of particular interest is the influence of estrogen on opioids. Estradiol colocalizes with the opioids endorphins, encephalin, and dynorphin in rat neurons of a number of brain regions, including the hypothalamus and the dorsal spinal cord sensory neurons. It induces the expression and release of the endogenous opioid peptides and activate µ-pioid receptor activation in the hypothalamus and in the amygdala (88). Expression of endorphin in hypothalamic neurons and the release of opioids into the hypothalamic-portal cir- culation fluctuates during the menstrual cycle. It is high- est at the time of ovulation (estrus) and falls as serum estrogen levels fall (89). Thus, estradiol potentiates the analgesic effects of endogenous opioids. It may, possibly, by its effect in the amygdala, even alter the subjective perception or “emotional content” of painful stimuli. Its withdrawal perimenstrually may contribute to the menstrually related migraine. Conversely, its large rise during the last two trimesters is associated with an elevation of the pain threshold during gestation (90). Thus, it may contribute to the alleviation of migraine during this part of pregnancy. These theories have led to limited therapeutic trials with estrogen and, paradoxically, antiestrogen therapy, for example, with tamoxifen, with androgens such as danazol, and with dopamine agonists such as bromocriptine and pergolide to suppress prolactin secretion (91). These studies have been limited in scope and therapeutic success, although anecdotal reports of success using all these agents abound. Multiple Sclerosis Multiple sclerosis (MS) is also more common in women than men, with approximately a 2.5:1 ratio. The onset of the disease is also most common during the second and third decades of life, although the incidence rises after puberty, during the second half of the second decade. Anecdotal reports of MS show perimenstrual exacerbation (92), but also improvement with estrogen contraceptive treatment (93). One of the most notable features of MS, however, is the reduction of relapsing attacks in remitting and relapsing MS during the last trimester of pregnancy, with a subsequent rebound of attacks during the postpartum period (94). The relapse decrease of the last trimester may be mediated by a shift in immune responses from the inflammatory response promoting T helper 1 lymphocytes (Th1 cells) to the inflammatory response dampening T helper 2 lymphocytes (Th 2 cells). A number of hormones rise dramatically during the second half of pregnancy. The serum levels of estradiol, estriol, progesterone, cortisol, and 1,25-vitamin D, among others, rise tenfold during this time, compared with their preconception levels. All these hormones affect the immune system. Estradiol, estriol, cortisol, and 1,25-vitamin D have been shown to have an immunosupressant effect and a suppressant effect on experimental allergic encephalomyelitis (EAE), the animal model of MS (95). Estrogens affect CD4+ T lymphocytes, with differential effects at low versus high dose. High levels of estrogen favor T-2 anti-inflammatory cytokine and humoral immune response (96). Proges- terone also facilitates the T-2 profile, with the induction of the messenger RNA of the anti-inflammatory inter- leukin-4 (97). Clinically, the number and volume of gadolinium- enhancing MRI lesions in women with MS do not fluctuate between the follicular and the luteal phases of the menstrual cycle. A positive relationship, however, has been demonstrated between MRI lesion number and volume and the serum progesterone:estradiol ratio (98). Attempts at the therapeutic manipulation of reproductive hormones other than in MS have not been system- atic and have been largely unsuccessful. Bromocriptine, which suppresses the secretion of prolactin, was found to be very effective in suppressing EAE in animals when administered both before and after the EAE-inducing agent EFFECT OF OVARIAN HORMONES ON THE NERVOUS SYSTEM 87 (95). Attempts at human studies, however, were not promising and have been abandoned (99). 1,25-vitamin D was similarly promising in EAE models and disappointing in limited human studies (100). Recently, the weak estrogen estriol, a major estrogen product of the second half of human pregnancy, was found to suppress EAE and to decrease delayed-type hypersensitivity responses in peripheral blood mononuclear cells and gadolinium-enhancing MRI lesion number and volumes in nonpregnant women with MS compared with pretreatment baseline. The bene- ficial MRI effects receded when the treatment was stopped and re-emerged when it was reinstituted (101). A placebo- controlled study is being planned. Neuropsychiatric Diseases As already mentioned, most neuropsychiatric diseases are “sexually dimorphic,” with a greater predilection for women (depression, anxiety disorders, anorexia-bulimia) or for men (aggression, schizophrenia) (16). The differences in incidence and prevalence of these disorders between men and women emerges during puberty. Menar- che has been aptly named “the forgotten milestone” of female psychiatric diseases (16). Affective and anxiety disorders are commonly affected by the menstrual cycle, and commonly exacerbate or present de novo during the postpartum period or during the perimenopause (22). Both estrogens and progesterone have psychoactive properties. Estrogens, via diverse mechanisms that may include augmentation of NMDA and non-NMDA glutamatergic activity, serotonergic, noradrenergic, and opiate activity, have an arousing, antidepressant, and potentially anxiogenic effect (102). Progesterone and allopregnanolone, by contrast, have anxiolytic, sedating and, in higher doses, depressive and anesthetic effects similar to those of the benzodiazepines, due to their potentiation of GABA-ergic activity. Progesterone withdrawal may there- fore be pathophysiologically important in the perimenstrual exacerbation of anxiety disorders, and of rapid cycling in bipolar affective disorders, and in premenstrual dysphoric dysfunction (PMDD) or premenstrual syndrome (PMS). PMDD women with greater levels of premenstrual anxiety and irritability have significantly reduced allopregnanolone levels in the luteal phase relative to less symptomatic PMDD women (103). This suggests that a dysfunction of metabolism of progesterone to allopregnanolone may be one factor in the causation of PMDD. The withdrawal of progesterone and low serum allopregnanolone levels may also be implicated in postpartum depression. Serum allopregnanolone levels were similarly decreased after delivery in women with postpartum dys- thymia compared to euhymic women (104), with a nega- tive correlation between Hamilton Depression Rating score and serum allopregnanolone level. A significant neg- ative correlation was observed between the Hamilton score and levels of serum allopregnanolone. Movement Disorders Parkinsonian symptoms can worsen perimenstrually in women with Parkinson disease. In one large survey, 75% of women with natural menstrual cycles noted a worsening of symptoms before or during the period (105). The pathophysiologic mechanisms have not been investigated. In chorea gravidarum, chorea occurs during pregnancy, sometimes in patients with previous post- rheumatic fever chorea (Sydenham chorea). Its patho- genesis is unclear, but may be related to a pregnancy-associated rise in gonadal hormones, particularly estrogens. This hypothesis is supported by the observation that estrogen-containing oral contraceptive may be a trigger for chorea, sometimes in a patient who also suffers from chorea gravidarum (106). (See also Chapter 24.) CONCLUSION The study of the effects of hormones on the nervous system, mood, memory, cognition, and behavior in health and in disease is beginning to receive the attention that it deserves. Hopefully, over the next few years, the complex interrelationships between hormonal fluctuations and the various neurotransmitter systems and metabolic pathways, as well as neuronal survival, brain plasticity, neuronal remodeling, and synaptogenesis will be more fully understood so that we might predict and treat the normal and pathologic conditions that arise from the cyclical behavior of ovarian hormones. On a final note, a word of caution. Although a good deal is known about the effects of ovarian hormones on the nervous system, very little is known about two aspects that may be important. The first is the adaptive response of the nervous system to the fluctuation levels of the steroids. Serum steroid levels may change dramatically without clinical effects. During the last trimester of the pregnancy, for instance, serum levels of progesterone and estradiol rise to approximately 10 times the level of the luteal phase of the menstrual cycle and approximately 40 to 200 times the level of the early follicular phase. Within 24 to 48 hours after delivery, the secretion returns to the follicular phase level. Yet in the majority of women, no neurologic complications occur during the last trimester of the pregnancy or the puerperium (2). Thus, adaptive changes must mitigate the effects of such large fluctuations in serum levels on the nervous system. Second, we know very little about the functional significance of in situ synthesis of neurosteroids in the CNS. This synthesis is larger than peripheral steroid synthesis for several major gonadal and adrenal steroids such NEUROLOGIC DISEASE IN WOMEN 88 DHEA, DHEAS, and pregnenolone (brain levels of which are up to 10 times higher than serum levels), as well as for neuroactive progesterone metabolites such as allopregnanolone and TH-DOC (105). Such knowledge will be important in determining the overall role of steroids, including ovarian steroids, in the healthy and diseased functioning of the nervous system. References 1. Greenspan FS, Strewler GJ, (eds.) Basic and clinical endocrinology , 5th ed. Stamford, Conn: Appleton and Lange, 1997. 2. Yen SSC, Jaffe RB, Barbieri RL, (eds.) Reproductive endocrinology , 4th ed. Philadelphia, Pa: WB Saunders, 1999. 3. Funabashi R, Shinohara K, Kimura F. Neuronal control circuit for the gonadotropin-releasing hormone surge in rats. 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Uniquely, in genetics, the clinician is concerned about manifestations not only in the patient but also in her relatives, especially actual or potential offspring to whom disease may be transmitted. Some genetic diseases are different in women than in men. In others, the only difference is in transmission; the offspring of an affected woman being at different risk than those of an affected man. In still others, notably the sex-linked disorders, both the disease and transmission pattern are different in men and women. EXPRESSION OF GENETIC DISEASES IN WOMEN Gender differences in disease phenotype are either sex- linked, the underlying gene(s) being located on a sex chromosome, or sex-limited autosomal disorders, such as male-pattern baldness. In theory, sex-linked disorders could result from alterations of either the X or the Y chromosome. However, the Y chromosome is not only small but also has a low density of genes (1). Its known con- tribution to human neurogenetic disorders appears to be limited to a behavioral and mildly dysmorphic phenotype, the XYY syndrome (2). In practice, virtually all sex-linked disorders are encoded by genes on the X chromosome. Sex-Linked Disorders Recognized X-linked disorders are slightly more frequent than would be predicted by the ratio of one X chromosome to 22 autosomes. As of this writing, of the 14,561 entries in the catalog of human genes and genetic disorders, Online Mendelian Inheritance in Man (OMIM), 810 (5.56% of the total) are in the X chromosome catalog (1). Indeed, 101 of the 1,348 phenotype descriptions in OMIM are in the X chromosome catalog, representing 7.49% of the total number of all phenotypic descriptions in the entire catalog. This is a higher percentage than would be expected from the relative size of the X chromosome, the 151,567,156 base pairs (bp) of which rep- resent only 4.67% of the 3,242,415,757 bp that consti- tute the haploid human genome. Indeed, Ensembl, a joint project between the European Bioinformatics Institute and the Sanger Institute, currently predicts the existence of 24,847 human genes, of which 869 (only 3.49%) are on the X chromosome (3). Thus, there are roughly twice as many known human X-linked traits as would be predicted by the proportion of human genes that is currently 91 Genetic Disorders in Women Orest Hurko, MD 7 F [...]... syndrome 30 0100 30 335 0 31 2920 30 8750 Xq28 Xq28 Xq22 X? Peroxisomal ATP-binding transport protein L-CAM cell adhesion molecule Proteolipid protein PRODUCT PROGRESSIVE ATAXIAS DISORDER OMIM LOCUS GENE Menkes kinky-hair disease 30 9400 Pelizaeus-Merzbacher PRPS deficiency X-linked cerebellar ataxia (X-linked OPCA included) X-linked ataxia-deafness syndrome Arts fatal X-linked ataxia syndrome 31 2080 31 1850 30 2500... 31 0200 31 030 0 Xp21.1 Xq28 Dystrophin Emerine, serine-rich vesicular transport protein 30 9660 X 31 0400 Xq28 30 5550 31 1800 X 31 1800 Fingerprint myopathy Phosphoglycerate kinase deficiency PRODUCT MTM1 myotubularin, putative tyrosine phosphatase PGK-I PERIPHERAL NEUROPATHIES DISORDER OMIM LOCUS GENE Charcot-Marie-Tooth, X-linked dominant (CMTX1) Charcot-Marie-Tooth, X-linked recessive (CMTX2) Charcot-Marie-Tooth,... Charcot-Marie-Tooth, X-linked recessive (CMTX3) Charcot-Marie-Tooth, 2D (Cowchock variant with deafness and mental retardation) Charcot-Marie-Tooth, with deafness and optic atrophy (Rosenberg-Chutorian disease) Charcot-Marie-Tooth, with aplasia cutis congenita Fabry disease (angiokeratoma diffusa) 30 2800 XP11 .3 Connexin 32 , gap junction protein 30 2801 Xp22.2 30 2802 Xp26 31 0490 Xq24-q26 1 31 1070 X 30 28 03 301500... H Sex-linked recessive inheritance in Charcot-Marie-Tooth disease with partial manifestation in female carriers Hum Genet 1980;55: 4 13 415 85 Hanemann CO, Bergmann C, Senderek J, et al Transient, recurrent, white matter lesions in X-linked Charcot-Marie-Tooth disease with novel connexin 32 mutation Arch Neurol 20 03; 60:605–609 86 Bergoffen J, Scherer SS, Wang S, et al Connexin mutations in X-linked... no report of clinical or subclinical neurologic involvement in true female carriers in this disorder or in the other X-linked motor neuron disease, lethal infantile sex-linked spinal muscular atrophy (SMAX2) (1 03) .] Motor neuron disease may underly some forms of distal infantile arthrogryposis, of which there may be as many as three distinct X-linked types (104) In one such family, the disease was transmitted... ganglia disease, Dandy-Walker malformation with mental retardation and seizures HHHH syndrome (hereditary hemihypotrophy hemiparesis hemiathetosis) Goeminne TKCR syndrome (torticollis, keloids, cryptorchidism, renal dysplasia) 31 4250 Xq12-q 13. 1 31 1510 Xq28 30 434 0 Xq25-q27 30 6960 X? 31 430 0 Xq28 PRODUCT (continued) NEUROLOGIC DISEASE IN WOMEN 108 TABLE 7.2 X-Linked Neurogenetic Disorders Seen in Males... 31 2080 31 1850 30 2500 Xq 13. 2q 13. 3 Xq28 Xq22-q24 X Cu(2+)-transporting ATPase, alpha polypeptide Proteolipid protein Phosphoribosyl pyrophosphate synthetase 30 1790 30 1 835 X X PRODUCT MOVEMENT DISORDERS DISORDER OMIM LOCUS GENE Lesch-Nyhan syndrome 30 8000 X Hypoxanthine-guanine phosphoribosyltransferase Torsion-dystonia 3 with parkinsonism, Filipino type Waisman early-onset parkinsonism and mental retardation... 170 Machin GA, Walther GL, Fraser VM, et al Autopsy findings in two adult siblings with Coffin-Lowry syndrome Am J Med Genet 1987;(suppl 3) :30 3 30 9 171 Simensen R J, Abidi F, Collins JS, et al Cognitive function in Coffin-Lowry syndrome Clin Genet 2002;61: 299 30 4 172 Sivagamasundari U, Fernando H, Jardine P, et al The association between Coffin-Lowry syndrome and psychosis: a family study J Intellect... 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Allo- pregnanolone and the 3 ,5␣-hydroxylated natural metabolite of the mineralocorticoid. Estradiol is a protective factor in the adult and aging brain: understand- ing of mechanisms derived from in vivo and in vitro studies. Brain Res Brain Res Rev 2001 ;37 :31 3 31 9. 60. Veliskova. report of clinical or subclinical neurologic involvement in true female carriers in this disorder or in the other X-linked motor neuron disease, lethal infantile sex-linked spinal muscular