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Sex Hormone, Pituitary, Parathyroid, and Adrenal Disorders and the Nervous System
The most common endocrine disorders causing neurologic disease are thyroid disease and diabetes mellitus, which are addressed in Chapter 18, Chapter 19 . Nevertheless, sex hormone, pituitary, parathyroid, and adrenal disorders may have important neurologic implications or consequences and are therefore reviewed here, with emphasis on features relevant to neurologic practice.
Sex Hormones and the Nervous System
The effects of sex steroids on neurologic function in health and disease constitute a rich and rapidly expanding area of basic and clinical neuroscience. Sex steroids exert both organizational and activational effects within the nervous system. Organizational effects refer to the irreversible differentiation of neural circuitry resulting from exposure to sex steroids during critical periods of brain development and are discussed in the previous edition of this book. The activational effects of sex steroids encompass a myriad of largely reversible neurophysiologic influences exerted by gonadal hormones on the mature nervous system. Such interactions are essential for regulation of the brain–pituitary–gonadal axis ( Fig. 20-1 ) and the establishment of normal patterns of sexual, aggressive, cognitive, and autonomic behaviors. Furthermore, by impacting neurosteroidogenesis and the metabolism and release of various central neurotransmitters and neuromodulators, hormonal fluctuations associated with (1) specific phases of the menstrual cycle, (2) pregnancy, (3) the menopause, and (4) exposure to exogenous sex hormones may induce or modify a host of neurologic and neuropsychiatric disorders.
Migraine
Although no gender difference in its prevalence is apparent before puberty, migraine is three times as common in adult women (18%) as in men (6%). Approximately 60 percent of women with migraine experience perimenstrual exacerbations of their headaches (catamenial migraine). The late luteal-phase decline in plasma estradiol (but not progesterone) appears to play an important role in the precipitation of catamenial migraine. The frequency or severity (or both) of migraine attacks often diminishes with gestation, particularly in patients whose headaches are linked to the menstrual cycle. The absence of rhythmic estrogen “withdrawal” characteristic of the pregnant state is believed to be responsible for the reduction in migraine activity. Indeed, many women whose headaches are attenuated by pregnancy experience relapses at the time of parturition, when sex hormone levels fall precipitously. In some women, breastfeeding appears to protect against migraine recurrence. Occasionally, migraine arises for the first time or appears to worsen during gestation or the perimenopausal period. A first approach to the management of gestational migraine should be nonpharmacologic (e.g., relaxation training, biofeedback), especially during the first trimester when risks of teratogenicity and embryotoxicity are greatest. For severe attacks, acetaminophen with codeine or nonsteroidal anti-inflammatory drugs (NSAIDs) may have to be used. Further discussion is provided in Chapter 31, Chapter 59 . For status migrainosus in pregnancy, chlorpromazine, meperidine, morphine, or prednisone may need to be administered. Perimenopausal migraine often responds to standard estrogen replacement therapy, but this must be weighed against the risk of developing breast cancer in individual patients. Fluoxetine and venlafaxine may be beneficial in women with perimenopausal migraine and comorbid hot flashes.
An association between migraine and oral contraceptives is frequently encountered in clinical practice. Women often exhibit new onset or exacerbation of migraine while taking oral contraceptives. Attacks tend to manifest during the first few cycles (particularly on placebo days in accord with the estrogen withdrawal hypothesis) and usually, but not invariably, resolve on discontinuation of the medication. A qualitative change in the pattern of migraine is noted in some patients. For example, a migraineur may develop a focal prodrome for the first time while taking oral contraceptives. Women in this category may be at high risk of infarction in regions reflecting the distribution of their auras. Amelioration of migraine after exposure to oral contraceptives is sometimes observed, perhaps related at least in part to psychologic factors.
The pathophysiology of estrogen-related migraine is incompletely understood. Estrogens may act directly on vascular smooth muscle as well as modulate the activity of vasoactive substances at the neurovascular junction. In addition, by altering central prostaglandin, serotonin, opioid, prolactin, or calcitonin gene-related peptide metabolism, premenstrual changes in circulating estrogens may activate vasoregulatory elements in the brainstem or hypothalamus, which, in turn, may trigger symptomatic alterations in cerebrovascular tone.
First-line therapy for menstrual migraine should include the standard pharmacologic, dietary, and psychologic modalities employed in the general migraine population. Sumatriptan and related serotonin 5-HT 1D (presynaptic autoinhibitory) receptor agonists are equally effective for noncatamenial and menstrual migraine. Refractory cases of severe catamenial migraine may benefit from late luteal-phase therapy with prostaglandin inhibitors (e.g., naproxen, 250 to 500 mg orally twice daily) and mild diuretics. Hormonal interventions in catamenial migraine have been largely unsuccessful and are often complicated by unpleasant side effects. Oral contraceptives usually exacerbate migraine and probably should not be used in the treatment of this disorder. The use of estrogen implants has yielded contradictory results. The risk–benefit ratio accruing to long-term estrogen therapy must be carefully assessed before such treatment can be advocated for this relatively benign condition. The antiestrogen tamoxifen may either alleviate or precipitate catamenial migraine. The beneficial effect of tamoxifen may be due to inhibition of calcium uptake or prostaglandin E synthesis in these subjects. In several reports, danazol (200 mg twice daily for 25 days), a testosterone derivative used in the management of endometriosis, aborted or ameliorated premenstrual migraine for the duration of treatment; catamenial headaches resumed on its discontinuation. Continuous bromocriptine therapy (2.5 mg three times daily) results in a substantial decline of headache frequency in menstrual migraine. In addition to migraine, menstruation, pregnancy, and menopause may also influence cluster headache, other autonomic cephalalgias, and hemicrania continua.
Stroke
Oral contraceptives have been implicated as a significant risk factor in thromboembolic cerebral infarction, subarachnoid hemorrhage, and cerebral venous thrombosis. In the late 1960s, case-control studies revealed a 6- to 19-fold increased risk of ischemic stroke in young women related to the use of oral contraceptives. Hypertension, migraine, and age older than 35 years are associated, but independent, risk factors for cerebral infarction in patients taking oral contraceptives. Cigarette smoking by women on oral contraceptives was found to increase further the likelihood of hemorrhagic but not thromboembolic stroke. Ingestion of lower-dose (30 µg) estrogen preparations appears to be responsible for a decline in rates of thromboembolic disease among users of oral contraceptives. In a population-based case-control study, the odds ratio of ischemic stroke in current users of low-dose estrogen contraceptives (20 to 35 µg) was only slightly higher compared with former users or women who were never exposed to oral contraceptives. However, the risk of stroke remains unacceptably high in low-dose oral contraceptive users if they smoke and are older than the age of 35. Recent evidence suggests that exposure to ultralow-dose oral contraceptives (containing <25 µg ethinyl estradiol) may not enhance stroke risk when used in normotensive nonsmokers. Although less often implicated than estrogens, progestins may contribute to the danger of cerebral infarction by promoting hypertension, hypercoagulability, and adverse serum lipoprotein levels.
Ischemic strokes in users of oral contraceptives have been localized to the carotid (usually the middle cerebral artery or its deep penetrating branches) and vertebrobasilar distributions. There is usually no radiologic or pathologic evidence of disseminated vascular disease in young women with oral contraceptive-related stroke. Cerebral thromboembolism resulting from estrogen-induced hypercoagulability is a likely etiology for such strokes. Estrogen increases plasma levels of fibrinogen and clotting factors VII, VIII, IX, X, and XII. The steroid also enhances platelet aggregation and suppresses antithrombin III activity and the fibrinolytic system. A host of estrogen-regulated genes may impact the risk of ischemic stroke, either positively or negatively. Certain inherited prothrombotic conditions (e.g., G20210A prothrombin, factor V Leiden, or methylenetetrahydrofolate reductase C677T polymorphism) augment the risk of ischemic stroke substantially if present in oral contraceptive users. Sex hormone-induced hypercoagulability is thought to play an important role in the pathogenesis of cerebral venous thrombosis complicating pregnancy, the puerperium, and use of hormonal contraceptives.
Increased levels of endogenous free estradiol may be an indicator of atherothrombotic stroke risk in older postmenopausal women, particularly in those with greater central adiposity. Dyslipidemia, insulin resistance, inflammation, and several adipose-derived hormones (e.g., adiponectin, leptin, ghrelin) are potential mediators of this association. On the other hand, estrogens may mitigate atherosclerotic vascular disease by inhibiting NFκB signaling in macrophages and the production of proinflammatory cytokines such as IL-1β, IL-6, and tumor necrosis factor (TNF)-α. Data concerning the impact of hormone replacement therapy (HRT) on stroke incidence and severity are conflicting, with reports of neutral, increased, and decreased stroke risk accruing from this intervention. In some observational studies, HRT-related stroke risk was significantly modified by the presence or absence of associated factors such as hypertension or smoking. Importantly, several large randomized controlled studies indicated that HRT with conjugated equine estrogen or 17β-estradiol, alone or combined with medroxyprogesterone acetate, does not protect against stroke (or coronary artery disease) in women with established vascular disease and may actually worsen outcomes in this high-risk population. In healthy women without prior cerebrovascular history, an increased risk of ischemic but not fatal or hemorrhagic stroke has been attributed to 17β-estradiol replacement therapy. The risk of ischemic stroke in women receiving HRT does not appear to be modified by age of hormone initiation or by temporal proximity to menopause.
HRT with transdermal low-dose estrogens alone or combined with micronized progesterone may be particularly favorable in minimizing risk of ischemic stroke. Interestingly, men with the common ESR1 c.454–397CC variant of the estrogen receptor-alpha ( ESR a) gene may be more prone to ischemic stroke than men bearing other ESR a genotypes after adjusting for age, hypertension, diabetes, blood lipid levels, and smoking status.
The relative risks of subarachnoid hemorrhage in former users and current users of moderate- to high-dose oral contraceptives were four times those of the general population. The odds ratio for hemorrhagic stroke in current users of low-dose estrogen contraceptives (20 to 35 µg) in comparison with former users or nonusers is negligible. As in the case of ischemic stroke, cigarette smoking and age older than 35 years substantially increase the risk of subarachnoid hemorrhage in users of oral contraceptives. Female sex hormones may predispose tobleeding from both aneurysms and arteriovenous malformations, although the pathophysiologic mechanisms underlying these phenomena remain controversial. By analogy to their effects on endometrial spiral arteries, fluctuating sex hormone levels may compromise the integrity of cerebral arterial walls, rendering them more susceptible to rupture. During pregnancy, hemodynamic changes may facilitate engorgement and bleeding from cerebral arteriovenous malformations. In addition, sex hormones may exert direct trophic influences on these malformations, analogous to their effects on other highly vascularized lesions such as spider angiomas, gingival epulis, and meningiomas (discussed later). Rarely, subarachnoid hemorrhage is secondary to cyclic bleeding from hormone-sensitive ectopic endometriomas of the spinal canal.
Epilepsy
Normal reproductive processes may be disrupted by seizure disorders and their therapies. Abnormal limbic discharges may be responsible for the hyposexuality and increased prevalence of hypogonadotropic hypogonadism and polycystic ovary syndrome noted in patients with temporal lobe epilepsy.
As discussed in Chapter 31 , anticonvulsant therapy in women of childbearing age may result in failure of oral contraceptives and in teratogenicity. Phenytoin, phenobarbital, primidone, ethosuximide, and carbamazepine have been implicated in oral contraceptive failure. These anticonvulsants induce the hepatic cytochrome P450 microsomal enzyme system, which, in turn, accelerates catabolism of endogenous and exogenous sex hormones. In addition, the anticonvulsants augment the synthesis of sex hormone-binding globulins, resulting in reduced levels of circulating free (active) hormone. Anticonvulsants may also promote the clearance of sex hormones by influencing sulfate conjugation and glucuronidation of the latter in the gut wall and liver. Oral contraceptive failure does not occur with valproic acid, which may actually inhibit cytochrome P450 enzymes, causing elevations in plasma steroid concentrations. Valproic acid, however, may cause hyperandrogenism and polycystic ovaries. Of the newer antiepileptic medications, lamotrigine, gabapentin, vigabatrin, levetiracetam, zonisamide, clobazam, and lacosamide do not induce the hepatic P450 microsomal enzyme system, and oral contraceptive failure is less likely to occur with concomitant use of these drugs. Topiramate and felbamate have modest effects on sex hormone pharmacokinetics and may affect contraceptive efficacy. Although breakthrough bleeding has been reported with tiagabine, the impact of this drug on ovarian hormone metabolism is believed to be minimal.
The course of epilepsy and its management may be greatly influenced by specific phases of the reproductive cycle and exposure to steroid contraceptives. A variety of seizure disorders have been documented to worsen around the time of ovulation or premenstrually (catamenial epilepsy) and during pregnancy. An increased risk of epilepsy is associated with menstrual irregularity around age 20. Curiously, left-sided temporal lobe seizures appear more likely to cluster at the onset of menses than right-sided temporal seizures, which tend to occur more randomly throughout the cycle. Data amassed from human and animal studies indicate that estrogens and progestins have epileptogenic and anticonvulsant properties, respectively. Estrogen augments glutamatergic and suppresses GABAergic neurotransmission, favoring epileptogenesis, whereas progesterone has the opposite effects. A rising estrogen–progesterone ratio during the late luteal phase may trigger catamenial seizure activity. Furthermore, the markedly elevated estrogen–progesterone ratio characteristic of the polycystic ovary syndrome may, in part, contribute to the relatively frequent association of this reproductive disorder with temporal lobe epilepsy. Exposure to oral contraceptives consisting of estrogen–progestin combinations does not appear to worsen seizure control significantly. However, spikes in circulating estrogen concentrations accruing from gonadotropin therapy for assisted reproduction may exacerbate seizures in women with epilepsy. Also of concern are interactions between enzyme-inducing anticonvulsants and hormones used for gender-affirming treatment in transgender persons. Management strategies for catamenial epilepsy include (1) premenstrual or periovulatory supplementation of anticonvulsant doses or addition of an adjunctive antiepileptic drug such as clobazam; (2) cyclic administration of acetazolamide, a mild diuretic with weak antiepileptic activity; and (3) progesterone supplementation by mouth or suppository. The allopregnanolone analogue ganaxolone (3α-hydroxy-3β-methyl-5β-pregnane- 20-one), a positive allosteric modulator of GABA-A receptors, may diminish epileptic activity in adults with partial-onset seizures and children with refractory infantile spasms. This neurosteroid appears to be well tolerated and, importantly, lacks hormonal activity.
With respect to gestational epilepsy, factors such as maternal sleep deprivation, stress, and inadequate anticonvulsant levels are probably more important than direct hormonal epileptogenesis. During pregnancy, serum levels of phenytoin, phenobarbital, and valproic acid may decrease by 30 to 40 percent of pregestational levels, with a lesser decline in carbamazepine. Primidone levels are reportedly stable during pregnancy, but the concentration of primidone-derived phenobarbital is reduced. Decreased drug compliance, bioavailability, and protein binding, as well as an increased volume of distribution and metabolic clearance, are factors contributing to the fall in anticonvulsant levels during pregnancy. The influences of the menstrual cycle and of oral contraceptive preparations on anticonvulsant disposition appear to be of minor clinical significance.
Movement Disorders
Chorea
Pregnancy and steroid contraceptive therapy have infrequently been complicated by the acute or subacute development of choreiform movements of the face and extremities associated with limb hypotonia and pendular reflexes. Fever, dysarthria, and neuropsychiatric symptoms may complete the clinical picture. Gestational and oral contraceptive-related chorea have a close association with previous rheumatic fever and Sydenham chorea. Estrogen-containing medications may elicit chorea in patients with a history of congenital cyanotic heart disease, Henoch–Schönlein purpura, systemic lupus erythematosus, and antiphospholipid antibody syndrome and exacerbate dyskinesias in chorea-acanthocytosis. Pharmacologic, epidemiologic, and pathologic evidence suggests that altered hormonal patterns characteristic of pregnancy and ingestion of oral contraceptives may unmask latent chorea by modulating dopaminergic neurotransmission in basal ganglia previously damaged by rheumatic or hypoxic encephalopathy. In most cases, chorea gravidarum and oral contraceptive-related dyskinesias resolve completely by the end of pregnancy or after discontinuation of the medication, respectively. As many as 20 percent of women experience recurrences of chorea with subsequent pregnancies. Patients with chorea gravidarum are at increased risk of later developing oral contraceptive-related dyskinesias, and vice versa.
In patients with suspected chorea gravidarum, appropriate clinical and laboratory investigations may be required to exclude other causes of chorea, such as acute rheumatic fever, systemic lupus erythematosus, hyperthyroidism, and Wilson disease. Chorea gravidarum is usually self-limited, and abortion or premature delivery is rarely indicated. Judicious use of neuroleptics or other medications may afford symptomatic relief in severe cases. Women with a history of gestational or oral contraceptive-induced chorea should probably minimize further exposure to any estrogen-containing medications.
Parkinsonism
There are anecdotal reports in the early clinical literature of motor deterioration in idiopathic and neuroleptic-induced parkinsonism after exposure to exogenous estrogen. Furthermore, premenopausal women were reportedly more susceptible to drug-induced parkinsonism than men of similar age. These observations argued for a potentially antidopaminergic role of estrogen in this condition. Yet, in subsequent studies of premenopausal women with idiopathic Parkinson disease, motor symptoms were noted to worsen premenstrually when estrogen titers were falling, favoring a stimulatory influence of estrogen on striatal dopamine. Data from several studies suggest that postmenopausal estrogen replacement is beneficial in women with Parkinson disease. In other studies, postmenopausal estrogen therapy either had no significant dopaminergic effect or was associated with worsening motor scores. Epidemiologic studies suggested that early menopause (natural or surgical) may be a risk factor for the development of Parkinson disease and that the latter may be offset by postmenopausal estrogen replacement. However, larger prospective studies have disclosed no evidence of a beneficial effect of exogenous or endogenous estrogens on the risk of developing Parkinson disease. Exposure to oral contraceptives may be a risk factor for the disease, and polymorphisms of the estrogen receptor-β gene (an important mediator of estrogenic effects on the nigrostriatal pathway), although not associated with an overall risk of contracting Parkinson disease, may impact the age of symptom onset. Several studies have documented that exposure to the antiestrogen tamoxifen may substantially augment the risk of contracting Parkinson disease in women with breast cancer. Of potential therapeutic relevance, CSF and plasma concentrations of allopregnanolone are reportedly low in idiopathic Parkinson disease and this neurosteroid stimulates neurogenesis in the substantia nigra, modulates dopamine release, and improves motor control in animal models of the disease.
Wilson Disease
Wilson disease is an inborn error of copper metabolism that is characterized by hepatic cirrhosis and degenerative changes in the basal ganglia. Patients exhibit decreased serum ceruloplasmin levels, increased plasma levels of nonceruloplasmin copper, and reduced biliary excretion of the heavy metal. Movement disorders, seizures, and psychosis result from the toxic effects of excessive copper deposition in neural tissues. In normal individuals, serum ceruloplasmin and copper levels increase during pregnancy and after administration of estrogen or estrogen–progestogen contraceptives. The rise in ceruloplasmin resulting from exposure to oral contraceptives is responsible for the green-tinged serum occasionally noted in these women. In patients with Wilson disease, increased serum ceruloplasmin levels occur during pregnancy and after treatment with exogenous estrogens. Effects on serum copper, however, are inconsistent. Normalization of serum ceruloplasmin levels by estrogen administration has no therapeutic benefit, and such exposure sometimes leads to neurologic deterioration. Exposure to hormonal contraceptives may yield “falsely normal” ceruloplasmin levels in patients with Wilson disease, resulting in a delay in diagnosis. Whether sex hormones similarly raise blood ceruloplasmin concentrations in other conditions featuring low levels of the protein, such as hypoceruloplasminemia and acquired copper deficiency, remains to be determined.
Other Movement Disorders
A broad spectrum of movement disturbances may be influenced by prior or current sex steroid exposure. Included are cases of posthypoxic and hereditary myoclonus, dominantly inherited myoclonic dystonia, tardive dyskinesia, hemiballismus, drop attacks, familial episodic ataxia, Gilles de la Tourette syndrome, the neuroleptic malignant syndrome, essential tremor, restless legs syndrome, and progressive supranuclear palsy.
Nervous System Neoplasms
Meningiomas
Meningiomas occur more frequently in women than men and are rarely diagnosed before puberty or during the senium, corresponding to the time of maximal gonadal activity. They are more common in patients with hormone-dependent breast carcinoma and in obese women, perhaps because of higher circulating estrogen levels derived from the aromatization of androstenedione to estrone in adipocytes. Meningiomas have been documented clinically and radiologically to undergo relatively rapid expansion during pregnancy, followed by spontaneous regression postpartum. Some women suffer exacerbations of symptoms in the luteal phase of the menstrual cycle. These fluctuations in tumor size have been attributed to steroid-induced fluid retention by the lesion, increased vascular engorgement of the tumor, and direct trophic effects of gonadal hormones on meningioma cells. Although there is an increase in the incidence of meningioma in women receiving HRT, this should not influence the practice of HRT as the overall frequency of meningiomas in this population remains low.
Numerous investigators have demonstrated the presence of progestin- and, to a lesser extent, estrogen- and androgen-binding proteins in a significant number of human meningioma specimens. These observations suggest that progestins and possibly other gonadal steroids may directly modify the growth and differentiation of these tumors. The presence of progestin receptors may indicate a more favorable prognosis because progesterone receptor-negative meningiomas have been associated with a greater tendency for brain invasiveness, higher mitotic indices and necrosis, and shorter disease-free intervals. Although the antiestrogen tamoxifen does not appreciably affect tumor size or neurologic status in patients with inoperable meningiomas, the antiprogestin RU486 has been reported to induce stabilization or regression of meningiomas, suggesting that antiprogesterone therapy may be useful in the management of these tumors. However, the effects of progestins and RU486 on meningioma growth in vitro are contradictory, and patients chronically treated with RU486 may require glucocorticoid replacement to counteract its antiglucocorticoid effects. Of note, gender-affirming treatment with estrogens, progestogens, or cyproterone acetate (a progestin with antiandrogen activity) may promote meningioma growth in transgender women.
Gliomas
There are anecdotal reports of astrocytomas enlarging during pregnancy, only to shrink spontaneously in the puerperium. As in the case of meningiomas, certain human gliomas may selectively bind estrogens, progestins, and androgens. Some may also contain enzymes (e.g., 17β-oxidoreductase and aromatase) that catalyze steroid hormone interconversions. The origin of putative steroid receptors in glial cell tumors is obscure, although significant numbers of normal astrocytes in certain brain regions possess estrogen receptors. Astroglial tumors predominantly express estrogen receptor-β, and expression levels reportedly decline with increasing histologic grade of malignancy. High-dose tamoxifen therapy may result in clinical and radiologic stabilization of astrocytomas and glioblastoma multiforme in some patients. These benefits are more likely to be due to the inhibitory effects of tamoxifen on protein kinase C or its role as a radiosensitizer than to any accruing antiestrogenic activity. Human oligodendrogliomas have also been reported to contain sex steroid receptors and could theoretically be subject to hormonal manipulations.
Other Tumors
Acoustic neuromas, pituitary adenomas, and breast cancer metastases to the nervous system may also be responsive to sex hormones. Sex steroid receptors have also been reported in hemangioblastomas, anaplastic ependymomas, malignant lymphomas, melanomas, renal cell carcinomas, medulloblastomas, and primitive neuroectodermal tumors, suggesting that the natural history of these neoplasms may be influenced by sex hormones and their antagonists.
Multiple Sclerosis
Multiple sclerosis (MS) is an immune-mediated demyelinating disorder of the central nervous system (CNS) that often occurs during the reproductive years. An association between specific ESR1 gene polymorphisms and MS has been reported in some studies but not others and may be population dependent.
Epidemiologic studies have indicated that the overall effect of age at menarche, pregnancies, and breastfeeding on MS-related morbidity is nil. As discussed in Chapter 31 , subsequent studies involving larger patient cohorts have amply demonstrated a tendency for MS exacerbation during the first 3 postpartum months that is counterbalanced by significant suppression of disease activity in the third trimester. Indeed, the approximately 70 percent reduction in the relapse rate of MS in the third trimester is more robust than that accruing from interferon-β, glatiramer acetate, or intravenous immunoglobulin therapy. Immunomodulation that is necessary to prevent rejection of the semiallogenic fetus is probably responsible for the dampening ofthird-trimester disease activity in MS and other immune-mediated conditions. Factors that have been implicated in gestational immunosuppression include estradiol, progesterone, human chorionic gonadotropin, human placental lactogen, cortisol, 1,25-dihydroxyvitamin D 3 , α-fetoprotein, pregnancy-associated glycoprotein, “blocking antibodies,” immune complexes, and interleukin-10. If necessary, intravenous steroids can be used for MS attacks in pregnancy. Interferon-β should be discontinued 3 months before planned conception and should not be used during pregnancy or while breastfeeding.
Earlier age at puberty may be a predisposing factor for MS in girls but not boys. Although the risk of developing MS does not appear to be impacted by oral contraceptive use, the latter may delay the onset of the disease. The disease-modifying therapies dimethyl fumarate and fingolimod do not appear to diminish the effectiveness of hormonal contraception. Less is known regarding the potential impact of cladribine and anti-MS biologics on sex steroid metabolism. Finally, there are early studies reporting potentially beneficial effects of oral estriol in women with MS.
Alzheimer Disease
Alzheimer disease is a common dementing illness characterized by progressive neuronal degeneration, gliosis, marked depletion of acetylcholine and other neurotransmitter disturbances, and the accumulation of senile (amyloid) plaques and neurofibrillary tangles in discrete regions of the basal forebrain, hippocampus, and association cortex. By the turn of the millennium, there were promising reports suggesting that estrogens play an important role in normal human cognition, have a salutary effect on the manifestations of Alzheimer disease, and may even protect against the development of this neurodegenerative disorder in women. Fundamental research indicates that estrogens exert trophic influences on cholinergic neurons of the rodent basal forebrain, induce dendritic spines (synapses) and functional N -methyl- d -aspartate (NMDA) receptors (important for memory) in adult rat hippocampus, and induce massive neuritic growth in rodent hypothalamic explants. In addition, estrogens were shown to manifest antioxidant properties, reduce the deposition of fibrillar β-amyloid, modulate apolipoprotein E expression, suppress inflammatory responses implicated in neuritic plaque formation, increase cerebral blood flow and glucose utilization (which are deficient in subjects with Alzheimer disease) and stabilize microRNA expression patterns and mitochondrial bioenergetics. There is also accumulating evidence that estrogens improve cognitive behaviors in rats and monkeys; that psychometric performance in women is influenced by the menstrual cycle phase; that transgender hormone therapy affects cognition in transsexual men and women; and that estrogen replacement therapy augments verbal memory scores in normal menopausal women. Moreover, early clinical studies suggested that estrogen replacement therapy may improve cognitive performance, especially language function, verbal memory, and attention, in menopausal women with Alzheimer disease, and enhance the likelihood of a beneficial response to acetylcholinesterase inhibitors in affected women. In several studies, postmenopausal estrogen replacement therapy appears to be associated with a significantly decreased risk of developing Alzheimer disease. There was some indication that postmenopausal estrogen replacement therapy protected against the development of dementia in women with Parkinson disease and that androgen (testosterone) or estrogen treatment conferred cognitive benefits in elderly men with Alzheimer disease or mild cognitive impairment. Lower postmenopausal estradiol levels have also been associated with increased risk of dementia in persons with Down syndrome.
The results of other large, randomized, placebo-controlled prospective trials evaluating the potential benefits of sex HRT in preventing the dementia of Alzheimer disease have been disappointing. Age-adjusted cognitive function scores are no different in women with coronary artery disease who received estrogen and progestin than in placebo-treated controls. Some studies have even demonstrated a slightly higher risk of dementia with HRT compared with placebo-treated controls. Of note, certain polymorphisms of the follicle-stimulating hormone receptor may confer protection against the disease in women (but not men).
The third Canadian Consensus Conference for the Diagnosis and Treatment of Dementia (2006) recommended against the use of estrogen/progestin replacement therapy for reducing the risk of dementia in postmenopausal women. It was also concluded that there is insufficient evidence for or against prescription of androgen replacement for cognitive dysfunction in elderly men. Since these recommendations were published, it has been hypothesized that there may be a critical perimenopausal “window” during which HRT may protect against the development of Alzheimer disease. Importantly, the purportedly salutary influences of estrogen on cognition and hippocampal volumes may be offset in aging women bearing one or two copies of the apolipoprotein E ε4 allele. Regarding androgens, higher serum levels of bioavailable testosterone in late life predict a diminished risk of developing Alzheimer disease in men, perhaps due to androgen-induced down-modulation of brain β-amyloid deposition. Prospective clinical trials amply powered to determine the efficacy of androgen treatment in forestalling dementia in men (and possibly women) may be warranted.
Neurosteroidogenesis has also been implicated in the pathophysiology of Alzheimer disease. There are reports of reduced levels of DHEA-S in the plasma and cerebrospinal fluid and allopregnanolone concentrations in the prefrontal cortex of persons with Alzheimer disease. Allopregnanolone may contribute to cognitive well-being insofar as it suppresses neuroinflammation (microglial activation), diminishes β-amyloid pathology, increases hippocampal neurogenesis, and reverses learning and memory deficits in animal models of Alzheimer disease.
Neuropsychiatric Disorders
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