Sex Hormone, Pituitary, Parathyroid, and Adrenal Disorders and the Nervous System




Keywords

pituitary adenoma, hyperprolactinemia, acromegaly, brain tumors, Cushing syndrome, pituitary apoplexy, hypopituitarism, diabetes insipidus, syndrome of inappropriate antidiuretic hormone secretion, SIADH, hyperparathyroidism, hypoparathyroidism, hypoadrenalism, pheochromocytoma, migraine, meningiomas, movement disorders, neuroendocrine tumor, neuromuscular disorders, sex hormones, Wilson disease

 


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 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.




Figure 20-1


The brain–pituitary–ovarian axis. Δ 4 A, delta-4-androstenedione; ACh, acetylcholine; DA, dopamine; E 1 , estrone; E 2 , estradiol; FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; 5-HT, 5-hydroxytryptamine (serotonin); LH, luteinizing hormone; NE, norepinephrine; P, progesterone; T, testosterone.


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 . 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 “the pill” 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, or prolactin 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. Various hormonal interventions in catamenial migraine have been largely unsuccessful and 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) resulted in a 72 percent decline in headache frequency in a study involving 24 women with menstrual migraine. In addition to migraine, menstruation, pregnancy and menopause may also influence cluster headache, other autonomic cephalalgias, and hemicrania continua.


Stroke


“The pill” has been implicated as a significant risk factor in thromboembolic cerebral infarction, subarachnoid hemorrhage, and cerebral venous thrombosis. In 1969, American and British case-control studies revealed, respectively, a 19- and 6-fold increased risk of ischemic stroke in young women related to the use of oral contraceptives. Hypertension, migraine, and age older than 35 years were associated, but independent, risk factors for cerebral infarction in patients taking oral contraceptives. Cigarette smoking by women on “the pill” 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 1.18 in comparison 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, and inflammation are potential mediators of this association. 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 enrolled in the Women’s Health Initiative study, an increased risk of ischemic but not fatal or hemorrhagic stroke was again 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. In a large, nested case-control study, the use of transdermal HRT containing low doses of estrogen did not seem to increase the risk of stroke in women aged 50 to 79 years. 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.


In a study by the Royal College of General Practitioners, the relative risks of subarachnoid hemorrhage in former users, current users, or subjects who had never used moderate- to high-dose oral contraceptives were 4.5, 3.2, and 4.0, respectively. 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 (1.14). 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 to bleeding 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 and clobazam 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. In a large study, an increased risk of epilepsy (RR 1.67, 95% CI 1.12–2.51) was associated with menstrual irregularity at ages 18 to 22 years. 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. Conceivably, a rising estrogen–progesterone ratio during the late luteal phase triggers 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. 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. Of note, the magnitude of perimenstrual seizure exacerbation may predict the response rate to progestin therapy.


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. Oral contraceptives may elicit chorea in patients with a history of congenital cyanotic heart disease and Henoch–Schönlein purpura 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 two 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, a large prospective study disclosed no evidence of a beneficial effect of exogenous or endogenous estrogens on the risk of developing Parkinson disease. In an Italian case-control study, exposure to oral contraceptives emerged as a risk factor for the disease with an adjusted OR of 3.27 (95% CI, 1.24–8.59; P =0.01). In a Swedish population, polymorphisms of the estrogen receptor–beta gene (an important mediator of estrogenic effects on the nigrostriatal pathway), although not associated with an overall risk of contracting Parkinson disease, might have impacted the age of symptom onset.


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 appear to be influenced by changes in the sex steroid milieu. Included are cases of posthypoxic and hereditary myoclonus, dominantly inherited myoclonic dystonia, tardive dyskinesia, a pyramidal-extrapyramidal syndrome, hemiballismus, ill-defined tremors and drop attacks, familial episodic ataxia, Gilles de la Tourette’s syndrome, and the neuroleptic malignant syndrome.


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. A large Finnish study found an increase in the incidence of meningioma in women receiving HRT, but 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. In an early study, the antiestrogen tamoxifen did not appreciably affect tumor size or neurologic status in patients with inoperable meningiomas. By contrast, the antiprogestin RU486 has been reported to induce stabilization or regression of meningiomas in a cohort of patients, 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.


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–beta, 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, 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.


Initial epidemiologic studies indicated that the overall effect of one or more pregnancies 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-beta, glatiramer acetate, or intravenous immunoglobulin therapy. Immunomodulation that is necessary to prevent rejection of the semiallogenic fetus is probably responsible for the dampening of third-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-beta should be discontinued 3 months before planned conception and should not be used during pregnancy or while breast-feeding. In one study, none of 14 pregnant women with relapsing-remitting MS who received prophylactic intravenous immunoglobulins immediately postpartum exhibited disease relapse in the first 6 months after delivery.


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. Finally, there are pilot studies reporting potentially beneficial effects of oral estriol in women with MS and transdermal testosterone in men with the disease.


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 millenium, 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 indicated that estrogens exert trophic influences on cholinergic neurons of the rodent basal forebrain, induce dendritic spines (synapses) and functional N -methyl- d -aspartate 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, and increase cerebral blood flow and glucose utilization (which are deficient in subjects with Alzheimer disease). There was also accumulating evidence that estrogens improve cognitive behaviors in rats and monkeys; that psychometric performance in women is influenced by menstrual cycle phase; that cross-gender 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 case-controlled studies, in initial prospective studies, and in a meta-analysis of 12 observational studies, postmenopausal estrogen replacement therapy appeared to be associated with a significantly decreased risk of developing Alzheimer disease. There was also 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 some cognitive benefits in elderly men with Alzheimer disease or mild cognitive impairment.


The results of other large, randomized, placebo-controlled prospective trials evaluating the potential benefits of sex hormone replacement therapy in preventing the dementia of Alzheimer disease have been disappointing. In a substudy of the Heart and Estrogen/Progestin Replacement Study (HERS), age-adjusted cognitive function scores were no different in women with coronary artery disease who received estrogen and progestin than in placebo-treated controls. Surprisingly, in the Women’s Health Initiative Memory Study (WHIMS) involving over 6,000 participants, the hazard ratios for development of dementia were 1.49 for women randomized to receive 0.625 mg conjugated equine estrogen and 2.05 for those receiving 0.625 mg estrogen plus 2.5 mg medroxyprogesterone acetate relative to 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 peri- menopausal “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, a prospective study in 2010 indicated that higher serum levels of bioavailable testosterone in late life predicts 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. Several insightful analyses of the risks and benefits of sex hormones in the management of Alzheimer disease are available.


Neuropsychiatric Disorders


The Porphyrias


The porphyrias are characterized by the excessive production of porphyrins and porphyrin precursors resulting from specific enzymatic defects in the heme biosynthetic pathway. Neurologic manifestations, when present, include seizures, neuropsychiatric symptoms, and sensorimotor and autonomic neuropathies. Estradiol and other steroids with a 5β configuration induce the enzyme δ-aminolevulinic acid synthase and may thereby precipitate porphyric crises. Oral contraceptives increase urinary excretion of this enzyme in normal individuals, and it has been suggested that asymptomatic relatives of patients with porphyria should avoid “the pill.” In many women with acute intermittent porphyria, cyclic attacks of variable severity occur during the late luteal phase or, less commonly, at ovulation. Paradoxically, some patients exhibit prolonged remissions after suppression of ovarian cyclicity with oral contraceptives.


Although acute treatment with gonadotropin-releasing hormone (GnRH) agonists, such as d -His or leuprolide, stimulates the pituitary–ovarian axis, chronic administration of these agents downregulates gonadotrope GnRH receptors, resulting in long-term suppression of pituitary–ovarian function. In the first reported case, d -His administration (5 µg subcutaneously daily) yielded complete remission of severe premenstrual acute intermittent porphyria for the duration (8 months) of therapy. Similar benefits were observed in subsequent cases of catamenial acute intermittent porphyria and hereditary coproporphyria in response to GnRH analogue therapy. Side effects of long-term GnRH treatment include hot flashes, diminished breast size, and bone demineralization. GnRH analogues, unlike sex steroids, do not appear to induce porphyrin accumulation in chick embryo hepatic cell culture and provide a rational approach to the management of catamenial porphyria.


Premenstrual Syndrome


The premenstrual syndrome (or premenstrual dysphoric disorder) occurs in approximately 30 percent of women during their reproductive years. Common neuropsychiatric symptoms include headache, fatigue, depression, irritability, increased thirst or appetite, and craving for sweet or salty foods. Symptoms typically begin toward the end of the luteal phase of the cycle and usually, but not invariably, resolve with the onset of flow. The pathophysiology of this disorder remains obscure. An increased luteal-phase estrogen–progesterone ratio, hyperprolactinemia, disturbances of the renin–angiotensin–aldosterone axis, hypothyroidism, and abnormal secretion of opioid peptides are among the causes considered for this enigmatic condition.


Numerous hormonal and nonhormonal therapies—including natural progesterone, oral contraceptives, bromocriptine, GnRH agonists, diuretics, prostaglandin inhibitors, vitamin B 6 , and lithium—are prescribed for the management of premenstrual syndrome. The efficacy of these treatments remains uncertain. In a double-blind crossover trial, induction of “artificial menopause” with a GnRH agonist ( d -Trp-Pro-NEt-Gn-RH, 50 µg per day subcutaneously) relieved both physical and neuropsychiatric symptoms in eight women with rigorously defined premenstrual syndrome. Although the authors reported no side effects (except for hot flashes in one patient), prolonged hypoestrogenemia resulting from the long-term use of these agents may predispose to osteoporosis. Such therapy should probably be reserved for patients with incapacitating symptoms, and low-dose estrogen replacement may have to be considered when the duration of treatment exceeds several months. In a recent study, continuous daily administration of levonorgestrel 90 µg/ethinyl estradiol 20 µg was reportedly well-tolerated and possibly useful in controlling physical, psychologic and behavioral symptoms of the premenstrual syndrome.


Depression and Psychosis


Depression and other major affective disorders may surface in relation to the menstrual cycle, the puerperium, and menopause. Approximately 15 percent of women experience postpartum depression whereas 50 to 80 percent report milder dysphoria (“maternal blues”). In patients with postmenopausal depression, mood elevation and anxiolysis often occur promptly in response to estrogen replacement. Paradoxically, oral contraceptives may precipitate depression in susceptible individuals. Estrogen has also been implicated in the pathogenesis of anorexia nervosa because of the high preponderance of this condition in women and the potent anorexic effects of estrogen in animals.


Psychotic disorders characterized by extreme agitation, hallucinations, paranoid delusions, incoherent speech, and mood lability may arise during the postpartum period or may recur consistently during the late luteal phase of the cycle. Such disorders may be refractory to conventional therapies (neuroleptics, lithium, electroconvulsive treatment) but may respond well to specific hormonal interventions, including the use of oral contraceptives, intramuscular progesterone, and danazol. “Menopause” induced by GnRH analogues may also be of considerable benefit in the management of cyclical psychosis.


Sleep Disorders


Estrogen and progestin replacement may shorten mean sleep latencies, extend the duration of rapid-eye-movement sleep periods, and diminish nocturnal movement arousals, thereby improving sleep in hypogonadal women. The GABA-active metabolites allopregnanolone and pregnanolone may mediate the reduction in vigilance during wakefulness observed after the administration of progesterone to healthy men. Progestins may also provide stimulatory drive to brainstem respiratory centers in subjects with central sleep apnea and thereby improve hypoventilation. The hypocapnic apnea threshold is lower in women than men, and testosterone administration increases this threshold in premenopausal women. In one case, obstructive sleep apnea resolved in a nonobese woman after removal of a benign testosterone-producing ovarian tumor. In a study involving 33 postmenopausal women, estrogen plus progesterone decreased the prevalence of nocturnal arousals, breathing irregularities, periodic limb movements, hot flashes and bruxism.


Intracranial Hypertension


Progesterone suppresses post-traumatic cerebral edema and intracranial hypertension in rodents. This progestational effect has been attributed to reduction in blood–brain barrier permeability and inhibition of cerebrospinal fluid production by the choroid plexus. Estrogens, by contrast, appear to enhance cerebral endothelial cell permeability and post-traumatic brain edema in female rats. Estrogenic attenuation of the blood–brain barrier may also play a role in the pathogenesis of pseudotumor cerebri (benign intracranial hypertension) in humans and explain the robust female predilection for this disorder.


Neuromuscular Diseases


Catamenial Sciatica


Ectopic endometrial tissue (endometriosis) is hormone sensitive and undergoes epithelial sloughing and hemorrhaging at the time of menses. Ectopic endometrial tissue may destroy lumbar vertebrae, producing back pain, invade the lumbosacral plexus in the retroperitoneal space, and implant within the sheath of the sciatic nerve. In this last instance, radicular pain in the distribution of the nerve usually begins 2 to 3 days before the onset of menses and may continue for a variable duration after cessation of flow (catamenial sciatica). In addition to pain, there is often numbness, weakness, and loss of ankle reflexes. In contrast to far more common discogenic radiculopathy, endometriotic sciatica is less likely to respond to bed rest, and the imaging findings are usually unimpressive. There may be evidence of endometriosis elsewhere, and surgical exploration of the sciatic nerve may be required for diagnosis. In positive cases, the nerve appears blue and a dark, hemorrhagic fluid is expressed after incision of the sheath. Biopsy specimens reveal characteristic glandular elements. Symptoms of catamenial sciatica may show dramatic improvement with standard therapy for endometriosis, including danazol, progestins, GnRH agonist, and in refractory cases, bilateral oophorectomy.


Other Neuromuscular Disorders


Endogenous and administered sex hormones (mainly estrogens) may influence the natural history of Bell palsy, recurrent brachial plexopathy, and the carpal tunnel syndrome. Abnormally high estrogen levels have been reported in male patients with amyotrophic lateral sclerosis, Kugelberg–Welander disease, bulbospinal muscular atrophy (Kennedy syndrome), Duchenne muscular dystrophy, and the Crow–Fukase syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes [POEMS syndrome], usually associated with plasma cell dyscrasias). It is unclear whether hyperestrogenemia plays any significant role in the pathogenesis of these neuromuscular disorders. In an anecdotal report, high-dose testosterone therapy yielded considerable symptomatic improvement in a patient with bulbospinal muscular atrophy. The authors conjectured that the testosterone therapy may have ameliorated some toxic gain of function ascribed to the mutated androgen receptor in this condition. Finally, Mastrogiacomo and co-workers have hypothesized that dysfunction of testicular peritubular myoid cells and corpus cavernosum smooth muscle contributes to the hypergonadotropic hypogonadism and impotence that complicate myotonic dystrophy in men.




Pituitary Gland


The endocrine and nervous systems interact in intricate ways, and disorders in one system may cause dysfunction of the other in diverse ways. For example, small anterior pituitary tumors produce symptoms principally as the result of hormonal excess, but large tumors cause symptoms of either hypersecretion or hyposecretion as well as dysfunction of adjacent cranial nerves or cerebral structures. The protean clinical features of hormonal excess and deficiency states include both central and peripheral nervous system dysfunction.


The complex anatomy of the sellar region influences the clinical features of pituitary disorders. The pituitary gland, or hypophysis, sits in a bony depression in the posterior sphenoid bone called the sella turcica, bounded anteriorly by the tuberculum sellae and anterior clinoid process and posteriorly by the dorsum sellae. Dural reflections border the pituitary superiorly and laterally. The diaphragma sellae forms the roof of the sella turcica and lies beneath the optic chiasm. Adjacent bilaterally is the cavernous sinus, through which passes the internal carotid artery and cranial nerves III, IV, V (upper two divisions), and VI. In addition the cavernous sinus serves to drain the ophthalmic and middle and inferior cerebral veins.


The anterior pituitary, or adenohypophysis, derives embryologically from Rathke pouch, of ectodermal origin, and has blood supplied by the hypophyseal-portal system. Hormones secreted by the anterior pituitary include prolactin, growth hormone (GH), adrenocorticotropic hormone (ACTH), thyrotropin (TSH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH). The hypothalamus controls anterior pituitary hormone secretions through various hypophysiotropic substances, most of which are peptides ( Table 20-1 ). The hypophyseal-portal system provides the basis for feedback loops that regulate the hypothalamic–pituitary axis.



Table 20-1

Anterior Pituitary and Hypothalamic Hormones






















Pituitary Hormone Hypothalamic Factor
Prolactin Dopamine (inhibitory)
Growth hormone (GH) Growth hormone–releasing hormone (GHRH)
Somatastatin (inhibitory)
Adrenocorticotropin (ACTH) Corticotropin-releasing hormone (CRH)
Thyrotropin (TSH) Thyrotropin-releasing hormone (TRH)
Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) Gonadotropin-releasing hormone (GnRH)


The posterior pituitary, known also as the neurohypophysis or pars nervosa, derives from a neuroectodermal extension of diencephalon that fuses with Rathke pouch. Also of neuroectodermal origin is the infundibulum linking the pituitary to the hypothalamus at the median eminence, which also forms the floor of the third ventricle. The inferior hypophyseal artery, a branch of the intracavernous carotid, supplies the neurohypophysis. Neurohypophyseal hormones include oxytocin and antidiuretic hormone (ADH), or arginine vasopressin.


The juxtaposition of the pituitary gland to hypothalamus, third ventricle, intracavernous carotid arteries, and cranial nerves related to vision, extraocular movements, and mid- and upper facial sensation accounts for many of the neurologic manifestations of lesions in and around the sella. Endocrine disturbances arising from excess or insufficient secretion of one or more pituitary hormones may also cause neurologic as well as systemic symptoms and signs, and laboratory abnormalities. Improved neuroimaging techniques have greatly facilitated assessment of sellar and parasellar lesions. A detailed discussion of the increasingly complex array of stimulation and inhibition studies used to assess the integrity of specific elements of the hypothalamic–pituitary axis is provided elsewhere. However, a basic understanding of pituitary hormone physiology is essential to evaluating patients with mass lesions in and around the gland and it is reviewed here after a discussion of the neurologic symptoms and signs resulting from these lesions.


Sellar and Parasellar Lesions


Pituitary adenomas are the most common mass in the sellar region and account for up to 25 percent of intracranial neoplasms. Previous classification schemes based on histologic staining properties have given way to categorization based on hormone secretion. Pituitary adenomas are also classified by size. Microadenomas ( Fig. 20-2A ), lesions that are 10 mm or smaller, typically spare adjacent neural or vascular structures and generally come to medical attention during evaluation for symptoms and signs of hormone oversecretion. Lesions larger than 10 mm, known as macroadenomas ( Fig. 20-2B ), also may present with manifestations of hormone excess or may impair normal glandular function, resulting in hypopituitarism. When macroadenomas compress adjacent neural or vascular structures, neurologic dysfunction, such as headache, visual loss, ophthalmoparesis, and facial sensory symptoms, may develop. Adenoma size does not correlate with headache, which may have features similar to migraine or trigeminal autonomic cephalgia. Macroadenomas extending superiorly may compress the optic chiasm, nerves, or tracts. Bitemporal hemianopia is the classic consequence, although monocular visual loss or junctional scotoma also may occur. Because adenomas grow slowly, patients may not appreciate visual deficits until they are quite advanced. Third ventricular extension occasionally causes acute or chronic hydrocephalus. Lateral extension, with subsequent cavernous sinus involvement, disturbs extraocular motility and sensation in the upper and middle face. Very large lesions involving inferior frontal or medial temporal lobes are rare but may cause cognitive impairment, behavioral changes, or seizures. A few pituitary tumors extend inferiorly, causing epistaxis or cerebrospinal fluid (CSF) rhinorrhea.




Figure 20-2


Neuroimaging of pituitary adenoma. A , Microadenoma. Gadolinium-enhanced T1-weighted magnetic resonance imaging (MRI) shows a small focus of decreased enhancement compatible with microadenoma in a young woman with galactorrhea-amenorrhea. B , Macroadenoma. Large sellar lesion, subsequently shown to be a nonsecretory adenoma, in a gadolinium-enhanced T1-weighted MRI obtained in a middle-aged man with progressive visual loss.


Pituitary adenomas account for 90 percent of masses in the sellar region, with other pituitary tumors, nonpituitary neoplasms, metastases, infectious and inflammatory disorders, vascular lesions, and cysts accounting for the rest ( Table 20-2 ). Craniopharyngiomas arise from epithelial cell rests of Rathke pouch. Among malignant lesions, pituitary carcinomas are quite rare, and metastases to the pituitary are recognized more frequently at autopsy than during life.



Table 20-2

Differential Diagnosis of Sellar Masses





























































Neoplasms
Pituitary origin



  • Anterior: pituitary adenoma or carcinoma



  • Posterior: granular cell tumor, stalk or posterior lobe astrocytoma

Nonpituitary origin



  • Craniopharyngioma



  • Germ cell tumor



  • Meningioma



  • Glioma (hypothalamic, optic nerve or chiasm)



  • Skull base: chordoma, giant cell tumor, chondroma, fibrous dysplasia

Others



  • Lipoma



  • Hemangioblastoma



  • Sarcoma



  • Schwannoma



  • Paraganglioma



  • Esthesioneuroblastoma

Metastatic



  • Carcinoma



  • Melanoma



  • Hematopoietic malignancies

Vascular Lesions
Intracavernous carotid aneurysm
Cavernous sinus thrombosis
Pituitary apoplexy
Cysts
Rathke cleft cyst
Arachnoid cyst
Epidermoid
Dermoid
Inflammatory Disorders
Granulomatous: sarcoidosis, tuberculosis, syphilitic gumma, giant cell granuloma
Pituitary abscess
Lymphocytic hypophysitis
Histiocytosis
Mucocele
Empty Sella Syndrome
Pituitary Hypertrophy
Puberty (in girls)
Pregnancy
Chronic primary hypothyroidism


Among more common disorders, primary empty sella is often associated with an incompetent diaphragma sellae, which allows arachnoid and CSF to herniate into the sella. Typically an incidental finding on neuroimaging studies, primary empty sella syndrome is not usually associated with endocrinopathy. Secondary empty sella occurs after spontaneous or treatment-induced regression of pituitary disease. Other important non-neoplastic sellar lesions include granulomatous processes, such as tuberculosis or sarcoidosis, and vascular lesions such as aneurysms of the intracavernous carotid artery.


Magnetic resonance imaging (MRI) before and after gadolinium enhancement, with high-resolution thin sections in the sagittal and coronal planes, is the test of choice for pituitary-region imaging. On T1-weighted images, high signal intensity in the posterior pituitary is referred to as the “bright spot” and is believed to represent ADH in neurosecretory vessels. Pituitary adenomas typically enhance less intensely than normal glandular tissue ( Fig. 20-2A ). In patients who cannot undergo MRI, precontrast and postcontrast computed tomography (CT) images through the area can be obtained. A consequence of modern neuroimaging is detection of the asymptomatic pituitary mass, the so-called pituitary “incidentaloma.”


Anterior Pituitary


Prolactin


Prolactin acts on mammary tissue to promote lactation and inhibit cyclic gonadotropin secretion. Hypothalamic control of prolactin secretion occurs primarily by inhibition, and thus pituitary stalk disruption from lesions other than prolactinomas may elevate serum prolactin levels, although rarely above 200 µg/L (normal<25 µg/L). Dopamine is the major inhibitory factor. Accordingly, neuroleptics and other dopamine antagonists can cause mild hyperprolactinemia, although the risk may be lower for some atypical antipsychotics; dopaminergic drugs are therefore used therapeutically to lower prolactin levels. Prolactin-releasing factors are less well understood, although thyrotropin-releasing factor (TRH) plays a role. Consequently, in primary hypothyroidism, when TRH is elevated, the resulting hyperprolactinemia and pituitary enlargement may cause diagnostic confusion with prolactinoma. The differential diagnosis of hyperprolactinemia ( Table 20-3 ) also includes pregnancy, lactation, and chest wall stimulation. Serum prolactin may be modestly increased in the first hour after a generalized tonic-clonic or complex partial seizure and, when measured at 10 to 20 minutes after a suspected event, is sometimes a useful adjunct for the differentiation of generalized tonic-clonic epileptic from nonepileptic seizures.


Aug 12, 2019 | Posted by in NEUROLOGY | Comments Off on Sex Hormone, Pituitary, Parathyroid, and Adrenal Disorders and the Nervous System

Full access? Get Clinical Tree

Get Clinical Tree app for offline access