Sex Hormones and The Nervous System

21
Sex Hormones and the Nervous

System
Hyman M. Schipper
SEX STEROIDNEURAL
INTERACTIONS
Organizational Effects
Activational Effects
HUMAN MENSTRUAL CYCLE AND
HORMONAL CONTRACEPTIVES
MIGRAINE
STROKE
EPILEPSY
MOVEMENT DISORDERS
Chorea
Parkinsonism
Wilsons Disease
Other Movement Disorders
The effects of sex steroids on neurological function

in health and disease constitute a rich and rapidly expanding area of basic and clinical neuroscience. Several
factors account for the burgeoning of this eld over the
past several decades. First, the development of radioimmunoassay, autoradiography, immunocytochemistry, and
in situ hybridization has permitted meticulous determinations of circulating hormone proles and mapping of
steroid hormone binding sites within the nervous system. Second, ample evidence has accumulated attesting
to the potent modulatory effects of sex hormones on
monoaminergic, cholinergic, and peptidergic neurotransmission and the role of such interactions in diverse
normal and pathophysiological states. Finally, there is
the recognition by clinicians that a large array of neurological conditions is inuenced by hormonal uctuations
associated with the menstrual cycle, pregnancy, the
menopause, and use of oral contraceptives. A growing
appreciation of these relationships is currently being
rewarded by the development of specic hormonal and
antihormonal therapies for neurological disorders as disparate as catamenial epilepsy, acute intermittent porphyria, and possibly even Alzheimers disease.
NERVOUS SYSTEM NEOPLASMS

Meningiomas
Gliomas
Other Tumors
MULTIPLE SCLEROSIS
ALZHEIMERS DISEASE
NEUROPSYCHIATRIC DISORDERS
The Porphyrias
Premenstrual Syndrome
Depression and Psychosis
SLEEP DISORDERS
INTRACRANIAL HYPERTENSION
NEUROMUSCULAR DISEASES
Catamenial Sciatica
Other Neuromuscular Disorders
CONCLUDING COMMENT
SEX STEROIDNEURAL
INTERACTIONS
In mammals of both sexes, estrogens, progestins, and
androgens represent the three major classes of endogenous sex steroids (Fig. 211). Prototypical hormones
in each class include 17-estradiol, progesterone, and
testosterone. Plasma sex hormones are secreted directly
from ovaries, testes, and adrenal glands but may also be
derived from enzyme-mediated conversions from prohormones in extraglandular tissues (Fig. 212). Important examples of the latter include the aromatization
of the androgens 4-androstenedione and testosterone
to estrone and 17-estradiol, respectively, in brain and
adipose tissue. Approximately 98 percent of the circulating sex hormone pool is protein bound and functionally
inert. The remaining free fraction is highly lipophilic
and readily penetrates the blood-brain barrier and neuronal cell membranes. Within the cytoplasm or nucleus
of the target cells, sex hormones form complexes with
specic receptor proteins. Subsequent binding of these
complexes to steroid response elements within the pro365
366
NEUROLOGY AND GENERAL MEDICINE
moter regions of various genes induces or suppresses the

transcription of these genes. In neurons, sex steroids
modulate the biosynthesis of enzymes and structural
proteins concerned with cell membrane function, energy
metabolism, hormonal sensitivity, and neurotransmission. In addition, steroid hormones are capable of far
more rapid modulation of neuronal ring by direct
(nongenomic) interactions with nerve cell membranes.1, 2
In rodents and primates of both sexes, estrogen-binding neurons are located in the preoptic area, medial basal
hypothalamus, medial amygdala, and circumventricular
organs. Estrogen-binding neurons also reside, albeit to
a lesser extent, in the basal forebrain, hippocampus,
several thalamic nuclei, sensory regions of the brainstem
and spinal cord, and the neonatal neocortex.3, 4 The
topographies of the progestin and androgen target neurons exhibit considerable overlap with the estrogen-concentrating populations.3 In addition to neurons, some
periventricular astrocytes also contain estrogen
receptors4, 5 and undergo morphological and histochemical changes after sex hormone exposure.6 These latter
observations may be important in so far as some human
glial tumors appear to be responsive to sex hormones.
Visual
Pineal
ACh
DA
NE
5-HT
-Endorphin
Olfactory
+
Stress
BRAIN
+
GnRH
Hypothalamus
+
ANTERIOR
PITUITARY
GnRH
FSH
LH
ADRENAL
CORTEX
OVARY
FSH
LH
aromatase
E2
4A
UTERUS
4A
aromatase
Organizational Effects
E2
Organizational effects refer to the irreversible differentiation of neural circuitry resulting from exposure to
sex steroids during critical periods of brain development.
This is perhaps best exemplied by the role sex steroids
play in the gender-specic organization of the hypothalamic-pituitary-gonadal axis in neonatal rodents7 (Fig.
213). Sexually dimorphic regions have been dened in
the human brain, including the sexually dimorphic nu-
OH
12
Progesterone
10
N
C
11
OH
CH
Norethindrone
RU 486
(antiprogesterone)
I
N
OH
OH
HO
Estradiol
HO
Diethylstilbestrol
Tamoxifen
(antiestrogen)
OH
OH
OH
O
Testosterone
OH
2-Hydroxyestradiol
(catechol-estrogen)
Figure 211 Sex steroids, nonsteroidal estrogens, and steroid antagonists. (Courtesy of Dr. E. E. Baulieu, Faculte de
Medecine de Bicetre, France, with modications.18)
ADIPOSE
TISSUE
E1
Figure 212 The brain-pituitary-ovarian axis. 4A, delta4-androstenedione; ACh, acetylcholine; DA, dopamine; E1,
estrone; E2, estradiol; FSH, follicle-stimulating hormone;
GnRH, gonadotropin-releasing hormone; 5-HT, 5-hydroxytryptamine (serotonin); LH, luteinizing hormone; NE, norepinephrine; P, progesterone; T, testosterone.
cleus of the preoptic area, subregions of the hypothalamic suprachiasmatic nucleus, the bed nucleus of the stria
terminalis, and certain white matter tracts.8 Clinical and
experimental evidence suggests that abnormal exposure
to circulating sex hormones in utero or during infancy,
as might occur after maternal exposure to diethylstilbestrol (Fig. 211) or in children with congenital adrenal
hyperplasia, may result in altered development of one
or more sexually dimorphic brain regions and expression
of gender-associated behaviors. 8 Whereas during the
neonatal and peripubertal periods estrogens and aromatizable androgens induce trophic (synaptogenic) changes
in the rodent hypothalamus, in later life estrogens accelerate aging-related changes in the endocrine hypothalamus that may contribute to the onset of reproductive
senescence.
Activational Effects
The activational effects of sex steroids encompass a
myriad of largely reversible neurophysiological inu-
Sex Hormones and the Nervous System
367
The Classic Organization Hypothesis

HYPOTHALAMUS
HYPOTHALAMUS
Intrinsic
T aromatase
circuitry
Phasic
GnRH
Neonatal
critical period
FP
E2
E2
circuitry
Tonic
GnRH
Neonatal
critical
period
PITUITARY
PITUITARY
FP
FP
E2
LH
LH
Puberty
OVARY
Tonic
androgen
production
Puberty
TESTIS
Ovulation
Figure 213 The classic organizational hypothesis. I. Female (left panel ): During the rst week of life (neonatal critical period )
in female rodents, ovary-derived estradiol (E2) is bound to circulating -fetoprotein (FP) and does not readily cross into the
brain. The hypothalamic circuitry subserving pituitary gonadotropin regulation is intrinsically female in organization and
releases gonadotropin-releasing hormone (GnRH) in a pulsatile (phasic) fashion. The latter is necessary for stimulating the
luteinizing hormone (LH) surge that sustains ovulation. FP levels progressively decline after birth, permitting ovarian estrogen
to modulate the brain-pituitary axis after puberty. Testosterone administered to female rodents during the critical period does
not bind to FP and thus gains access to the developing hypothalamus, where it is converted to E2 by the enzyme aromatase.
This E2 (ironically) masculinizes the gonadotropin-regulating hypothalamic pathways, resulting in permanent nonpulsatile
(tonic) release of GnRH and LH. At puberty, in the absence of LH surges, the animal develops irreversible anovulatory sterility
and multicystic ovaries. II. Male (right panel ): Testosterone secreted from neonatal testes during the critical period does not bind
FP, undergoes aromatization to E2 within the hypothalamus, and reorganizes the intrinsically female circuitry to express
male (tonic) patterns of GnRH and LH secretion. This nonpulsatile pattern of LH release sufces to maintain normal levels
of testicular androgen production at puberty. In genetic males, female (pulsatile) patterns of GnRH-LH secretion occur at
puberty if the animals are castrated at birth or treated with antiestrogens or aromatase inhibitors during the critical period.
ences exerted by gonadal hormones on the mature nervous system. Such interactions are essential for regulation of the brain-pituitary-gonadal axis 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
uctuations associated with (1) specic phases of the
menstrual cycle, (2) pregnancy, (3) the menopause, and
(4) exposure to exogenous sex hormones may induce
or modify a host of neurological and neuropsychiatric
disorders.
HUMAN MENSTRUAL CYCLE AND

HORMONAL CONTRACEPTIVES
Sex steroid uctuations in the course of a typical
menstrual cycle are depicted in Figure 214A. Plasma
estradiol levels increase during the late follicular phase
of the cycle and peak just before ovulation. A smaller
but more sustained elevation in circulating 17-estradiol
occurs during the luteal phase. Progesterone levels are
negligible during the follicular phase and rise markedly
during the luteal phase in synchrony with the second

17-estradiol surge. In the late luteal phase, a decline in
sex hormone levels triggers the menstrual ow.
High concentrations of circulating sex steroids resulting from ingestion of oral contraceptives inhibit ovulation through a negative feedback action on the hypothalamic-pituitary unit (Fig. 212). In the most widely
used combined oral contraceptives, xed doses of estrogen and progestin are administered for 21 days, followed
by a 7-day placebo period during which time menstruation occurs. The estrogenic component of the pill
consists of either ethinyl estradiol or mestranol (which
is metabolized to ethinyl estradiol). Commonly used
progestogens include ethynodiol diacetate, norethindrone, norethynodrel, norgestrel, and, more recently,
norgestimate, gestodene, and desogestrel.9 The synthetic
steroids are readily absorbed from the gut, freely traverse the blood-brain barrier, and are metabolized by
the microsomal enzyme system in the liver.
Common minor adverse effects of the pill include
nonvascular headaches, dysphoria, and decreased libido.
The remainder of this chapter is concerned with major
neurological complications of endogenous sex steroids
and oral contraceptives. Wherever possible, a distinction
368
26
Plasma estradiol
Progesterone
Plasma estradiol (ng/100ml)
24
22
20
15
14
13
12
11
18
10
16
9
14
12
10
6
5
4
6
Plasma progesterone (ng/ml)
Migraine duration,
twenty-four hours
0
2
10
12
Plasma estradiol (ng/100ml)
200
100
50
16
18
20
22
24
26
28
Days of cycle
Estradiol
valerate, 10mg
Menstruation
14
Estradiol treated cycle
Migraine: unilateral: nausea:

duration, twelve hours
Migraine unilateral:
nausea: duration,
eight hours
Normal
cycles
20
10
5
2
1
-6
-5
-4
-3
-2
-1
Days from onset of menstruation
Figure 214 A, Daily plasma concentrations of estradiol

and progesterone throughout a normal menstrual cycle in a
woman with premenstrual migraine (vertical arrow indicates
onset of headache). B, Plasma estradiol concentrations during a
normal and estradiol-treated cycle in a woman with premenstrual migraine. (From Somerville B: The role of estradiol
withdrawal in the etiology of menstrual migraine. Neurology
22:355, 1972, with permission.)
will be made between high-dose (50 g) and the

more recently introduced low-dose (2035 g) estrogen preparations because there appear to be signicantly
fewer neurological and non-neurological complications
with use of the latter.
MIGRAINE
Although no gender difference in the prevalence of
migraine is apparent before puberty, the condition is
three times as common in adult women (18%) than
men (6%).10 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 migraine11 (Fig. 214). The frequency or
severity (or both) of migraine attacks often diminishes
with gestation, particularly in patients whose headaches

are linked to the menstrual cycle.12 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.13 In some patients, migraine arises de novo or appears to worsen during
gestation14 or the perimenopausal period.15 A rst approach to the management of gestational migraine
should be nonpharmacological (e.g., relaxation training,
biofeedback), especially during the rst trimester when
risks of teratogenicity and embryotoxicity are greatest.
For severe attacks, acetaminophen with codeine or nonsteroidal anti-inammatory drugs (NSAIDs) can be
used. Further discussion is provided in Chapter 32. For
status migrainosus in pregnancy, chlorpromazine, meperidine, morphine, or prednisone may need to be administered.16 Perimenopausal migraine often responds
to standard estrogen replacement therapy, but this must
be weighed against the risk of developing breast cancer
in individual patients.15
An association between migraine and the pill is
frequently encountered in general and neurological
practices. Women often exhibit new-onset or exacerbation of migraine while taking oral contraceptives. Attacks tend to manifest during the rst 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 rst time while taking oral contraceptives. Women in this category may be at high risk for
infarction in regions reecting the distribution of their
auras.9 Amelioration of migraine after exposure to oral
contraceptives is observed in a few women. Psychological factors, such as the diminished fear of accidental
pregnancy, may in part contribute to the improvement.
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,17 premenstrual changes
in circulating estrogens may activate vasoregulatory elements in the brainstem or hypothalamus, which, in turn,
may trigger symptomatic alterations in cerebrovascular
tone.18
First-line therapy for menstrual migraine should include the standard pharmacological, dietary, and psychological modalities employed in the general migraine
population. Sumatriptan and related serotonin 5-HT1D
(presynaptic autoinhibitory) receptor agonists are
equally effective for noncatamenial and menstrual migraine.19 Refractory cases of severe catamenial migraine
may benet from late luteal phase therapy with prostaglandin inhibitors (e.g., naproxen, 250500 mg orally
twice daily) and mild diuretics.20 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.21 The risk-benet 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
(Fig. 211) may either alleviate22 or precipitate23 catamenial migraine. The benecial effect of tamoxifen may be
due to inhibition of calcium uptake or prostaglandin E
synthesis in these subjects.22 In several reports,24, 25 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 discontinuation of this medication. Continuous bromocriptine therapy (2.5 mg thrice daily) resulted in a 72
percent decline in headache frequency in a study involving 24 women with menstrual migraine.26
STROKE
The pill has been implicated as a signicant risk
factor in thromboembolic cerebral infarction, subarachnoid hemorrhage, and cerebral venous thrombosis. In
1969, American27 and British28 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.29 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 g) estrogen preparations appears to
be responsible for a recent decline in rates of thromboembolic disease among users of oral contraceptives.30 In
a recent, population-based case-control study, the odds
ratio of ischemic stroke in current users of low-dose
estrogen contraceptives (2035 g) was only 1.18 in
comparison with former users or women who were
never exposed to oral contraceptives.31 However, the risk
of stroke remains unacceptably high in low-dose oral
contraceptive users if they smoke and are older than the
age of 35.32 Although less often implicated than estrogens, progestins may contribute to the danger of cerebral infarction by promoting hypertension, hypercoagulability, and adverse serum lipoprotein levels.33, 34
Ischemic strokes in users of oral contraceptives have
been localized to the carotid (usually the middle cerebral
artery or its deep penetrating branches) and vertebrobas-
369
ilar distributions. There is usually no radiological or

pathological evidence of disseminated vascular disease in
young women with oral contraceptiverelated stroke.35
Cerebral thromboembolism resulting from estrogeninduced hypercoagulability is a likely etiology for such
strokes. Estrogen increases plasma levels of brinogen
and clotting factors VII, VIII, IX, X, and XII. The
steroid also enhances platelet aggregation and suppresses
antithrombin III activity and the brinolytic system. A
host of estrogen-regulated genes that may impact the
risk of ischemic stroke are listed in Table 211.36 Elam
and associates have reported an increased prevalence of
mitral valve prolapse among users of oral contraceptives
with ischemic stroke.37 The combination of a xed valvular anomaly and an estrogen-related hypercoagulable
state may render patients particularly vulnerable to
thromboembolic complications. There is also evidence
implicating antibodies to ethinyl estradiol and the development of immune-mediated vasculitis in the pathogenesis of oral contraceptiverelated stroke. Beaumont and
co-workers hypothesized that inltration of serum immune complexes containing such antibodies into vessel
walls may promote thrombosis and that use of tobacco
may alter vascular permeability, facilitating the deposition of these immune complexes. 38 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.39 In contrast to
oral contraceptive exposure, postmenopausal estrogen
replacement has a benecial effect on lipoprotein proles, coagulability, and hypertension and may thereby
confer protection against cardiovascular and cerebrovascular disease.40, 41
In a study by the Royal College of General Practitioners, the relative risks for subarachnoid hemorrhage
in former users, current users, or subjects who had ever
used moderate- to high-dose oral contraceptives were
4.5, 3.2, and 4.0, respectively.42 The odds ratio for hemorrhagic stroke in current users of low-dose estrogen
contraceptives (2035 g) 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.31, 42 Female
sex hormones may predispose to bleeding from both
aneurysms and arteriovenous malformations, although
the pathophysiological mechanisms underlying these
phenomena remain controversial.35 By analogy to their
effects on endometrial spiral arteries, uctuating sex
hormone levels may compromise the integrity of cerebral arterial walls, rendering them more susceptible to
rupture. 43 During pregnancy, hemodynamic changes
may facilitate engorgement and bleeding from cerebral
arteriovenous malformations. In addition, sex hormones
may exert direct trophic inuences on these malformations analogous to their effects on other highly vascu-
370
TABLE 211
ESTROGEN-REGULATED GENES OF POTENTIAL RELEVANCE TO

VASCULAR PHYSIOLOGY AND STROKE
Gene Product
Role
Candidate Estrogen-Regulated Genes (Vascular Cells)

Prostacyclin synthase
Endothelial nitric oxide synthase
Inducible nitric oxide synthase
Endothelin-1
Collagen
Matrix metalloproteinase 2
E-selectin
Vascular-cell adhesion molecule
Vascular endothelial growth factor
Vasodilatation
Vasodilatation
Vasodilatation in response to vascular injury
Vasoconstriction
Vascular-matrix formation
Vascular-matrix remodeling
Cell adhesion
Cell adhesion
Angiogenesis and endothelial-cell proliferation
Candidate Estrogen-Regulated Genes (Nonvascular

Cells)
Growth- and development-related genes
Transforming growth factor-1
Epidermal growth factor receptor
Platelet-derived growth factor
t-4-tyrosine kinase
Coagulation- and brinolysis-related genes
Tissue factor
Fibrinogen
Protein S
Coagulation factor VII
Coagulation factor XII
Plasminogen-activator inhibitor 1
Tissue plasminogen activator
Antithrombin
Signaling-related and miscellaneous genes
Estrogen receptor
Estrogen receptor
Monocyte chemotactic protein 1
Leptin
Apolipoproteins A, B, D, and E and lipoprotein (a)
Angiotensin-converting enzyme
Angiotensin II receptor, type 1
Wound healing
Cell growth in response to vascular injury
Cell growth in response to vascular injury
Angiogenesis and endothelial-cell proliferation
Hemostasis in response
Fibrinolysis
Anticoagulation
to
to
to
to
to
to
thrombosis
thrombosis
thrombosis
thrombosis
thrombosis
thrombosis
Hormonal regulation and gene expression

Hormonal regulation and gene expression
Monocyte recruitment and atherosclerosis
Fat metabolism and obesity
Lipid metabolism and atherosclerosis
Vasoconstriction
Vasoconstriction
Adapted from Mendelsohn MR, Karas RH: The protective effects of estrogen on the cardiovascular system. N Engl J Med 240:1801, 1999,
with permission.
larized lesions such as spider angiomas, 44 gingival

epulis,45 and meningiomas (discussed later). Rarely, subarachnoid hemorrhage is secondary to cyclic bleeding
from hormone-sensitive ectopic endometriomas of the
spinal canal.46
EPILEPSY
Normal reproductive processes may be disrupted by
seizure disorders and their therapies. Abnormal limbic
discharges may be responsible for the hyposexuality47
and increased prevalence of hypogonadotropic hypogonadism and polycystic ovary syndrome48 noted in patients with temporal lobe epilepsy. Pregnant epileptic
women experience higher rates of maternal and fetal
complications, including vaginal hemorrhage, prematurity, low birth-weight, and perinatal mortality.49
As discussed in Chapter 32, anticonvulsant therapy in
women of childbearing age may result in failure of oral
contraceptives and in teratogenicity.50 On the basis of
the expected oral contraceptive failure rates reported
for the general population by Tietze,51 Coulam and
Annegers52 calculated a 25-fold increased risk of oral
contraceptive failure in patients concomitantly exposed
to anticonvulsants. Phenytoin, phenobarbital, primidone, ethosuximide, and carbamazepine have been implicated in oral contraceptive failure.53 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.54 Anticonvulsants may also promote the clearance of sex hormones
by inuencing sulfate conjugation and glucuronidation
of the latter in the gut wall and liver.53 Oral contraceptive failure does not occur with valproic acid, which
may actually inhibit cytochrome P450 enzymes, causing
elevations in plasma steroid concentrations. Valproic
acid, on the other hand, may cause hyperandrogenism
and polycystic ovaries.55 Of the newer antiepileptic medications, lamotrigine, gabapentin, vigabatrin, and clobazam do not induce the hepatic P450 microsomal enzyme
system and oral contraceptive failure has not been reported with concomitant use of these drugs.56 Topiramate and felbamate have modest effects on sex hormone
pharmacokinetics and may affect contraceptive efcacy.57
Although breakthrough bleeding has been reported with
tiagabine, the impact of this drug on ovarian hormone
metabolism is believed to be minimal.58
The course of epilepsy and its management may be
greatly inuenced by specic 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.59, 60 Data amassed
from human61 and animal62, 63 studies indicate that estrogens and progestins have epileptogenic and anticonvulsant properties, respectively 55 (Table 212). Estrogen
augments glutamatergic and suppresses GABAergic neurotransmission, favoring epileptogenesis, whereas progesterone has the opposite effects.55 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
TABLE 212
Neurochemistry
371
reproductive disorder with temporal lobe epilepsy.48 Exposure to oral contraceptives consisting of estrogenprogestin combinations does not appear to worsen seizure control signicantly.64 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.65, 66
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.67 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.67
The inuences of the menstrual cycle and of oral contraceptive preparations on anticonvulsant disposition appear to be of minor clinical signicance.68
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
SEX HORMONES AND EPILEPSY

Neurophysiology
Estrogen
Reduces chloride conductance at GABAA receptor
Reduces electroconvulsive shock threshold
Stimulates the NMDA receptor in CA-1 hippocampus
Creates new seizure focus when applied topically to the
cortex
Alters mRNA for GAD and inhibits GABA synthesis
Increases severity and duration of chemically induced
seizures
Alters mRNA for GABAA receptor subunits
Activates pre-existing epileptogenic foci
Progesterone
Increases chloride conductance at GABAA receptor
Increases electroconvulsive shock threshold
Attenuates the excitatory response to glutamate
Suppresses seizures induced by kindling, focal lesions,
and alcohol withdrawal
Alters mRNA for GAD and increases GABA synthesis
Increases threshold for seizures induced by chemical
convulsant
Alters mRNA coding for GABAA receptor subunits
Induces sedation and anesthesia in rats and humans
GABAA, -aminobutyric acid A; GAD, glutamic acid decarboxylase; NMDA, N-methyl-D-aspartate.
Modied from Morrell MJ: Epilepsy in women: the science of why it is special. Neurology 53:542, 1999, with permission.
372
reexes. Fever, dysarthria, and neuropsychiatric symptoms may complete the clinical picture. Gestational and
oral contraceptiverelated chorea have a close association with previous rheumatic fever. 35 Contraceptiverelated chorea has also been reported in patients with a
history of congenital cyanotic heart disease and HenochSchonlein purpura.69, 70 Pharmacological, epidemiological, and pathological evidence suggests that altered hormonal patterns characteristic of pregnancy and ingestion
of oral contraceptives may unmask latent chorea by
augmenting dopaminergic neurotransmission in basal
ganglia previously damaged by rheumatic or hypoxic
encephalopathy.18 Estrogens may facilitate dopaminergic
neurotransmission by upregulation of postsynaptic dopamine receptors, by inhibition of central monoamine oxidase activity, and possibly through conversion to catechol-estrogens (Fig. 211). The latter may compete for
the catecholamine degrading enzyme, catechol-Omethyl transferase, resulting in the excessive accumulation of dopamine and other neurotransmitters within
the affected brain regions.71 In most cases, chorea gravidarum and oral contraceptiverelated 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.72 Patients with chorea gravidarum are at increased risk of later developing oral
contraceptiverelated dyskinesias,73 and vice versa.74
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 Wilsons 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 contraceptiveinduced chorea should probably minimize
further exposure to any estrogen-containing medications.
from several recent investigations suggest that postmenopausal estrogen replacement is benecial in women
with Parkinsons disease.78, 79 In other studies, postmenopausal estrogen therapy either had no signicant dopaminergic effect80 or was associated with worsening motor
scores.81 There is evidence for both prodopaminergic
and antidopaminergic effects of estradiol in various rodent models of striatal dysfunction (reviewed elsewhere18). Variations in methodology, multimodal doseresponse relations, and species, age, and sex differences
may account for these conicting observations.82, 83
Wilsons Disease
Wilsons disease is an inborn error of copper metabolism that is characterized by hepatic cirrhosis and degenerative changes in the basal ganglia. Patients with this
rare condition 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.84 In normal individuals, serum ceruloplasmin and
copper levels increase during pregnancy 85 and after administration of estrogen or estrogen-progestogen contraceptives.18 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 Wilsons 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 benet, and such exposure may lead to neurological deterioration in some individuals. Exposure
to hormonal contraceptives may yield falsely normal
ceruloplasmin levels in patients with Wilsons disease,
resulting in a delay in diagnosis.18
Other Movement Disorders

Parkinsonism
Data concerning the effects of estrogen on patients
with parkinsonism are contradictory. There are anecdotal reports of clinical deterioration in idiopathic and
neuroleptic-induced parkinsonism after exposure to exogenous estrogen. 75 Furthermore, premenopausal
women are reportedly more susceptible to drug-induced
parkinsonism than men of similar age. These observations argue for a potentially antidopaminergic role of
estrogen in this condition. Yet, in two studies of premenopausal women with idiopathic Parkinsons disease,
motor symptoms were noted to worsen premenstrually
when estrogen titers were falling, favoring a stimulatory
inuence of estrogen on striatal dopamine.76, 77 Data
A broad spectrum of movement disturbances appear

to be inuenced 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-dened tremors and drop attacks, familial episodic ataxia, Gilles de la Tourettes syndrome,
and the neuroleptic malignant syndrome.18, 86, 87
NERVOUS SYSTEM NEOPLASMS

Meningiomas
Sex steroids may play an important role in the biology
of meningiomas. These tumors occur more frequently
in women than in men88 and are rarely diagnosed before

puberty or during the senium, corresponding to the time
of maximal gonadal activity.89 Meningiomas are more
common in obese women90 and in patients with hormone-dependent breast carcinoma.91 The greater prevalence of these tumors in obese individuals may be related
to higher circulating estrogen levels derived from the
aromatization of androstenedione to estrone in adipocytes92 (Fig. 212). Meningiomas have been documented
clinically and radiologically to undergo relatively rapid
expansion during pregnancy, followed by spontaneous
regression postpartum.18, 93 Some women suffer exacerbations of symptoms in the luteal phase of the menstrual
cycle. These uctuations in tumor size have been attributed to steroid-induced uid retention by the lesion,
increased vascular engorgement of the tumor, or direct
trophic effects of gonadal hormones on meningioma
cells.94, 95
Numerous investigators have demonstrated the presence of progestin- and, to a lesser extent, estrogen- and
androgen-binding proteins in a signicant number of
human meningioma specimens. 18 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 receptornegative meningiomas have been associated with a greater tendency for brain invasiveness,
higher mitotic indices and necrosis,96 and shorter disease-free intervals.97 In an early study, the antiestrogen
tamoxifen (Fig. 211) did not appreciably affect tumor
size or neurological status in patients with inoperable
meningiomas.98 On the other hand, the antiprogestin
RU486 (Fig. 211) 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.99 However,
the effects of progestins and RU486 on meningioma
growth in vitro are contradictory, 100102 and patients
chronically treated with RU486 may require glucocorticoid replacement to counteract the antiglucocorticoid
effects of this agent.103
Gliomas
There are anecdotal reports of astrocytomas enlarging during pregnancy, only to shrink spontaneously in
the puerperium.104 As in the case of meningiomas, certain human gliomas may selectively bind estrogens, progestins, and androgens. Some of these tumors may also
contain enzymes (e.g., 17-oxidoreductase and aromatase) that catalyze steroid hormone interconversions.105, 106 The origin of putative steroid receptors
in glial cell tumors is obscure, although signicant numbers of normal astrocytes in certain brain regions possess
estrogen receptors.4, 5 In one study of human astrocyto-
373
mas, a possible correlation was observed between grade

of malignancy (possibly de-differentiation) and the presence of hormone binding.107 If substantiated, the detection of steroid-binding proteins in tumor biopsy specimens could provide important prognostic information.
High-dose tamoxifen therapy (Fig. 211) may result in
clinical and radiological stabilization of astrocytomas
and glioblastoma multiforme in some patients. 108110
These benets are more likely due to the inhibitory
effects of tamoxifen on protein kinase C108, 109 or its role
as a radiosensitizer111 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.112
Other Tumors
Responsiveness to sex hormones has been reported in
cases of acoustic neuromas,113 pituitary adenomas,114 and
breast metastases to the nervous system.115 Sex steroid
receptors have also been reported in hemangioblastomas, anaplastic ependymomas, and malignant lymphomas, suggesting that the natural history of these neoplasms may be inuenced by sex hormones and their
antagonists.116
MULTIPLE SCLEROSIS
Multiple sclerosis (MS) is an immune-mediated demyelinating disorder of the central nervous system that
often aficts men and women during their reproductive
years. Physicians are often asked by young women with
MS whether their condition will be worsened by pregnancy. Contrary to medical dogma promulgated before
World War II, initial epidemiological studies have indicated that the overall effect of one or more pregnancies
on MS-related morbidity is nil.117, 118
As discussed in Chapter 32, subsequent studies involving larger patient cohorts have amply demonstrated
a tendency for MS exacerbation during the rst 3 postpartum months that is counterbalanced by signicant
suppression of disease activity in the third trimester.119, 120 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 (33%),
copolymer-1 (29%), or intravenous immunoglobulin
(59%) therapy.121 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 D3, -fetoprotein, pregnancy-associated glycoprotein, blocking antibodies,
374
immune complexes, and interleukin-10.121, 122 In animals,

pregnancy signicantly delays the onset of experimental
allergic encephalomyelitis (a model for MS) after inoculation with spinal cord homogenate or myelin basic
protein.123, 124
If necessary, intravenous steroids can be used for MS
attacks in pregnancy. Interferon-beta should be discontinued 3 months before planned conception and not be
used during pregnancy or while breast-feeding.121 In a
recent study, none of 14 pregnant women with relapsing-remitting MS who received prophylactic intravenous
immunoglobulins immediately postpartum exhibited
disease relapse in the rst 6 months after delivery.125
ALZHEIMERS DISEASE
Alzheimers disease is a dementing illness characterized by progressive neuronal degeneration, gliosis,
marked depletion of acetylcholine and other neurotransmitter disturbances, and the accumulation of senile (amyloid) plaques and neurobrillary tangles in discrete regions of the basal forebrain, hippocampus, and
association cortex.126 The following evidence, derived
from both basic and clinical studies, strongly suggests
that estrogens play an important role in normal human
cognition, have a salutary effect on the manifestations
of Alzheimers disease, and may even protect against the
development of this neurodegenerative disorder in
women:
1. Estrogens exert trophic inuences on cholinergic
neurons of the rodent basal forebrain. McEwens laboratory at Rockefeller University demonstrated that
estrogen administration to ovariectomized rats signicantly increases levels of the acetylcholine-synthesizing enzyme choline acetyltransferase.127 More recently, it was shown that estrogen induces dendritic
spines (synapses) and functional N-methyl-D-aspartate receptors (important for memory) in adult rat
hippocampus.128
2. Toran-Allerand has found that estrogens massively
induce neuritic growth in rodent hypothalamic
explants and provide trophic support to cholinergic
neurons in the basal forebrain by upregulating nerve
growth factor receptors in these cells.129
3. Estrogens have antioxidant properties, reduce the
deposition of brillar -amyloid by favoring the metabolism of the amyloid precursor protein to a more
soluble form of the peptide, modulate apolipoprotein
E expression, and suppress inammatory responses
implicated in neuritic plaque formation.130, 131
4. Estrogens increase cerebral blood ow and glucose
utilization, both of which are relatively decient in
subjects with Alzheimers disease.130, 131
5. Hypercortisolemia occurs in a signicant proportion
of patients with Alzheimers disease and may be dele-
terious to the survival of hippocampal neurons affected by the disease.132 Estrogens may partly offset
this hippocampal endangerment by attenuating the
reactivity of the hypothalamic-pituitary-adrenal
axis.130 Biological effects of estrogen potentially relevant to the pathogenesis of Alzheimers disease are
summarized in Table 213.
6. The 1990s brought to light evidence that estrogens
improve cognitive behaviors in rats and monkeys,
psychometric performance in women is inuenced by
menstrual cycle phase, cross-gender hormone therapy
affects cognition in transsexual men and women, and
estrogen replacement therapy augments verbal memory scores in normal menopausal women.130, 133135
7. Estrogen replacement therapy may improve cognitive
performance, especially language function, verbal
memory, and attention, in menopausal women with
Alzheimers disease.130, 133, 135, 136 It may also enhance
the likelihood of a benecial response to acetylcholinesterase inhibitors in women with Alzheimers
disease.137, 138
8. Most importantly, in a number of case-controlled
studies, 139141 and in two of three prospective
studies,142, 143 postmenopausal estrogen replacement
therapy was associated with a signicantly (up to
50%) decreased risk of developing Alzheimers disease. In one report,140 the relative risk varied inversely
with duration and dose of estrogen replacement therapy (Fig. 215). Postmenopausal estrogen replacement therapy may also protect against the development of dementia in women with Parkinsons
disease.144
Further large prospective clinical trials will be required to conrm the efcacy of estrogen replacement
therapy in forestalling Alzheimers disease. Risk/benet
TABLE 213 ESTROGEN ACTIONS

GERMANE TO THE ETIOPATHOGENESIS
OF ALZHEIMERS DISEASE
Organizational effects on developing neurons and
activational effects on mature neurons
Effects on neurite growth and synapse formation
Interactions with nerve growth factor and other
neurotrophins
Effects on acetylcholine and other neurotransmitter
systems
Reduced formation of -amyloid
Altered levels of apolipoprotein E
Reduced acute-phase inammatory response
Antioxidant effects
Increased cerebral blood ow
Augmented cerebral glucose utilization
Blunting of hypothalamic-pituitary-adrenal axis
From Henderson VW: Estrogen, cognition, and a womans risk of
Alzheimers disease. Am J Med 103:11S, 1997, with permission.
1.0
ERT Duration
Relative
Risk
ERT Dose
0.5
0.0
none
<7 years >7 years
none
.625 mg
1.25 mg
Figure 215 Relative risk of dementia among members of

the Leisure World retirement community cohort as a function
of estrogen replacement therapy (ERT). There were signicant effects for increasing duration (P 0.01) and for higher
dose (P 0.002) of oral estrogen exposure. (From PaganiniHill A, Henderson VW: Estrogen deciency and risk of Alzheimers disease in women. Am J Epidemiol 140:256, 1994,
with permission.)
ratios will need to be considered on an individual patient

basis. Optimal estrogen doses, formulations, and vehicles, and the effects of adding progestins or androgens
to the hormonal replacement regimen, will require analysis. If estrogens protect against the development of
Alzheimers disease, the impact of pregnancy, lactation,
hormonal contraception, tamoxifen, gonadotropin-releasing hormone (GnRH) analogues, ovarian resection,
and environmental endocrine disruptors on the epidemiology and natural history of the disease will need to
be delineated. Finally, the advent of pharmaceuticals
exhibiting the neuroprotective benets, but not the feminizing attributes, of estrogen may prove useful for the
treatment or prevention of Alzheimers disease in men.
NEUROPSYCHIATRIC DISORDERS
The Porphyrias
The porphyrias are characterized by the excessive
production of porphyrins and porphyrin precursors resulting from specic enzymatic defects in the heme biosynthetic pathway. Neurological manifestations, when
present, include seizures, neuropsychiatric symptoms,
and sensorimotor and autonomic neuropathies. Estradiol
and other steroids with a 5 conguration induce the
enzyme -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 may 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.18
375
Although acute treatment with GnRH agonists, such as

D-His or leuprolide, stimulates the pituitary-ovarian axis
(Fig. 212), chronic administration of these agents
downregulates gonadotrope GnRH receptors, resulting
in long-term suppression of pituitary-ovarian function.
In the rst reported case,145 D-His administration (5 g
subcutaneously daily) yielded complete remission of severe premenstrual acute intermittent porphyria for the
duration (8 months) of therapy (Fig. 216). Similar benets were observed in subsequent cases of catamenial
acute intermittent porphyria146 and hereditary coproporphyria147 in response to GnRH analogue therapy. Side
effects of long-term GnRH treatment include hot
ashes, diminished breast size, and bone demineralization.145, 147 GnRH analogs, unlike sex steroids, do
not appear to induce porphyrin accumulation in chick
embryo hepatic cell culture145 and provide a rational
approach to the management of catamenial porphyria.
Premenstrual Syndrome
The premenstrual syndrome occurs in approximately
30 percent of women during their reproductive years.
Common neuropsychiatric symptoms of this disorder
include headache, fatigue, depression, irritability, increased thirst or appetite, and craving for sweet or salty
foods.148 Symptoms typically begin toward the end of
the luteal phase of the cycle and usually, but not invariably, resolve with the onset of ow. 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.148 Numerous hormonal and nonhormonal
therapiesincluding natural progesterone, oral contraceptives, bromocriptine, GnRH agonists, diuretics, prostaglandin inhibitors, vitamin B6, and lithiumare prescribed for the management of premenstrual syndrome.
However, with the possible exception of the GnRH
agonists, none has proved to be unequivocally effective.148 In a double-blind crossover trial,149 induction of
articial menopause with a GnRH agonist (D-TrpPro-NEt-Gn-RH, 50 g per day subcutaneously) relieved both physical and neuropsychiatric symptoms in
eight women with rigorously dened premenstrual syndrome. Although the authors reported no side effects
(except for hot ashes 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 truly incapacitating symptoms, and low-dose estrogen replacement may have to be considered when the duration of
treatment exceeds several months.
376

D-His 5 g/day
Symptoms
Menses
60
LH
(mIU/ml)
40
20
FSH
(mIU/ml)
40
20
Progesterone
(ng/ml)
10
5
Estradiol
(pg/ml)
400
200
-8
-4
12
16
20
24
28
Weeks
Figure 216 Course of symptoms, menses, and plasma hormone levels in a patient with acute intermittent porphyria during
8 months of treatment with an agonist (D-His) of luteinizing hormonereleasing hormone. (From Anderson KE, Spitz IM, Sassa
S, et al: Prevention of cyclical attacks of acute intermittent porphyria with a long-acting agonist of luteinizing hormonereleasing
hormone. N Engl J Med 311:643, 1984, with permission.)
Depression and Psychosis

Depression and other major affective disorders may
surface in relation to the menstrual cycle, the puerperium, and menopause. In patients with postmenopausal
depression, mood elevation and anxiolysis often occur
promptly in response to estrogen replacement.1 Paradoxically, oral contraceptives may precipitate depression
in susceptible individuals.150 Estrogen has also been implicated in the pathogenesis of anorexia nervosa in view
of the high preponderance of this condition in women
and the potent anorexic effects of estrogen in animals.151
Psychotic disorders characterized by extreme agitation, hallucinations, paranoid delusions, incoherent
speech, and mood lability may arise during the postpartum period152 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
specic hormonal interventions, including the use of
oral contraceptives, 153 intramuscular progesterone, 154
and danazol.155 Menopause induced by GnRH analogs
may also be of considerable benet 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.156158 The GABA-active metabolites allopregnanolone and pregnanolone may mediate the reduction in
vigilance during wakefulness observed after the administration of progesterone to healthy men.159 Progestins
may also provide stimulatory drive to brainstem respiratory centers in subjects with central sleep apnea and
thereby improve hypoventilation.160 In one case, obstructive sleep apnea resolved in a nonobese woman
after removal of a benign testosterone-producing ovarian tumor.161
INTRACRANIAL HYPERTENSION
Progesterone has been shown to suppress 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 uid production by the choroid plexus.162164 Estrogens, by contrast, appear to enhance cerebral endothelial cell permeability and posttraumatic brain edema in female rats.165, 166 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.165
377
NEUROMUSCULAR DISEASES
CONCLUDING COMMENT
Catamenial Sciatica
Sex hormones inuence a broad spectrum of normal

and abnormal neurological functions. Relationships between endogenous and exogenous sex hormones and
many neurological conditions, such as migraine, stroke,
and chorea, are well established. In other diseases,
including such diverse entities as primary central nervous system neoplasms, various movement disorders,
and Alzheimers disease, this relationship has not been
conrmed but appears likely in the light of rapidly accumulating clinical, epidemiological, and biochemical data.
Fluctuating sex hormone levels also inuence the expression of certain neuropsychiatric states and neuroendocrine disorders. The ubiquitous nature of these interactions warrants routine inquiry into potential symptom
modications associated with the menstrual cycle, pregnancy, menopause, and hormonal contraceptive exposure
in woman with neurological and psychiatric illness. A
more thorough understanding of the mechanisms mediating sex hormonerelated neural function and dysfunction should facilitate the renement of rational hormonal and antihormonal therapies for many of the
conditions discussed in this chapter.
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.18, 167 The latter causes radicular pain in the
distribution of the nerve that usually begins 2 to 3 days
before the onset of menses and may continue for a
variable duration after cessation of ow (catamenial sciatica). In addition to pain, there is often numbness,
weakness, and loss of ankle reexes. In contrast to far
more common discogenic radiculopathy, endometriotic
sciatica is less likely to respond to bed rest and the
imaging ndings are usually unimpressive. There may
or may not 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 uid is expressed after incision
of the sheath. Biopsy specimens reveal characteristic
glandular elements.167 Symptoms of catamenial sciatica
may show dramatic improvement with standard therapy
for endometriosis, including danazol, progestins, and, in
refractory cases, bilateral oophorectomy.46, 167
Other Neuromuscular Disorders

Endogenous and administered sex hormones (mainly
estrogens) may inuence the natural history of Bells
palsy, recurrent brachial plexopathy, and the carpal tunnel syndrome.41 Abnormally high estrogen levels have
been reported in male patients with amyotrophic lateral
sclerosis, Kugelberg-Welander disease, bulbospinal muscular atrophy of the Kennedy-Alter-Sung type, Duchenne muscular dystrophy, and the Crow-Fukase syndrome (polyneuropathy associated with plasma cell
dyscrasias, anasarca, and altered skin pigmentation).18, 168
It is unclear whether hyperestrogenemia plays any signicant 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.169 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 may be
contributing to the hypergonadotropic hypogonadism
and impotence that complicate myotonic dystrophy in
men.170
ACKNOWLEDGMENTS
The author thanks Mr. Steven Kravitz for assistance
with computer surveillance of the literature and Mrs.
Rhona Rosenzweig for skilled secretarial support.
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21

Sex Hormones and the Nervous

The effects of sex steroids on neurological function

NERVOUS SYSTEM NEOPLASMS

NEUROLOGY AND GENERAL MEDICINE

moter regions of various genes induces or suppresses the

Sex Hormones and the Nervous System

The Classic Organization Hypothesis

HUMAN MENSTRUAL CYCLE AND

during the luteal phase in synchrony with the second

Plasma estradiol (ng/100ml)

Plasma progesterone (ng/ml)

NEUROLOGY AND GENERAL MEDICINE

Plasma estradiol (ng/100ml)

Estradiol treated cycle

Migraine: unilateral: nausea:

Days from onset of menstruation

Figure 214 A, Daily plasma concentrations of estradiol

will be made between high-dose (50 g) and the

with gestation, particularly in patients whose headaches

Sex Hormones and the Nervous System

ilar distributions. There is usually no radiological or

NEUROLOGY AND GENERAL MEDICINE

ESTROGEN-REGULATED GENES OF POTENTIAL RELEVANCE TO

Candidate Estrogen-Regulated Genes (Vascular Cells)

Candidate Estrogen-Regulated Genes (Nonvascular

Hormonal regulation and gene expression

larized lesions such as spider angiomas, 44 gingival

Sex Hormones and the Nervous System

of sex hormone binding globulins, resulting in reduced

SEX HORMONES AND EPILEPSY

NEUROLOGY AND GENERAL MEDICINE

Other Movement Disorders

A broad spectrum of movement disturbances appear

NERVOUS SYSTEM NEOPLASMS

Sex Hormones and the Nervous System

in women than in men88 and are rarely diagnosed before

mas, a possible correlation was observed between grade

NEUROLOGY AND GENERAL MEDICINE

immune complexes, and interleukin-10.121, 122 In animals,

TABLE 213 ESTROGEN ACTIONS

Sex Hormones and the Nervous System

<7 years >7 years

Figure 215 Relative risk of dementia among members of

ratios will need to be considered on an individual patient

Although acute treatment with GnRH agonists, such as

NEUROLOGY AND GENERAL MEDICINE

Depression and Psychosis

Sex Hormones and the Nervous System

Sex hormones inuence a broad spectrum of normal

Other Neuromuscular Disorders

NEUROLOGY AND GENERAL MEDICINE

orientationrelated differences in the human hypothalamus. Frontier Endocrinol 20:135, 1996

36. Mendelsohn MR, Karas RH: The protective effects of

Sex Hormones and the Nervous System

58. Mengel HB, Houston A, Back DJ: An evaluation of the

81. Weiner WJ, Shulman LM, Singer C, et al: Menopause

NEUROLOGY AND GENERAL MEDICINE

123. Keith AB: Effect of pregnancy on experimental allergic

Sex Hormones and the Nervous System

study of estrogen replacement therapy and the risk of

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