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Effects of ovarian hormones on human cortical excitability.

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Effects of Ovarian Hormones on Human
Cortical Excitability
Mark J. Smith, MD, PhD,1 Linda F. Adams, BA,2 Peter J. Schmidt, MD,2 David R. Rubinow, MD,2
and Eric M. Wassermann, MD1
Ovarian steroids appear to alter neuronal function in women, but direct physiological evidence is lacking. In animals,
estradiol enhances excitatory neurotransmission. Progesterone-derived neurosteroids increase GABAergic inhibition. The
effect of weak transcranial magnetic stimulation of the motor cortex on the motor evoked potential (MEP) from transcranial magnetic stimulation given milliseconds later is changed by GABAergic and glutamatergic agents. Using this
technique previously, we showed more inhibition in the luteal phase relative to the midfollicular menstrual phase, which
is consistent with a progesterone effect. To detect the effects of estradiol, we have now divided the follicular phase. We
tested 14 healthy women during the early follicular (low estradiol, low progesterone), late follicular (high estradiol, low
progesterone), and luteal (high estradiol, high progesterone) phases, with interstimulus intervals from 2 to 10msec (10
trials at each interval and 40 unconditioned trials). We calculated the ratio of the conditioned MEP at each interval to
the mean unconditioned MEP: the higher the ratio, the less inhibition and the more facilitation caused by the first
stimulus. The combined ratios increased significantly from the early follicular phase to the late follicular phase and then
decreased again in the luteal phase. These findings demonstrate an excitatory neuronal effect associated with estradiol
and confirm our earlier finding of inhibition associated with progesterone.
Ann Neurol 2002;51:599 – 603
Behavioral, biochemical, and physiological data from
animals indicate that ovarian hormones exert powerful
effects on brain function. The neurosteroid metabolites
of progesterone bind to a site on the ␥-aminobutyric
acid A (GABAA) receptor complex, increasing its
activity through an allosteric mechanism.1,2 This action, largely parallel to that of barbiturates and benzodiazepines, reduces neuronal excitability, raises the seizure threshold,1,3,4 and causes behavioral effects such as
those induced by benzodiazepines.5,6 In contrast,
estradiol increases glutamate-mediated neuronal excitability7–9 and lowers the seizure threshold.10 Estradiolinduced increases in the number of dendritic spines11
and the density of N-methyl-D-aspartate receptors have
been observed.12 A depressant effect on GABAergic
transmission may stimulate this change,13 and antiGABAergic effects of estradiol in the cortex14 and hypothalamus15,16 of the rat have been reported. Although direct evidence of the neural effects of ovarian
hormones in women has not been available, estradiol
and progesterone have important effects in the areas of
mood,17 seizure susceptibility,10,18 and, probably, cognitive function.19
Transcranial magnetic stimulation (TMS), a noninvasive cortical stimulation technique, has been used to
study the effects of drugs and diseases on the human
brain. The amplitude of the muscle response, or motor
evoked potential (MEP), produced by TMS of the motor cortex reflects the integration of synaptic inputs by
the cortical and spinal motoneurons. The MEP can be
modulated by a preceding conditioning pulse delivered
with an intensity below the MEP threshold.20 This occurs even when the conditioning pulse is too weak to
activate the corticospinal neurons,21 indicating a purely
cortical site of interaction. Depending on the interstimulus interval (ISI), the predominant effect of the
first stimulus upon the second is either inhibition or
facilitation. However, drug experiments suggest that inhibition and facilitation are present in varying degrees
at most ISIs. Benzodiazepines, barbiturates, and other
drugs that enhance ␥-aminobutyric acid-mediated inhibition increase paired-pulse inhibition and reduce facilitation.22 The glutamate (N-methyl-D-aspartate) antagonists dextromethorphan22 and memantine,23 as
well as riluzole,24 a postsynaptic modulator of glutamate action, produce similar effects, particularly reduc-
From the 1Brain Stimulation Unit, National Institute of Neurological Disorders and Stroke, and the 2Behavioral Endocrinology
Branch, National Institute of Mental Health, National Institutes of
Health, Bethesda, MD.
Address correspondence to Dr Wassermann, National Institute of
Neurological Disorders and Stroke, Building 10, Room 5N234, Bethesda, MD 20892-1430. E-mail: wassermann@nih.gov
Received Sep 24, 2001. Accepted for publication Jan 16, 2002.
This article is a US Government work and, as such, is in the public
domain of the United States of America.
Published online Apr 23, 2002 in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.10180
Published 2002 by Wiley-Liss, Inc.
599
ing the facilitation seen at the longer ISIs. Therefore,
the paired-pulse TMS technique has been proposed as
an assay for drugs affecting these neurotransmitter systems.22 Importantly, these agents have little or no effect on the threshold or size of the MEP to a single
stimulus. Drugs that affect cation channels, such as
carbamazepine25 and phenytoin,26 suppress MEPs but
have no effect on paired-pulse excitability. Therefore,
TMS appears to be able to distinguish between neuronal and synaptic effects.
In a previous TMS study of healthy women,27 we
observed increased inhibition and decreased facilitation
in the luteal phase relative to the midfollicular phase,
which is consistent with a GABAergic effect of progesterone metabolites. Here we describe a similar study
designed to detect the effects of estradiol as well, with
testing three times during the menstrual cycle. Testing
was conducted early in the follicular phase (F1), when
both low estradiol and progesterone are low; late in the
follicular phase (F2), when estradiol is high but progesterone remains low; and in the midluteal phase (L),
when both estradiol and progesterone are high.
Subjects and Methods
Eighteen healthy, medication-free women with regular menstrual cycles (age: mean, 33.4 years; SD, 7.9 years; range,
26 – 43 years) entered the study. In a screening period of 2 to
3 months, during which participants supplied daily symptom
ratings, none reported symptoms of or met criteria for premenstrual syndrome. All gave written informed consent, and
the protocol was approved by the Institutional Review Board
of the National Institute of Neurological Disorders and
Stroke. Because the study was designed to examine the effects of estradiol and progesterone, only women who showed
typical hormonal changes during the study were included in
the analysis. Of the 18 women tested, 4 were excluded. One
had no luteal phase progesterone increase, probably because
of an anovulatory cycle, and 3 showed less than the expected
(⬎150%) increase in estradiol from the early follicular phase
to the late follicular phase. Of the remaining 14 participants,
all had hormonal profiles consistent with normal ovulatory
cycles, as shown by estradiol and progesterone measurements
on the day of testing and evidence of a luteinizing hormone
surge on a home urine test (Clear Plan Easy; Unipath Diagnostics, Princeton, NJ). The women were tested at three
points in the menstrual cycle: F1 (days 2–5 after the onset of
the last menses), F2 (days 9 –12), and L (days 6 –12 after the
luteinizing hormone surge, when estradiol and progesterone
are both high). All participants completed the following rating scales at each time of testing: the Beck Depression Inventory,28 the Spielberger State-Trait Anxiety Inventory,29
and the Steiner-Carroll Premenstrual Tension Syndrome
Scale (self-rated and observer-rated versions).30
TMS was delivered to the hand area of the left motor
cortex through a 9cm round coil connected via a Bistim
module to two Magstim 200 stimulators (Magstim Company US, Winchester, MA). The surface electromyogram was
recorded from the abductor pollicis brevis muscle in the right
600
Annals of Neurology
Vol 51
No 5
May 2002
hand, amplified, analog-filtered (100/1,000Hz), digitized,
and stored on a computer. Analog–digital conversion and experiment control were done with Spike2 or Signal software
and a Micro1401 interface (CED, Cambridge, England).
Once the optimal position for producing an MEP in the
right abductor pollicis brevis was located and marked on the
scalp, the MEP threshold was determined as the lowest stimulation intensity that produced MEPs of 50␮V or greater in
at least 5 of 10 consecutive trials administered at least 5 seconds apart. The threshold was determined both with the
muscle at rest and during a slight voluntary contraction. The
conditioning stimulation intensity was set at 5% below the
MEP threshold determined during voluntary activation. This
intensity has been shown, by means of spinal recordings in
humans, to be below the level required to produce an effective descending volley in the corticospinal tract.31 Therefore,
the conditioning effects of this pulse were isolated to the cortex. The test stimulus intensity was set to produce an MEP
of 500 to 1,500␮V. Ten trials of paired-pulse TMS were
delivered at each of seven ISIs (2, 3, 4, 5, 6, 7, and 10msec).
In addition, there were 40 randomly interspersed trials in
which the test pulse was delivered alone as a control for the
effect of the conditioning pulse (unconditioned MEP). The
order of the ISIs was randomized, and the interval between
trials was varied randomly within a 20% range around a
mean of 6 seconds. Each session took about 1 hour.
The effect of the conditioning stimulus was measured as
the ratio of the average amplitude of the conditioned MEP
at each ISI to the average unconditioned MEP. Therefore,
when inhibition was the predominant effect of the conditioning pulse, the ratio was less than 1, and when facilitation
predominated, it was greater than 1. After the 10 trials at
each ISI were averaged for each individual, the curves relating the ISI to the conditioning effect were compared by
repeated-measures analyses of variance with menstrual phase
and ISI as within-subjects factors. No statistical testing was
done on the MEP threshold data. The hormone levels were
analyzed with one-way repeated-measures analyses of variance. The threshold for significance was set at p ⬍ 0.05.
When effects were significant, post hoc comparisons of the
mean values for each phase were made with the two-tailed
Bonferroni-Dunn test.
Results
The average days of the menstrual cycle for testing
were day 4.1 for the F1 measurement, day 10.7 for the
F2 measurement, and day 21.9 (or 9.5 days after the
luteinizing hormone surge) for the L measurement.
The mean estradiol level rose from 43.6 ⫾ 29.2pg/ml
at F1 to 148.4 ⫾ 77.7pg/ml at F2 and then declined
slightly to 116.8 ⫾ 61.6pg/ml at L. The phase effect
on the estradiol level was highly significant (F[2,13] ⫽
11.5, p ⫽ 0.0003), and the drop from F2 to L was not
significant in post hoc testing ( p ⫽ 0.17, uncorrected
for multiple comparisons). The average progesterone
level was 1.0 ⫾ 0.7ng/ml at F1, 1.1 ⫾ 0.7ng/ml at F2,
and 10.9 ⫾ 6.4ng/ml at L (F[2,13] ⫽ 34.6, p ⬍
0.0001 for the effect of phase).
No phase effect on the MEP threshold was observed
Fig 1. Average motor evoked potential threshold at rest (open
columns) and during voluntary muscle activation (shaded columns) across the menstrual cycle. Bars represent the standard
error. F1 ⫽ early follicular phase; F2 ⫽ late follicular phase;
L ⫽ luteal phase.
in either the resting state or the active muscle state (Fig
1). However, the ratio of the conditioned MEP to the
unconditioned MEP showed a significant phase effect
(F[2,13] ⫽ 4.0, p ⫽ 0.03), increasing from F1 to F2
and then decreasing in L (Fig 2). The increase in the
ratio of conditioned MEP to unconditioned MEP at
the F2 time point was present at each of the ISIs (Fig
3). As expected, there was a powerful main effect of ISI
(F[6,13] ⫽ 9.8, p ⬍ 0.0001), but there was no significant interaction of ISI and phase. Post hoc testing on
the main phase effect showed a significant difference
between F1 and F2 ( p ⫽ 0.016) and a trend level difference between F2 and L ( p ⫽ 0.032), which was not
significant after correction for multiple comparisons.
There was no difference between F1 and L ( p ⫽ 0.75).
There were no significant effects of the menstrual
phase on the results of the Beck Depression Inventory,
the Spielberger State-Trait Anxiety Inventory, or the
Steiner-Carroll Premenstrual Tension Syndrome Scale.
Discussion
These data are consistent with a hormonally driven
change in the differential tendency of a weak magnetic
stimulus to evoke inhibitory and facilitatory activity in
the human cerebral cortex. At F1, when circulating estradiol and progesterone were low, the tendency to
produce inhibition was high. Under the unopposed influence of estradiol at F2, there was less inhibition and
more facilitation. At the L time point, in the presence
of high progesterone and estradiol levels, inhibition returned essentially to the F1 level.
As discussed previously, drug experiments24,25,32
suggest that the paired-pulse technique may not always
be able to distinguish between ␥-aminobutyric acid
agonists and glutamate antagonists. However, it is pos-
Fig 2. Effect of the menstrual phase on hormone levels (above)
and on the ratio of the conditioned motor evoked potential
(MEP) to the unconditioned MEP (below; all interstimulus
intervals are combined). Bars represent the standard error.
F1 ⫽ early follicular phase; F2 ⫽ late follicular phase; L ⫽
luteal phase.
Fig 3. Plot of the ratio of the conditioned motor evoked potential (MEP) to the unconditioned MEP at each interstimulus interval in each menstrual phase. F1 ⫽ early follicular
phase; F2 ⫽ late follicular phase; L ⫽ luteal phase.
sible that fluctuations in estradiol levels can act on
both neurotransmitter systems33 to alter the balance of
facilitation and inhibition in favor of facilitation.
Most of the work on the neural effects of estradiol in
Smith et al: Ovarian Hormones and the Motor Cortex
601
animals has concentrated on the hippocampus and hypothalamus. However, there is evidence that estradiol
exerts effects on neurotransmission in the neocortex.
For instance, in the motor34 and frontal35 cortex, estradiol downregulates 5-HT1A receptors, which may
modulate GABAergic transmission.36 Estradiol also appears to exert a trophic effect on cultured neocortical
neurons.37 In humans, various cortical areas appear to
be affected by estrogens. Estrogen replacement in postmenopausal women has been shown to enhance working memory,38 a function subserved by the prefrontal
cortex, and estrogen treatment is also reported to improve paired associative learning, another frontal function, in male transsexuals.39 Positron emission tomography has shown increased prefrontal blood flow
during the Wisconsin Card Sorting Test after estrogen
replacement in hormone-depleted women.40 In a functional magnetic resonance imaging study, postmenopausal women showed relative increases in blood flow
and changes in activation patterns in parietal and frontal areas with mnemonic encoding and retrieval tasks
after estrogen replacement.41 In another study, women
with normal cycles showed similarly increased activation with motor and cognitive tasks during the follicular phase relative to the menses.42 Although these
phenomena and the changes that we report may have
been due to local effects of estradiol, it is also possible
that they were the results of increased tonic excitatory
drive coming directly from other areas, such as the hippocampus, or indirectly via thalamic relays.
Androgens, such as testosterone and androstenedione, also rise in women during the follicular
phase43– 45 but less than estradiol. These hormones
may produce excitatory effects under certain circumstances.46 However, most data suggest an inhibitory
role.33,47 Therefore, we do not think that they are implicated in the phenomenon described here.
The return of the ratios of conditioned MEP to unconditioned MEP to baseline at the L time point reproduces the findings of our earlier study,27 in which we
compared a single time point in the follicular phase to a
time point similar to L in this study. Because the principal change between the F2 and L time points was the
increase in progesterone, we infer that the increase in
inhibition was due to the well-described1,2 allosteric action of progesterone-derived neurosteroids on the
␥-aminobutyric acid A receptor. Biochemical evidence of
the action of progesterone’s neurosteroid metabolites
in the human brain is lacking. However, in vitro
experiments show that the cortisol-derived neurosteroid
tetrahydrodeoxycorticosterone increases binding at
␥-aminobutyric acid A receptors in the human motor
cortex.48 Nevertheless, it remains possible that the return to baseline levels of excitability in the luteal phase
could be due to antagonism of the excitatory effect of
602
Annals of Neurology
Vol 51
No 5
May 2002
estradiol by progesterone or its metabolites49 rather
than a direct neural action.
Despite the unanswered questions, we believe that
these findings are the first direct electrophysiological
evidence of a neuronal effect of estradiol in the human
brain and that they confirm our earlier findings related
to progesterone. Although the function of the motor
cortex may have limited relevance to many of the important clinical effects of ovarian steroids, the MEP
may provide a noninvasive, inexpensive, and readily
quantified indicator of the actions of hormones and
their mimics and modulators in brain areas that are
more difficult to study directly. Finally, we caution
those who study human motor neurophysiology that
menstrual variation in cortical excitability is a potential
confound in studies of women of reproductive age.
We thank Dr Michael A. Rogawski for his expert criticism of the
manuscript.
This work was published in abstract form in Annals of Neurology
(2001;50:S19) and was presented at the 126th Annual Meeting of
the American Neurological Association, Chicago, IL, September 30
to October 3, 2001.
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