Physiology of the menstrual cycle

SD Silberstein1 & GR Merriam2

1
Jefferson Headache Center, and Thomas Jefferson University Hospital, Philadelphia, PA, 2Division of Metabolism, Endocrinology and Nutrition,
University of Washington School of Medicine, Seattle, WA, USA

Silberstein SD & Merriam GR. Physiology of the menstrual cycle. Cephalalgia 2000;
20:148±154. London. ISSN 0333-1024
The normal female life cycle is associated with a number of hormonal milestones:
menarche, pregnancy, contraceptive use, menopause, and the use of replacement sex
hormones. All these events and interventions alter the levels and cycling of sex
hormones and may cause a change in the prevalence or intensity of headache. The
menstrual cycle is the result of a carefully orchestrated sequence of interactions among
the hypothalamus, pituitary, ovary, and endometrium, with the sex hormones acting as
modulators and effectors at each level. Oestrogen and progestins have potent effects on
central serotonergic and opioid neurons, modulating both neuronal activity and receptor
density. The primary trigger of menstrual migraine appears to be the withdrawal of
oestrogen rather than the maintenance of sustained high or low oestrogen levels.
However, changes in the sustained oestrogen levels with pregnancy (increased) and
menopause (decreased) appear to affect headaches. Headaches that occur with
premenstrual syndrome appear to be centrally generated, involving the inherent
rhythm of CNS neurons, including perhaps the serotonergic pain-modulating
systems. u Menstruation, migraine, oestrogen, progesterone
SD Silberstein, Department of Neurology, Jefferson Headache Centre, Thomas Jefferson
University Hospital, 111 South 11th Street STE 8130, Philadelphia, Pennsylvania 19107-
5092, USA. Received 10 February 2000, accepted 25 May 2000

Considerable evidence suggests that there is a link
between migraine and the female sex hormones,
oestrogen and progesterone (1±5). Although no gender
difference is apparent in prepubertal children, with
migraine occurring equally in 4% of boys and girls (2, 6),
migraine occurs more frequently in adult women (18%)
than in men (6%). Migraine develops most frequently in
the second decade, with the peak incidence occurring
with adolescence (1, 4).
Menstrually related migraine (MM) begins at
menarche in 33% of affected women (1). MM occurs
mainly at the time of menses in many migrainous
women, and exclusively with menses (true menstrual
migraine, TMM) in some (1). Menstrual migraine can be
associated with other somatic complaints that arise
before and often persist into menses, such as nausea,
backache, breast tenderness and cramps, and, like them,
appears to be the result of falling sex hormone levels (5,
7). In addition, pre-menstrual migraine can be associated
with late luteal phase dysphoric disorder (pre-menstrual
dysphoric disorder, PDD), also called `pre-menstrual
syndrome' (PMS), which is distinct from the physical
symptoms of the perimenstrual period and is probably
not directly driven by declining progesterone levels (see
below) (8). Migraine that occurs during (rather than
before) menstruation is usually not associated with PMS.
Migraine may worsen during the ®rst trimester of
pregnancy and, although many women become head-
ache-free during the last two trimesters, 25% have no
change in their migraine (9±11). Menstrual migraine
typically improves with pregnancy, perhaps due to
sustained high oestrogen levels (9±11). Hormonal
replacement with oestrogens can exacerbate migraine,
and oral contraceptives (OCs) can change its character
and frequency (12, 13). Migraine prevalence decreases
with advancing age but may either regress or worsen at
the menopause (2, 14, 15). Changes in the headache
pattern with OC use and during menarche, menstrua-
tion, pregnancy or menopause are related to changes in
oestrogen levels (16). These phenomena suggest a
relationship between migraine headaches and changes
in sex hormone levels (17).
This review will cover the endocrinology of the
menstrual cycle, the neuropharmacology of oestrogens
and progestins, and approaches to the therapy of
hormone-related headaches, in particular those head-

148 # Blackwell Science Ltd Cephalalgia, 2000, 20, 148±154

 Physiology of the menstrual cycle 149

Figure 1. Physiology of the hypothalamic-pituitary-ovarian axis. Gonadotropin releasing hormone (GnRH) stimulates pituitary
secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH). FSH and LH stimulate the ovary to secrete the sex
steroids, oestrogen (E) and progesterone (P), which feed back on the hypothalamus and pituitary to modulate GnRH and LH
secretion. Inhibins and activins feed back on the pituitary to modulate FSH production and secretion. E and P stimulate endometrial
prostaglandin synthesis. Inhibin blocks pituitary secretion of FSH.

aches associated with the menstrual cycle, the meno-
pause, and OC use.
Endocrinology of the menstrual cycle
Cyclic ovarian function spans the time between puberty
and menopause, which are transitional periods of
increasing or decreasing ovarian activity over several
years. Menarche is under central nervous system (CNS)
control. The age of menarche is genetically determined
and may be correlated with attaining a critical body
weight. The menstrual cycle, although a continuum, is
usually represented as beginning on the ®rst day of the
menses and ending on the last day before the next
menses. This arbitrary peripheral marker of steroid
hormone withdrawal bridges smooth changes in hor-
mone levels: follicular growth with rising oestrogens is
followed by ovulation and the organization and decline
of the corpus luteum. By the next menses, growth of the
next cohort of follicles has already begun. The average
length of the menstrual cycle is 28 days, with a range of
25±32 days. The greatest variability in cycle length
occurs in the years following the onset of menarche
and preceding menopause (18).
Normal ovarian functioning requires the coordinated
activity of: the hypothalamus, which secretes gonado-
tropin-releasing hormone (GnRH); the pituitary, which
secretes the glycoproteins luteinizing hormone (LH) and
follicle stimulating hormone (FSH); the ovary, which
secretes oestrogens and progesterone, inhibins, activins,
and other ovarian modulators; and the endometrial
lining of the uterus, which responds to oestrogen and
progesterone (Fig. 1). Under the control of norepinephr-
ine (NE), serotonin (5-HT), corticotropin-releasing hor-
mone (CRH), the opioids, and other neurotransmitters,
hypothalamic neurones in the pre-optic and arcuate
nucleus secrete GnRH into the hypophyseal portal
system in a pulsatile manner. This stimulates the
production and secretion of LH and FSH by the pituitary
(19). This in turn stimulates secretion of ovarian
oestrogen and progesterone, which feed back at the
pituitary to modulate the relative amounts of LH and
FSH and at the hypothalamus to regulate GnRH. NE
stimulates GnRH secretion; opiates, corticosteroids, and
CRH are inhibitory (20, 21). GnRH release also may be

# Blackwell Science Ltd Cephalalgia, 2000, 20, 148±154

150 SD Silberstein and GR Merriam

Mid-Follicular Mid-Luteal
35 35

30 30

25 25
LH, mlU/ml

LH, mlU/ml
20 20

15 15

10 10

5 5

0 0
0800 1200 1600 2000 2400 0400 0800 0800 1200 1600 2000 2400 0400 0800
Clock time

Figure 2. Patterns of episodic luteinizing hormone (LH) secretion during the menstrual cycle in women. During the follicular phase
(left), LH secretion is of relatively high frequency and low amplitude. During the luteal phase (right), LH secretion is of lower
frequency and higher amplitude (prior to cessation of secretion).

regulated directly by intraneuronal PGE2 (22). In
addition, ovarian modulators such as inhibin and activin
modulate FSH release (23).
CRH, a 41 amino acid peptide, is secreted along with
arginine-vasopressin by the parvicellular neurones of
the paraventricular nucleus of the hypothalamus.
Hypothalamic CRH is also found in sympathetic
postganglionic neurones, primary afferent neurones,
endothelial cells, macrophages, and tissue ®broblasts.
`Reproductive' immunologically distinct CRH is found
in ovarian, testicular, endometrial and placental tissue
(24). Decreased hypothalamic CRH secretion occurs in
the late luteal and perimenstrual phases of the menstrual
cycle (25, 26). Placental CRH secretion may be respon-
sible for the maternal hypercorticolism of pregnancy
(27).
GnRH is a decapeptide secreted by hypothalamic
neurones in a pulsatile fashion. This pulsatility is
obligatory (continuous GnRH secretion does not stimu-
late the pituitary; it produces inhibition of pituitary and
ovarian function) (19, 28) and both the amplitude and the
frequency of the pulses modulate the LH and FSH
output. Infrequent GnRH pulses favour FSH B chain
mRNA synthesis; more frequent pulses favour LH
mRNA B chain production. In the follicular phase of
the cycle, pulses occur at 1±2 h intervals (Fig. 2) (19, 28,
29). Changes in the pattern of episodic LH secretion
during the menstrual cycle largely re¯ect the effects of
progesterone on the hypothalamic pattern of GnRH
secretion and the effects of oestrogens and progestins on
pituitary gonadotropin secretion. In the luteal phase of
the cycle, progesterone secretion by the corpus luteum
progressively slows the frequency of episodic gonado-
tropin secretion, which nearly ceases just before menses
(30±32). GnRH secretion is also synchronized to daily
environmental cues by the suprachiasmatic nuclei of the
hypothalamus (33).
The target of the gonadotropins is the ovary, where
FSH and LH stimulate follicular growth. Most of the
follicles become atretic and atrophy, but one or two
mature with two layers of steroidogenic tissue: granu-
losa cells surrounded by theca cells. Ovulation carries
away the oocyte and a cumulus of granulosa cells; the
remaining theca and granulosa cells organize into a
progesterone-secreting corpus luteum, which is active
for about 2 weeks and then regresses.
The sex hormones are steroids synthesized in a
sequence of enzymatic steps that rearrange the side
groups on the steroid nucleus. Because of the rigidity of
the linked rings of the steroid nucleus, minor chemical
changes in these side groups can produce hormones of
distinctly different activity. Progesterone is a precursor
of both male sex hormones (androgens) and female sex
hormones (oestrogens). As related compounds, they
retain some receptor cross-af®nity. Progesterone has
some androgenic properties, and some synthetic steroids
and drugs, such as medroxyprogesterone and danazol,
show mixed hormonal activity.
The two cell layers of the ovarian follicle divide the
responsibility for steroidogenesis. The outer theca layer
responds to LH and can carry out steroid synthesis from
cholesterol to progesterone and androgens (34±36). The

# Blackwell Science Ltd Cephalalgia, 2000, 20, 148±154


inner granulosa layer responds to FSH and aromatizes
androgens to oestrogens. As the follicle develops, both
cell groups proliferate. Many ovarian regulators, includ-
ing growth factors (IGF-I and IGF-II), in¯uence the theca
cells to differentiate from ®broblasts of the ovarian
stroma outside the follicular basement membrane. The
ovary also produces inhibins and activins, which are
glycoproteins. Inhibin consists of alpha and beta
subunits linked by disulphide bonds and exists in two
forms: inhibin A and inhibin B. Inhibin production by
granulosa and luteal cells is stimulated by FSH; in turn,
inhibin selectively suppresses pituitary FSH secretion.
The testicular Sertoli cells, corpus luteum and placenta
also produce the inhibins. Low inhibin levels occur in the
early and midfollicular phase of the menstrual cycle;
higher levels occur in the mid to late luteal phase.
Inhibin levels decrease with menopause. Circulating
follicular phase inhibin levels are signi®cantly lower
among women aged 45±49 than among women younger
than age 45. The fall in inhibin levels may be due to
either a decreased number of ovarian follicles or
decreased granulosa cell function. As inhibin levels fall
there is a concomitant rise in FSH, which initially results
in greater oestradiol secretion. FSH levels increase by the
time women are 45±50 years old, while they are still
menstruating, whereas LH levels increase later, when
women are post-menopausal. GnRH concentrations in
the mediobasal hypothalamus are low, perhaps because
of prolonged high levels of release and decreased
synthesis. Later, oestradiol levels fall as the granulosa
cells become depleted. By the time a woman is 65 years
old, the ovary is virtually devoid of follicles and is no
longer the primary site of oestradiol or progesterone
synthesis (18).
Activin, a glycoprotein consisting of two of the same
beta subunits that make up inhibin, exists in three forms:
A, AB and B (18). Activin stimulates pituitary FSH
release to oppose the action of inhibin. Activins increase
ovarian FSH binding by regulating receptor concentra-
tions, enhance FSH stimulated oestrogen and inhibin
secretion, and interfere with inhibins' ability to increase
LH-stimulated androgen production. Activin also sup-
presses progesterone synthesis, which may prevent
premature ovulation (37).
Oestrogen and inhibin exert negative feedback reg-
ulation on the pituitary; thus, as the follicle grows and
oestrogen and inhibin levels rise, FSH initially falls. At
the middle of the cycle, however, there is a rapid reversal
from inhibition to stimulation and a large surge of LH
secretion occurs. A small rise in progesterone plays a
central role in this reversal, which in turn may re¯ect
inhibition of oestrogen synthesis due to product inhibi-
tion by the high levels of oestrogen in the dominant
# Blackwell Science Ltd Cephalalgia, 2000, 20, 148±154
Physiology of the menstrual cycle 151
follicle. Thus, the rise in progesterone can serve as a
signal that the follicle is ready to ovulate (38, 39).
High levels of LH at mid-cycle stimulate a further rise
in progesterone, activating enzymes that digest the wall
of the follicle. The oocyte and most of the granulosa cells
¯oat out. The crater of the ovulated follicle and the
remaining granulosa organize as the corpus luteum, an
evanescent gland that secretes progesterone for about 2
weeks and then regresses. Progesterone has two main
target organs: the hypothalamus, where the GnRH pulse
frequency is progressively reduced and where the
temperature set point is increased by half a degree
Celsius, and the uterus, which responds to both
oestrogens and progestins. Oestrogen stimulates
growth of the endometrium; progesterone causes it to
secrete mucus, speci®c proteins and vasoactive sub-
stances. Progesterone withdrawal leads to arterial spasm
and menses. The involved vasoactive substances include
peptides and prostaglandins. The succession of hor-
mones causes major changes in ¯uid balance, blood
pressure and uterine tone. The transition between these
states may not be smooth.
In men, gonadotropin and steroid hormone levels are
relatively stable over time, but in women, the menstrual
cycle requires a carefully coordinated sequence of
changes. It thus may be more readily interrupted by
subtle miscues that are not readily characterized as
simply hypogonadism. Stressors such as weight change
or exercise can result in amenorrhea in women, while
changes of comparable magnitude in men may be
clinically silent (30).
Oestrogen does more than just in¯uence the classical
reproductive tissues (the hypothalamus, anterior pitui-
tary, mammary glands, uterus and vagina). It also affects
a number of other functions, including urinary con-
tinence, nutrient absorption and metabolism, bone and
mineral metabolism, blood pressure and cardiovascular
function, memory and cognition, organization and
expression of daily rhythms, and the progression of
age-related diseases (33). Oestrogens have direct CNS
effects. Sex hormones bind to receptors in the area of the
brain that is responsible for reproductive behaviour and
gonadotropin release (40). They activate high-af®nity
intracellular receptors that undergo a process called
nucleocytoplasmic shuttling, in which the receptors exit
from the cell nucleus but are rapidly shuttled back in an
energy-dependent process. The oestrogen receptor (ER),
when activated, is a transcription factor. In the absence
of hormonal binding, the ER is an oligomeric complex
containing the heatshock protein, hsp 90. Following
oestrogen binding, the ER sheds the hsp 90, dimerizes,
and binds with high af®nity to oestrogen-responsive
genes (oestrogen response elements). This results in
transcription by means of two transcriptional activation
152 SD Silberstein and GR Merriam
functions (TAF-1 and TAF-2) (41). Steroids also mod-
ulate gene expression and the synthesis of new protein in
the brain.
In addition, steroid hormones rapidly exert beha-
vioural and electrophysiological effects through non-
genomic mechanisms by rapidly binding to neuronal
membranes. Effector systems that transduce the signal of
steroid±membrane interactions include neurotransmit-
ter receptors, release mechanisms and ion channels.
Oestradiol has rapid effects on membrane potentials in
pre-optic and septal neurones, and progesterone acts on
dorsal mid-brain neurones, presumably through recep-
tor sites on neuronal membranes (42). In rodents,
oestrogens increase the electrical activity of the neurones
that foster female reproductive behaviour and decrease
the electrical activity of the pre-optic neurones that
disrupt feminine behaviour. Progesterone initially facil-
itates and later inhibits sexual behaviour (43).
Oestradiol changes the potassium permeability of
post-synaptic medial amygdala neurones within min-
utes. Progestogen stimulates the release of dopamine
from striated tissue and GnRH from hypothalamic
tissue. Oestrogen increases the number of progesterone
and muscarinic receptors and modulates 5-HT1, 5-HT2
and b-adrenergic receptors (43). Chronic oestrogen
treatment decreases 5-HT1A receptor sensitivity in the
raphe pre-synaptically and enhances it in the hippo-
campus post-synaptically. These actions, in concert,
increase serotonergic transmission (44). Oestrogen with-
drawal increases the number of dopaminergic receptors
(45). Progesterone modulates the oestrogen effects on the
5-HT1 and 5-HT2 receptors. Oestrogen also affects the
peripheral nervous system, increasing the size of the
receptive ®elds of trigeminal mechanoreceptors in rats
(46).
Progesterone has other CNS effects. Some progester-
one metabolites and derivatives are neurosteroids that
have potent interactions with the GABAA receptor,
which regulates chloride channels in the brain (47).
Neurosteroids can be devoid of hormonal activity and
can interact with a novel epalon binding site and act as
allosteric modulators of the GABAA receptor (48, 49).
Progesterone metabolites may modulate anxiety pro-
cesses in susceptible individuals, perhaps by interacting
with the endogenous benzodiazepine receptor ligands or
with the epalon receptor, which normally suppress
anxiety (50). This interaction may account in part for the
mood changes of PMS. In self-scoring pro®les (51),
women with PMS show a distinctive pattern: anxiety
scores increase progressively during the late luteal
phase, resolve rapidly with the onset of menstruation,
and then remain stable until progesterone rises again.
Depression scores are similarly affected by the phases of
the menstrual cycle. Some, but not all, workers have
found diminished concentrations of allopregnanolone
(an anxiolytic neurosteroid metabolite of progesterone
without hormonal activity) in women with PMS (52).
Many believe that the symptoms of PMS are related to
changes in progesterone that occur during the late luteal
phase of the menstrual cycle. However, truncation of the
luteal phase with the progesterone-receptor antagonist
mifepristone (RU486) does not alter the symptoms of
PMS, despite producing the hormonal conditions of the
early follicular phase (53, 53). The cycle was maintained
by giving human chorionic gonadotropin, which main-
tained high serum progesterone levels; however, men-
struation still occurred as a result of blocking the
progesterone receptor with mifepristone. (Two women
who received mifepristone did not have PMS symptoms
when the menstrual cycle was reset, suggesting that in
some women there is an obligatory relationship between
PMS and the endocrine events of the late luteal phase.)
PMS symptoms may represent an autonomous cyclic
disorder that is cued by, but can be dissociated from, the
menstrual cycle. Alternatively, symptoms may be
triggered by hormonal events that occur before the late
luteal phase, consistent with reports that suppression of
ovulation with agonist analogues of GnRH usually (54±
56) decreases PMS symptoms (57).
Schmidt et al. (58) found that 10 women with PMS
who were given leuprolide had a signi®cant decrease in
symptoms compared with baseline values and values for
the 10 women who were given placebo. The 10 women
with PMS who were given leuprolide plus oestradiol or
progesterone had a signi®cant recurrence of symptoms,
but no changes in mood occurred in 15 normal women
who received the same regimen or in ®ve women with
PMS who were given placebo hormone during con-
tinued leuprolide administration (58). In women with
PMS the occurrence of these symptoms represents an
abnormal response to normal hormonal changes. PMS
and PMM may both result from a cyclic central
disturbance of pain perception and mood.
Conclusion
The normal female life cycle is associated with a number
of hormonal milestones: menarche, pregnancy, contra-
ceptive use, menopause, and the use of replacement sex
hormones. Menarche marks the onset of menses and
cyclic changes in hormone levels. Pregnancy is asso-
ciated with rising non-cyclic levels of sex hormones, and
menopause with declining non-cyclic levels. Hormonal
contraceptive use during the reproductive years and
hormone replacement in menopause are therapeutic
hormonal interventions that alter the levels and cycling
of sex hormones. These events and interventions may
cause a change in headache prevalence or intensity.
# Blackwell Science Ltd Cephalalgia, 2000, 20, 148±154

The menstrual cycle is the result of a carefully
orchestrated sequence of interactions between the
hypothalamus, pituitary, ovary and endometrium,
with the sex hormones acting as modulators and
effectors at each level. Oestrogen and progestins have
potent effects on central serotonergic and opioid
neurones, modulating both neuronal activity and
receptor density. The primary trigger of MM appears
to be the withdrawal of oestrogen rather than the
maintenance of sustained high or low oestrogen levels.
However, changes in the sustained oestrogen levels with
pregnancy (increased) and menopause (decreased)
appear to affect headaches.
Headaches occurring with PMS appear to be centrally
generated, involving the inherent rhythm of CNS
neurones, including perhaps the serotonergic pain-
modulating systems.
References
1 Epstein MT, Hockaday JM, Hockaday TDR. Migraine and
reproductive hormones throughout the menstrual cycle.
Lancet 1975;1:543±8.
2 Goldstein M, Chen TC. The epidemiology of disabling
headache. In: Critchley M ed. Advances in Neurology,
Volume 33. New York: Raven Press, 1982:377±90.
3 Raskin NH. Headache 2nd edn. New York: Churchill-
Livingstone, 1988.
4 Selby G, Lance JW. Observation on 500 cases of migraine and
allied vascular headaches. J Neurol Neurosurg Psychiatry
1960; 23:23±32.
5 Silberstein SD, Merriam GR. Estrogens, progestins, and
headache. Neurology 1991; 41:775±93.
6 Waters WE, O'Connor PJ. Epidemiology of headache and
migraine in women. J Neurol Neurosurg Psychiatry 1971;
34:148±53.
7 American Psychiatric Association. Diagnostic and Statistical
Manual of Mental Disorders 4th edn. Washington: 1994.
8 Mortola JF. Premenstrual syndrome ± pathophysiologic
considerations. N Engl J Med 1998; 338:256±7.
9 Lance JW, Anthony M. Some clinical aspects of migraine. Arch
Neurol 1966; 15:356±61.
10 Ratinahirana H, Darbois Y, Bousser MG. Migraine and
pregnancy: a prospective study in 703 women after delivery.
Neurology 1990; 40:437.
11 Somerville BW. A study of migraine in pregnancy. Neurology
1972; 22:824±8.
12 Kudrow L. The relationship of headache frequency to
hormone use in migraine. Headache 1975; 15:36±49.
13 Bickerstaff ER. Neurological complications of oral
contraceptives.Oxford: Clarendon Press, 1975.
14 Neri I, Granella F, Nappi RMGC, Facchinetti F, Genazzani AR.
Characteristics of headache at menopause: a clinico-epide-
miologic study. Maturitas 1993; 17:31±7.
15 Whitty CWM, Hockaday JM. Migraine: a follow-up study of
92 patients. Br Med J 1968; 1:735±6.
16 Welch KMA, Darnley D, Simkins RT. The role of estrogen in
migraine: a review. Cephalalgia 1984; 4:227±36.
# Blackwell Science Ltd Cephalalgia, 2000, 20, 148±154
Physiology of the menstrual cycle 153
17 Lundberg PO. Endocrine headaches. In: Rose FC ed.
Handbook of Clinical Neurology, Volume 48. New York:
Elsevier, 1986:431±40.
18 The American College of Obstetricians and Gynecologists.
Precis: an Update in Obstetrics and Gynecology. Danvers,
MA: American College of Obstetrics and Gynecology, 1998.
19 Conn PM, Crowley WF. Gonadotropin-releasing hormone and
its analogues. N Eng J Med 1991; 324:93±103.
20 Fink G, Stanley HF, Watts AG. Central nervous control of sex
and gonadotropin release: peptide and nonpeptide transmitter
interactions. In: Krieger D, Brownstein M, Martin J. eds. Brain
Peptides. New York: Wiley, 1983:413±35.
21 Chrousos GP, Torpy DJ, Gold PW. Interactions between the
hypothalamic-pituitary-adrenal axis and the female repro-
ductive system: clinical implications. Ann Intern Med 1998;
129:229±40.
22 Behrman HR, Caldwell BV. Prostaglandins, thromboxanes,
and leukotrienes. In: Yen SSC, Jaffe RB eds. Reproductive
Endocrinology: Physiology, Pathophysiology and Clinical
Management. Philadelphia: W B Saunders, 1986: 154±76.
23 Mishell DR, Stenchever MA, Droegemueller W et al.
Menopause: endocrinology, consequences of estrogen de®-
ciency, effects of hormonal replacement therapy, treatment
regimens. In: Mishell DR, Stenchever MA, Droegemueller W,
Herbst AL eds. Comprehensive Gynecology 3rd edn. St. Louis:
Mosby, 1997: 1159±98.
24 Chrousos GP. The hypothalamic-pituitary-adrenal axis and
immune-mediated in¯ammation. N Eng J Med 1995; 332:1351±
62.
25 Hayward C, Killen JD, Wilson DM et al. Psychiatric risk
associated with early puberty in adolescent girls. J Am Acad
Child Adolesc Psychiatry 1997; 36:255±62.
26 Rabin DS, Schmidt PJ, Campbell G et al. Hypothalamic-
pituitary-adrenal function in patients with the premenstrual
syndrome. J Clin Endocrinol Metab 1990; 71:1158±62.
27 McLean M, Bisits A, Davis DH et al. A placental clock
controlling the length of human pregnancy. Nature Med 1995;
1:460±3.
28 Dierschke DJ, Bhattacharya AN, Atkinson LE, Knobil E.
Circhoral oscillations of plasma LH in the ovariectomized
rhesus monkey. Endocrinology 1970; 87:850±953.
29 Belchetz P, Plant TM, Nakai Y, Keogh EJ, Knobil E.
Hypophysial responses to continuous and intermittent deliv-
ery of hypothalamic gonadotropin-releasing hormone. Science
1978; 202:631±3.
30 Merriam GR, Brody SA, Collins RL et al. Episodic
gonadotropin secretion in normal and hyperprolactinemic
men and women. In: Merriam GR, Brody SA, Collins RL et
al. eds. Gonadotropins and Prolactin. Milan: C Dotti,
1984:61±94.
31 Filicori M, Butler JP, Crowley WF. Neuroendocrine regulation
of the corpus luteum in the human: evidence for pulsatile
progesterone secretion. J Clin Invest 1984; 73:1639±47.
32 Backstrom CT, McNeilly AS, Leask RM, Baird DT. Pulsatile
secretion of LH, FSH, prolactin, estradiol and progesterone
during the human menstrual cycle. Clin Endocrinol 1998;
17:29±42.
33 Wise PM, Krajnak KM, Kashon ML. Menopause: the aging of
multiple pacemakers. Science 1996; 273:66±70.
34 McNatty PK, Makris A, DeGrazia C, Osathanondh R, Ryan J.
Effects of luteinizing hormone on steroidogenesis by thecal
154 SD Silberstein and GR Merriam
tissue from human ovarian follicles in vitro. Steroids 1980;
36:53±63.
35 Ryan KJ, Petro Z. Steroid biosynthesis by human ovarian
granulosa and theca cells. J Clin Endocrinol Metab 1966; 26:46±
52.
36 Ryan KJ, Petro Z, Kaiser J. Steroid formation by isolated and
recombined ovarian granulosa and thecal cells. J Clin
Endocrinol Metab 1968; 28:355±8.
37 Mishell DR. Reproductive endocrinology: neuroendocrinol-
ogy, gonadotrophins, sex steroids, prostaglandins, ovulation,
menstruation, hormone assay. In: Mishell DR, Stenchever MA,
Droegemueller W, Herbst AL eds. Comprehensive
Gynecology 3rd edn. St. Louis: Mosby, 1997: 73±128.
38 Batista MD, Cartledge TP, Zellmer A, Merriam GR, Nieman
LK. The antiprogesterone RU 486 delays ovulation in
spontaneous and GnRH induced menstrual cycles.
Endocrine Society 71st Annual Meeting. Endocrine Soc
Abstract 1989; 1634:431(Abstract).
39 Laborde N, Carril M, Cheviakoff A et al. The secretion of
progesterone during the periovulatory period in women with
certi®ed ovulations. J Clin Endocrinol Metab 1976; 43:1157±63.
40 Pfaff DW, McEwen BS. Actions of estrogens and progestins on
nerve cells. Science 1983; 219:808±14.
41 Parker MG. Structure and function of the estrogen receptor.
Neuroendocrinol 1993; 5:223±8.
42 Schumacher M. Rapid membrane effects of steroid hormones:
an emerging concept in neuroendocrinology. TINS 1990;
13:359±62.
43 Biegon A, Reches A, Snyder L, McEwen BS. Serotonergic and
noradrenergic receptors in the rat brain: modulation by
chronic exposure to ovarian hormones. Life Sci 1983;
32:2015±28.
44 Clarke WP, Goldfarb J. Estrogen enhances a 5-HT1A response
in hippocampal slices from female rats. Eur J Pharmacol 1989;
160:195±7.
45 Gordon JH, Diamond BI. Antagonism of dopamine super-
sensitivity by estrogen: neurochemical studies in an animal
model of tardive dyskinesia. Biol Psychiatry 1981; 16:365±71.
46 Bereiter DA, Stanford LR, Barker DJ. Hormone-induced
enlargement of receptive ®elds in trigeminal mechanorecep-
tive neurons. II. Possible mechanisms. Brain Res 1980; 184:411±
23.
47 Baunea A, Hajibeigi A, Trant JM, Mason JI. Expression of
steroid-metabolizing enzymes by brain cells in culture: a
model for developmental regulation of the progesterone 5X-
reductase pathway. Endocrinology 1990; 127:500±2.
48 Baulieu EE. Neurosteroids: Of the nervous system, by the
nervous system, for the nervous system. Recent Prog Horm
Res 1997; 52:1±32.
49 Monaghan EP, Navalta LA, Shum L, Ashbrook DW, Lee DA.
Initial human experience with ganaxolone, a neuroactive
steroid with antiepileptic activity. Epilepsia 1997; 38:1026±31.
50 Harris NL, Majewska MD, Harrington JW, Barker JL.
Structure-activity relationships for steroid interaction with
the gamma-aminobutyric acid receptor complex. J Pharmacol
Exp Ther 1987; 241:346±53.
51 Rubinow DR, Roy-Byrne P, Hoban MC, Gold PW, Post RM.
Prospective assessment of menstrually related mood dis-
orders. Am J Psychiatry 1984; 141:684±6.
52 Rapkin AJ, Morgan M, Goldman L et al. Progesterone
metabolite allopregnanolone in women with premenstrual
syndrome. Obstet Gynecol 1997; 90:709±14.
53 Schmidt PJ, Nieman LK, Grover GN et al. Lack of effect of
induced menses on symptoms in women with premenstrual
syndrome. N Eng J Med 1991; 324:1174±9.
54 Hammarback S, Backstrom T. Induced anovulation as a
treatment of premenstrual tension syndrome: a double-blind
cross-over study with GnRH-agonist versus placebo. Acta
Obstet Gynecol Scand 1988; 67:159±66.
55 Brown CS, Ling FW, Andersen RN, Farmer RG, Arheart KL.
Ef®cacy of depot leuprolide in premenstrual syndrome: effect
of symptom severity and type in a controlled trial. Obstet
Gynecol 1994; 84:779±86.
56 West CP, Hillier H. Ovarian suppression with the gonado-
trophin-releasing hormone agonist goserelin (Zoladex) in
management of the premenstrual tension syndrome. Hum
Reprod 1994; 9:1058±63.
57 Muse KN, Cetel NS, Fitterman LA, Yen SC. The premenstrual
syndrome: effects of `medical ovariectomy'. N Eng J Med 1984;
311:1345±9.
58 Schmidt PJ, Nieman LK, Danaceau MA, Adams LF, Rubinow
DR. Differential behavioral effects of gonadal steroids in
women with and in those without premenstrual syndrome.
N Eng J Med 1998; 338:209±16.
# Blackwell Science Ltd Cephalalgia, 2000, 20, 148±154