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 not directly driven by declining progesterone levels (see
between migraine and the female sex hormones, below) (8). Migraine that occurs during (rather than
oestrogen and progesterone (1±5). Although no gender before) menstruation is usually not associated with PMS.
difference is apparent in prepubertal children, with Migraine may worsen during the ®rst trimester of
migraine occurring equally in 4% of boys and girls (2, 6), pregnancy and, although many women become head-
migraine occurs more frequently in adult women (18%) ache-free during the last two trimesters, 25% have no
than in men (6%). Migraine develops most frequently in change in their migraine (9±11). Menstrual migraine
the second decade, with the peak incidence occurring typically improves with pregnancy, perhaps due to
with adolescence (1, 4). sustained high oestrogen levels (9±11). Hormonal
Menstrually related migraine (MM) begins at replacement with oestrogens can exacerbate migraine,
menarche in 33% of affected women (1). MM occurs and oral contraceptives (OCs) can change its character
mainly at the time of menses in many migrainous and frequency (12, 13). Migraine prevalence decreases
women, and exclusively with menses (true menstrual with advancing age but may either regress or worsen at
migraine, TMM) in some (1). Menstrual migraine can be the menopause (2, 14, 15). Changes in the headache
associated with other somatic complaints that arise pattern with OC use and during menarche, menstrua-
before and often persist into menses, such as nausea, tion, pregnancy or menopause are related to changes in
backache, breast tenderness and cramps, and, like them, oestrogen levels (16). These phenomena suggest a
appears to be the result of falling sex hormone levels (5, relationship between migraine headaches and changes
7). In addition, pre-menstrual migraine can be associated in sex hormone levels (17).
with late luteal phase dysphoric disorder (pre-menstrual This review will cover the endocrinology of the
dysphoric disorder, PDD), also called `pre-menstrual menstrual cycle, the neuropharmacology of oestrogens
syndrome' (PMS), which is distinct from the physical and progestins, and approaches to the therapy of
symptoms of the perimenstrual period and is probably 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- occurs in the years following the onset of menarche
pause, and OC use. and preceding menopause (18).
Normal ovarian functioning requires the coordinated
activity of: the hypothalamus, which secretes gonado-
tropin-releasing hormone (GnRH); the pituitary, which
Endocrinology of the menstrual cycle
secretes the glycoproteins luteinizing hormone (LH) and
Cyclic ovarian function spans the time between puberty follicle stimulating hormone (FSH); the ovary, which
and menopause, which are transitional periods of secretes oestrogens and progesterone, inhibins, activins,
increasing or decreasing ovarian activity over several and other ovarian modulators; and the endometrial
years. Menarche is under central nervous system (CNS) lining of the uterus, which responds to oestrogen and
control. The age of menarche is genetically determined progesterone (Fig. 1). Under the control of norepinephr-
and may be correlated with attaining a critical body ine (NE), serotonin (5-HT), corticotropin-releasing hor-
weight. The menstrual cycle, although a continuum, is mone (CRH), the opioids, and other neurotransmitters,
usually represented as beginning on the ®rst day of the hypothalamic neurones in the pre-optic and arcuate
menses and ending on the last day before the next nucleus secrete GnRH into the hypophyseal portal
menses. This arbitrary peripheral marker of steroid system in a pulsatile manner. This stimulates the
hormone withdrawal bridges smooth changes in hor- production and secretion of LH and FSH by the pituitary
mone levels: follicular growth with rising oestrogens is (19). This in turn stimulates secretion of ovarian
followed by ovulation and the organization and decline oestrogen and progesterone, which feed back at the
of the corpus luteum. By the next menses, growth of the pituitary to modulate the relative amounts of LH and
next cohort of follicles has already begun. The average FSH and at the hypothalamus to regulate GnRH. NE
length of the menstrual cycle is 28 days, with a range of stimulates GnRH secretion; opiates, corticosteroids, and
25±32 days. The greatest variability in cycle length CRH are inhibitory (20, 21). GnRH release also may be

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

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 Physiology of the menstrual cycle 151

inner granulosa layer responds to FSH and aromatizes follicle. Thus, the rise in progesterone can serve as a
androgens to oestrogens. As the follicle develops, both signal that the follicle is ready to ovulate (38, 39).
cell groups proliferate. Many ovarian regulators, includ- High levels of LH at mid-cycle stimulate a further rise
ing growth factors (IGF-I and IGF-II), in¯uence the theca in progesterone, activating enzymes that digest the wall
cells to differentiate from ®broblasts of the ovarian of the follicle. The oocyte and most of the granulosa cells
stroma outside the follicular basement membrane. The ¯oat out. The crater of the ovulated follicle and the
ovary also produces inhibins and activins, which are remaining granulosa organize as the corpus luteum, an
glycoproteins. Inhibin consists of alpha and beta evanescent gland that secretes progesterone for about 2
subunits linked by disulphide bonds and exists in two weeks and then regresses. Progesterone has two main
forms: inhibin A and inhibin B. Inhibin production by target organs: the hypothalamus, where the GnRH pulse
granulosa and luteal cells is stimulated by FSH; in turn, frequency is progressively reduced and where the
inhibin selectively suppresses pituitary FSH secretion. temperature set point is increased by half a degree
The testicular Sertoli cells, corpus luteum and placenta Celsius, and the uterus, which responds to both
also produce the inhibins. Low inhibin levels occur in the oestrogens and progestins. Oestrogen stimulates
early and midfollicular phase of the menstrual cycle; growth of the endometrium; progesterone causes it to
higher levels occur in the mid to late luteal phase. secrete mucus, speci®c proteins and vasoactive sub-
Inhibin levels decrease with menopause. Circulating stances. Progesterone withdrawal leads to arterial spasm
follicular phase inhibin levels are signi®cantly lower and menses. The involved vasoactive substances include
among women aged 45±49 than among women younger peptides and prostaglandins. The succession of hor-
than age 45. The fall in inhibin levels may be due to mones causes major changes in ¯uid balance, blood
pressure and uterine tone. The transition between these
either a decreased number of ovarian follicles or
states may not be smooth.
decreased granulosa cell function. As inhibin levels fall
In men, gonadotropin and steroid hormone levels are
there is a concomitant rise in FSH, which initially results
relatively stable over time, but in women, the menstrual
in greater oestradiol secretion. FSH levels increase by the
cycle requires a carefully coordinated sequence of
time women are 45±50 years old, while they are still
changes. It thus may be more readily interrupted by
menstruating, whereas LH levels increase later, when
subtle miscues that are not readily characterized as
women are post-menopausal. GnRH concentrations in
simply hypogonadism. Stressors such as weight change
the mediobasal hypothalamus are low, perhaps because
or exercise can result in amenorrhea in women, while
of prolonged high levels of release and decreased
changes of comparable magnitude in men may be
synthesis. Later, oestradiol levels fall as the granulosa
clinically silent (30).
cells become depleted. By the time a woman is 65 years
Oestrogen does more than just in¯uence the classical
old, the ovary is virtually devoid of follicles and is no reproductive tissues (the hypothalamus, anterior pitui-
longer the primary site of oestradiol or progesterone tary, mammary glands, uterus and vagina). It also affects
synthesis (18). a number of other functions, including urinary con-
Activin, a glycoprotein consisting of two of the same tinence, nutrient absorption and metabolism, bone and
beta subunits that make up inhibin, exists in three forms: mineral metabolism, blood pressure and cardiovascular
A, AB and B (18). Activin stimulates pituitary FSH function, memory and cognition, organization and
release to oppose the action of inhibin. Activins increase expression of daily rhythms, and the progression of
ovarian FSH binding by regulating receptor concentra- age-related diseases (33). Oestrogens have direct CNS
tions, enhance FSH stimulated oestrogen and inhibin effects. Sex hormones bind to receptors in the area of the
secretion, and interfere with inhibins' ability to increase brain that is responsible for reproductive behaviour and
LH-stimulated androgen production. Activin also sup- gonadotropin release (40). They activate high-af®nity
presses progesterone synthesis, which may prevent intracellular receptors that undergo a process called
premature ovulation (37). nucleocytoplasmic shuttling, in which the receptors exit
Oestrogen and inhibin exert negative feedback reg- from the cell nucleus but are rapidly shuttled back in an
ulation on the pituitary; thus, as the follicle grows and energy-dependent process. The oestrogen receptor (ER),
oestrogen and inhibin levels rise, FSH initially falls. At when activated, is a transcription factor. In the absence
the middle of the cycle, however, there is a rapid reversal of hormonal binding, the ER is an oligomeric complex
from inhibition to stimulation and a large surge of LH containing the heatshock protein, hsp 90. Following
secretion occurs. A small rise in progesterone plays a oestrogen binding, the ER sheds the hsp 90, dimerizes,
central role in this reversal, which in turn may re¯ect and binds with high af®nity to oestrogen-responsive
inhibition of oestrogen synthesis due to product inhibi- genes (oestrogen response elements). This results in
tion by the high levels of oestrogen in the dominant transcription by means of two transcriptional activation

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152 SD Silberstein and GR Merriam

functions (TAF-1 and TAF-2) (41). Steroids also mod- found diminished concentrations of allopregnanolone
ulate gene expression and the synthesis of new protein in (an anxiolytic neurosteroid metabolite of progesterone
the brain. without hormonal activity) in women with PMS (52).
In addition, steroid hormones rapidly exert beha- Many believe that the symptoms of PMS are related to
vioural and electrophysiological effects through non- changes in progesterone that occur during the late luteal
genomic mechanisms by rapidly binding to neuronal phase of the menstrual cycle. However, truncation of the
membranes. Effector systems that transduce the signal of luteal phase with the progesterone-receptor antagonist
steroid±membrane interactions include neurotransmit- mifepristone (RU486) does not alter the symptoms of
ter receptors, release mechanisms and ion channels. PMS, despite producing the hormonal conditions of the
Oestradiol has rapid effects on membrane potentials in early follicular phase (53, 53). The cycle was maintained
pre-optic and septal neurones, and progesterone acts on by giving human chorionic gonadotropin, which main-
dorsal mid-brain neurones, presumably through recep- tained high serum progesterone levels; however, men-
tor sites on neuronal membranes (42). In rodents, struation still occurred as a result of blocking the
oestrogens increase the electrical activity of the neurones progesterone receptor with mifepristone. (Two women
that foster female reproductive behaviour and decrease who received mifepristone did not have PMS symptoms
the electrical activity of the pre-optic neurones that when the menstrual cycle was reset, suggesting that in
disrupt feminine behaviour. Progesterone initially facil- some women there is an obligatory relationship between
itates and later inhibits sexual behaviour (43). PMS and the endocrine events of the late luteal phase.)
Oestradiol changes the potassium permeability of PMS symptoms may represent an autonomous cyclic
post-synaptic medial amygdala neurones within min- disorder that is cued by, but can be dissociated from, the
utes. Progestogen stimulates the release of dopamine menstrual cycle. Alternatively, symptoms may be
from striated tissue and GnRH from hypothalamic triggered by hormonal events that occur before the late
tissue. Oestrogen increases the number of progesterone luteal phase, consistent with reports that suppression of
and muscarinic receptors and modulates 5-HT1, 5-HT2 ovulation with agonist analogues of GnRH usually (54±
and b-adrenergic receptors (43). Chronic oestrogen 56) decreases PMS symptoms (57).
treatment decreases 5-HT1A receptor sensitivity in the Schmidt et al. (58) found that 10 women with PMS
raphe pre-synaptically and enhances it in the hippo- who were given leuprolide had a signi®cant decrease in
campus post-synaptically. These actions, in concert, symptoms compared with baseline values and values for
increase serotonergic transmission (44). Oestrogen with- the 10 women who were given placebo. The 10 women
drawal increases the number of dopaminergic receptors with PMS who were given leuprolide plus oestradiol or
(45). Progesterone modulates the oestrogen effects on the progesterone had a signi®cant recurrence of symptoms,
5-HT1 and 5-HT2 receptors. Oestrogen also affects the but no changes in mood occurred in 15 normal women
peripheral nervous system, increasing the size of the who received the same regimen or in ®ve women with
receptive ®elds of trigeminal mechanoreceptors in rats PMS who were given placebo hormone during con-
(46). tinued leuprolide administration (58). In women with
Progesterone has other CNS effects. Some progester- PMS the occurrence of these symptoms represents an
one metabolites and derivatives are neurosteroids that abnormal response to normal hormonal changes. PMS
have potent interactions with the GABAA receptor, and PMM may both result from a cyclic central
which regulates chloride channels in the brain (47). disturbance of pain perception and mood.
Neurosteroids can be devoid of hormonal activity and
can interact with a novel epalon binding site and act as
Conclusion
allosteric modulators of the GABAA receptor (48, 49).
Progesterone metabolites may modulate anxiety pro- The normal female life cycle is associated with a number
cesses in susceptible individuals, perhaps by interacting of hormonal milestones: menarche, pregnancy, contra-
with the endogenous benzodiazepine receptor ligands or ceptive use, menopause, and the use of replacement sex
with the epalon receptor, which normally suppress hormones. Menarche marks the onset of menses and
anxiety (50). This interaction may account in part for the cyclic changes in hormone levels. Pregnancy is asso-
mood changes of PMS. In self-scoring pro®les (51), ciated with rising non-cyclic levels of sex hormones, and
women with PMS show a distinctive pattern: anxiety menopause with declining non-cyclic levels. Hormonal
scores increase progressively during the late luteal contraceptive use during the reproductive years and
phase, resolve rapidly with the onset of menstruation, hormone replacement in menopause are therapeutic
and then remain stable until progesterone rises again. hormonal interventions that alter the levels and cycling
Depression scores are similarly affected by the phases of of sex hormones. These events and interventions may
the menstrual cycle. Some, but not all, workers have cause a change in headache prevalence or intensity.

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 Physiology of the menstrual cycle 153

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