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Abstract

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.

Keywords

Menstruation migraine oestrogen progesterone

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 first trimester of pregnancy and, although many women become headache-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, menstruation, 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 headaches associated with the menstrual cycle, the menopause, 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 first 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 hormone 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 gonadotropin-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 norepinephrine (NE), serotonin (5-HT), corticotropin-releasing hormone (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 regulated directly by intraneuronal PGE₂ (22). In addition, ovarian modulators such as inhibin and activin modulate FSH release (23).

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.

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 fibroblasts. ‘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 responsible 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 stimulate 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 reflect 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 gonadotropin 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).

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).

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: granulosa 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-affinity. 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 inner granulosa layer responds to FSH and aromatizes androgens to oestrogens. As the follicle develops, both cell groups proliferate. Many ovarian regulators, including growth factors (IGF-I and IGF-II), influence the theca cells to differentiate from fibroblasts 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 significantly 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 concentrations, enhance FSH stimulated oestrogen and inhibin secretion, and interfere with inhibins' ability to increase LH-stimulated androgen production. Activin also suppresses progesterone synthesis, which may prevent premature ovulation (37).

Oestrogen and inhibin exert negative feedback regulation 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 reflect inhibition of oestrogen synthesis due to product inhibition by the high levels of oestrogen in the dominant 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 float 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, specific proteins and vasoactive substances. Progesterone withdrawal leads to arterial spasm and menses. The involved vasoactive substances include peptides and prostaglandins. The succession of hormones causes major changes in fluid 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 influence the classical reproductive tissues (the hypothalamus, anterior pituitary, mammary glands, uterus and vagina). It also affects a number of other functions, including urinary continence, 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-affinity 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 affinity to oestrogen-responsive genes (oestrogen response elements). This results in transcription by means of two transcriptional activation functions (TAF-1 and TAF-2) (41). Steroids also modulate gene expression and the synthesis of new protein in the brain.

In addition, steroid hormones rapidly exert behavioural and electrophysiological effects through non-genomic mechanisms by rapidly binding to neuronal membranes. Effector systems that transduce the signal of steroid–membrane interactions include neurotransmitter 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 receptor 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 facilitates and later inhibits sexual behaviour (43).

Oestradiol changes the potassium permeability of post-synaptic medial amygdala neurones within minutes. 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 β-adrenergic receptors (43). Chronic oestrogen treatment decreases 5-HT_1A receptor sensitivity in the raphe pre-synaptically and enhances it in the hippocampus post-synaptically. These actions, in concert, increase serotonergic transmission (44). Oestrogen withdrawal 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 fields of trigeminal mechanoreceptors in rats (46).

Progesterone has other CNS effects. Some progesterone metabolites and derivatives are neurosteroids that have potent interactions with the GABA_A 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 GABA_A receptor (48, 49). Progesterone metabolites may modulate anxiety processes 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 profiles (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 maintained high serum progesterone levels; however, menstruation 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 significant 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 significant recurrence of symptoms, but no changes in mood occurred in 15 normal women who received the same regimen or in five women with PMS who were given placebo hormone during continued 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, contraceptive use, menopause, and the use of replacement sex hormones. Menarche marks the onset of menses and cyclic changes in hormone levels. Pregnancy is associated 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.

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.

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Physiology of the Menstrual Cycle

Abstract

Keywords

Endocrinology of the menstrual cycle

Conclusion

References