Sex hormones and headache

The normal female life cycle is associated with a number of hormonal milest ones: menarche, pregnancy, contraceptive use, menopause, and the use of rep lacement sex hormones. Menarche marks the onset of menses and cyclic change s in hormone levels. Pregnancy is associated with rising noncyclic levels o f sex hormones, and menopause with declining noncyclic levels. Hormonal con traceptive use during the reproductive years and hormone replacement in men opause are therapeutic hormonal interventions that alter the levels and cyc ling of sex hormones. These events and interventions may cause a change in the prevalence or intensity of headache. The menstrual cycle is the result of a carefully orchestrated sequence of i nteractions between the hypothalamus, pituitary, ovary, and endometrium, wi th the sex hormones acting as modulators and effectors at each level. Estro gen and progestins have potent effects on central serotonergic and opioid n eurons, modulating both neuronal activity and receptor density. The primary trigger of Menstrually-related migraine (MM) appears to be the withdrawal of estrogen rather than the maintenance of sustained high or low estrogen l evels. However, changes in the sustained estrogen levels with pregnancy (in creased) and menopause (decreased) appear to affect headaches. Headaches associated with OC use or menopausal hormonal replacement therapy may be related, in part, to periodic discontinuation of oral sex hormone p reparations. The treatment of migraine associated with changes in sex hormo ne levels is frequently difficult and the patients are often refractory to therapy. Based on what is known of the pathophysiology of migraine, we have attempted to provide a logical approach to the treatment of headaches that are associated with menses, menopause, and OCs using abortive and preventi ve medications and hormonal manipulations. Considerable evidence suggests a link between estrogen and progesterone, th e female sex hormones, and migraine. (Silberstein and Merriam, 1997; Lipton and Stewart, 1993; Epstein et al., 1975; Goldstein and Chen, 1982; Selby a nd Lance, 1960) Although no gender difference is apparent in prepubertal ch ildren, with migraine occurring equally in 4p. 100 of boys and girls, (Gold stein and Chen, 1982, Waters and O'Connor, 1971) migraine occurs more frequ ently in adult women (18p. 100) than in men (6p. 100). (Lipton and Stewart, 1993) Migraine develops most frequently in the second decade, with the pea k incidence occurring with adolescence. (Selby and Lance, 1960; Epstein et at., 1975) Menstrually-related migraine (MM) begins at menarche in 33p. 100 of affected women (Epstein et al., 1975). MM occurs mainly at the time of menses in many migrainous women, and exclusively with menses (true menstrua l migraine [TMM]) in some (Epstein et at., 1975). Menstrual migraine can be associated with other somatic complaints arising before and often persisti ng into menses, such as nausea, backache, breast tenderness, and cramps and like them appears to be the result of falling sex hormone levels (Silberst ein and Merriam, 1997; American Psychiatric Association, 1994). In addition , premenstrual migraine can be associated with premenstrual dysphoric disor der (PDD), also called "premenstrual syndrome" (PMS), which is distinct fro m the physical symptoms of the perimenstrual period and is probably not dir ectly driven by declining progesterone levels (Mortola, 1998). Migraine occ urring during (rather than prior to) menstruation is usually not associated with PMS (Silberstein and Merriam, 1997). Migraine may worsen during the first trimester of pregnancy and, although m any women become headache-free during the last two trimesters, 25p. 100 hav e no change in their migraine (Silberstein, 1997). MM typically improves wi th pregnancy, perhaps due to sustained high estrogen levels (Silberstein, 1 997). Hormonal replacement with estrogens can exacerbate migraine and oral contraceptives (OCs) can change its character and frequency (Kudrow, 1975; Bickerstaff, 1975). Migraine prevalence decreases with advancing age but ma y either regress or worsen at the menopause (Goldstein and Chen, 1982; Neri et al., 1993 Whitty and Hockaday, 1968). Changes in the headache pattern w ith OC use and during menarche, menstruation, pregnancy, or menopause are r elated to changes in estrogen levels.