Serum levels of allopregnanolone, progesterone and testosterone in menstrually-related and postmenopausal migraine: A cross-sectional study

Abstract

Background Reduced blood or cerebrospinal fluid levels of allopregnanolone are involved in menstrual cycle-linked CNS disorders, such as catamenial epilepsy. This condition, like menstrually-related migraine, is characterized by severe, treatment-resistant attacks. We explored whether there were differences in allopregnanolone, progesterone and testosterone serum levels between women with menstrually-related migraine (MM, n = 30) or postmenopausal migraine without aura who had suffered from menstrually-related migraine during their fertile age (PM, n = 30) and non-headache control women in fertile age (FAC, n = 30) or post-menopause (PC, n = 30). Methods Participants were women with migraine afferent to a headache centre; controls were female patients’ acquaintances. Serum samples obtained were analyzed by HPLC-ESI-MS/MS. Results In menstrually-related migraine and postmenopausal migraine groups, allopregnanolone levels were lower than in the respective control groups (fertile age and post-menopause) ( p < 0.001, one-way analysis of variance followed by Tukey-Kramer post-hoc comparison test) while progesterone and testosterone levels were similar. By grouping together patients with migraine, allopregnanolone levels were inversely correlated with the number of years and days of migraine/3 months ( p ≤ 0.005, linear regression analysis). Conclusion Decreased GABAergic inhibition, due to low allopregnanolone serum levels, could contribute to menstrually-related migraine and persistence of migraine after menopause. For the management of these disorders, a rise in the GABAergic transmission by increasing inhibitory neurosteroids might represent a novel strategy.

Patterns of Migraine in Postmenopausal Women: A Systematic Review

“…The electronic searches in the scientific databases identified 1296 potentially relevant records: after removing duplicates, we assessed for eligibility titles and abstracts of 1265 references. Afterwards, we evaluated 50 full-text articles and included 12 studies [12][13][14][15][16][17][18][19][20][21][22][23] in the systematic review ( Figure 1). In the eligibility and inclusion stage, the agreement among the judgements of the authors (Krippendorff's alpha coefficient, α) was 0.90 and 0.96, respectively.…”

“…18. natural sex hormones in postmenopausal women with migraine. 23 The randomized controlled trial compared tibolone, a non-estrogen synthetic steroid, with conventional estrogen-progestogen over a 6-month follow-up in postmenopausal women with migraine without aura; this study found that tibolone did not increase headache days compared with baseline, while decreasing headache intensity and analgesic consumption; on the contrary, conventional estrogen-progestin treatment increased headache days and analgesic consumption, while not decreasing headache intensity. 16 Two cross-sectional studies assessed the association between the use of postmenopausal HRT and migraine.…”

“…19 One study assessed the natural serum levels of different sex hormones in menopausal women according to their migraine status; the levels of allopregnanolone were significantly lower in postmenopausal women with migraine compared with those without migraine, while the levels of other sex hormones did not differ between the two groups. 23…”

Comparison of pregnenolone sulfate, pregnanolone and estradiol levels between patients with menstrually-related migraine and controls: an exploratory study

“…In a previous study, we found lower levels of allopregnanolone, a positive allosteric modulator of the γ-aminobutyric acid type A (GABAA) receptor, in women with menstrually-related migraine than in controls. These data suggested that the reduced levels of allopregnanolone, an inhibitory neurosteroid, were insufficient to counteract the neuronal hyperexcitability associated with migraine [ 2 ], thus contributing to the severity of menstrual related migraine attacks [ 3 ]. Indeed, migraine is characterized by generalized neuronal hyperexcitability [ 4 ], probably mediated by an increased or impaired glutamate transmission [ 5 ].…”

“…Furthermore, variation of estrogen levels modulate the signalling of the CGRP receptor in the trigeminovascular system [ 12 , 13 ]. In the previous study, we found no differences in progesterone levels between women with menstrually-related migraine and non-headache women, but we did not measure estradiol or pregnanolone, an isomer of allopregnanolone, also an agonist of the GABAA receptor [ 3 ].…”