Given the evidence that progestogen-only contraception is a safer option for women with migraine, the main question is whether such contraceptive choice may influence the course of both MA and MO and offer a better management of the disease. Indeed, even though the excess risk of death for a woman taking modern CHCs is 1 in 100,000, which is much lower than the risk of everyday activities such as cycling
[
56], there is a biological plausibility that in women with migraine should be wiser to use an estrogen-free containing contraception to avoid any potential vascular risk. Two recent very large epidemiologic studies
[
36,
57] reported the association between CHC and progestogen-only methods and cardiovascular risk, thrombo-embolic risk and stroke. Whereas no increased risk for deep venous thormbosis, myocardial infarction and thrombotic stroke was found for the progestogen-only methods, the risk were two-sixfold elevated in CHC users. The role of progesterone/progestins in the pathophysiology of migraine has been overshadowed by Somerville’s early observations that it was the prevention of estrogen but not of progesterone withdrawal in the late phase of the cycle to be able to prevent the occurrence of migraine attacks
[
58,
59]. Indeed, at variance with the influence of estrogens upon the cerebral structures implicated in the pathophysiology of migraine
[
60], cyclic variations in progestin levels were not related to migrainous headaches, but they rather seem to be protective. Progesterone apparently attenuates trigemino-vascular nociception
[
61] and its receptors are localized in areas of the central nervous system, which are involved in neuronal excitability and neurotransmitter synthesis release and transport
[
62]. It has been shown that progesterone can antagonize neuronal estrogenic effects by downregulating estrogen receptors
[
63]. Whereas estrogen peak decrease the threshold for cortical spreading depression (CSD), the neurobiological event underlying MA, estrogen withdrawal increased the susceptibility to CSD in an animal model
[
64]. Therefore, the maintenance of low estrogen levels and the avoidance of estrogen withdrawal by the administration of progestins in ovulation inhibiting dosages might decrease cortical excitability. Indeed, progestogen-only contraception has a continuous administration, without the hormone-free interval, and does not induce withdrawal stabilizing circulating estrogens, but some fluctuations according to different preparations may still occur
[
65]. Clinical data are scarce and no comparative studies with progestogen-only contraceptives and placebo or COCs are available in the literature
[
27]. Diagnoses are often inaccurate, without distinction between headache and migraine, and headache is reported in contraceptive progestin implant users as a potential cause of discontinuation
[
66]. Similarly, there is an increase in headache, but not migraine, reported over time with both norethisterone enanthate and, especially with depot medroxyprogesterone acetate
[
67]. Anecdotally, migraine is more likely to improve in women who achieve amenorrhea
[
68]. In a large, cross-sectional, population-based study in Norway of 13944 women, a significant association between CHC and headaches, but no significant association between progestin-only pills and migraine (OR 1.3, 95% CI: 0.9–1.8) was found but the number of users was small
[
18]. To date two diary-based studies pilot studies on the effect of desogestrel 75 μg on migraine have been published
[
69,
70]. Such oral daily pill inhibits ovulation and the dose allows the ovary to synthesize stable amounts of estrogen which are relevant for wellbeing and bone density
[
71]. The first study included thirty women with MA
[
69]. The use of desogestrel 75 μg resulted in a significant reduction in MA attacks and in the duration of aura symptoms, already after three months of observation. Interestingly, the beneficial effect of desogestrel 75 μg on visual and other neurological symptoms of aura was significantly present only in those women in whom MA onset was related to previous COCs treatment. These findings suggest that the reduction in estrogen levels may be relevant to the amelioration of MA, but do not exclude a direct effect of the progestin on CSD. The second study on the effect of desogestrel 75 μg included women with MA (n°=6) and with MO (n°=32) and evaluated migraine days, pain score and pain medication
[
70]. An improvement of each parameter was observed during 3 months use of desogestrel 75 μg in comparison to a three months pretreatment interval. A subanalyses of the effect on 32 women with MO revealed significant improvements in number of migraine days, pain medication and pain intensity. The mean number of migraine attacks at baseline was higher in comparison to that in the study of Nappi et al.
[
69], indicating that also very severe migraineurs might profit from such a progestin-only contraception. Chronic migraineurs often develop medication overuse headaches with severe limitation of their quality of life. The reduction of pain medication by progestin-only contraception is an interesting approach and it should be studied further. Indeed, there is a broad variation in the intensity of improvement with a reduction in migraine frequency ranging from 20% and 100%
[
70]. No indicators to identify those women who will profit from desogestrel 75 μg could be ascertained. On the other hand, there were few dropouts of women experiencing more migraine after starting contraception with this progestin in both studies, indicating that progestins can also deteriorate migraine in few cases.