Dr. Ron’s Research Review – March 20, 2014

© 2014

This week’s research review focuses on hormone therapy for migraines.

Migraine is often a part of the premenstrual syndrome from which about 30 percent of women suffer one way or another to a greater or lesser extent. The commonest form of the syndrome is a minor endocrine disorder that most women accept as part of the business of being a woman. When the syndrome includes migraine it becomes serious. Progesterone was used successfully in 32 of 39 cases (84%). (Greene 1963)

Estradiol with progesterone was also reported successful. Twenty-three (of 24) patients improved with treatment, 20 (83%) became completely or almost completely headache-free. (Magos, Zilkha et al. 1983)

In a study of 18 women, estradiol (15 mg in 2.5 g gel) was compared with placebo (2.5 g gel) over three cycles. Menstrual attacks occurred in eight of the 26 estradiol cycles (30.8%) and in 26 of the placebo cycles (96.3%) (de Lignieres, Vincens et al. 1986)

A study published in Lancet (1447) successfully treated migraine with progesterone, which not only terminated but also prevented attacks. In all 23 cases the attacks could be induced or increased by oral or parenteral administration of 2-10 mg. of oestradiol (Clinaestrol), and was relieved by the administration of 5-15 mg. of progesterone (Lutocyclin). (Singh and Singh 1947)

A recent article describes several complex mechanisms for the effects of hormones on migraines. (Dhillon, Singh et al. 2011)

Dr. Ron


Prevention of menstrual migraine by percutaneous oestradiol

         (de Lignieres, Vincens et al. 1986) Download

A new horizon into the pathobiology, etiology and treatment of migraine

         (Dhillon, Singh et al. 2011) Download

Sexual dimorphism in the prevalence of migraine (70% women 30% men) suggests the involvement of reproductive hormones in a women's life. Excessive estrogen during menstruation directly stimulate estrogen receptor alpha thickly populated in trigeminal ganglia and periaqueductal gray which manifest as menstrual migraine. In contrast increased progesterone during pregnancy evokes progesterone receptors A/B, which coexist with ERs, providing complete remission from migraine episodes. Moreover, estrogen also increases nociception through extracellularly signal-regulated kinase (ERK) stimulation and down-regulating antinociceptive GABA, IL-R1 and Zn-fingers. Hormones may provoke migraine indirectly by disrupting mineral homeostasis. Estrogen enhances the absorption and half-life of copper which in turn inhibits the absorption of zinc. Zinc is required for the synthesis of melatonin and CoQ10 essential for growing women. Excess of copper exacerbates the deficiency of zinc, melatonin and CoQ10 typically low in migraineurs. Melatonin is an antioxidant, free radical scavenger and activates antioxidant enzymes like CuZn-superoxide dismutase, catalase, glutathione peroxidase (a Se-enzyme) and glutathione reductase. Zinc deficiency reduces activity of CuZn-SOD. Magnesium and vitamin B6 modulates the level of NO in the cell, both of which are deficient in migraineurs. Magnesium is essential for the removal of trapped NO from within the cell which does not occur under low magnesium levels, which reacts with superoxide generating dangerous peroxynitrite. Iron stimulates nitric oxide synthase producing more NO which is inhibited by zinc, thus, antagonizing peroxynitrite generation. Female hormones lowers magnesium but increase calcium levels which enhance migraine ubiquitousness. Accumulation of copper and iron in deep areas of brain and peripheral nerves typically catalyses the oxidation of catecholamines and generate free radicals involved in lipid-peroxidation, demyelination, denudation of axons and neurodegeneration in specific areas exposing hyperalgesic axons provoking Classical migraine. Furthermore, zinc is an essential component of Zn-fingers (Krox20 and Krox24) which play a pivotal role in the differentiation of Schwann cells-the mainstay for the myelination/remyelination of peripheral nerves. Taken together, conceptually and logically, 30 migraineurs were administered 75 mg of zinc sulfate orally in water daily for 6 weeks+one capsule of vitamin B-complex+one capsule of vitamin A or E (first 10 days) which almost cured all of them. Placebo controlled trials with incremental doses of zinc sulfate along with magnesium and selenium are proposed to augment recovery involving large population of migraineurs. Monitoring of hair and blood mineral analysis for rational therapy is recommended.

Migraine--the Menstrual Aspect

         (Greene 1963) Download

Treatment of menstrual migraine by oestradiol implants

         (Magos, Zilkha et al. 1983) Download

The suppression of cyclical ovarian activity and the creation of constant oestradiol levels in blood by subcutaneous oestradiol implants has been used to treat 24 patients with menstrual migraine for up to five years. Twenty-three patients improved with treatment, 20 (83%) became completely or almost completely headache-free. Regular monthly periods were induced with cyclical oral progestogens. The treatment was not associated with any problems. The results support the concept that oestrogen withdrawal in the late luteal and menstrual phases of the ovarian cycle is the important precipitating factor in menstrual migraine, and such attacks can be prevented by suppressing the hormonal fluctuations associated with the ovarian cycle.

Progesterone in the treatment of migraine

         (Singh and Singh 1947) Download

We record here our results in 23 cases of migraine in women, in whom, clinically and therapeutically, estrogens were established as causal factors in precipitating attacks of migraine. The patients were all successfully treated with progesterone, which not only terminated but also prevented attacks.


de Lignieres, B., M. Vincens, et al. (1986). "Prevention of menstrual migraine by percutaneous oestradiol." Br Med J (Clin Res Ed) 293(6561): 1540. [PMID: 3099950]

Dhillon, K. S., J. Singh, et al. (2011). "A new horizon into the pathobiology, etiology and treatment of migraine." Med Hypotheses 77(1): 147-51. [PMID: 21530095]

Greene, R. (1963). "Migraine--the Menstrual Aspect." J Coll Gen Pract 6: SUPPL4:15-7. [PMID: 14076386]

Magos, A. L., K. J. Zilkha, et al. (1983). "Treatment of menstrual migraine by oestradiol implants." J Neurol Neurosurg Psychiatry 46(11): 1044-6. [PMID: 6686248]

Martin, V. T., S. Wernke, et al. (2005). "Defining the relationship between ovarian hormones and migraine headache." Headache 45(9): 1190-201. [PMID: 16178949]