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Rossella E. Nappi, MD, PhD
Research Centre for Reproductive Medicine, Gynecological endocrinology and Menopause
IRCCS Policlinico San Matteo, University of Pavia,
Pavia, Italy

Case

CP is a 47-year-old woman with perimenopausal symptoms. When she came to our clinic, CP had had irregular bleeding for a year, associated with moderate climacteric syndrome (hot-flushes, fatigue, anxiety, low mood, vaginal dryness). She also lamented an increased frequency and intensity of migraine with aura and less responsivity to pain killers (indomethacin, NSAIDs) documented by a headache diary over the last six months. She had a history of nulliparity, autoimmune thyroid dysfunction for which she took L-thyroxine 50 mcg/day, hypertension treated with beta-blockers. At the pelvic ultrasound examination, she had normal ovaries, a normal uterus with an endometrial thickness of 6 mm. Her blood FSH level was 32 UI/L, and the estradiol level was 45 pg/ml. CP was prescribed treatment with transdermal estradiol (50 mcg/day) associated with micronized progesterone (200 mg/day) for 12 days per month. Now, CP has an average of 1-2 perimenstrual attacks with moderate pain and a very satisfactory level of pain-control following analgesics

Discussion

Migraine with aura (MA) accounts for about 20-30% of attacks of pulsating head pain preceded by transient and progressive focal neurologic symptoms (mostly visual, but also sensory, aphasic, or motor) lasting no more than 1 hour and resolving before a migraine occurs. MA usually presents before the age of 40 years; high estrogen levels seem to predispose to aura by modulating the threshold for cortical spreading depression, the neurobiological event underlying MA. Estrogens affect the vascular system in many ways, including endothelial dysfunction, hemostatic balance, neuroendocrine and metabolic factors, and their fluctuations likely explain the striking female preponderance of migraine, with and without aura, across the life span [1].

With advancing age, incidence generally decreases, and about two-thirds of patients no longer have any type of migraine and its associated phenomena by age 65. De novo diagnosis above the age of 40 may require investigation to exclude other causes (transient ischemic attacks, neoplasm, temporal arteritis, epilepsy, pituitary macroadenoma). However, during a long menopausal transition, erratic estrogenic secretion and unbalanced estrogenic exposure due to anovulatory cycle and/or to progesterone deficiency may increase the frequency and severity of migraine, or even initiate it. Also, the intensity of menopausal symptoms such as hot flushes, palpitations, night sweats, disturbed sleep, negative emotions may contribute to the burden of migraine, explaining why the fifth decade of life is exceptionally critical for first consultations. The greatest challenge for the clinician is to pharmacologically manage symptoms related to the hypoestrogenic state of menopause and migraine concurrently [2].

Indeed, caution is mandatory in the prescription of menopausal hormone therapy (MHT), owing to that MA, especially, is[RN1] an established marker of roughly a double risk of ischemic stroke (IS). Younger menopausal age and a high frequency of MA attacks increase the risk of IS. However, the hypothetical increased risk of cardiac vascular events remains questionable in migraine sufferers [3[RN2] ].

In the context of menopause medicine, there are no absolute contraindications to the use of MHT for symptomatic women with MA. However, clinicians should consider the cardio-vascular and metabolic profile, as well as MA disease activity at menopause and beyond [2, 4, 5]. MHT in perimenopausal patients with MA has been associated with an increase in pain severity and visual auras. Moreover, estrogen users report greater use of anti-migraine preparations than nonusers and current MHT use is associated with higher rates of migraine compared with no use. Prescribing the lowest effective dose of estrogen seems to prevent this undesired effect, bearing in mind that if aura starts for the first time in a woman with no history of migraine, a neurological consultation is mandatory. If aura becomes more frequent or starts again after a long period of remission in a previous migraine sufferer, the indication is to reassess cardiovascular and metabolic risk factors and to stop estrogen for clinical re-evaluation.

In non-hysterectomized women with MA, who require endometrial protection, the best MHT option should aim at 1) stabilizing estrogenic fluctuations, 2) avoiding “estrogen withdrawal” and 3) achieving amenorrhea by using continuous combined estrogen-progestin regimens. Transdermal estrogens should be favoured as they avoid the “first pass” liver metabolism. The low metabolic and prothrombotic impact is relevant not only for the clinical management of MA but also given the higher cardiovascular and cerebrovascular risk in these postmenopausal women. Progestins with low metabolic impact such as micronized natural progesterone are preferred for safety reasons. A levonorgestrel intrauterine system as a continuous progestogen component of MHT may also be used.

In conclusion, MHT use in women with MA is possible and safe by tailoring the best estrogen-progestin combination at the lowest dose to manage menopausal symptoms effectively and to contain MA disability and potential associated-risk.

REFERENCES

  1. Nappi RE, Berga SL. Migraine and reproductive life. Handb Clin Neurol. 2010;97:303-22.
    https://pubmed.ncbi.nlm.nih.gov/20816431/
  2. MacGregor EA. Perimenopausal migraine in women with vasomotor symptoms. Maturitas. 2012;71(1):79-82.
    https://pubmed.ncbi.nlm.nih.gov/22115567/
  3. Mawet J, Kurth T, Ayata C. Migraine and stroke: in search of shared mechanisms. Cephalalgia. 2015;35(2):165-81.
    https://pubmed.ncbi.nlm.nih.gov/25228681/
  4. Ibrahimi K, Couturier EG, Maassen Van Den Brink A. Migraine and perimenopause. Maturitas. 2014;78(4):277-80.
    https://pubmed.ncbi.nlm.nih.gov/24954701/
  5. Nappi RE, Sances G, Detaddei S, Ornati A, Chiovato L, Polatti F. Hormonal management of migraine at menopause. Menopause Int. 2009;15(2):82-6.
    https://pubmed.ncbi.nlm.nih.gov/19465675/
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