Response to Diet and Metformin in Women With Idiopathic Intracranial Hypertension With and Without Concurrent Polycystic Ovary Syndrome or Hyperinsulinemia

Charles J Glueck MD, Karl C Golnik MD, Dawit Aregawi MD, Naila Goldenberg MD, Luann Sieve, BS, Ping Wang, PhD

Disclosures

In the current issue of Medscape General Medicine, Bagga and colleagues[1] review therapies for idiopathic intracranial hypertension (IIH) during pregnancy and suggest that "...most therapies used during non-pregnant state can also be used during pregnancy." One novel therapy that we have used successfully during pregnancy in 4 women with both IIH and polycystic ovary syndrome (PCOS) is glucophage, which is safe for both mother and fetus during pregnancy, is not teratogenic, and leads to a median average weight gain during pregnancy of zero pounds. Glucophage safely promoted weight loss in a predominantly morbidly obese cohort during pregnancy,[2,3,4,5,6,7,8,9,10,11] and thus was beneficial for IIH, particularly during pregnancy.

Our 2 previous studies revealed that 15 of 38 (39%)[12,13] and 37 of 65 (57%)[12] women referred solely for IIH had PCOS -- a prevalence 5 to 8 times higher than the 7% prevalence seen in the general unselected population.[14] Obesity is a clinical characteristic of both PCOS [15,16,17,18,19,20] and IIH.[21,22,23,24,25] The increased prevalence of PCOS in women with IIH speculatively reflects PCOS-driven morbid obesity, [15,16,17,18] which, in turn, facilitates development of IIH.[26]There are also links between obesity, PCOS, hypofibrinolysis, and thrombophilia.[15,16,17,18,27] Obesity, often with concurrent hyperinsulinemia and PCOS, is associated with hypofibrinolysis through elevation of plasminogen activator inhibitor activity (PAI-Fx).[15,16,17,18,28] Reduction of obesity by metformin in PCOS[15,16,17,18,28] and by gastric banding[29] lowers PAI-Fx. Obesity is also prothrombotic through its associations with high Factor VIII.[30] Obesity by itself is characterized by increased adipose tissue production of tumor necrosis factor-alfa and other prothrombotic pro-inflammatory adipokines.[31,32,33,34,35] Moreover, paradoxically high endogenous estrogens, common in PCOS[19] and in severe obesity,[36] are thrombophilic, and might play a role in the development of IIH, particularly in patients with coagulation disorders.[12,13,37]

After documentation of PCOS in women referred with IIH, the next step should be metformin (1.5-2.55 g/day) coupled with a calorie-restricted, high-protein, low-carbohydrate diet.[15,16,17,18] These interventions sharply lower weight, reduce insulin resistance, lower insulin-driven high PAI-Fx,[9,15,16,17,18] and reduce aromatization of testosterone, [19] diminishing testosterone conversion to estradiol[19] and thus reducing paradoxical hyperestrogenemia, which is also prothrombotic.

Weight loss has been shown to be the major catalyst for reduction of papilledema in women with IIH.[25] In a study of 15 obese women (mean BMI 40.7) with IIH, Johnson and colleagues[25] reported that "... an average of 3.3% weight loss (± 0.5% SEM) was observed in patients having a one-grade change in papilledema." Weight loss of 6.2% (± 0.6% SEM) had a 3-grade change in papilledema (complete resolution of marked papilledema).[25] No patient without weight loss had improvement in papilledema despite treatment with acetazolamide.[25] Because conventional therapy for IIH,[38] as in the report by Bagga and colleagues,[1] still leaves a substantial percentage of patients with headache[39]and a lesser percentage with persistent papilledema and visual field deficits,[40] any novel medical therapy should be welcome. We speculate that PCOS, associated with obesity and extreme obesity in adolescence and young adulthood,[9,15,16,17,18] is a treatable promoter[12,13] of IIH, since metformin effectively promotes weight loss in women with PCOS[16,17,18,41] and weight loss improves signs and symptoms of IIH[24,25,42] in patients with and without PCOS.[43]

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