Chronic mountain sickness (CMS) or Monge's disease, first described by Carlos Monge Medrano in Peru in 1925 (1), is characterized by excessive erythrocytosis (a hemoglobin level of ≥19 g/dl in females or ≥21 g/dl in males) in combination with chronic hypoxemia; in certain cases pulmonary hypertension is also apparent (2–4). Severe pulmonary hypertension may evolve to cor pulmonale, resulting in congestive heart failure. Therefore, CMS frequently leads to right cardiac failure and/or neurological disorders (3–5). The clinical signs in patients with CMS include breathlessness and/or palpitations, sleep disturbance, cyanosis, dilatation of veins, paresthesia, headache and tinnitus (2,4). On the Qinghai-Tibetan plateau, the incidence of CMS is 2.43–37.5% (3,000–4,700 m) and increases with elevation (4,6). Furthermore, the prevalence of CMS is significantly increased in migrants compared with that in the native population of high altitudes, and the disease occurs more frequently in males than in females (7–9). CMS is a severe public health problem for the Qinghai-Tibetan plateau, which has >60 million people in residence (4).

Despite a number of trials with medroxyprogesterone, enalapril and almitrine, no pharmacological treatment is currently widely used to impede the progressive loss of adaptation to chronic hypoxia (10–13). Acetazolamide (Acz) is useful for reducing hematocrit and improving pulmonary circulation in CMS. However, Acz has adverse effects, including paresthesia and diuresis (14). Therefore, the only management for CMS, at present, is repetitive bloodletting or the displacement of dwellers to lower altitudes. The latter option has an important negative social and economic impact on the development of high-altitude regions.

Excessive erythropoiesis in CMS is a process that is hormonally regulated (15,16). High serum testosterone levels are correlated with excessive erythrocytosis in males at high altitude, and female sex hormones suppress polycythemic and cardiopulmonary responses in vivo during chronic hypoxic exposure (16,17). It is generally accepted that an excessive number of red blood cells in the vessels is likely to increase blood viscosity, thereby inducing pulmonary hypertension and even cardiac failure. However, the underlying mechanism of pulmonary hypertension in CMS is only partially understood. Data from Bailey et al(18) indicated that increased pulmonary arterial systolic pressure at high altitude was correlated with a reduction in pulmonary nitric oxide (NO) bioavailability (18). Therefore, the inhibition of erythropoiesis and the increase of circulating NO levels are likely to alleviate the clinical signs of patients with CMS.

Soy isoflavones (Ifs) are the most studied and most potent phytoestrogens, and are predominantly present in soy-based foods (19). Genistein and daidzein, the two most abundant Ifs (19), have chemical structures similar to that of estradiol (E2) and exert estrogen-like effects (20), which are able to inhibit excessive erythropoiesis. Experimental studies have shown the beneficial effects of Ifs on the production of NO in endothelial cells, which include inhibition of the proliferation of vascular smooth muscle and reduction of the tissue damage caused by reactive oxygen species (ROS) (21,22). Animal studies have also indicated that genistein and daidzein, through estrogen receptor (ER)-independent mechanisms, restore endothelial cell function by increasing NO production and the protection of NO from O₂^•−driven inactivation (23). In addition, our previous studies showed that treatment with genistein inhibited pulmonary vascular structural remodeling and right ventricular hypertrophy induced by chronic hypoxia (5,000 m, 21 days) in male Wistar rats without adverse effects, such as feminizing and oncogenic effects (24–26).

Therefore, in the present study it was hypothesized that Ifs may reduce excessive erythropoiesis and ameliorate right ventricular index and pulmonary hemodynamics in CMS. The study aimed to observe the effects of Ifs in patients with CMS and to evaluate the treatment of CMS.

CMS is an excessive polycythemia that is common among high-altitude residents, particularly in migrants (2). According to the prevalence of CMS, millions of residents on the Qinghai-Tibetan plateau suffer from CMS. Therefore, these residents may benefit from a treatment that reduces their hemoglobin concentration and pulmonary arterial pressure.

The physiopathology of CMS has been attributed to the following sequence: hypoxemia, excessive erythropoiesis and pulmonary hypertension (4,7). In the present study, following treatment with Ifs, the hematocrit and hemoglobin concentrations of the subjects were significantly decreased compared with the values prior to treatment. Therefore, the number of polycythemic individuals (hemoglobin ≥21 g/dl) decreased from 28 to 17 following treatment with Ifs. Moreover, 45 days of treatment with Ifs significantly increased SaO₂ and decreased HR and the CMS score compared with the values prior to treatment, which indicated a reduction in hypoxemia and clinical indisposition. In addition, Ifs significantly reduced MPA, RVEAD, RVETD, RVAW and RVOT. Therefore, these results indicated improvements in hypoxia and clinical indisposition, and an amelioration of the right ventricular index and pulmonary hemodynamics in patients with CMS following treatment with Ifs. Furthermore, these results were consistent with our previous observations in rats, which showed the preventive effects of phytoestrogens on chronic hypoxic pulmonary hypertension and right ventricular hypertrophy (25,26). In addition, there were no adverse effects, such as diuresis, paresthesia and heartburn, following treatment with Ifs in the present study. Data from Hamilton-Reeves et al(28) and our own laboratory showed that Ifs elicited no effects on reproductive hormones in men or male rats (26,28). Ifs may have a more extensive applications in patients with CMS compared with Acz, which exhibits beneficial and adverse effects.

Furthermore, the present study demonstrated that treatment with Ifs significantly decreased plasma MDA levels and increased SOD activity, indicating an attenuation of oxidative damage in patients with CMS. This may result in the relief of malaise in patients with CMS during long-term exposure to high-altitude hypoxia. Marked increases in the plasma activity of NOS and circulating NO levels were observed following 45 days of treatment with Ifs compared with the values prior to treatment. NO has been demonstrated to be important in adaptation or acclimatization to high altitude. Scherrer et al(29) revealed that NO reduced pulmonary arterial pressure and improved oxygen saturation among patients suffering from high-altitude pulmonary edema (29). Furthermore, total NO has been demonstrated to be negatively correlated with pulmonary arterial systolic pressure and positively correlated with pulmonary blood flow and oxygen delivery at 4,200 m (30). In age and biomarker-adjusted logistic regression, NOS was also shown to be inversely predictive of CMS (31). In the present study, the increased plasma activity of NOS and circulating NO levels, induced by 45 days of treatment with Ifs, relaxed small pulmonary arteries and reduced MPA and right ventricular ejection resistance. These observations were consistent with the results from our previous studies, in which treatment with genistein, the most active form of Ifs, inhibited pulmonary vascular structural remodeling and right ventricular hypertrophy induced by chronic hypoxia (5,000 m, 21 days) in male Wistar rats (25,26).

In conclusion, the present study demonstrated the potential beneficial effects of Ifs in reducing excessive erythrocytosis, alleviating oxidative damage and ameliorating right ventricular index and pulmonary hemodynamics in CMS. We propose that Ifs are a potential low-cost treatment for CMS. Studies with a control group and a dose-effect analysis, and large-scale trials are required to evaluate the feasibility of the implementation of treatment for CMS in the Tibetan region.