Reversal of an Unfavorable Effect of Hydrochlorothiazide Compared to Angiotensin Converting Enzyme Inhibitor on Serum Uric Acid and Oxypurines Levels by Estrogen-progestin Therapy in Hypertensive Postmenopausal Women.

Hyperuricemia is considered one of the risk factors for arterial hypertension in postmenopausal women. The recent analysis by Loeffler confirmed that, as indicated in the NHANES survey, uric acid is a powerful cardiovascular risk factor.Analysis of age and sex strata in a meta-analysis showed hyperuricemia to be independently predictive of new-onset hypertension with a stronger association in women. In women, a positive relationship was found between age and serum uric acid levels. This phenomenon can also be explained by impaired renal uric acid excretion progressing with age. Moreover, menopause is independently associated with higher serum uric acid levels, whereas postmenopausal hormone use is associated with lower uric acid levels among postmenopausal women.

According to the guidelines on the management of arterial hypertension, first-line drugs in hypertensive elderly patients also include thiazide diuretics. This is particularly justified in postmenopausal women at risk of osteoporosis because thiazides have a positive effect on calcium balance, which is disordered in postmenopausal women. The natriuretic effect of thiazide diuretics itself is also desired due to increased sodium sensitivity after menopause. Meta-analysis performed by Mussini et al. covering 60 studies with thiazide diuretics in antihypertensive therapy (from years 1946-2014) showed their superiority in reducing pulse pressure over other classes of antihypertensive drugs. However; at the same time, it is known that thiazides increase serum uric acid levels.It has been suggested that increase in serum uric acid caused by diuretic treatment may partially offset the benefits of blood pressure reduction. This has been confirmed in an analysis of data from the Systolic Hypertension in the Elderly Program (SHEP) that showed that increase in uric acid levels in hypertensive patients treated with diuretics was associated with smaller clinical benefits from antihypertensive therapy assessed as a risk for episodes of ischemic heart disease.

Since menopause depends to a great extent on age, it is difficult to separate the influence of uric acid levels and its renal clearance on the development of hyperuricemia. This is possible to achieve only if uric acid metabolism is compared in postmenopausal women receiving and not receiving estrogen-progestin therapy (EPT). A potential factor limiting the unfavorable effect of thiazides on uric acid levels in hypertensive women may be EPT. Mihmanli et al. demonstrated benefits from estrogen supplementation on the renal vessels. Experimental studies on rats showed that estrogens (through a non-genomic mechanism of action) have a vasodilating effect on the renal arteries due to the mechanism of endothelium generating nitric oxide by 17-B-estradiol; and through the "NO-dependent" and "NO-independent" mechanisms, estrogens have a suppressive effect on its vasoconstrictive activity. Moreover, Xiao et al. demonstrated the effect of estradiol on regression of hardening of the renal glomeruli.

Therefore, the aim of the study was to assess the effect of EPT on serum levels of uric acid and its precursors and on its renal excretion in postmenopausal women receiving antihypertensive treatment with ACEI or thiazide diuretics as well as to explain if EPT prevents hyperuricemia caused by thiazide diuretics in postmenopausal hypertensive patients.

Methods Subjects: Treatment-naive postmenopausal women with recently diagnosed essential hypertension (grade 1 or 2 according to ESH(European Society of Hypertension)/ESC(European Society of Cardiology) 2013 guidelines) were included in the study. They were assessed by a primary care physician or gynecologist as postmenopausal, with age ranging from 49 to 53 years old, of Caucasian race. The final menstrual period (FMP) was identified retrospectively. In order to determine this criterion, I used STRAW (Stages of Reproductive Aging Workshop) guidelines. According to the authors, a lack of menstruation for 12 months indicates clinical menopause and is referred to as "postmenopause". All the women had the expected postmenopausal increase in follicle-stimulating hormone concentrations (FSH 78.32 ± 8.73 IU/ml) and experienced flushes or other vasomotor symptoms associated with menopause. For this reason and due to hypertension, they were randomized to EPT and hypotensive treatment. Normotensive women with vasomotor symptoms received randomly either EPT or nothing. The exclusion criteria included: breast cancer in a first-degree relative, hyperplasia diagnosed by endometrial biopsy, history of thromboembolic diseases, current or history of use of estrogen-progestin therapy or contraceptives, diabetes, kidney failure, thyroid disease, and heart and other chronic diseases (secondary hypertension, atrial fibrillation). Results of mammography performed 12 months prior to the study were negative in all the screened women.