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.
Condition: Hypertension; Hyperuricemia; Menopause
MeSH terms: Hypertension; Hyperuricemia
Study type: Interventional
Phase: Phase 4

Summary: 
      The aim was to assess the effect of estrogen-progestin therapy (EPT) on serum levels of uric
      acid (SUA) and its precursors: xanthine (X) and hypoxanthine (HX) and on uric acid (UA) renal
      excretion in hypertensive postmenopausal women treated with an angiotensin-converting enzyme
      inhibitor (ACEI) or thiazide diuretic (HCTZ).
    

Detailed description: 
      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.

      In the invitation letter, women with arterial hypertension were invited to take part in a
      study on hypertension management and menopause-related symptoms, or menopause-related
      symptoms only in normotensive women. Informed consent was obtained from the subjects prior to
      the study. The study was carried out in accordance with The Declaration of Helsinki and was
      also registered and approved by the local Ethics Committee at the University of Medical
      Sciences in Poznan with the registration number 1319/99. A physical examination and
      biochemical screening was performed in all women at baseline.

      Study design: The screening phase included 140 women with vasomotor symptoms associated with
      menopause. They met inclusion, but not exclusion criteria, and were treatment-naive for
      hypertension. At two separate visits at a weekly interval (wash-out period), hypertension was
      defined as the mean of three office-based measurements between ≥140/90 mmHg and <180/110
      mmHg. Subjects included in the study had no contraindications to transdermal
      estrogen-progestin therapy or hypotensive treatment. The study's control group consisted of
      40 normotensive women (<140/90 mmHg, measured at two separate visits under similar
      conditions) who had also the possibility to receive transdermal estrogen-progestin therapy
      due to vasomotor symptoms associated with menopause.

      At the beginning of the study, hypertensive women were assigned randomly (sealed envelopes)
      to two treatment groups: with a diuretic - hydrochlorothiazide 25 mg/day p.o. (n=50) or with
      an ACEI - perindopril 4 mg/day p.o. (n=50), and to a group receiving estrogen-progestin
      therapy (EPT+) and a group not receiving hormones (EPT-). Normotensive women were assigned
      randomly only to either EPT+ or EPT- groups. Estrogen-progestin therapy was given in the form
      of transdermal patches releasing 17β-estradiol (0.05 mg/24 hours) and norethisterone (0.25
      mg/24 hours) Estracomb TTS®.

      Control measurements were performed in all subjects after one year. At the end, 20 females
      did not complete the study (4 due to an adverse reaction of perindopril in the form of cough,
      6 needed additional antihypertensive therapy - 2 with ACEI and 4 with HCTZ and 10 for no
      reason). All females from the normotensive group completed the trial.

      Finally, groups of 20 women with hypertension in each treatment group and 20 women with
      normal blood pressure, treated with or without EPT, were chosen for statistical analyses in
      the order in which they had finished the 12-month follow-up of the study.

      Measurements: Systolic (SBP) and diastolic (DBP) office-based blood pressure was measured
      after five minutes in sitting position by means of a validated automatic device (Omron 705
      CP) placed on the arm with higher blood pressure. In each time, the average of three
      measurements was used. Ambulatory blood pressure measurements were performed in all study
      participants at entrance and after 6 and 12 months using an automatic device (MOBIL-O-GRAPH).
      The device was set up to perform a blood pressure recording every 15 minutes during the day
      and every 30 minutes at night, over a 24-hour period. 80% of the correct measurements were
      needed to validate the result.

      Measurement of renal function: Renal plasma flow (RPF) was measured as the clearance of
      125I-iodohippuran using a constant infusion technique with timed urine sampling [20]. Based
      on RPF, additional renal hemodynamic parameters: filtration fraction (FF) and renal vascular
      resistance (RVR) were estimated [21].

      Laboratory tests: Serum and urine creatinine levels were determined with a spectrophotometric
      method [22] using an autoanalyzer (MEGA, Merck, Darmstadt, Germany) and the Mascot software
      package (Matrix Science, UK). Serum and urine uric acid levels were determined with an
      enzymatic uricase method using PAP 150 kits by bioMérieux SA (Marcy l'Etoile, France). Serum
      hypoxanthine and xanthine levels were determined with high-performance liquid chromatography
      (HPLC) [23] using a Hewlett-Packard 1050 system with UV detector by HP Inc. (Palo Alto, CA,
      USA).

      Serum creatinine levels were determined using Jaffé reaction. Glomerular filtration rate
      (GFR) was calculated using the Cockcroft-Gault equation for women.

      Statistical analysis: Student's t-test was used to compare continuous variables and the
      normality of distribution of an investigated feature in both study populations. T-test with
      the Cochran-Cox adjustment was used in cases where variances of analyzed variables in both
      study populations differed, or Wilcoxon Mann-Whitney test in cases where there were no normal
      distribution.

      Baseline characteristics were compared using ANOVA (in the case of parametric variables) or
      by means of the Kruskal-Wallis test (in the case of nonparametric variables); subsequently,
      the different groups were compared in pairs. Means were compared by means of the
      Kruskal-Wallis test one-way analysis of ranks; then, the relevant groups were compared in
      pairs. If the groups differed significantly, multiple comparison Dunn test was applied.

      Multiple linear regression models were constructed for selected parameters of the effects of
      HCTZ and EPT (women with arterial hypertension). Models with interactions were also
      developed. If β regression coefficients for interactions of independent variables were
      significant, these models were used to interpret the variability of the dependent variable.
      F-test verifies the statistical significance of all variables in the model. Similar multiple
      linear regression models were also constructed to show the effect of hypertension and EPT.

      Values represent mean ± standard deviation (SD) if not stated otherwise. A p value < 0.05 was
      considered statistically significant.
    

Intervention name(s): Perindopril; Hydrochlorothiazide; Estracomb TTS
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 4 mg/day p.o. for 12 months; hydrochlorothiazide 25 mg/day p.o. for 12 months; Transdermal patches releasing 17β-estradiol (0.05 mg/24 hours) and norethisterone (0.25 mg/24 hours) for 12 months
Intervention MeSH terms: Hydrochlorothiazide; Perindopril
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Postmenopausal women with, untreated essential hypertension were recruited to the study. The control group consisted of 40 postmenopausal women with normal blood pressure.
Masking: Single (Investigator)
Primary purpose: Treatment
Keywords: estrogen-progestin therapy; hypertension; uric acid; xanthine; hypoxanthine; menopause; thiazide diuretic; angiotensin-converting enzyme inhibitor