Osteoporos Int (2014) 25:1123–1129 DOI 10.1007/s00198-013-2512-5
ORIGINAL ARTICLE
Genistein effects on quality of life and depression symptoms in osteopenic postmenopausal women: a 2-year randomized, double-blind, controlled study M. Atteritano & S. Mazzaferro & A. Bitto & M. L. Cannata & R. D’Anna & F. Squadrito & I. Macrì & A. Frisina & N. Frisina & G. Bagnato
Received: 15 April 2013 / Accepted: 9 September 2013 / Published online: 10 October 2013 # International Osteoporosis Foundation and National Osteoporosis Foundation 2013
Abstract Summary Postmenopausal estrogen decline is implicated in several age-related physical and psychological changes in women, including decreases in perceived quality of life. The phytoestrogen genistein at a dose of 54 mg daily in osteopenic postmenopausal women after 2 years implies an improvement on quality of life and depression symptoms. Introduction Postmenopausal estrogen decline is implicated in several age-related physical and psychological changes in women, including decreases in perceived quality of life (QoL). A number of trials with hormone therapy showed beneficial effects of the intervention on quality of life parameters. However, because of known or suspected serious side effects of conventional hormone therapy, there is a need for alternatives. Methods We conducted a double-blind randomized placebocontrolled trial using the isoflavone genistein, 54 mg, or placebo for 2 years. In this trial, we recruited 262 postmenopausal women aged 49 to 67 years. Results At baseline, after 1 year, and at final visit, participants filled in the Short Form of 36 questions (SF-36) and the Zung Self-rating Depression Scale (ZSDS). For the placebo group, scores on all dimensions of the SF-36 decreased after 1 and
M. Atteritano (*) : S. Mazzaferro : I. Macrì : A. Frisina : N. Frisina : G. Bagnato Department of Internal Medicine, University of Messina, Pad. C, 3rd floor, A.O.U. Policlinico “G. Martino” Via C. Valeria, 98125 Messina, Italy e-mail:
[email protected] A. Bitto : F. Squadrito Section of Pharmacology, Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Messina, Italy M. L. Cannata : R. D’Anna Department of Obstetrical and Gynecological Sciences, University of Messina, Messina, Italy
2 years. The genistein group showed increases on all dimensions of the SF-36 at the end of the study. There were, however, statistically significant differences in changes of scores between the two intervention groups. For the ZSDS, similarly, significant differences were found between groups. Conclusion In conclusion, the findings of this randomized trial showed that genistein improves quality of life (health status, life satisfaction, and depression) in osteopenic postmenopausal women. Keywords Genistein . Osteopenia . Postmenopausal . Quality of life
Introduction Estrogen deprivation has been held responsible for physical and psychological changes occurring during menopause. Among these changes, increased incidence of cardiovascular diseases is included [1], as well as increased fracture risk [2, 3] and decreased perceived quality of life, including disturbed sleep patterns, mood changes, and vasomotor symptoms [4]. Accordingly, estrogen therapy was expected to prevent chronic diseases and improve quality of life [5]. However, recent findings have suggested that hormone replacement therapy (HRT) is associated with a higher risk of breast, endometrial, and ovarian cancer; cardiovascular disease; venous thromboembolism and stroke [6–8]. Whether the net effect of postmenopausal hormones is to increase life expectancy is still unclear [9]. The isoflavone genistein may offer an alternative for HRT, sharing the benefits but not the risks. Studies on pure genistein from our research group have focused on cardiovascular outcomes, menopausal symptoms, bone health, and safety in osteopenic postmenopausal women [10–17]. In both trials, isolated genistein administration exhibited a highly standardized bioavailability
1124
Osteoporos Int (2014) 25:1123–1129
and pharmacokinetic behavior. The quality of an individual’s life is an important end point in medical and health outcomes research [18]. In many circumstances, quality of survival is as important as quantity [19]. Health-related quality of life (HRQL) is a reflection of the way patients feel or function. To date, no data exist in literature on the effects of genistein on quality of life. The goal of this study was to evaluate the effect of genistein treatment on health-related quality of life in osteopenic postmenopausal women.
Methods Study population The study was approved by the Local Ethics Committee for Medical Research, Messina University Hospital “G. Martino,” and carried out in accordance with the Helsinki Declaration. All subjects gave their informed written consent. A total of 575 women from the parent study met the inclusion criteria, and 186 of these women refused to participate, leaving 389 women. After a 4-week stabilization with consumption of the standard fat-reduced diet, the 389 women were randomly assigned to receive genistein (n =198) or placebo (n =191). A computerized database was used for randomization. About 40 % of women in both groups have compiled the questionnaires; therefore, the evaluation of HRQL and depression symptoms was carried out only in 262 participants after randomization: 139 in the genistein group and 123 in the placebo group. Placebo and genistein tablets were identical in appearance and taste. Both genistein and placebo tablets contained calcium carbonate (500 mg) and vitamin D (400 IU). The flowchart describing the progress of the participants during the trial is represented in Fig. 1. All the
women were between 49 and 67 years of age, with at least 12 months of menopause at baseline, were in good general health, had not had a menstrual period in the preceding year or had undergone surgically induced menopause, had a follicle stimulating hormone level >50 IU/L, and had a serum 17βestradiol (E2) level ≤100 pmol/L. Exclusion criteria were clinical or laboratory evidence of confounding systemic diseases such as cardiovascular, hepatic, endocrine, and renal disorders; rheumatoid arthritis; coagulopathy; use of oral or transdermal estrogens, progestin, androgen, or other steroids; cholesterollowering therapy or cardiovascular medications in the preceding 6 months; smoking habit of more than two cigarettes per day; previous treatment with bisphosphonates or any drug that could affect the skeleton in the preceding year; a family history of estrogen-dependent cancer and BMD at the femoral neck ≥0.795 g/cm2. This BMD value corresponds to a T-score of −1 SD.
Genistein plasma level Genistein levels were measured at baseline and after 1 and 2 years in serum samples by using a time-resolved fluorimetric assay, following the manufacturer’s instruction (Labmaster TR-FIA test, Turku, Finland) [20]. Briefly, 200 μl of 100 mM acetate buffer, pH 5.0, containing 0.2 U/ml of βglucuronidase and 2 U/ml of sulfatase was added to 200 μl of serum. Samples were then incubated overnight at 37 °C. The day after, the free genistein was extracted twice with 1.5 ml of diethyl ether by careful mixing for 3 min, then 200 μl of assay buffer was added to the samples to achieve a concentration corresponding to the original genistein concentration in plasma. Twenty microliters of this solution was then
Fig. 1 Flowchart describing the progress of the participants during the trial
Parent study: effects of genistein on bone loss and cardiovascular risk prevention Randomized: N= 389
Baseline Placebo N=191
Subgroup Placebo N=108 included in analyses for Quality of life evaluation
Subgroup placebo Drop out N=15
Genistein N=198
2 nd year
Subgroup Genistein N=121 included in analyses for Quality of life evaluation
Subgroup Genistein Drop out N=18
Osteoporos Int (2014) 25:1123–1129
1125
used for time-resolved fluoroimmunoassay. Fluorescence was read by using a PerkinElmer Victor 1420 Multilabel Counter.
Quality of life We assessed participants’ HRQL using the Italian version of the Short Form-36 (SF-36) questionnaire and Zung Self-rating Depression Scale (ZSDS) at baseline, after 1 year and at the end of the intervention period. We asked participants to fill in the forms at home, 1 day before their visit at our outpatient clinic. The Italian version of SF-36 is a self-administered questionnaire containing 36 items that measure the perception of health on eight dimensions: physical functioning, social functioning, role limitations because of physical problems, role limitations because of emotional problems, mental health, vitality, pain, and general health perception. The eight dimensions cover functional status, well-being, and overall evaluation of health. For each dimension, the possible scores range from 0 to 100, with higher scores indicating a better quality of life [21]. Domain scores can be summarized into a physical component score (PCS) and mental component score (MCS) [21]. For these two summary scales, a score below 50 reflects a worse HRQL compared to the average of the general population [21]. The Zung Self-rating Depression Scale is a short self-administered survey to quantify the depressed status of a patient. There are 20 items on the scale that rate the four common characteristics of depression: the pervasive effect, the physiological equivalents, other disturbances, and psychomotor activities. There are ten positively worded and ten
Table 1 Clinical characteristics of patients in the two groups
Values are mean ± SD
negatively worded questions. Each question is scored on a scale of 1 through 4 (based on these replies: “a little of the time,” “some of the time,” “good part of the time,” “most of the time”). Scores on the test range from 20 through 80. The scores fall into four ranges: 20–49, normal range; 50–59, mildly depressed; 60–69, moderately depressed; and 70 and above, severely depressed [22]. Statistical analyses The primary evaluation of the efficacy data, according to the intention to treat, included all 262 postmenopausal women in which SF-36 and ZSDS were measured at baseline and after 1 and 2 years of treatment. Comparisons between groups were performed by the unpaired t test or Mann–Whitney test, and within-group comparisons were determined with the paired t test or Wilcoxon matched paired rank sum test for paired data, as appropriate. The Fisher exact test was used to calculate differences in the proportion of categorical variables. A p value
