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huihui zhang, fan qi, xiongbing zu, liang xu, jianguang miao, lin qi
department of urology, xiangya hospital, central south university, changsha, 410008, hunan, pr china
abstract
objectives: to assess the efficacy and safety of fufang xuanju capsule in males with late-onset hypogonadism (loh) complaining of sexual dysfunction during three months.
methods: a double-blind, randomized, placebo-controlled study was conducted with a treatment group (n=57) and placebo group (n=50). we assessed through androgen deficiency in aging male (adam), international index of erectile function (iief-5) questionnaires and clinical and laboratorial examinations. patients in the treatment group and placebo group received fufang xuanju capsules (3.78 g) and placebo capsules daily for 3 months, respectively.
results: after treatment, the plasma total testosterone of both groups sustained, however, libido and erectile dysfunction in patients of the treatment group but not placebo group were significantly improved, measured by elevated scores of iief-5 (p < 0.05). the overall efficacy rate of fufang xuanju capsule for loh was 71.9% (p < 0.05). the most striking clinical effects were observed in patients exhibiting mild and moderate erectile dysfunction (p < 0.05). no severe adverse effects were observed during the period of study. the remaining parameters such as total prostate-specific antigen (tpsa), prostate volume and uroflow rate remained stable.
conclusions: fufang xuanju capsule proves to be an effective and safe treatment in a short time to alleviate symptoms of sexual dysfunction in loh patients, especially in those exhibiting mild and moderate ed. little effect on the level of total testosterone makes it well suitable for loh patients which have contraindications of testosterone replacement therapy (trt).
keywords: late-onset hypogonadism; fufang xuanju capsule; sexual dysfunction; treatment.
1. introduction
late-onset hypogonadism (loh) is defined as a clinical and biochemical syndrome associated with advancing age and characterized by typical symptoms and a deficiency in serum testosterone levels (below the young healthy adult male reference range)[1]. it may significantly reduce quality of life and adversely affects the function of multiple organ systems. sexual dysfunction is a common complain in patients of loh [2]. at present, testosterone replacement therapy (trt) has been applied to alleviate the symptoms of sexual dysfunction in loh patients. several studies have reported clinical and laboratorial improvement when they are submitted to trt, contributing to their quality of life, libido and erectile function (ed) [3-5]. nevertheless, trt has the risks of therapy. these concerns are primarily in regards to liver, prostate, lipid profile and cardiovascular system, hematological changes, sleep patterns, social behavior and emotional state [6]. prostate disease, particularly prostate cancer, and cardiovascular disease are the main safety concerns [7]. thus, there is a need to explore alternative effective pharmacotherapy for loh patients, especially for those who have contraindications of trtcontraindicationcontraindicationcontraindicationcontraindication.
in theory of traditional chinese medicine, loh is considered as a disease associated with hyperlink "http://www.ncbi.nlm.nih.gov/pubmed/20180429" kidney-yang deficiency [8]. the corresponding treatment is to tonify the kidney and strengthen yang. fufang xuanju capsule, a traditional chinese medicine product, has been developed for the treatment of sexual dysfunction. it�s organized by four chinese medical herbs: xuanju, epimedium brevicornum maxim, fructus cnidii, lycium barbarum l. all active ingredients have a primary effect on tonifying the kidney and strengthening yang. previous researches have demonstrated that fufang xuanju capsule can improve the sexual function [9,10]. but the clinical effects of fufang xuanju capsule in patients with loh remain unknown. the purpose of the present study was to evaluate the short-term effectiveness and safety of fufang xuanju capsule for the treatment of patients with loh.
2. materials and methods
2.1 subjects
from january 2009 to september 2010, those middle-aged and elderly patients complaining of sexual dysfunction (decreased libido and organic ed) were screened out from our outpatient department. they all received an androgen deficiency in aging male (adam) questionnaire and plasma testosterone detection. then 111 patients with low serum total testosterone levels (tt<11.5 nmol/ml) [11], and adam positive (questions 1 or 7, or other three questions, except for questions 1 and 7, are positive) [12] were diagnosed as loh and enrolled in this study. they were randomly divided into treatment group (n=58) or placebo group (n=53). exclusion criteria were pathologies which might be aggravated by testosterone administration, such as male breast cancer, biopsy-confirmed prostate cancer, elevated plasma levels of total prostate-specific antigen (tpsa > 4 ng/ml), abnormal findings in digital rectal examination (until prostate cancer was ruled out), severe cardiac disease, diabetes mellitus, severe lower urinary tract obstructive symptoms, polycythemia, severe renal and liver disease. all patients were informed on the purposes of the research and its potential benefits as well as of adverse effects of the drugs, and the study was approved by the ethics committee of the hospital.
2.2 treatment
all enrolled patients were subjected to the treatment with fufang xuanju capsules (strong pharmaceutical group, licence no. z20060462) or placebo capsules as three capsules (0.42 g per capsule) in the morning, afternoon and evening respectively, immediately after meals.
2.3 measurements
before and after the treatment, all patients should be evaluated by international index of erectile function (iief-5), transrectal ultrasound and laboratory tests. the iief-5 is a questionnaire for assessing erectile dysfunction [13]. the higher the scoring in a total of 25 points, the better the sexual function: scores above 22 on are considered normal, without any ed; between 17 and 21, mild ed; between 12 and 16, mild to moderate ed; between 8 and 11, moderate ed; and between 5 and 7, severe ed. transrectal ultrasound was performed for measurement of prostate volume. laboratory tests included sexual hormone levels, liver function, blood lipid, blood glucose, hematocrit value, uroflow rate, tpsa. blood sample for laboratory tests was taken in the early morning between 8:00 and 10:00 a.m.
after 3 months of treatment, all patients were followed up within 2 months. in the end, the efficacy of fufang xuanju capsule for loh is defined as follows: excellent response group (excellent), iief-5 score were normalized; medium response group (medium), iief-5 score was improved and turned to a better grade, but still not normalized.; poor response group (poor), iief-5 score was improved but did not turn to a better grade. no response group (ineffectiveness), iief-5 score was not improved.
2.4 statistical analysis
statistical analyses were performed using paired t-test or chi-square �2 test. p value < 0.05 was considered significant. the values are presented as the mean � standard deviation (sd).
3. results
no severe adverse events were observed in this study period. well-tolerated mild inappetence or nausea was found in 3 patients. however, another 4 patients needed to be excluded from the study for discontinued treatment. therefore, finally 57 patients of treatment group and 50 patients of placebo group were included for analysis in our study. the characteristics of them are listed in table1.
through clinical assessment of the iief-5 questionnaire scores in the present study, the general sexual function of loh men improved significantly as the total score increased from 11.2�5.6 to 17.9�6.3 after 3 months of treatment with fufang xuanju capsule (table 2). in detail, it might be most beneficial to erection firmness, maintaining erection frequency and intercourse satisfaction (p < 0.01), followed by erection confidence and maintaining erection ability (p < 0.05). moreover, increased libido was reflected in more than 90% patients (data not shown). however, no improved erectile function was found in patients of placebo group.
among the 57 patients with loh who received fufang xuanju capsule, 8 (14.0%) achieved normalized iief-5 scores, 20 (35.1%) achieved improved iief-5 scores and turned to a better grade, and 13 (22.8%) achieved improved iief-5 scores but did not turn to a better grade. thus, the overall efficacy rate of fufang xuanju capsule for loh was 71.9% (excellent medium poor) (table 3).
no significant changes in tt, serum tpsa, prostate volume and uroflow rate were noticed while receiving fufang xuanju capsules and placebo capsules (p < 0.05) (table 4). liver function, blood lipid, blood glucose and hematocrit value were all stable as before (data not shown).
4. discussion
aging is characterized by a progressive decline of virtually all physiological functions. among them is the secretory capacity of the endocrine glands [14]. the testosterone concentration in men remains stable until around the age of 40 years, after which the circulating level of tt decreases by 1%~2% annually and that of the biologically active free testosterone by 2%~3% [15]. the recommended indications for trt in loh include low t levels together with typical symptoms [1]. according to a recent guideline [16], a total testosterone level below 12 nmol/l is considered pathological. however, abnormal testosterone level is still controversial, due to the uncertainty of different individuals, aged groups, race and laboratory test. thus, a lower cut-off value for definition of androgen deficiency from chinese men is used in our study [17]. that was defined as tt < 11.5 nmol/l.
the adam questionnaire is widely used for screening loh cases because of its high sensitivity, time saving and easy operation. it has 88% sensitivity and 60% specificity [12]. the adam questionnaire is applicable to the chinese population. the sensitivity and specificity of adam in the chinese population are basically consistent with the results of most studies abroad. the iief-5 was reorganized using iief question 15 (erection confidence), question 2 (erection firmness), question 4 (erection frequency), question 5 (ability to maintain an erection), and question 7 (intercourse satisfaction) [13]. the iief-5 has been proved to be a reliable test for the diagnosis of the presence and severity of ed. thus, the adam and iief-5 were selected to apply in our study accordingly.
it considers in traditional chinese medicine that loh belongs to the category of �yang-insufficiency of the kidney�. fufang xuanju capsule is considered as a drug which can nourish the kidney-yang. in our trial, fufang xuanju capsule also showed satisfying therapeutic effect in loh patients with sexual dysfunction which was not found in the placebo group. the pre-treatment baseline of 57 patients revealed low tt, low libido and low iief-5 scores. after 3 months treatment with fufang xuanju capsule, low libido and low iief-5 scores had significantly improved, though they were not yet within normal range. the overall efficacy rate of fufang xuanju capsule for loh was 71.9% (excellent medium poor). the response to loh treatment is also variable. compared with the severe subgroup, the moderate and mild group showed more significant efficacy rate. this may be due to insufficient course of treatment or complex etiology existing in these patients. actually, in contrast to western medicine, traditional chinese medicine is often characterized by comparatively mild but long lasting effect. interestingly, the level of tt did not changed after treatment, although the symptoms had been significantly alleviated.
in our study, the unchanged level of tt was observed after treatment. thus, it seems that fufang xuanju capsule performs in a non-hormonal way. it may directly targets the gonadal tissues, not through effects on the level of testosterone. although the functional mechanism of fufang xuanju capsule in loh patients remains largely unknown. from the perspective of modern western medicine, several hypotheses or experimental data have been advanced to explain its mechanism and effects. fufang xuanju capsule includes four chinese medical herbs: xuanju, epimedium brevicornum maxim, fructus cnidii, lycium barbarum l. in rats treatment with xuanju, erection function and mating ability were significantly enhanced, with increasing capture rate and mating rate [9]. icariinis, the major compound of epimedium brevicornum maxim, has testosterone mimetic properties and biological effects on selectively inhibiting phosphodiesterase-5 (pde5), suggesting it a therapeutic potential on erectile dysfunction [18, 19]. as to another component, fructus cnidii, active ingredient of which is called osthole. osthole possesses a relaxing effect on rabbit corpus cavernosum tissues which was attributable to the release of no from sinusoidal endothelium and to the potentiation of the no-stimulated cgmp and/or camp signal mediating relaxation of cavernosal smooth muscle by inhibition of phosphodiesterase [20]. these results might confirm further the therapeutic effect of fufang xuanju capsule in loh patients with sexual dysfunction. despite these, the underlying mechanism need to be further studied.
the adverse reactions of fufang xuanju capsule can be neglected. furthermore, the prostate volume and tpsa did not increase after treatment. the liver function, hematocrit value, blood lipid, blood glucose uroflow rate were not significantly changed.
the present study has suggested that fufang xuanju capsule is very beneficial to the libido and erectile function of loh patients when evaluated using the iief-5 questionnaire. however, compared with the results of the clinical trials of the pde5 inhibitors, the improvement in erections is not yet optimal. but improvement of libido, few adverse events and considerably cheaper cost made it a good compliance with the treatment in our study. lack of libido, high cost or the adverse events appeared to be the reasons to discontinue treatment with sildenafil [21]. moreover, without elevation of serum testosterone level, worry about side effects of trt may be precluded, also leading to a good compliance.
in conclusion, this is a pilot study and it has shown sexual dysfunction in patients with loh were alleviated after administration of fufang xuanju capsule, without serious adverse reactions. the most striking clinical effects were observed in patients exhibiting mild and moderate ed. hence, fufang xuanju capsule may be a novel candidate for the treatment of loh patients with sexual dysfunction, especially for cases which are not suitable for trt, in view of unchanged tt level. admittedly, this is only a single-centre and short-term study, so we recommend a rigorous, randomized controlled, multicentre, long-term study to confirm our results.
acknowledgement
this work was supported by traditional chinese medicine research project, hunan, china (no.2010114).
declaration of interest
the authors declare no conflicts of interest. the authors alone are responsible for the content and writing of the paper.
reference
1. nieschlag e, swerdloff r, behre hm, gooren lj, kaufman jm, legros jj, lunenfeld b, morley je, schulman c, wang c weidner w, wu fc: investigation, treatment, and monitoring of late-onset hypogonadism in males: isa, issam, and eau recommendations. j androl 2006, 27(2):135-137.
2. travison tg, morley je, araujo ab, o'donnell ab, mckinlay jb: the relationship between libido and testosterone levels in aging men. j clin endocrinol metab 2006, 91(7):2509-2513.
3. andrade es, jr., clapauch r, buksman s: short term testosterone replacement therapy improves libido and body composition. arq bras endocrinol metabol 2009, 53(8):996-1004.
4. chiang hs, cho sl, lin yc, hwang ti: testosterone gel monotherapy improves sexual function of hypogonadal men mainly through restoring erection: evaluation by iief score. urology 2009, 73(4):762-766.
5. yassin aa, saad f: improvement of sexual function in men with late-onset hypogonadism treated with testosterone only. j sex med 2007, 4(2):497-501.
6. lunenfeld b: androgen therapy in the aging male. world j urol 2003, 21(5):292-305.
7. liu py, swerdloff rs, veldhuis jd: clinical review 171: the rationale, efficacy and safety of androgen therapy in older men: future research and current practice recommendations. j clin endocrinol metab 2004, 89(10):4789-4796.
8. zhang ch, li yf, zhao hm: curative effect of chinese drugs combined with andriol in the treatment on 30 cases of late onset hypogonadism in males. chinese journal of andrology 2007, 6:46-47.(in chinese)
9. jiang h, shang xj, guo j, li z, zhao lm, shao y, ping p, huang yf, zhu jc: multi-centered clinical trial of fufang xuanju capsule for oligoasthenospermia. zhonghua nan ke xue 2008, 14(8):755-758. (in chinese)
10. zhang fb, tian y, du ld: xuanju compound capsule combined with erogenous focus exercise is effective for premature ejaculation. zhonghua nan ke xue 2006, 12(12):1139-1140. (in chinese)
11. li jy, li xy, li m, zhang gk, ma fl, liu zm, zhang ny, meng p: decline of serum levels of free testosterone in aging healthy chinese men. aging male 2005, 8(3-4):203-206.
12. morley je, charlton e, patrick p, kaiser fe, cadeau p, mccready d, perry hm, 3rd: validation of a screening questionnaire for androgen deficiency in aging males. metabolism 2000, 49(9):1239-1242.
13. rosen rc, cappelleri jc, smith md, lipsky j, pena bm: development and evaluation of an abridged, 5-item version of the international index of erectile function (iief-5) as a diagnostic tool for erectile dysfunction. int j impot res 1999, 11(6):319-326.
14. kalinchenko s, vishnevskiy el, koval an, mskhalaya gj, saad f: beneficial effects of testosterone administration on symptoms of the lower urinary tract in men with late-onset hypogonadism: a pilot study. aging male 2008, 11(2):57-61.
15. feldman ha, longcope c, derby ca, johannes cb, araujo ab, coviello ad, bremner wj, mckinlay jb: age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the massachusetts male aging study. j clin endocrinol metab 2002, 87(2):589-598.
16. wu fc, tajar a, pye sr, silman aj, finn jd, o'neill tw, bartfai g, casanueva f, forti g, giwercman a et al: hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the european male aging study. j clin endocrinol metab 2008, 93(7):2737-2745.
17. wang c, nieschlag e, swerdloff r, behre hm, hellstrom wj, gooren lj, kaufman jm, legros jj, lunenfeld b, morales a, morley je, schulman c, thompson im, weidner w, wu fc .investigation, treatment, and monitoring of late-onset hypogonadism in males: isa, issam, eau, eaa, and asa recommendations. j androl 2009, 30(1):1-9.
18. liu wj, xin zc, xin h, yuan ym, tian l, guo yl: effects of icariin on erectile function and expression of nitric oxide synthase isoforms in castrated rats. asian j androl 2005, 7(4):381-388.
19. zhang zb, yang qt: the testosterone mimetic properties of icariin. asian j androl 2006, 8(5):601-605.
20. chen j, chiou wf, chen cc, chen cf: effect of the plant-extract osthole on the relaxation of rabbit corpus cavernosum tissue in vitro. j urol 2000, 163(6):1975-1980.
21. klotz t, mathers m, klotz r, sommer f: why do patients with erectile dysfunction abandon effective therapy with sildenafil (viagra)? int j impot res 2005, 17(1):2-4.
table 1. characteristics of 57 loh patients represented with ed
characteristicsmean age
(years)age range (years)duration of ed (months)ed severity (n)mildmild to moderatemoderatesevereplacebo group5845-72151552010treatment group5641-69161672311
table 2. erectile function of patients before and after treatment with fufang xuanju capsule evaluated by iief-5
iief-5placebo grouptreatment groupbaselineafter treatmentbaselineafter treatmentq1, erection confidence *1.6�0.51.8�0.41.8�0.53.3�0.9q2, erection firmness �%2.2�1.22.0�1.52.0�1.13.6�1.5q3, maintain erection frequency �%2.0�1.52.5�1.22.3�1.03.7�1.2q4, maintain erection ability *2.5�1.33.3�1.32.4�1.53.5�1.4q5, intercourse satisfaction �%2.8�1.43.0�1.12.7�1.23.8�1.3total score �%11.2�5.611.8�4.911.2�5.617.9�6.3q, question. *p<0.05, baseline versus after treatment for treatment group; �%p<0.01, baseline versus after treatment for treatment group, paired t-test. no significant differences were found in the placebo group.
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