Abstract
The purpose of this study was to evaluate the efficacy and safety of saikokaryukotsuboreito (SKRBT), which is widely used for a variety of clinical conditions, neuropsychiatric disorders, for patients with LOH-related symptoms. Twenty-two eugonadal patients over 40 years of age with LOH-related symptoms were included in this study. SKRBT was given orally to these patients three times daily to a total of 7.5 g/day for more than two months. Laboratory and endocrinological profiles were reviewed, and LOH symptoms were judged by means of several health assessment instruments such as the Aging Males' Symptoms (AMS) scale, Self-rated Depression Scale (SDS), International Prostate Symptom Score (IPSS), and King's Health Questionnaire (KHQ). Total AMS scores and AMS subscores were significantly decreased after the treatment. The KHQ, general health perception and impact on life scores were also significantly decreased, although no significant improvement was observed in other KHQ factors or the SDS score or IPSS. The serum concentrations of testosterone fractions did not change with treatment. Laboratory values did not change, and no adverse effects were identified after treatment. We conclude that SKRBT may be considered for treatment of patients with LOH-related symptoms for eugonadal patients.
Introduction
It is well known that the serum androgen level declines with age and that androgens play many physiological roles in various organs and tissues. Late-onset hypogonadism (LOH), a biochemical syndrome associated with advancing age and characterized by a deficiency in serum androgen with or without decreased genomic sensitivity to androgen, has received widespread attention in the popular and medical media Citation[1]. Reported symptoms are easily recognized and include diminished sexual desire and erectile quality, particularly nocturnal erections; changes in mood with concomitant decreases in intellectual activity and spatial orientation, fatigue, depression and anger; decrease in lean body mass with associated decreases in muscle volume and strength; decrease in body hair and skin alterations; decreased bone mineral density resulting in osteoporosis; and increase in visceral fat Citation[2-7].
Because the concept of LOH has been accepted in Japan as a systemic disorder associated with aging, the treatment of LOH with respect to quality of life has recently received increased attention. The first-line treatment for LOH is androgen supplementation because the main cause of this disorder is the age-related decrease in androgens. Androgen replacement therapy (ART) aims to substitute the deficient hormone with a perfect copy of the natural hormone at a dosing schedule that generates physiological hormone levels 24 hours a day [3]. There have been reports that ART can improve LOH-related symptoms by enhancing sexual function, libido, and the sense of well-being and that bone and muscle mass are maintained Citation[8-12]. However, no significant difference in LOH-related symptoms has been found between patients with and without hypogonadism, as we and others previously reported Citation[13-15]. Furthermore, it has also been reported that LOH-related symptoms are not significantly related to serum levels of total testosterone (TT), analogue ligand-free testosterone (aFT), estradiol (E2), luteinizing hormone (LH), follicle-stimulating hormone (FSH), dehydroepiandrosterone-sulphate (DHEA-S) or growth hormone (GH) Citation[16]. Thus, it is not surprising that many eugonadal patients complain of LOH-related symptoms. Currently, the treatment of such patients is problematic, although we know that symptom-based medications, such as phosphodiesterase type 5 inhibitor (PDE5I) for erectile dysfunction, serotonin-noradrenalin reuptake inhibitor or selective serotonin reuptake inhibitor for depression, and sleeping pills for disordered sleep, are effective. Herbal medicines may be an option for the treatment for men with LOH-related symptoms; several herbal medicines are used to treat symptoms in menopausal women Citation[17],Citation[18]. Saikokaryukotsuboreito (SKRBT) is an important Japanese herbal preparation (kampo medicine, which uses most of the Chinese medical system including acupuncture and moxibustion but is primarily concerned with the study of herbs) that is widely used for a variety of clinical conditions, particularly neuropsychiatric disorders, in Japan. It is indicated for the relief of hypertension, arteriosclerosis, chronic renal disease, neurasthenia, neurotic palpitations, epilepsy, hysteria and erectile dysfunction (ED).
In the current study, we evaluated the efficacy of SKRBT for eugonadal patients with LOH-related symptoms, and we evaluated endocrinological changes associated with the treatment.
Materials and methods
Twenty-two men over 40 years of age with a chief complaint of decreased libido, erectile dysfunction, depression, general fatigue, or another LOH-related symptom, who visited our special clinic for LOH at Osaka University Hospital between April 2005 and December 2006 and in whom the serum concentration of TT was more than 3.0 ng/ml, were included in the study. No patients with a serious disease such as malignancy or suicidal depression, with a high prostate-specific antigen (PSA) level (more than 4.0 ng/ml), or refusing treatment was included in the study. Patients ranged in age from 40 to 67 years (53.8 ± 9.2 years). All patients provided written informed consent for participation in this study.
SKRBT was supplied in the form of a water-extracted dried powder that was manufactured from a mixture of the crude drugs listed in (Tsumura & Co., Tokyo, Japan). SKRBT was given orally 3 times a day (before meals) to a total dose of 7.5 g/day for more than 2 months. General symptoms of LOH were judged according to the Aging Males' Symptoms (AMS) scale Citation[19]. Depressive states were judged according to the Self-rated Depression Scale (SDS) Citation[20]. Voiding function was evaluated by the International Prostate Symptom Score (IPSS) Citation[21] and the King's Health Questionnaire (KHQ) Citation[22] Haematopoiesis, liver function, lipid levels and serum PSA were also evaluated. Endocrinological variables, serum TT, aFT, E2, LH, FSH, prolactin (PRL), GH, insulin-like growth factor-1 (IGF-1), DHEA and DHEA-S levels were examined. Calculated free testosterone (cFT) and calculated bioavailable testosterone (cBT) were determined on the basis of TT and sex hormone binding globulin levels according to the formula provided by the International Society for the Study of the Aging Male (available at http://www.issam.ch/freetesto.htm) Citation[1]. All blood samples were collected between 9:00 am and 11:00 am for monitoring of endocrinological variables. Laboratory and endocrinological values and LOH-related symptoms determined before and after treatment were compared to evaluate the efficacy and safety of SKRBT for LOH.
Table I. Components of SKRBT. Seven point five g of this product contains 4.5 g of dried extract obtained from mixed raw herbs in the preceding.
Data are presented as mean ± SD, and differences in values determined before and after treatment were analysed by paired Student's t-test. A P-value of less than 0.05 was considered statistically significant.
Results
Laboratory values before and after SKRBT treatment are shown in . None changed significantly in response to SKRBT treatment. Endocrinological variables before and after SKRBT treatment are shown in No endocrinological variables, including TT, aFT, cFT and cBT, were altered. With respect to LOH-related symptoms, AMS scores were significantly decreased after treatment. Furthermore, each of the AMS subscores (psychological, somatovegetative, sexual) was significantly decreased. No significant improvement was observed in the SDS score or IPSS (). KHQ scores pertaining to general health perception and impact on life were significantly decreased, whereas other domain scores including role limitations, physical limitations, social limitations, personal relationships, emotions, sleep/energy, and incontinence severity did not change (). No sleep disturbances or increased urinary symptoms such as dysuria, pollakisuria, nocturia, and weak stream were identified after treatment.
Table II. Laboratory values before and after SKRBT treatment.
Table III. Endocrinologic variables before and after SKRBT treatment.
Table IV. LOH-related symptom scores before and after SKRBT treatment.
Table V. KHQ scores before and after SKRBT treatment.
Discussion
The efficacy of ART for patients with LOH has been reported Citation[10]. However, in a study of 161 healthy, elderly men, none of the AMS subscores (psychological, somatovegetative, sexual) correlated significantly with any testosterone fraction Citation[14]. Likewise, no correlation was found between AMS scores and testosterone levels in a study of 81 self-referred patients with LOH Citation[13]. We have also reported that LOH-related symptoms as evaluated by the AMS scale and other quality-of-life questionnaires were not related to serum testosterone concentrations in a study of 90 patients with LOH Citation[15]. Furthermore, about 50% of patients who complain of LOH symptoms and visiting a special clinic for LOH present with eugonadism. Thus, it remains unclear whether all LOH-related symptoms can be explained by a decrease in the serum testosterone concentration alone. In addition, an increased prevalence of major depressive disorder was reported in Japanese patients with LOH Citation[23],Citation[24]. Therefore, the current problem is how to treat eugonadal patients with LOH-related symptoms by any means other than a testosterone preparation.
In recent years, studies using herbal medicines to treat several psychological diseases, such as anxiety disorders and depression, have emerged. Piper methysticum (kava) is the most popular south pacific medicinal plant. Seven randomized controlled trials (RCTs) have shown that kava reduced Hamilton Anxiety Scale scores significantly on patients with generalized anxiety disorder Citation[25]. St John's wort (SJW) is another popular supplement for treating depression. Several RCTs suggested that SJW extract and standard antidepressants have similar beneficial effects Citation[25]. In traditional Persian medicine, Crocus sativus (saffron) has been to treat depression, with four RCTs currently existing supporting the use Citation[25]. Furthermore, Rhodiola rosea (Roseroot) is also one of the most promising plant medicines in the treatment of depression Citation[26]. Regarding kampo it was reported that saikokeishikankyoto was effective for depression in peri- and post-menopausal women Citation[27]. It was also reported that keishibukuryogan, tokishyakuyakusan and kamishoyosan improved climacteric symptoms Citation[28]. Furthermore, kamishoyosan was proved to possess an antidepressant-like effect at a behavioural and molecular level in rats Citation[29]. We used SKRBT in this study. SKRBT is familiar to Japanese urologists because it has been used for ED in Japan. PDE5Is are first-line therapeutics for ED, but SKRBT has been used clinically for patients in whom PDE5Is cannot be used because of heart failure and other contraindications. Atherosclerosis together with hyperlipidemia is a well-known risk factor for ED Citation[30]. SKRBT has recently been reported to have potential for decreasing total cholesterol and trigriceride levels, and preventing the development of vascular complications in patients with hyperlipidemia Citation[31]. Improvement in ED by SKRBT may be via this pharmacodynamic action; however, the mechanism by which SKRBT improves erection has not been fully elucidated. In addition, several studies have shown that SKRBT is effective for treating depression, neurosis, anxiety, and insomnia Citation[32],Citation[33]. Basic research has shown that SKRBT attenuates acute stress-induced elevation of the serum corticosterone level and that it increases motor activity of mice subjected to a behavioural despair test Citation[34]. Stress activates the hypothalamo-pituitary-adrenal axis. Generally, the glucocorticoids secreted from the adrenals following secretions of hypothalamic corticotrophin-releasing hormone (CRH) and pituitary adrenocorticotropic hormone (ACTH) induced by stress serve as feedback inhibitors of CRH and ACTH to increase resistance to stress. Disruption of this hypothalamo-pituitary-adrenal axis system is thought to be one of the causes of depression. Recently, it was shown in an animal model that chronic stress-induced disruption of the feedback system was improved by treatment with SKRBT Citation[35]. Systemic dysfunction of neurotransmitters such as dopamine and serotonin is also thought to be a cause of depression. Treatment with SKRBT was reported to significantly prevent chronic stress-induced decreases in extracellular concentrations of dopamine and serotonin in the prefrontal cortex Citation[36]. These two mechanisms underlie the effect of SKRBT on depression. Our tests showed no alteration in endocrinological variables including any testosterone fraction. Thus, the effect of SKRBT on LOH-related symptoms does not depend on the patient's serum testosterone concentration, although subjects of the present study were eugonadal patients. It was also reported that the non-toxic dose of this drug in rats exceeds 200 mg/kg/day Citation[35]. SKRBT is given orally. This simple method of administration and the non-toxicity and effectiveness of SKRBT are the main reasons why Japanese physicians prefer to use SKRBT for patients with LOH-related symptoms including depression and ED.
In the present study, the total AMS score was significantly decreased after treatment with SKRBT. Sexual and psychological subscores as well as the somatovegetative subscore were significantly decreased, as expected, although the change in the SDS score did not reach statistical significance. There was also no alteration in laboratory and endocrinological values with SKRBT treatment. This points to another benefit of treatment with SKRBT. Instead, our data showed that the KHQ general health perception and impact on life scores decreased significantly. This means that SKRBT may affect urinary function positively to some degree. Furthermore, treatment with SKRBT did not result in polycythemia in our patients, although we and others have reported a transient increase in the haematocrit of patients given a testosterone preparation or human chorionic gonadotropin Citation[37],Citation[38]. Indeed, we did not find any other adverse symptom associated with SKRBT treatment. Therefore, we emphasize that treatment with SKRBT is quite safe for elderly patients.
Conclusion
We conclude that SKRBT is a safe and effective treatment for patients with LOH-related symptoms. Although a placebo effect cannot be ruled out, treatment with SKRBT should be considered as an option for patients with LOH-related symptoms, especially for eugonadal patients.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
Related Research Data
References
- Morales A, Lunenfeld B. Investigation, treatment and monitoring of late-onset hypogonadism in males. Official recommendations of ISSAM. International Society for the Study of the Aging Male. Aging Male 2002; 5: 74–86
- Morley J E. Androgens and aging. Maturitas 2001; 38: 61–71, discussion 71–63
- Morales A, Buvat J, Gooren L J, Guay A T, Kaufman J M, Tan H M, Torres L O. Endocrine aspects of sexual dysfunction in men. J Sex Med 2004; 1: 69–81
- Morley J E, Perry H M, III. Androgen deficiency in aging men. Med Clin North Am 1999; 83: 1279–1289, vii
- Vermeulen A. Andropause. Maturitas 2000; 34: 5–15
- Morales A, Heaton J P, Carson C C, III. Andropause: A misnomer for a true clinical entity. J Urol 2000; 163: 705–712
- Tsujimura A, Matsumiya K, Matsuoka Y, Takahashi T, Koga M, Iwasa A, Takeyama M, Okuyama A. Bioavailable testosterone with age and erectile dysfunction. J Urol 2003; 170: 2345–2347
- Morley J E. Testosterone replacement and the physiologic aspects of aging in men. Mayo Clin Proc 2000; 75: S83–87
- Morley J E. Testosterone replacement in older men and women. J Gend Specif Med 2001; 4: 49–53
- Morley J E, Perry H M, III. Androgen treatment of male hypogonadism in older males. J Steroid Biochem Mol Biol 2003; 85: 367–373
- Comhaire F H. Andropause: Hormone replacement therapy in the ageing male. Eur Urol 2000; 38: 655–662
- Morales A, Johnston B, Heaton J P, Lundie M. Testosterone supplementation for hypogonadal impotence: Assessment of biochemical measures and therapeutic outcomes. J Urol 1997; 157: 849–854
- T'Sjoen G, Feyen E, De Kuyper P, Comhaire F, Kaufman J M. Self-referred patients in an aging male clinic: Much more than androgen deficiency alone. Aging Male 2003; 6: 157–165
- T'Sjoen G, Goemaere S, De Meyere M, Kaufman J M. Perception of males' aging symptoms, health and well-being in elderly community-dwelling men is not related to circulating androgen levels. Psychoneuroendocrinology 2004; 29: 201–214
- Tsujimura A, Matsumiya K, Miyagawa Y, Takao T, Fujita K, Takada S, Koga M, Iwasa A, Takeyama M, Okuyama A. Comparative study on evaluation methods for serum testosterone level for PADAM diagnosis. Int J Impot Res 2005; 17: 259–263
- Miwa Y, Kaneda T, Yokoyama O. Correlation between the Aging Males' Symptoms Scale and sex steroids, gonadotropins, dehydroepiandrosterone sulfate, and growth hormone levels in ambulatory men. J Sex Med 2006; 3: 723–726
- Chen J T, Shiraki M. Menopausal hot flash and calciotonin gene-related peptide; Effect of Keishi-bukuryo-gan, a kampo medicine, related to plasma calciotonin gene-related peptide level. Maturitas 2003; 45: 199–204
- Ushiroyama T, Ikeda A, Sakuma K, Ueki M. Changes in serum tumor necrosis factor (TNF-alpha) with kami-shoyo-san administration in depressed climacteric patients. Am J Chin Med 2004; 32: 621–629
- Heinemann L A, Zimmermann T, Vermeulen A, Thiel C. A new ‘aging males' symptoms' (AMS) rating scale. Aging Male 1999; 2: 105–114
- Zung W W, Richards C B, Short M J. Self-rating depression scale in an outpatient clinic. Further validation of the SDS. Arch Gen Psychiatry 1965; 13: 508–515
- Barry M J, Fowler F J, Jr, O'Leary M P, Bruskewitz R C, Holtgrewe H L, Mebust W K, Cockett A T. The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. J Urol 1992; 148: 1549–1557, discussion 1564
- Kelleher C J, Cardozo L D, Khullar V, Salvatore S. A new questionnaire to assess the quality of life of urinary incontinent women. Br J Obstet Gynaecol 1997; 104: 1374–1379
- Yoshida N M, Kumano H, Kuboki T. Does the Aging Males' Symptoms scale assess major depressive disorder? A pilot study. Maturitas 2006; 53: 171–175
- Sato Y, Tanda H, Kato S, Onishi S, Nakajima H, Nanbu A, Nitta T, Koroku M, Akagashi K, Hanzawa T. Prevalence of major depressive disorder in self-referred patients in a late onset hypogonadism clinic. Int J Impot Res 2007; 19: 407–410
- Pittler M H, Ernst E. Kava extract for treating anxiety. Cochrane Database Syst Rev 2003, CD003383
- Shevtsov V A, Zholus B I, Shervarly V I, Vol'skij V B, Korovin Y P, Khristich M P, Roslyakova N A, Wikman G. A randomized trial of two different doses of a SHR‐5 Rhodiola rosea extract versus placebo and control of capacity for mental work. Phytomedicine 2003; 10: 95–105
- Ushiroyama T, Ikeda A, Sakuma K, Ueki M. Chai-hu-gui-zhi-gan-jiang-tang regulates plasma interleukin-6 and soluble interleukin-6 receptor concentrations and improves depressed mood in climacteric women with insomnia. Am J Chin Med 2005; 33: 703–711
- Pan B, Kato Y, Sengoku K, Takuma N, Niizeki N, Ishikawa M. Treatment of climacteric symptoms with herbal formulas of traditional Chinese medicine. Gynecol Obstet Invest 2004; 57: 144–148
- Park S W, Kim Y K, Lee J G, Kim S H, Kim J M, Yoon J S, Park Y K, Lee Y K, Kim Y H. Antidepressant-like effects of the traditional Chinese medicine kami-shoyo-san in rats. Psychiatry Clin Neurosci 2007; 61: 401–406
- Saltzman E A, Guay A T, Jacobson J. Improvement in erectile function in men with organic erectile dysfunction by correction of elevated cholesterol levels: A clinical observation. J Urol 2004; 172: 255–258
- Nomura S, Hattori N, Sakakibara I, Fukuhara S. Effects of Saiko-ka-ryukotsu-borei-to in patients with hyperlipidemia. Phytomedicine 2001; 8: 165–173
- Sarai K. Oriental medicine as therapy for resistant depression: Use of some herbal drugs in the Far East (Japan). Prog Neuropsychopharmacol Biol Psychiatry 1992; 16: 171–180
- Kanba S, Yamada K, Mizushima H, Asai M. Use of herbal medicine for treating psychiatric disorders in Japan. Psychiatry Clin Neurosci 1998; 52: S331–333
- Sasaki K, Suzuki K, Yoshizaki F, Ando T. Effect of saiko-ka-ryukotsu-borei-to on the stress-induced increase of serum corticosterone in mice. Biol Pharm Bull 1995; 18: 563–565
- Mizoguchi K, Yuzurihara M, Ishige A, Sasaki H, Tabira T. Saiko-ka-ryukotsu-borei-to, an herbal medicine, prevents chronic stress-induced disruption of glucocorticoid negative feedback in rats. Life Sci 2002; 72: 67–77
- Mizoguchi K, Yuzurihara M, Ishige A, Aburada M, Tabira T. Saiko-ka-ryukotsu-borei-to, a herbal medicine, ameliorates chronic stress-induced depressive state in rotarod performance. Pharmacol Biochem Behav 2003; 75: 419–425
- Tenover J S. Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab 1992; 75: 1092–1098
- Tsujimura A, Matsumiya K, Takao T, Miyagawa Y, Takada S, Koga M, Iwasa A, Takeyama M, Okuyama A. Treatment with human chorionic gonadotropin for PADAM: A preliminary report. Aging Male 2005; 8: 175–179