Clinical efficacy of Japanese traditional herbal medicine (Kampo) in patients with late-onset hypogonadism

Abstract

Introduction. In addition to hormone replacement therapy, non-hormonal therapy, particularly Japanese traditional herbal medicine (Kampo), has been used to alleviate the various symptoms of female menopause. The efficacy and safety of Japanese traditional herbal medicine for male late-onset hypogonadism (LOH) are investigated.

Methods. One hundred fifty-one patients with LOH were treated via the administration of Japanese traditional herbal medicine. The most appropriate Japanese traditional herbal medicine was administered to patients according to their pathogenic alteration. After 4 weeks, the clinical efficacy was evaluated based on improvement of LOH symptoms and the score of the simplified menopausal index (SMI). Additionally, predictive factors of efficacy of Japanese traditional herbal medicine were analyzed.

Results. Among 151 patients with LOH, 63 (41.8%) achieved both relief from LOH symptoms and normalized SMI score (Excellent response group), whereas 44 (29.1%) achieved either relief from LOH symptoms or normalized SMI score (Fair). However, 44 (29.1%) patients displayed neither relief from LOH symptoms nor normalized SMI score (Poor). Adverse reactions were observed only in four (2.6%) patients. Patients displaying excess conditions and mild LOH symptoms appeared to be superior candidates for Japanese traditional herbal medicine.

Conclusion. Japanese traditional herbal medicine is an effective and safe treatment for LOH.

Keywords:

• Japanese traditional herbal medicine
• LOH
• pathogenic alteration
• complementary and alternative medicine
• non-hormonal therapy

Introduction

Japanese traditional herbal medicine (Kampo), which originated from traditional Chinese herbal medicine, developed during the 17–19th centuries in Japan. Each patient is treated with combinations of natural herbal products. These traditional treatments are predecessors to current Japanese medicine; moreover, these traditional treatments have been administered widely in many medical fields in Japan.

Female climacteric disorders improved significantly following treatment with Japanese traditional herbal medicine in many cases when a suitable drug is administered according to the patients' pathogenic alteration (Zheng (in Chinese)/SHO (in Japanese); excess or insufficiency symptom-complex) conditions [1]. Japanese traditional herbal medicine in powder form packed in pouches, i.e., single-use doses, is available in Japan. These preparations are approved by the Japanese Food and Drug Administration (FDA) and covered by national medical insurance. Thus, Japanese traditional herbal medicine has been widely used for the treatment of menopausal symptoms in Japanese women in addition to hormone replacement therapy.

On the other hand, testosterone replacement therapy (TRT) has been applied primarily in order to alleviate the various symptoms in male patients with late-onset hypogonadism (LOH) [2–9]. However, TRT treatments, which exhibit several adverse reactions, should be implemented only after conformation of serum testosterone levels. Japanese traditional herbal medicine affords an alternative non-hormonal treatment for female climacteric disorders with few side effects. Both LOH and menopausal symptoms originate as a result of the decline in sex hormones due to aging; thus, these two conditions are similar to one another. Although the efficacy of Japanese traditional herbal medicine in female climacteric disorders has been confirmed [1,10–12], little data appear in the literature regarding Japanese traditional herbal medicine for LOH [13].

The objective of this study was to clarify the clinical efficacy of Japanese traditional herbal medicine in the treatment of patients with LOH. Furthermore, the predictive factors of patient background in terms of efficacy of Japanese traditional herbal treatments were examined.

Methods

The principal treatment for LOH is TRT. Prior to implementation of TRT, serum testosterone level should be confirmed. Nearly all patients presenting with LOH wish to begin treatment as quickly as possible. Thus, we have administered Japanese traditional herbal medicine as an initial treatment for LOH after obtaining the patient's informed consent.

According to the Japanese LOH guideline [14], normal range of serum free testosterone (FT) level in Japanese men indicates more than 11.8 pg/ml. Aging male symptoms (AMS) [15] score is widely accepted for LOH diagnosis, and the diagnosis of LOH is not made for the patients with AMS score of 17 to 26. Thus, the patients with low serum free testosterone levels (<11.8 pg/ml), and high AMS score (>26) were enrolled in this study.

From September 2002 to August 2009, 151 patients with LOH were treated via the administration of Japanese traditional herbal medicine for at least 4 weeks. The pathogenic alteration (Zheng (in Chinese)/SHO (in Japanese); excess or insufficiency symptom-complex), which indicates both general physical and mental conditions of each patient, was determined using the excess (Shi (in Chinese)/Jitsu (in Japanese)) – insufficiency (Xu (in Chinese)/Kyo (in Japanese)) scoring system questionnaire (Table I) [16,17]. Determination of patient's pathogenic alteration was extremely difficult; special traditional medical training is required in order to do so. However, determination of each patient's pathogenic alteration is facilitated by the excess (Shi/Jitsu) – insufficiency (Xu/Kyo) scoring system questionnaire. This questionnaire consists of 10 questions and a total score can be readily calculated. Patient's pathogenic alteration is considered as excess (Shi/Jitsu) (score of 56–100), intermediate (45–55), and insufficiency (Xu/Kyo) (0–44). Subsequently, the most appropriate Japanese traditional herbal medicine is administered to patients according to their pathogenic alteration (excess, intermediate or insufficiency). The six Japanese traditional herbal medicines (Kampo), namely, Keishibukuryogan (TJ-25), Kamishoyosan (TJ-24), Tokishakuyakusan (TJ-23), Hachimijiogan (TJ-7), Hochuekkito (TJ-41), and Saikokaryukotsuboreito (TJ-12) (Tsumura & Co., Tokyo), are candidates for LOH treatment in this study. The compositions of these six Kampo medicines are described in Table II. The basic concepts regarding how to choose among these six Japanese traditional medicines are presented in Table III.

Table I.  The excess (Shi/Jitsu)−insufficiency (Xu/Kyo) scoring system questionnaire for decisions regarding patient's pathogenic alteration.

Each patient answered 10 questions according to their condition at their option. Total score was calculated. Patient's pathogenic alteration was determined per these scores as follows: excess; score of 55 to 100, intermediate; 45 to 54; insufficiency; 0 to 44.

Table II.  Composition of the six Japanese traditional herbal medicines for LOH treatment.

7.5 g of Keishibukuryogan (TJ-25) extractgranules contains 1.75 g of a dried extract of the following mixed crude drugs.		7.5 g of Kamishoyosan (TJ-24) extractgranules contains 4.0 g of a dried extract of the following mixed crude drugs.		7.5 g of Tokishakuyakusan (TJ-23) extractgranules contains 4.0 g of a dried extract of the following mixed crude drugs.
Cinnamon bark	3.0 g	Bupleurum root	3.0 g	Peony root	4.0 g
Peony root	3.0 g	Peony root	3.0 g	Atractylodes lancea rhizome	4.0 g
Peach kernel	3.0 g	Atractylodes lancea rhizome	3.0 g	Alisma rhizome	4.0 g
Poria sclerotium	3.0 g	Japanese angelica root	3.0 g	Poria sclerotium	4.0 g
Mountain bark	3.0 g	Poria sclerotium	3.0 g	Cnidium rhizome	3.0 g
		Gardenia fruit	2.0 g	Japanese angelica root	3.0 g
		Moutan bark	2.0 g
		Glycyrrhiza	1.5 g
		Ginger	1.0 g
		Mentha herb	1.0 g
7.5 g of Hachimijiogan (TJ-7) extractgranules contains 4.0 g of a dried extract of the following mixed crude drugs.		7.5 g of Hochuekkito (TJ-41) extractgranules contains 5.0 g of a dried extract of the following mixed crude drugs.		7.5 g of Saikokaryukotsuboreito (TJ-12) extractgranules contains 4.5 g of a dried extract of the following mixed crude drugs.
Rehmannia root	6.0 g	Astragalus root	4.0 g	Bupleurum root	5.0 g
Cornus fruit	3.0 g	Atractylodes lancea rhizome	4.0 g	Pinellia tuber	4.0 g
Dioscorea rhizome	3.0 g	Ginseng	4.0 g	Cinnamon bark	3.0 g
Alisma rhizome	3.0 g	Japanese angelica root	3.0 g	Poria sclerotium	3.0 g
Poria sclerotium	3.0 g	Bupleurum root	2.0 g	Scutellaria root	2.5 g
Moutan bark	2.5 g	Jujube	2.0 g	Jujube	2.5 g
Cinnamon bark	1.0 g	Citrus unshiu peel	2.0 g	Ginseng	2.5 g
Powdered processed aconite root	0.5 g	Glycyrrhiza	1.5 g	Oyster shell	2.5 g
		Cimicifuga rhizome	1.0 g	Longgu	2.5 g
		Ginger	0.5 g	Ginger	1.0 g

Table III.  Index for the selection of Japanese traditional herbal medicine corresponding to the conditions of patients with LOH.

• Keishibukuryogan (TJ-25)

Strong build, ruddy face, substantial abdomen, lower abdominal defiance; Excess

• Kamishoyosan (TJ-24)

Infirm, shoulder stiffness, fatigue, anxiety; Intermediate

• Tokishakuyakusan (TJ-23)

Weak muscle, fatigue, sensitive to cold (lumber∼lower extremities); Insufficiency

• Hachimijiogan (TJ-7)

Severe fatigue, pollakisuria, erectile; Insufficiency

• Hochuekkito(TJ-41)

Lower digestive function, severe lower extremities fatigue, infirm; Insufficiency

• Saikokaryukotsuboreito (TJ-12)

Good∼fair physical strength, palpitation, sleep disturbance, irritated; Excess∼intermediate

Each Japanese traditional herbal medicine was administered for at least 4 weeks. After 4 weeks, the clinical efficacy was evaluated based on improvement of subjective LOH symptoms and the score of the simplified menopausal index (SMI) (Table IV) [1]. The patients with LOH suffered from several symptoms, including physical-, psychological-, and sexual-related symptoms, and the relief from those symptoms is very important for patients with LOH. The SMI score is generally accepted for the evaluation of efficacy for menopausal treatment with Japanese traditional herbal medicine. It is quite practical for clinical use in determining the extent of climacteric disorders and efficacy of treatment, since scoring of symptoms can be done within few minutes [1]. Therefore, the efficacy of Japanese traditional herbal medicine for LOH is defined as follows: Excellent response group (Excellent), both subjective LOH symptoms and SMI score were normalized (SMI score after Japanese traditional herbal medicine becomes less than that before therapy and less than 50 points [1]); Fair response group (Fair), either of these parameters was normalized; Poor response group (Poor), neither of these parameters was normalized.

Table IV.  SMI for evaluation of LOH symptom severity.

Symptoms	Severity of symptoms				Score
	Severe	Moderate	Mild	Absent
1. Hot flash	10	6	3	0
2. Tendency to sweet	10	6	3	0
3. Sensation of chilling in hip and extremities	14	9	5	0
4. Shortness of breath, palpitation	12	8	4	0
5. Difficulty of sleep, or lack of deep sleep	14	9	5	0
6. Predisposition to anger, easily irritated	12	8	4	0
7. Anxious, occasionally depressed	7	5	3	0
8. Often has headache, dizziness and/or vomiting	7	5	3	0
9. Fatigability	7	4	2	0
10. Shoulder stiffness, lumber pain, pains in the extremities	7	5	3	0
			Total score

Each patient answered 10 questions in terms of their LOH symptoms. Higher scores represented severe LOH symptoms; an SMI score >50 indicated serious LOH symptoms.

Furthermore, the relationships between the efficacy of Japanese traditional herbal medicine and the patient background/parameters were investigated. To clarify the predictive factors of the efficacy of Japanese traditional herbal medicine, several parameters, including age, pathogenic alteration score, SMI score, international index of erectile function (IIEF 5) [18], AMS [15], serum total and free testosterone levels and international prostate symptoms score (IPSS), were analyzed in the Excellent, Fair and Poor response groups.

Results

Table V indicated the pre-treatment values of several parameters obtained from 151 patients with LOH. The age of the 151 patients with LOH ranged from 31 to 86 (55.4 ± 10.1) years. The total and free testosterone levels of these patients were from 0.58 to 10.6 ng/ml and 2.0 to 11.7 pg/ml, respectively. AMS score ranged from 34 to 75. All these patients indicated lower FT levels (Japanese LOH criteria [14]) and AMS score [15].

Table V.  The pre-treatment values of several parameters obtained from 151 patients with LOH, such as age, pathogenic alternation score, SMI, IIEF 5, AMS total and free testerone levels and IPSS were indicated.

	Mean ± SD	Range
Age	55.4 ± 10.1	31–86
Excess – insufficiency score	47.4 ± 10.2	10–73
SMI	59.2 ± 15.2	20–100
IIEF 5	9.6 ± 6.6	1–24
AMS	52.6 ± 9.8	34–75
Total testosterone (ng/mL)	3.64 ± 1.34	0.58–10.6
Free testosterone (pg/mL)	7.5 ± 2.0	2.0–11.7
Total IPSS	11.0 ± 8.5	1–28

The pathogenic alteration score determined by the excess – insufficiency scoring system questionnaire prior to treatment was 47.4 ± 10.2, and of 151 patients with LOH, 26 were diagnosed as excess (Shi/Jitsu), 73 in intermediate, and 52 in insufficiency (Xu/Kyo), respectively. These data indicated that many patients with LOH were characterized by intermediate to insufficiency conditions of the pathogenic alteration. In accordance with the pathogenic alteration, Keishibukuryogan (TJ-25), Kamishoyosan (TJ-24), Tokishakuyakusan (TJ-23), Hachimijiogan (TJ-7), Hochuekkito (TJ-41), and Saikokaryukotsuboreito (TJ-12) were administered in 15 (10%), 88 (58%), 20 (13%), 24 (16%), two (1.5%), and two (1.5%) patients with LOH, respectively (Figure 1).

Figure 1.  The rate of Japanese traditional herbal medicine administration. More than half of patients with LOH received Kamishoyosan (TJ-24), followed by Hachimijiogan (TJ-7) and Tokishakuyakusan (TJ-23).

The mean score of SMI prior to treatment was 59.2 ± 15.2, which indicates that many patients in this study experienced rather severe LOH symptoms. The mean score of SMI 4 weeks following treatment with Japanese traditional herbal medicines was 41.3 ± 19.4, which is significantly lower in comparison to the scores before treatment (p < 0.0001; Student t test) (Figure 2).

Figure 2.  The mean score of SMI of patients with LOH decreased significantly four weeks after Japanese traditional herbal medicine administration. (*p < 0.0001; Student t test).

Among the 151 patients with LOH who received Japanese traditional herbal medicine, 63 (41.8%) achieved both relief from LOH symptoms and normalized SMI score (Excellent), 44 (29.1%) achieved either relief from LOH symptoms or normalized SMI score (Fair), and 44 (29.1%) displayed neither symptom relief nor normalized SMI score (Poor). Thus, the overall efficacy rate of Japanese traditional herbal medicine for LOH was 70.9% (Excellent + Fair) (Figure 3). The efficacy rates were 88.5% in excess (Shi/Jitsu) patients, 74.0% in intermediate, and 57.7% in insufficiency (Xu/Kyo), respectively (Table VI). Furthermore, the efficacy rates of each Japanese traditional herbal medicine (Kampo) are indicated in Table VII.

Figure 3.  The efficacy of Japanese traditional herbal medicine for LOH was 41.8, 29.1, and 29.1% in the Excellent, Fair, and Poor response groups, respectively. Accordingly, 70.9% of patients with LOH treated with Japanese traditional herbal medicine experienced favorable effects.

Table VI.  The efficacy rate of Kampo for 151 patients with LOH according to their pathogenic alteration.

	Excellent	Fair	Poor	Efficacy rate (%)
Excess	15	8	3	23/26 (88.5)
Intermediate	36	18	19	54/73 (74.0)
Insufficiency	12	18	22	30/52 (57.7)
Total	63	44	44	107/151 (70.9)

Table VII.  The efficacy rate of six Japanese traditional herbal medicines (Kampo) for 151 patients with LOH.

	Excellent	Fair	Poor	Efficacy rate (%)
Keishibukuryogan (TJ-25)	9	3	3	12/15 (80.0)
Kamishoyosan (TJ-24)	40	25	23	65/88 (73.9)
Tokishakuyakusan (TJ-23)	4	6	10	10/20 (50.0)
Hachimijiogan (TJ-7)	8	8	8	16/24 (66.7)
Hochuekkito (TJ-41)	0	2	0	2/2 (100)
Saikokaryukotsuboreito (TJ-12)	2	0	0	2/2 (100)
Total	63	44	44	107/151 (70.9)

Adverse reactions of Japanese traditional herbal medicine, e.g., diarrhea, nausea and eruption, were observed in four (2.6%) patients. This result was not severe.

Furthermore, relationships between the efficacy of Japanese traditional herbal medicine and patient background, including age, pathogenic alteration score, SMI score, IIEF 5, AMS, serum total and free testosterone levels, and IPSS in the Excellent, Fair, and Poor response groups were examined.

Mean ages were 54.3 ± 9.1, 55.9 ± 11.2, and 56.3 ± 10.3 years in the Excellent, Fair, and Poor response groups, respectively. No significant difference was apparent in any group.

Pathogenic alteration scores prior to treatment were 50.7 ± 8.2 in the Excellent, 45.9 ± 11.1 in the Fair, and 44.1 ± 10.8 in the Poor response groups. The pathogenic alteration score in Excellent response group patients was significantly higher than those in Fair and Poor response group subjects (p = 0.0497 and p = 0.0035; ANOVA Scheffe's procedure) (Figure 4). Thus, the efficacy of Japanese traditional herbal medicine for LOH is higher in patients displaying an excess (Shi/Jitsu) condition than in those characterized by an intermediate or insufficiency (Xu/Kyo) situation.

Figure 4.  Pathogenic alteration scores in Excellent response group patients were significantly higher than those in the Fair and Poor response groups (*p = 0.0497, +p = 0.0035; ANOVA Scheffe's procedure).

SMI scores before treatment were 55.2 ± 12.8, 59.8 ± 13.3, and 64.3 ± 18.5 in the Excellent, Fair, and Poor response groups, respectively. The SMI score in Excellent response group patients was significantly lower than that of the Poor response group (p = 0.0092; ANOVA Scheffe's procedure) (Figure 5). Thus, the efficacy of Japanese traditional herbal medicine for LOH is higher in patients presenting with slight LOH symptoms than in those exhibiting severe LOH symptoms.

Figure 5.  SMI scores in Excellent response group patients were significantly lower than those in the Poor response group (*p = 0.0092; ANOVA Scheffe's procedure).

IIEF 5 scores prior to treatment were 10.2 ± 6.7, 8.5 ± 6.9, and 9.8 ± 6.1 in the Excellent, Fair, and Poor response groups, respectively. AMS scores before treatment were 52.2 ± 9.6, 52.1 ± 11.3, and 53.7 ± 9.1 in the Excellent, Fair, and Poor response groups, respectively. Total testosterone levels prior to treatment were 3.75 ± 1.61 ng/ml in the Excellent, 3.78 ± 1.27 ng/ml in the Fair, and 3.35 ± 0.90 ng/ml in the Poor response groups. Free testosterone levels before treatment were 7.7 ± 2.0 pg/ml in the Excellent, 7.8 ± 2.1 pg/ml in the Fair, and 7.0 ± 1.8 pg/ml in the Poor response groups. IPSS scores prior to treatment were 12.7 ± 10.3, 9.7 ± 8.3, and 10.7 ± 6.5 in the Excellent, Fair, and Poor response groups, respectively. No significant differences were evident in these parameters.

Discussion

According to the recommendation of the International Society for the Study of the Aging Male (ISSAM), LOH is defined as a clinical and biochemical syndrome associated with advancing age characterized by typical symptoms and deficiency in serum testosterone levels [2]. Thus, the basic essential treatment for LOH involves TRT [3–9]. However, TRT should be implemented only after clarification of serum testosterone levels. Some patients who visit LOH out-patient clinics are eager to receive adequate treatment for the relief from several symptoms as quickly as possible. In addition, other patients cannot undergo TRT due to high PSA levels, liver dysfunction, etc. In such cases, palliative treatment to alleviate these symptoms should be considered.

Japanese traditional herbal medicine (Kampo) has been widely applied for female climacteric disorders; moreover, the clinical efficacy and safety of Kampo have been documented [1,10–12]. Both LOH and female menopausal disorders originate consequent to a decline in sex hormones associated with aging. Japanese traditional herbal medicines were utilized for the treatment of male infertility [16]; basic and clinical data support the efficacy of these agents [19–21]. Thus, complementary and alternative treatments involving Japanese traditional herbal medicines are familiar to Japanese urologists and andrologists. The efficacy of Saikokaryukotsuboreito (TJ-12) in eugonadal patients with LOH symptoms has been described [13]. Our preliminary report also indicated the possibility with respect to improvement of LOH symptoms using Japanese traditional herbal medicine [22]. In this study, six Japanese traditional herbal medicines were administered; subsequently, the clinical efficacy and safety of Japanese traditional herbal medicine in LOH were assessed.

Drug selection is one of the most important points regarding treatment with Japanese traditional herbal medicine. Despite the administration of the same Japanese traditional herbal medicine, the efficacy and adverse reactions are not identical; they are dependent on the pathogenic alteration (Zheng/SHO; excess or insufficiency symptom-complex), which indicates both general physical and mental conditions of each patient. Pathogenic alteration is defined as the process of obtaining information regarding the physical and psychological conditions employing the six parameters – (1) KI (Chi (in Chinese), the basic, all-penetrating and maintaining force and energy) and body fluids, (2) Yin (heat, fever, restlessness, overactivity, exaltation) and Yang (cold, inactivity, lethargy), (3) deficiency and excess, (4) exterior and interior, (5) cold and heat, (6)five organs (lover, heart, spleen, lung, kidney) – and including those particular pathological symptoms provided by the patient to describe his current status [23].

However, this definition is subjective in nature; furthermore, special training and experience with traditional herbal medicine are required to master how to determine the patient's pathogenic alteration. Thus, selection of the correct Japanese traditional herbal medicine based on the pathogenic alteration is very difficult for general practitioners. Under these circumstances, the utility of the excess (Shi/Jitsu) – insufficiency (Xu/Kyo) scoring system questionnaire facilitates the determination of the pathogenic alteration even for general practitioners [16]. The efficacy and safety of Japanese traditional herbal medicine are enhanced by appropriate selection in individual patients.

In this study, the appropriate Japanese traditional herbal medicine was selected according to the affinity of patients' pathogenic alteration and character of each herbal medicine (Table III). The LOH patients' pathogenic alteration score was 47.0 ± 10.9, which indicated that patients with LOH demonstrated intermediate to insufficiency conditions of the pathogenic alteration. Therefore, the particular Japanese traditional herbal medicine which would be effective for intermediate to insufficiency type LOH, namely, Kamishoyosan (TJ-24), Hachimijiogan (TJ-7), and Toukishakuyakusan (TJ-23), was frequently administered.

As a result of these careful selections of Japanese traditional herbal medicine, the mean score of SMI significantly decreased 4 weeks after the treatment. Furthermore, among 151 patients with LOH who received Japanese traditional herbal medicine, 63 (41.8%) subjects achieved both relief from LOH symptoms and normalized SMI score (Excellent), whereas 44 (20.1%) achieved either relief from LOH symptoms or normalized SMI score (Fair). Thus, the overall efficacy rate of Japanese traditional herbal medicine for LOH was 70.9% (Excellent + Fair). These data are quite similar to the efficacy of Japanese traditional herbal medicine in menopausal women [1]. This coincidence, which is very interesting, may be reasonable due to the mechanism of LOH and menopause.

There is a possibility that the efficacy of these Japanese traditional herbal medicines show a placebo effect. However, Japanese FDA has admitted the clinical usage of Japanese traditional herbal medicine, and national medical insurance has financially supported the administration of these Japanese traditional herbal medicines. However, national authorities do not allow a placebo because the National insurance pays for Kampo only and will not pay for placebo. These government regulations and also due to the unique color and taste of Kampo, a placebo version is unrealistic. Thus, it is impossible to perform a randomized, double-blind, placebo (or non-specific herbal medicine) for this study in Japan. Even the efficacy rate of Japanese traditional herbal medicine for LOH might be including a placebo effect, 70% of patients with LOH have achieved relief from these several bothersome symptoms. We believe that this high efficacy rate is considered to be very significant and important for LOH treatment strategy.

From the perspective of modern Western medicine, several hypotheses or experimental data have been advanced to explain the mechanism and effects of Japanese traditional herbal medicine. However, the mechanism of action governing Japanese traditional herbal medicine in LOH remains unclear. Japanese traditional herbal medicines cannot elevate sex hormone levels after treatment [13,24]. Regardless of unchanged hormonal levels, nearly 70% of both male and female climacteric patients achieved relief from symptoms in the presence of Japanese traditional herbal medicine. Hence, the treatment with Japanese traditional herbal medicine is categorized as non-hormonal, complementary, and alternative medicine.

When patients with LOH realize amelioration of troublesome symptoms without unnecessary elevation of serum testosterone level, several side effects, e.g., liver dysfunction, polycycemia, prostate cancer, etc., may be precluded. In actuality, the adverse reactions rate was only 2.6% with no serious instance; thus, it appears that issues concerning the safety of Japanese traditional herbal medicine are non-existent.

Additionally, these herbal medicines are available packed in pouches as single-use doses in Japan. These preparations are approved by the Japanese FDA and covered by national medical insurance. Moreover, patients need not wait for the results regarding testosterone level to begin LOH treatment. Under these circumstances, Japanese traditional herbal medicine is the first-line treatment strategy for female climacteric disorder. The current data revealed that Japanese traditional herbal medicine is also promising with respect to alleviation of several bothersome LOH symptoms.

Patients with LOH complain of several symptoms, which include physical, psychological, and sexual aspects; moreover, symptom variation is large. The response to LOH treatment is also variable. We previously evaluated the efficacy of testosterone ointment for LOH according to LOH severity [25]. Our previous data demonstrated that testosterone ointment therapy is more effective in patients displaying more severe LOH symptoms in four areas, e.g., AMS (1. psychological) score, SF36 [26] (2. body pain, 3. social function, 4. role emotion), in comparison to patients with slight LOH symptoms. Likewise, determination of the predictive factors or parameters of more effective Japanese traditional herbal medicine for LOH is significant.

In this study, no differences were observed in Japanese traditional herbal medicine response concerning several factors, including age, IIEF 5 score, IPSS score, and total and free testosterone levels. However, the pathogenic alteration score in Excellent response group patients was significantly higher than those in the Fair and Poor response groups; furthermore, SMI scores in Excellent response group patients were significantly lower than those in the Poor response group. Accordingly, high pathogenic alteration score and low SMI score are favorable signs in terms of promising efficacy of Japanese traditional herbal medicine in LOH. In other words, those patients in excess conditions and displaying mild LOH symptoms are considered more appropriate candidates for Japanese traditional herbal medicine.

The adverse reactions of Japanese traditional herbal medicine can be neglected. Thus, treatment of LOH with Japanese traditional herbal medicine is effective and safe, especially in patients with LOH in which TRT is contra-indicated or in whom early treatment is desirable prior to determination of serum testosterone levels.

Conclusion

The current data demonstrated that nearly 70% of patients with LOH experienced relief from various symptoms after 4 weeks of Japanese traditional herbal medicine administration; moreover, no serious adverse reactions were evident. Treatment of patients with LOH with Japanese traditional herbal medicine without fluctuation of serum TT and FT levels appears to be beneficial. The most striking clinical effects of Japanese traditional herbal medicine were observed in patients exhibiting excess conditions and mild LOH symptoms. This pilot study with a small number of subjects and of short duration indicated that Japanese traditional herbal medicine is an effective and safe treatment for some LOH symptoms.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.