Traditional Chinese medicine for idiopathic precocious puberty: A hospital-based retrospective observational study

Traditional Chinese Medicine for Idiopathic Precocious Puberty:

A Hospital-Based Retrospective Observational Study

Authors:

Chao-Hui Yu

, Pi-Hua Liu

, Yang-Hau Van

, Angela Shin-Yu Lien

, Tzu-Ping Huang

, Hung-Rong Yen

* These authors have equal contribution.

Affiliations:

1

Department of Traditional Chinese Medicine, Center for Traditional Chinese Medicine, and

4

Department of Pediatrics, Chang Gung Memorial Hospital,

School of Traditional Chinese Medicine,

Clinical Informatics and Medical Statistics Research Center, and

School of Nursing, College of Medicine, Chang Gung University, Taoyuan 333,

Research Center for Traditional Chinese Medicine, Department of Traditional Chinese Medicine and Department of Medical Research, China Medical University Hospital,

School of Traditional Chinese Medicine, China Medical University, Taichung 404, Taiwan.

Corresponding Author:

Hung-Rong Yen, M.D., Ph.D.

Department of Traditional Chinese Medicine, Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital

123 Ding-hu Road, Kweishan, Taoyuan 333, Taiwan Office: +886-3-319-6200 ext 2611

Fax: +886-3-329-8995

E-mail: hungrongyen@gmail.com

Word Count: 2919 words

Abstract

Objectives

To characterize the application of Traditional Chinese Medicine among children with idiopathic precocious puberty.

Design and setting

This study examined data sets from patients diagnosed with idiopathic precicous puberty at Chang Gung Memorial Hospital between 2010 and 2012. The patients were separated into three groups: Traditional Chinese Medicine users, Western Medicine users and “no treatment” users.

Main Outcome Measures

The demographic data of children with idiopathic precocious puberty were characterized. The prescription patterns and frequencies of Traditional Chinese Medicine for precocious puberty patients were analyzed. The patients’ bone maturation rate and the change of predicted height after different approaches were measured as outcomes.

Results

There were 3390 patients enrolled in the study. Zhi-Bai-Di-Huang-Wan (70.62%) was the

most common herbal formula and Mai-Ya (Hordei Fructus Germinatus) (51.58%) was the

most common single herb prescribed for idiopathic precocious puberty in all of the 2784

TCM prescriptions. The bone maturation rates of Traditional Chinese Medicine users

(0.95±0.20) and Western Medicine users (0.69±0.05) were both decelerated but the “no

treatment” group had an accelerated bone maturation rate of 1.33±0.04. Traditional Chinese

Medicine and Western Medicine users also had higher predicted height after treatment

(1.15±1.19 cm versus 1.73±0.29 cm), while the “no treatment” group had a decreased

predicted height (-0.52±0.23 cm).

Conclusions

Our study revealed a comprehensive list of TCM prescriptions for idiopathic PP patients.

Future well-designed, randomized, double-blinded, and placebo-controlled clinical trials are warranted to evaluate the efficacy and safety of TCM medications for PP.

Keywords: Precocious Puberty, Traditional Chinese Medicine, Complementary and

Alternative Medicine, Zhi-Bai-Di-Huang-Wan

Background

Puberty is an important developmental milestone for children. It is a complicated sequence of biological events leading to the progressive maturation of sexual characteristics and reproductive capacity. Precocious puberty (PP) means the early onset of puberty, such as the early development of secondary sexual characteristics, early skeletal maturation and early closure of the epiphyses, which may lead to a shorter adult height

. PP has a prevalence of 1 in 5000 children and a female to male ratio of more than 10:1

, which can result from excess sex hormone exposure, fatty tissue, environmental factors and several congenital organic diseases. A comprehensive history and physical examination, emphasizing the early detection of pathologic PP such as central nervous system abnormalities, brain tumors, adrenal pathologic problems, gonadal tumors, and genetic problems is mandatory

. Approximately 10-20% of girls and the majority of boys have underlying pathologic causes, while the others have an idiopathic etiology

. If left untreated, discrepancies between physical and chronological ages may lead to a shorter stature. The psychosocial developmental problem is also a major concern for school-aged children

.

Currently, the use of gonadotropin-releasing hormone (GnRH) analogues is the first-line therapy for idiopathic PP . These analogues suppress gonadotropin secretion and negatively regulate GnRH receptors, leading to a reduction of gonadal steroids to prepubertal levels

. GnRH analogues can slow down pubertal progression and bone maturation to improve adult stature . However, side effects of GnRH analogues have been reported such as local erythema, hyperlipidemia, central obesity, temporary vaginal bleeding, and loss of bone density

. Besides, GnRH analogues are expensive and cost approximately $150 U.S.

dollars every month in Taiwan.

TCM practitioners have been using oral herbs to treat many pediatric diseases for

thousands of years. Nevertheless, PP has been less described in the ancient literature, most

likely because it was less common than diseases involving infection, the respiratory tract, and the gastrointestinal tract in the past. It will be very interesting to understand how TCM practitioners treat PP and whether TCM can work on PP. However, there is no large-scale study on TCM treatment for PP so far. Therefore, we undertook a pragmatic approach to retrospectively review the TCM prescription patterns and the treatment outcome at a large medical institution in Taiwan from 2010 to 2012.

Methods

Data source

The data were collected from the records of outpatient clinics between January 1

, 2010, and December 31

, 2012, in the three branches of Chang Gung Memorial Hospital (CGMH) in northern Taiwan—the Taipei, Linkou, and Taoyuan branches. CGMH is not only a tertiary university-affiliated medical center but is also an institution of medication research and education. The TCM clinical service started in 1996 at CGMH. There are currently 79 TCM doctors in the Department of Traditional Chinese Medicine.

Study subjects and variables

We retrospectively reviewed the electronic records of patients with the diagnosis of PP

using the International Classification of Disease, 9

Revision, Clinical Modification (ICD-9-

CM) code of 259.1 at CGMH between January 1

, 2010, and December 31

, 2012. Although

PP is classically defined as the development of secondary sexual characteristics before 8

years of age in girls and before 9 years of age in boys

, we enrolled all of the patients with

the diagnosed code of 259.1 who were 6-12 years old at their first visit; this approach was

taken in order to not exclude the patients who had been diagnosed previously or had been

diagnosed at other hospitals. Patients who had pathological precocity were excluded by

hormonal, abdominal ultrasound and/or brain image studies. Patients received both TCM and

Western Medicine (WM) treatments were also excluded. The collected data contained the

patients’ gender, the date of birth, the date of encounter, diagnosis, skeletal evaluation of bone age by X-ray, WM prescription, and TCM prescription. We described their gender distributions, age at the first visit, time of visit, and duration of treatment for demographic data. In addition, we analyzed the common comorbidities and the TCM prescription patterns for PP patients. Only the concentrated scientific herbal granules, which have been the only form of TCM prescription reimbursed by the National Health Insurance, were taken into account. We calculated the number of times that each formula, single herb, and different combination patterns of formulae or herbs were prescribed to understand the prescribing probability of formulae and herbs in all of the prescriptions. Patients who had received more than one skeletal evaluation of their bone ages (BA) during the treatment were enrolled to determine their outcomes. Two senior physicians independently examined the X-ray films of the left hand and wrist. The average of the assessed skeletal ages was determined as a patient’s BA. The predicted height (PH) was calculated based on the Bayley and Pinneau tables

. The bone maturation rate (BMR) was calculated as the ratio of the change of BA to the change of chronological age (ΔBA/ΔCA).

Statistics

Categorical data were presented as absolute numbers and percentages. Continuous data were summarized as means ± standard deviations (SD). The characteristics and demographic data were compared by ANOVA or χ

test when appropriate. We used multiple linear regression techniques to estimate the independent impact of treatment on the BMR and PH.

The adjusted means of the BMR and the change of PH after treatment (ΔPH) were obtained with the number of months of treatment (follow-up) as a covariate in the model. The statistical significance was considered if the P value was less than 0.05. All of the statistical analyses were processed using the software SAS 9.0 (SAS Institute, Inc.).

Ethical considerations

The Institutional Review Board (IRB) of the Chang Gung Medical Foundation approved this study with a reference number 101-4287B on December 24, 2012. The organized IRB operates according to the Good Clinical Practice and applicable laws and regulations.

Results

In sum, 3856 patients with a diagnosis of PP by ICD-9-CM code of 259.1 were identified from the outpatient records of CGMH between 2010 and 2012 (Figure 1). Among them, 466 patients were excluded because they were either younger than 6 years of age or older than 12 years of age at the first visit, had pathological precocity diagnosed by hormonal, abdominal ultrasound and/or brain image studies, or received both TCM and WM treatments. Among the 3390 enrolled patients, 461 patients (13.60%) only received TCM treatment (TCM users), 751 patients (22.15%) only received WM treatment (WM users), and 2178 (64.25%) patients received no treatment (“no treatment” group).

Characteristics of idiopathic PP patients

Demographic data including the gender distributions, ages of first visit, times of visit, and

treatment duration of the three groups were collected (Table 1). Females were predominant in

all of the groups, but there were more males visiting the TCM clinics. The age at the first visit

was significantly different among these groups (P<0.0001). TCM users were older than the

patients of the other two groups. More than half of the TCM users visited TCM clinics at ages

older than 10 years (N=239, 51.84%), whereas patients who received WM treatment were

younger. WM users had more clinic visits than the other two groups (P<0.0001). Regarding

the duration of treatment, the WM users had a longer treatment duration (16.54±14.91

months) compared to that of the TCM users (7.03±7.62 months) (P<0.0001). Half of the

TCM users (50.24%) received treatment from two months to one year, whereas half of the

WM users (52.07%) received treatment for more than one year.

Among the patients with idiopathic PP, short stature (ICD-9-CM code of 783.4X) was the most common accompanied diagnosis (93.84%) during the clinical visits, followed by allergic rhinitis (29.48%), diseases of the digestive system (27.53%), dermatitis (5.88%), and nutritional deficiencies (5.29%) (Figure 2).

Prescription patterns for idiopathic PP

We collected all of the TCM prescriptions for the TCM users at CGMH between 2010 and 2012. The 461 patients who visited TCM clinics had a total of 2784 TCM prescriptions.

Among these prescriptions, Zhi-Bai-Di-Huang-Wan was the most common herbal formula for PP (1966 times, 70.62% of all of the TCM prescriptions). The second and third most frequently prescribed herbal formulae were Xiang-Sha-Liu-Jun-Zi-Tang (639 times, 22.95%) and Jia-Wei-Xiao-Yao-San (621 times, 22.31%), respectively. Mai-Ya (Hordei Fructus Germinatus) was the most frequently prescribed single herb for idiopathic PP patients, which accounted for more than half of all of the prescriptions (1436 times, 51.58%). The second one was Xia-Ku-Cao (Prunellae Spica), prescribed 658 times (23.64% of all of the prescriptions) (Table 2).

Clinically, TCM practitioners often prescribed more than one herbal formula or single herbs in one prescription. Therefore, we investigated the combination patterns of TCM herbal formulae for the idiopathic PP patients. We found that Zhi-Bai-Di-Huang-Wan plus Jia-Wei- Xiao-Yao-San was the most common combination of herbal formulae, which was prescribed 560 times (20.11% of 2784 prescriptions) (Table 3).

To understand the TCM prescription patterns in depth, we collected the most common

combinations of one herbal formula and one single herb for idiopathic PP patients. We found

that Zhi-Bai-Di-Huang-Wan plus Mai-Ya was the most frequent combination, which was

prescribed 1311 times (47.09% of all of the prescriptions), followed by Jia-Wei-Xiao-Yao-

San plus Mai-Ya (447 times, 16.06% of all of the prescriptions). Other common combinations for idiopathic PP patients were shown in Table 3.

Outcome measurement among TCM users, WM users, and the “no treatment” group

There were 9 TCM users, 164 WM users and 259 “no treatment” control patients who had received two skeletal evaluations of their bone age by X-ray. Obviously, the duration of treatment (months of follow-up) in WM users was significantly longer than that of the TCM users (17.47±7.44 months versus 11.22±7.89 months) (Table 4).

As described in the Materials and Methods section, we took the BMR and ΔPH for the outcome comparison. The BMRs of TCM and WM users were both decelerated (0.95±0.20 in TCM users versus 0.69±0.05 in WM users) with higher PH after treatment (ΔPH was 1.15±1.19 cm in TCM users versus 1.73±0.29 cm in WM users). In the “no treatment”

control group, the BMR was accelerated with a shorter PH (Table 4). Among these three groups, the BMR and ΔPH had significant differences after adjusting for the follow-up duration (P<0.0001). To compare each of the two groups separately, the TCM and WM treatments had similar effects on the BMR and ΔPH with P>0.05 (Figure 3). Although there was no significant difference between the TCM and “no treatment” groups, TCM users seemed to have a trend toward a significant deceleration of the BMR compared with the “no treatment” control group (P=0.0585) (Figure 3).

Discussion

Precocious puberty in children is an emerging pediatric disease that needs proper

management physically and psychologically. Early development of breast, pubic hair and

axillary hair, and early commencement of menstruation usually create a false impression of

higher stature. However, the fact is that early pubertal changes and rapid bone maturation

may lead to a limited adult height in PP patients. Without treatment, approximately 30% of

girls and an even larger percentage of boys achieve a height less than the 5th percentile as

adults

. In this study, we retrospectively reviewed the medical records to investigate the TCM prescription patterns for idiopathic PP at CGMH in the past three years. This is the first study to characterize the patients visiting TCM and WM clinics due to idiopathic PP in a tertiary medical center.

Our results showed that there were more males receiving TCM therapy, while females were still much more predominant in all of the groups. This finding was in agreement with the general gender distribution of PP . Patients seeking TCM treatment were older and the treatment duration was shorter than that of the WM users. This result may imply that TCM was not their first choice for idiopathic PP in the beginning.

In our study, Zhi-Bai-Di-Huang-Wan, also called Anemarrhena, Phellodendron, and

Rehmannia Pill, was the most commonly prescribed herbal formula for idiopathic PP. The

formula consists of eight herbs: Huang-Bai (Phellodendri Cortex), Zhi-Mu (Anemarrhenae

Rhizoma), Shou-Di (Rehmanniae Radix Praeparata), Shan-Zhu-Yu (Corni Fructus), Shan-

Yao (Dioscoreae Rhizoma), Ze-Xie (Alismatis Rhizoma), Fu-Ling (Poria), and Mu-Dan-Pi

(Moutan Cortex)

. According to the TCM theory, Zhi-Bai-Di-Huang-Wan can nourish yin

and remove fire, similar to the effect of Da-Bu-Yin-Wan, which has been shown to suppress

the hypothalamic-pituitary-gonadal axis by down-regulating Kiss-1/GPR54 mRNA

expression in the hypothalamus and to inhibit the synthesis and release of GnRH in an animal

model

. Additionally, "nourishing yin - removing fire" Chinese herbal mixtures were found

to work on hypothalamic Kisspeptin expression, to down-regulate the increased GnRH

expression, and to significantly delay the sexual development in animal studies . There were

also several Chinese reports indicating that “nourishing yin-purging fire” Chinese herbs could

modulate the function of the hypothalamic-pituitary-ovarian axis, decelerate skeletal

development, and delay skeletal maturity in idiopathic PP patients . Although there is no

current research focusing on Zhi-Bai-Di-Huang-Wan, our study suggested that Zhi-Bai-Di-

Huang-Wan is a potential herbal formula for the treatment of precocity and warrants further research and clinical trials.

In addition to Zhi-Bai-Di-Huang-Wan, Xin-Yi-San (Magnolia Flower Powder), Xiao- Qing-Long-Tang (Minor Green-Blue Dragon Decoction), Xin-Yi-Qing-Fei-Tang (Magnolia Flower Lung-Clearing Decoction), Ge-Gen-Tang (Pueraria Decoction), and Cang-Er-San (Xanthium Powder) were among the top ten list of our most commonly prescribed formulae for idiopathic PP (Figure 2). This result was compatible with the high prevalence of allergic diseases in Taiwan

. Indeed, allergic rhinitis was one of the common comorbidities with idiopathic PP in our study (Figure 2).

In addition to the herbal formula, the most commonly prescribed single herb was Mai-Ya (Hordei Fructus Germinatus), which accounted for approximately half of all of the prescriptions. According to the ancient TCM theory, Mai-Ya harmonizes the stomach and disperses the food passage. Nevertheless, a high dose of Mai-Ya can also terminate lactation and relieve the distention of breasts

. In girls, breast growth is usually the first sign of sexual development during puberty

. Therefore, Mai-Ya is supposed to discontinue or reverse the first step of puberty, i.e., breast development, in girls.

In this study, we also investigated the combination patterns of TCM formulae for PP. Zhi-

Bai-Di-Huang-Wan plus Jia-Wei-Xiao-Yao-San was the most common combined formulae

for PP. The effects of Jia-Wei-Xiao-Yao-San (Supplemented Free Wanderer Powder) are

dispersing stagnated liver qi, clearing heat, and fortifying the spleen. Several studies showed

that Jia-Wei-Xiao-Yao-San could relieve the climacteric symptoms of menopausal women .

In an animal model, Jia-Wei-Xiao-Yao-San was demonstrated to have an anti-depressive

effect

. One clinical study also showed that Jia-Wei-Xiao-Yao-San could reduce the

circulating IL-8 level, which was involved in thermoregulation in perimenopausal women

with hot flashes

. Zhi-Bai-Di-Huang-Wan plus Jia-Wei-Xiao-Yao-San could possibly have an effect on hormone regulation, but further studies will be needed.

Patients receiving WM treatment seemed to have a more decelerated BMR in our study.

To standardize the various durations of treatment or the time of follow-up, we adjusted the means of the BMR and ΔPH by the duration of treatment. There were no significant differences in the adjusted BMR and ΔPH between TCM and WM users. This result indicated that TCM and WM seemed to have comparable effects on the treatment of precocity.

However, GnRH analogues cost approximately $150 U.S. dollars every month. Assuming that a patient takes 9 grams of TCM concentrated herbal granules everyday, the cost of concentrated TCM herbal granule is approximately $15 U.S. dollars per month. Comparing the BMRs between TCM users and the “no treatment” patients, there was a tendency to be different, with a P value close to 0.05. We are currently establishing a TCM-WM Integrated Pediatric Clinic at CGMH to provide TCM and WM consultations for PP patients and parents. A larger scale and comprehensive evaluation the safety and efficacy of TCM treatment will also be conducted in this integrated clinic.

There are several limitations of this study. First, this retrospective study only included the

patients diagnosed with the ICD-9-CM code of PP (259.1) from one tertiary medical center,

which might not represent the whole picture of PP in Taiwan. Fortunately, the diagnosis code

of PP (259.1) is quite specific and cannot be used indiscriminately. Second, we did not

include the prescriptions that were outside of the TCM concentrated scientific herbal

granules, such as a TCM herbal decoction. Scientific herbal granules are more commonly

used and fully reimbursed by the National Health Insurance since 1996 in Taiwan; the effect

of excluding herbal decoction is therefore minimized. Third, the sample size of TCM users

with two skeletal evaluations was limited. The routine X-ray examination is fully reimbursed

by the National Health Insurance when the patients visited WM clinics. However, the TCM

users were arranged to follow their bone ages, typically under clinical conditions due to the poor growth of their body height. Therefore, the effect of TCM might be underestimated.

Lastly, there were certain uncontrollable biases, and we could not expect to measure the final heights of these patients due to the nature of this retrospective study design. However, this study provided the common TCM prescriptions for idiopathic PP in clinical practice and determined a list of TCM formulae and herbs that could be used to design further pharmacological and clinical studies.

Conclusions

In conclusion, our study illustrated the characteristics and utilization patterns of TCM in idiopathic PP patients at a tertiary medical center in Taiwan. Based on this study, Zhi-Bai-Di- Huang-Wan plus Mai-Ya could be practically considered as a commonly accepted TCM prescription for idiopathic PP. TCM herbs could possibly benefit idiopathic PP patients with regard to decelerated bone maturation and a higher predicted adult height with much lower costs. Further studies such as randomized controlled clinical trials and pharmacological investigations are warranted.

Competing Interests

The authors declare that they have no competing interests.

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Figure Legends

Figure 1. Recruitment flowchart. Patients diagnosed with PP at CGMH between 2010 and 2012. TCM users: patients only received Traditional Chinese Medicine treatment. WM users:

patients only received Western Medicine treatment. No treatment group: patients visited and consulted at the clinics but did not receive any medical treatment.

Figure 2. Comorbidities of precocious patients at CGMH between 2010 and 2012. The diagnoses accompanied with precocious puberty (259.1) were collected and analyzed. The x- axis represented the percentage of comorbidities. The ICD-9 codes were categorized by the following:

Short stature includes ICD-9 codes 783.40, 783.41, 783.42, and 783.43. Allergic rhinitis includes ICD-9 code 477.9. Disease of the digestive system includes ICD-9 codes 536.8, 536.9, 564.0, and 564.1. Dermatitis includes ICD-9 codes 691.8 and 692.9. Nutritional deficiency includes ICD-9 code 261.

Figure 3. A. Outcomes of bone maturation rate (ΔBA/ΔCA). B. Outcomes of change in the

predicted height (ΔPH). The data were presented as the adjusted means ± 95% confidence

intervals. The statistical significance was considered when the P value was less than 0.05.