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Complementary Therapies in Medicine
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Effects of traditional Korean medicine on anti-Mullerian hormone in patients with diminished ovarian reserve: A retrospective study
JunyoungJoab, MyungJa Kangb, Jin Moo Leea, Hyunho Kimc, Ui MinJerng
a Department of Korean Gynecology, Graduate School, KyungHee University, Seoul 130-702, Republic of Korea b Department of Korean Gynecology, Conmaul Hospital, Seoul 137-881, Republic of Korea
c Department of Biofunctional Medicine & Diagnostics, College of Korean Medicine, KyungHee University, Seoul 130-702, Republic of Korea d Clinical Research Division, Korea Institute of Oriental Medicine, Daejon 34054, Republic of Korea
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ARTICLE INFO
ABSTRACT
Article history:
Received 20 November 2014 Received in revised form 22 September 2015 Accepted 12 December 2015 Available online 18 December 2015
Keywords: Herbal medicine Anti-Mullerian hormone Ovarian reserve Traditional Korean medicine Infertility
Objective: The purpose of the present study is to retrospectively evaluate the effect of traditional Korean medicine (TKM) on ovarian reserve by measuring serum anti-Mullerian hormone (AMH) levels in patients with diminished ovarian reserve (DOR).
Study design: We performed a retrospective chart review of patients with DOR who had received TKM for at least 2 months and had undergone serum AMH tests before and after TKM treatment. A total of 22 patients with DOR were included in the study.
Results: There were no significant differences in AMH levels before and after TKM in all patients (n = 22, p = 0.237). However, when the study population was divided into two age groups (<38 (n =12) and >38 years (n = 10)) to determine whether there was a age-related difference in the effect of TKM with DOR, a significant increase in AMH levels before and after TKM was observed in the age <38 (p < 0.05). Conclusions: TKM may provide an effective option for patients aged <38 years with DOR, but it should be interpreted cautiously as more rigorous research is needed. Further studies in a larger population are needed to confirm these results and to evaluate the effects of improved ovarian reserve on fertility outcomes following TKM in patients with DOR.
© 2016 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction
Infertility is defined by the failure to achieve a successful pregnancy after 12 months or more of appropriate, timed unprotected intercourse or therapeutic donor insemination.1 The infertility rate ranged from 3.5% to 16.7% in more developed nations and from 6.9% to 9.3% in less-developed nations, with an estimated overall median prevalence of 9%.2 In Korea, the infertility rate was reported approximately 13.5% by Korea Institute for Health and Social Affairs in 2003.3
Abbreviations: AMH, anti-Mullerian hormone; TKM, traditional Korean medicine; DOR, diminished ovarian reserve; FSH, follicle stimulating hormone; ART, assisted reproductive technology; IVF, in vitro fertilization; HM, herbal medicine; DHEA, dehydroepiandrosterone; SD, standard deviation.
* Corresponding author at: 1672 Yuseongdae-ro, Yuseong-gu, Daejeon, Republic of Korea. Fax: +82 42 863 9463.
E-mail addresses: studd@naver.com (J. Jo), womannature@naver.com (M.J. Kang), hanbang9597@hanmail.net (J.M. Lee), hyunho.kim@khu.ac.kr(H. Kim), breeze@kiom.re.kr, healmind@paran.com (U.M. Jerng).
Ovarian reserve, defined as a woman's remaining follicular pool, declines with advancing age.4 Diminished ovarian reserve (DOR) is defined when the size and quantity of the remaining ovarian follicular pool is smaller than expected at any given age.5 DOR, also known as age-related infertility, is an important and challenging aspect of assisted reproductive technology (ART) because infertile women with DOR are at risk for reduced natural fecundability and have lower pregnancy rates and higher rates of cycle cancellation.6,7 Despite the availability of various treatment options for patients with DOR, no consensus exists regarding the most effective treatment approach.6
The most widely used laboratory test in the assessment of ovarian reserve is measurement of follicle stimulating hormone (FSH).8 However, over the last few years, anti-Mullerian hormone (AMH) has emerged as a key marker of ovarian reserve.9 A big potential advantage of AMH over FSH measurement as a clinical test is that AMH levels are stable throughout the menstrual cycle and hence serum can be drawn randomly.8
AMH is secreted by the granulosa cells of growing follicles. AMH appears to better reflect the total quantity of the remaining follicular pool, and, therefore, is a better marker of declining reproductive
http://dx.doi.org/10.1016/j.ctim.2015.12.005
0965-2299/© 2016 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4. 0/).
ability.9 AMH has been reported as a predictor of natural fecund-ability and has been positively associated with pregnancy and live birth rates after assisted reproduction.7,10
Acupuncture and herbal medicine (HM) has been widely used in reproductive medicine.11,12 A study reported that 22% of the couples had utilized acupuncture and 17% used HM as a modality for treatment of infertility.13 Acupuncture has been used to manage ovulation disorders, and it has been shown to improve pregnancy outcomes in women undergoing in vitro fertilization (IVF).11,14 Pharmacopuncture, also known as acupoint injection, is a new therapy that combines acupuncture therapy with the injection of pharmacological medication or purified herbal medicine to acupoints.15 Pharmacopuncture provokes higher de-qi sensation compared to traditional acupuncture, which might be an indication that pharmacopuncture provides a stronger clinical response than traditional acupuncture.16 Two systematic reviews have also suggested that HM can improve pregnancy rates among female infertility patients undergoing IVF.17,18
Traditional Korean medicine (TKM), including pharmacopuncture and HM, has been widely used in patients with infertility in Korea. It is reported that about 60% of infertile patients had tried TKM treatment before using assisted reproduction by Korea Institute for Health and Social Affairs in 2012.19 However, there have been no studies about the effects of TKM on AMH in patients with DOR. The aims of the present study were to investigate the effect of TKM on ovarian reserve by measuring AMH levels in patients with DOR.
2. Materials and methods
2.1. Subjects
We performed a retrospective chart review of patients with DOR who presented at the Department of Gynecology of Korean Medicine, Conmaul Hospital, Seoul, Republic of Korea, from March 2013 to June 2015. The institutional review board of Kyung Hee University Korean Medicine Hospital at Gangdong approved this retrospective observational study; the requirement of patient approval or informed consent for the review of medical records was waived (KHNMCOH 2014-10-002).
The eligibility criteria for inclusion were female outpatients who had been treated for DOR for at least 2 months and had undergone AMH tests before and after TKM treatment. TKM treatment was started within two weeks after the serum AMH level test and second AMH test was conducted within two weeks after TKM treatment during follicular phase of menstrual cycle. There were no restrictions in terms of age, body mass index. We re-evaluated the AMH level to assess the effect of the TKM treatment for at least 2 month treatment in our clinic based on the criterion which in established dehydroepiandrosterone (DHEA) studies.4,6 DOR was defined as AMH level <1.1 ng/mL.20,21 Exclusion criteria were: (1) patients with primary ovarian insufficiency; (2) contraceptive pill use for at least four weeks prior to the study; (3) hormone replacement therapy; (4) cancer treatments or gonadotropin treatment.
2.2. Serum anti-Mullerian hormone analysis
Serum AMH levels were measured before and after TKM treatments at the laboratories of GC Labs, Yongin (AMH: AMH Gen II enzyme-linked immunosorbent assay [ELISA], Beckman Coulter, USA). The detection limit ofthe assay was 0.08 ng/mL. The intra- and inter-assay coefficients of variation were 12.3% and 14.2%, respectively.
2.3. Therapeutic intervention
The therapeutic interventions for patients with DOR were the same as those described in our previous study in 2010.22 These treatments included (1) water-extracted decoctions (120 mL) of herbal prescriptions customized to individual pattern diagnosis and given two times a day 30 min after meals. These herbal prescriptions were Soyoondam-tang, Anjunyichun-tang, Bohyuldodam-tang, Yukmihabyiseon-tang, and Gamiyorkbohabyiseon-tang. Detailed compositions of herbal prescriptions are shown in Table 1. (2) One pack of Seung Keum Dan taken with warm water three times a day 30min before meals. This HM formula contains 214 mg of dried powder of Moutan Radicis Cortex, Ligustici Tenuissimi Rhizoma et Radix, Ginseng Radix, Angelicae Gigantis Radix, Poria Sclerotium, Angelicae Dahuricae Radix, Cinnamomi Cortex, Cnidii Rhizoma, Corydalis Tuber, Paeoniae Radix, and Atractylodis Rhizoma Alba and 107 mg of dried powder of Glycyrrhizae Radix et Rhizoma and Achyranthis Radix per pack; (3) moxibustion to CV8 at home once daily, except during the menstrual period; and (4) pharmacopuncture injection of extracted solution of dried Cervi parvum cornu and Hominis placenta, which were prepared in the laboratories of the Korean Pharmacopuncture Institute (KPI), 0.1 mL of each, mainly at CV4, BL19, and BL22, using a sterile insulin syringe (29 gauge and 1/2 inch, Shinchang, Gyeongsangbuk-do, Republic of Korea).22 The HM and pharmacopuncture treatments were administered by two doctors of Korean medicine (K.M.D.) with ten years of clinical and research experience.
2.4. Statistical analysis
SPSS 19.0 for Windows (SPSS Inc., Chicago, IL, USA) was used for data management and statistical analysis. All continuous variables are expressed as means ± standard deviation (SD). Wilcoxon signed-rank test was used to measure the difference between values at baseline and at the end of treatment. We divided the study population into two age groups (<38 years and >38 years) to determine whether there was an age-related difference in the effect of TKM in patients with DOR as a post hoc analysis. Age 38 was chosen as cut-off because it has been reported to represents the beginning of accelerated decline in ovarian reserve.4 All p-values <0.05 were considered statistically significant.
3. Results
A total of 245 patients took AMH test, and of these 34 patients with AMH level <1.1 ng/mL took AMH test again after TKM treatment. We screened 34 patients' medical records, and 12 patients of them were excluded because they were with primary ovarian insufficiency. Finally, 22 patients with DOR were included in the study. Baseline descriptive parameters for all patients are shown in Table 1. The baseline AMH levels of four patients were unde-tectable. We postulated undetectable values as 0.08 because the detection limit ofthe AMH assay was 0.08 ng/mL. There were no significant differences in AMH levels before and after TKM treatment in all patients (p = 0.237) (Table 2). However, when the study population was divided into two age groups (<38 years and >38 years) to determine whether there was an age-related difference in the effect of TKM in patients with DOR, there were significant differences in AMH levels before and after TKM treatment in the younger group (p <0.05) (Table 3).The AMH levels in the younger group increased from 0.30 ± 0.26 ng/mL before treatment to 0.63 ± 0.59 ng/mL after treatment. No adverse effects were observed during the treatments. After TKM treatment, two patients conceived spontaneously were ongoing at 34 and 36 gestational weeks and one patient gave birth
Table l
Compositions of herbal medicines.
Korean medicine formulae
Compositions & dose (per day)
Soyoondam-tang
Anjunyichun-tang Bohyuldodam-tang
Yukmihabyiseon-tang
Gamiyorkbohabyiseon-tang
Cyperi Rhizoma 9 g, Citri Unshius Pericarpium 4.5 g, Bupleuri Radix 4g, Liriopis seu Ophiopogonis Tuber 4g, Atractylodis Rhizoma Alba 4g, Angelicae Gigantis Radix 4 g, Paeoniae Radix 4g, Zingiberis Rhizoma Recens 4 g, Zizyphi Fructus 4g, Pinelliae Tuber 3g, Ponciri Fructus Immaturus 3g, Phyllostachyos Caulis inTaeniam 3g, Ginseng Radix 2.25 g, Platycodonis Radix 2.25g, Menthae Herba 2g, Glycyrrhizae Radix et Rhizoma 2g
Ginseng Radix 20g, Rehmanniae Radix Preparata 20g, Atractylodis Rhizoma Alba 20g, Dioscoreae Rhizoma 10g, Corni Fructus 10g, Eucommiae Cortex 6g, Dolichoris Semen 4g, Lycii Fructus 4g, Glycyrrhizae Radix et Rhizoma 2g
Rehmanniae Radix Preparata 12g, Cyperi Rhizoma 9g, Angelicae Gigantis Radix 8g, Atractylodis Rhizoma Alba 6g, Cnidii Rhizoma 6g, Paeoniae Radix 6g, Citri Unshius Pericarpium 4.5g, Poria Sclerotium 4g, Amomi Fructus Rotundus 4g, Amomi Fructus 4g, Eucommiae Cortex 4g, Dipsaci Radix 4g, Zingiberis Rhizoma Recens 4g, Pinelliae Tuber3g, Ponciri Fructus Immaturus 3 g, Phyllostachyos Caulis in Taeniam 3 g, Zizyphi Fructus 3 g, Liriopis seu Ophiopogonis Tuber 2.25 g, Bupleuri Radix 2.25 g, Ginseng Radix 2.25 g, Platycodonis Radix 2.25 g, Crataegi Fructus 2g, Massa Medicata Fermentata 2g, Hordei Fructus Germinatus 2g, Glycyrrhizae Radix et Rhizoma 2g
Rehmanniae Radix Preparata 16g, Dioscoreae Rhizoma 8g, Corni Fructus 8g, Poria Sclerotium 6g, Moutan Radicis Cortex 6g, Alismatis Rhizoma 6g, Epimedii Herba 12g, Curculiginis Rhizoma 12g, Angelicae Gigantis Radix 9g, Morindae Radix 9 g, Anemarrhenae Rhizoma 5 g, Phellodendri Cortex 5 g
Japanese Angelicae Radix 6g, Liriopis seu Ophiopogonis Tuber 5.2g, Paeoniae Radix 5.2 g, Bupleuri Radix 5.2g, Asparagi Tuber 5.2 g, Dioscoreae Rhizoma 5.2 g, Alismatis Rhizoma 5.2 g, Atractylodis Rhizoma Alba 4.8 g, Poria Sclerotium 4.8 g, Citri Unshius Pericarpium 4.8 g, Fritillariae Thunbergii Bulbus 4.8 g, Cyperi Rhizoma 4.8 g, Lycii Radicis Cortex 4.8 g, Moutan Radicis Cortex 4g, Menthae Herba 4 g, Glycyrrhizae Radix et Rhizoma 4 g, Epimedii Herba 12 g, Curculiginis Rhizoma 12 g, Angelicae Gigantis Radix 9 g, Morindae Radix 9 g, Anemarrhenae Rhizoma 5 g, Phellodendri Cortex 5 g
Clinical parameters, including anti-MUllerian hormone (AMH) levels, in all patients before and after traditional Korean medicine (TKM) therapies.
Before TKM therapies (n = 22) After TKM therapies (n = 22) p-Value
36.68 ± 6.18 20.42 ± 2.09
3.64 ± 1.43
0.30 ± 0.29 0.42 ± 0.49 0.237
Values are given as means ± standard deviation. AMH—anti-MUllerian hormone.
Age (years)
Body mass index (kg/m2) Duration of treatment (months) AMH (ng/mL)
Anti-MUllerian hormone (AMH) levels in patients aged <38 or >38 years before and after traditional Korean medicine (TKM) therapies.
Age<38years, n =12 p-Value Age >38years, n = 10 p-Value
Before TKM therapies After TKM therapies Before TKM therapies After TKM therapies
Duration of treatment (months) 4.17 ± 1.59 - 3.00 ±0.94
AMH (ng/mL) 0.30 ± 0.26 0.63 ± 0.59 0.021 0.29 ± 0.35 0.18 ± 0.14 0.263
Values are given as means ± standard deviation. AMH—anti-MUllerian hormone.
to twins through ART treatment. The results for all patients are shown in Table 4.
4. Discussion
We found that TKM therapies were associated with significant increments in serum AMH concentrations in DOR patients who were <38 years old. To our knowledge, this study is the first to present objective evidence that AMH levels can be improved with TKM in patients with DOR. However, TKM therapies did not affect significantly serum AMH levels in patients aged 38 years and older related with physiological ovarian ageing.
To evaluate the effect of TKM therapies in DOR patients, prospective randomized clinical trials are needed. But TKM therapies combining acupuncture and HM are usually utilized to achieve better effect in real clinic for DOR patients. There were few studies evaluating this clinical setting. To explore the role of TKM in the treatment of DOR, retrospective chart review would be better than randomized clinical trials.
4.1. Mechanisms of action
According to TKM physiological theory, reproductive and endocrine systems are related to the 'kidney'. Women with normal fecundability have been considered to have abundant 'kidney qi' as well as essence and blood in TKM.23 The HM and pharma-copuncture therapies in the present study are used on the purpose of regulating 'kidney yinyang', replenishing essence and blood, and stimulating the proper flow of'qi'.
It has been suggested that HM can promote the luteotropic release of estrogen and progesterone in the ovary and stimulate the synthesis and pulsatile secretion of gonadotropins in the pituitary in anovulatory infertile women.24 The mechanism of action has not been fully elucidated, but it is believed that HM might reduce resistance in ovarian blood flow and increase ovarian perfusion, thus promoting follicular development. Consequently, HM improves oocyte quality and embryo quality and can result in higher pregnancy rates.14
Table 4
Patient characteristics and anti-Mullerian hormone (AMH) levels during the study.
Patient Number Age Duration of treatment (months) Number of acupuncture treatments Dosage of herbal medicine (days) Water extracted decoction Seung Keum Dan AMH level (ng/mL) Before treatment After treatmen
1 42 6 15 150 135 0.7 0.53
2 44 5 11 100 80 UD 0.12
3 43 6 21 100 132 0.30 0.16
4 44 2 11 60 60 0.16 0.08
5 40 3 11 75 40 0.08 0.08
6 36 2 3 65 32 0.67 0.98
7 35 4 11 110 80 UD 0.37
8 35 6 31 180 95 0.11 0.08
9 32 4 11 100 30 UD 1.99
10 36 3 7 70 35 UD 0.08
11 19 3 6 60 15 0.36 0.77
12 44 6 29 180 120 0.08 0.08
13 32 3 13 60 30 0.62 1.01
14 42 3 11 60 15 0.14 0.08
15 30 2 10 60 15 0.08 0.08
16 27 2 7 60 20 0.27 0.23
17 39 4 9 60 130 1.12 0.48
18 37 3 10 60 40 0.62 1.1
19 38 3 13 60 75 0.3 0.08
20 34 5 22 135 60 0.08 0.08
21 41 2 9 60 50 0.08 0.25
22 37 3 6 60 15 0.61 0.74
AMH—anti-Mullerian hormone; UD—undetectable.
4.2. Comparison with relevant literature
One of the most controversial issues in reproductive medicine is the question of whether DOR can be treated pharmacologically.25 To date, no treatment regimen for patients with DOR has been shown to be effective.6 It has been proposed that oral administration of DHEA may improve ovarian response and pregnancy rates in women with DOR during IVF, but there are insufficient data to support a beneficial role of DHEA as an adjuvant to controlled ovarian stimulation during the IVF cycle.26
Several studies have shown that AMH levels were improved after DHEA supplementation.4,6 One study reported that the AMH level was increased by 0.43 ng/mL after DHEA supplementation for at least 6 weeks, and the results and the age of that study group are comparable to our study.6 Another study showed significant improvement in AMH levels following DHEA supplementation especially in women aged <38 years.4 The finding that the therapeutic effects were more pronounced in a younger group with premature ovarian aging was in line with our result, and the degree of improvement of AMH levels was comparable to ours.4 Both studies reported that it appears to increase the chance of pregnancy among DOR patients, both spontaneously and while undergoing ART with improvement of AMH levels.4,6 In this context, our result that AMH level was increased by 0.33 ng/mL after TKM treatment might be meaningful to increase the fecundability. Future trials comparing the effects of TKM and DHEA are needed.
4.3. Limitations
This study has the inherent limitations of retrospective research. Also, the sample sizes were very small. Although serum AMH levels were significantly increased in women under the age of 38 years, we could not follow up all the patients on pregnancy outcomes. Further studies in a larger population and longer prospective randomized clinical trials are needed in order to confirm these results and to evaluate the effects of improved ovarian reserve following TKM on pregnancy outcomes in patients with DOR.
5. Conclusions
TKM may provide an effective option for patients aged <38 years with DOR, but it should be interpreted cautiously because this study was exploratory study for feasibility of TKM in patients with DOR. Further rigorous studies in a larger population are needed in order to confirm these results and to evaluate the effects of improved ovarian reserve after TKM on pregnancy outcomes in patients with DOR.
Conflicts of interest
The authors declare that there are no conflicts of interest.
Acknowledgments
This study was supported by the Development of Korean Medicine contents for clinical practice (No. K16124) of the Korea Institute of Oriental Medicine.
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