Table 1. List of Clinical Studies Related to Gyejibokryeong-hwan
KCD code	Year	Subjects	Method	No.
D25 Leiomyoma of uterus	1992	Pharmacotherapeutic effects of kuei-chih-fu-ling-wan on human uterine myomas9)	Clinical trials	1
	2014	Chinese herbal medicine Guizhi Fuling formula for treatment of uterine fibroids: a systematic review of randomised clinical trials10)	Systematic review	2
	2023	Efficacy and safety of mifepristone combined with Guzhi Fuling capsules in the treatment of non-surgical patients with uterine fibroids: a meta-analysis11)	Systematic review	3
	2023	The efficacy and safety of Chinese herbal medicine Guizhi Fuling capsule combined with low dose mifepristone in the treatment of uterine fibroids: a systematic review and meta-analysis of 28 randomized controlled trials12)	Systematic review	4
E28.2 Polycystic ovarian syndrome	2022	Add-on effect of the Guizhi Fuling formula for management of reduced fertility potential in women with polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials13)	Systematic review	5
N73.4 Female chronic pelvic peritonitis; N73.9 Female pelvic inflammatory disease, unspecified	2017	Guizhi Fuling capsule/pill treatment for chronic pelvic inflammatory disease: a systematic review of randomized clinical trials14)	Systematic review	6
N80 Endometriosis	2019	Add-on effect of Guizhi Fuling formula to mifepristone for endometriosis: a meta-analysis of randomized controlled trials15)	Systematic review	7
N94.4 Primary dysmenorrhoea; N94.5 Secondary dysmenorrhoea; N94.6 Dysmenorrhoea, unspecified	2004	Clinical study on the efficacy of Gyejibongnyeong-hwan in the treatment of menorrhalgia16)	Clinical trials	8
	2006	Clinical study on the effect of Gyebongnyeong capsule in the treatment of primary dysmenorrhea17)	Clinical trials	9
	2007	A pilot study of the difference between Gyejibongnyeong-hwan and Gyejibongnyeong-hwan combined acupuncture therapy on the primary dysmenorrhea18)	Clinical trials	10
	2013	Effects and safety of varying doses of guizhi fuling capsule in patients with primary dysmenorrhea: a multi-center, randomized, double-blind, placebo-controlled clinical study19)	Clinical trials	11
	2016	The difference between the two representative Kampo formulas for treating dysmenorrhea: An observational study20)	Clinical observational study	12
	2023	Effect of Guizhi Fuling Wan in primary dysmenorrhea: A randomized controlled trial21)	Clinical trials	13
N95.1 Menopausal and female climacteric states	2003	Menopausal hot flash and calcitonin gene-related peptide; effect of Keishi-bukuryo-gan, a kampo medicine, related to plasma calcitonin gene related peptide level22)	Clinical trials	14
	2005	Comparing the effects of estrogen and an herbal medicine on peripheral blood flow in post-menopausal women with hot flashes: Hormone replacement therapy and Gui-zhi-fu-ling-wan, a Kampo medicine23)	Clinical trials	15
	2007	A clinical trial to verity the quality of life improvement efficacy of Dangguijakyak-san and Gyejibongnyeong-hwan granulation in postmenopausal women 24)	Clinical trials	16
	2011	Effect of Gui-zhi-fu-ling-wan on hot flashes in young patients: a retrospective case series25)	Clinical observational study	17
	2011	Effects of the Kampo medication keishibukuryogan on blood pressure in perimenopausal and postmenopausal women26)	Clinical observational study	18
	2011	Effects of three Kampo formulae: Tokishakuyakusan, Kamishoyosan, and Keishibukuryogan on Japanese peri- and postmenopausal women with sleep disturbances27)	Clinical observational study	19
	2011	Effects of Japanese traditional medicines on circulating cytokine levels in women with hot flashes28)	Clinical trials	20
	2011	The TU-025 keishibukuryogan clinical trial for hot flash management in postmenopausal women: results and lessons for future research30)	Clinical trials	21
	2012	A herbal-drug interaction study of keishi-bukuryo-gan, a traditional herbal preparation used for menopausal symptoms, in healthy female volunteers31)	Clinical trials	22
	2014	Identification of a predictive biomarker for the beneficial effect of Keishibukuryogan, a Kampo medicine, on patients with climacteric syndrome32)	Clinical trials	23
	2019	A classic herbal formula Guizhi Fuling Wan for menopausal hot flushes: from experimental findings to clinical applications33)	Systematic review	24
	2023	Beneficial effect of Gyejibokryeong-hwan on climacteric syndrome with blood stasis pattern: A randomized, double-blinded, placebo-controlled clinical pilot trial34)	Clinical trials	25
non-specific	1990	Endothelin-1 levels are not influenced by tokishakuyakusan and keishibukuryogan treatment in women35)	Clinical trials	26

Table 2. A Clinical Study on Leiomyoma of Uterus Using Gyejibokryeong-hwan
Author /year /language	Diagnosis /sex /age	Drug type /dosage /period /control group	Main results	Adverse effects
Sakamoto et al. 9) /1992 /English	Uterine myomas, diameter, ≤ 10 cm /Female, 110 /Age: 43.2 ± 5.0	GBH, extract granules (n = 110) /1.5 g/day /More than 12 weeks administration /No control group	Uterine myoma size in 110 cases: Normalized, 21 (19%), improved, 47 (43%), unchanged, 37 (34%), progressed 5 (4%) Hypermenorrhea in 63 cases (57%): Normalized, 29 (16%), improved, 31 (49%), unchanged, 3 (5%), progressed 0 (0%) Dysmenorrhea in 51 cases (46%): Normalized, 26 (51%), improved, 22 (43%), unchanged, 3 (6%), progressed 0 (0%) Anemia in 14 cases (13%): Normalized, 6 (43%), improved, 8 (57%), unchanged, 0 (0%), progressed 0 (0%)	-
GBH, Gyejibokryeong-hwan

Table 3. Systematic Reviews of Gyejibokryeong-hwan on Leiomyoma of Uterus
Author /year /language	Diagnosis /papers /patients	Main results
Chen et al.10) /2014 /English	Uterine fibroids /RCT, 16 /3,816	- Combination of GBH and mifepristone showed superiority in reducing the volume of fibroids and average volume of multiple fibroids, improving symptoms of dysmenorrhea.
Lei et al.11) /2023 /English	Uterine fibroids /RCT, 28 /2,813	- Combination of GBH and mifepristone showed superiority in reducing the volume of fibroids and uterus, reducing FSH, estradiol, progesterone, LH, menstrual flow and increasing clinical efficiency rate.
Xu et al.12) /2023 /English	Uterine fibroids /RCT, 20 /2,252	- Combination of GBH and mifepristone showed superiority in shrinking fibroids size, controlling serum hormone levels and fewer adverse events.
GBH, Gyejibokryeong-hwan; RCT, randomized controlled trials; FSH, folicle stimulating hormone; LH, luteinizing hormone

Table 4. Systematic Reviews of Gyejibokryeong-hwan on Polycystic Ovarian Syndrome
Author /year /language	Diagnosis /papers /patients	Main results
Rong et al.13) /2023 /English	Polycystic ovary syndrome /RCT, 16 /1,385	- GBH combination with clomifene or ethinylestradiol/cyproterone acetate showed superiority in rates of ovulation and pregnancy, and lower levels of plasma FSH, total testosterone, LH, and HOMA-IR.
GBH, Gyejibokryeong-hwan; RCT, randomized controlled trials; LH, luteinizing hormone; HOMA-IR, Homeostatic Model Assessment of Insulin Resistance

Table 5. Systematic Reviews of Gyejibokryeong-hwan on Chronic Pelvic Inflammatory disease
Author /year /language	Diagnosis /papers /patients	Main results
Zhang et al.14) /2017 /Chinese	Chronic pelvic inflammatory disease /RCT, 30 /3,586	- Combination of GBH and western medicine showed superiority in clinical effcacy, and reducing recurrence rate, reducing plasma hs-CRP, TNF and fibrin.
GBH, Gyejibokryeong-hwan; RCT, randomized controlled trials; hs-CRP, high sensitivity C-reavtive protein; TNF, tumor necrosis factor

Table 6. Systematic Reviews of Gyejibokryeong-hwan on Endometriosis
Author /year /language	Diagnosis /papers /patients	Main results
Meng et al.15) /2019 /English	Endometriosis /RCT, 10 /1,052	- Combination of GBH and mifepristone showed superiority in reducing the recurrence of endometriosis, improving the pregnancy and reducing serum estradiol, progesterone.
GBH, Gyejibokryeong-hwan; RCT, randomized controlled trials

Table 7. Clinical Studies on Dysmenorrhea Using Gyejibokryeong-hwan
Author /year /language	Diagnosis /sex /age	Drug type /dosage /period /control group	Main results	Adverse effects
Choi et al.16) /2004 /Korean	Primary dysmenorrhea /female, 13 /Age: 27.13 ± 6.91 (17-45)	- GBH extracts / 12.5 g/day / 8 weeks	1. MVRS (baseline → 4 weeks → 8 weeks): 5.15 ± 2.73 → 3.96 ± 2.38* → 4.23 ± 2.42* 2. VRS: 2.85 ± 1.34 → 2.00 ± 1.22** → 2.00 ± 1.15** 3. VAS for pain : 8.08 ± 2.47 → 6.00 ± 2.96** → 5.65 ± 2.97***	- Intermittent diarrhea, 3 cases; abnormal feeling of urination, 2 cases; irregular bleeding, 1 case
Nam et al.17) /2006 /Korean	Primary dysmenorrhea /female, 10 /Age: 22.10 ± 2.64 (20-29)	- GBH capsule / 9 g/day / for 2 menstrual cycle / No control group	1. VAS for normal pain (baseline → 4 weeks → 8 weeks): 81.30 ± 5.98 → 54.00 ± 21.19** → 34.00 ± 13.90**, ## 2. VAS for maximum pain : 97.00 ± 4.83 → 71.50 ± 20.01* → 54.00 ± 13.29**,## 3. PGA: 35.90 ± 3.76 → 28.40 ± 6.60** → 19.00 ± 7.60**,##	- Dyspepsia, 1 case
Cho18) /2007 /Korean	Primary dysmenorrhea /female, 10 /Age: 25.25 ± 3.30	-GBH, extract granules / 12.5 g/day / 8 weeks / GBH plus acupuncture therapy, 2 times a week	1. VAS improvement (baseline → 4 weeks → 8 weeks) [GBH] 88.75 ± 14.36 → 64.50 ± 29.96 → 55.00 ± 36.97; [GBH plus Acupuncture] 95.00 ± 8.37 → 93.33 ± 4.08 → 80.50 ± 18.15	-
Liu et al.19) /2013 /Chinese	Primary dysmenorrhea /Female, 240 /Age, 18～30	GBH, extract granules / high dose (4.19 g/day, n = 80), low dose (2.79 g/day, n = 80) /3 menstrual cycles administration and follow-up after 3 menstrual cycles / Control group: placebo (n = 39)	1. Reduction of VAS for pain intensity (12 weeks*** → 24 weeks**): - [high GBH] 68.42% → 73.68%; [low GBH] 67.57% → 72.97%; [Placebo] 47.89% → 53.52% 2. Reduction of pain duration (12 weeks*** → 24 weeks*): - [high GBH] 57.88% → 67.93%; [low GBH] 46.17% → 53.56%; [Placebo] 30.40% → 47.46% 3. TCM diagnostic symptoms (12 weeks → 24 weeks): - [high GBH] 85.53% → 94.73%; [low GBH] 87.84% → 87.84%; [Placebo] 57.75% → 67.61%	-
Yoshino et al.20) /2016 /English	Primary and secondary dysmenorrhea, prescribed GBH or DJS /female, 128(+40) /Age: 33.3(12-50)	-	1. Five Subjective symptoms with significant difference out of 128 symptoms Tendency to sweat: [GBH] 28/68 (41.2%) Heat intolerance: [GBH] 28/68 (41.2%) Leg numbness: [GBH] 9/68 (13.2%) Cold sensation in lower back: [GBH] 12/68 (17.6%) Lightheadness: [DJS] 30/60 (50.0%) 2. Four objective findings with significant difference out of 12 diagnostic findings Weak abdomen: [DJS] 32/60 (53.3%) Strong abdomen: [GBH] 18/68 (26.5%) Paraumblical tenderness: and resistance: [GBH] 58/68 (85.3%) Body mess index (BMI, < 18.5 kg/m2): [DJS] 21/60 (35.0 %)	-
Luo et al.21) /2023 /English	Primary dysmenorrhea /Female, 128 /Age, 16-30	GBH, Extract granules (n = 64) /6.5 g/day /3 menstrual cycles administration and follow-up after 3 menstrual cycles /Placebo (n = 64)	1. VAS change in pain intensity at 6 months (Mean, 95% CI): [GBH] 3.45 (2.90, 4.00); [Placebo] 1.21 (0.62, 1.79)†† 2. CMSS of severity (Mean, 95% CI): [GBH] 11.23 (8.78, 13.57); [Placebo] 4.07 (1.91, 6.22)†† 3. CMSS of duration (Mean, 95% CI): [GBH] 8.91 (6.80, 11.01); [Placebo] 2.59 (0.59, 4.60)†† 4. SAS score (Mean, 95% CI): [GBH] 11.79 (8.47, 15.11); [Placebo] 2.09 (− 0.06, 4.25)†† 5. TCM syndrome: [GBH] 4.55 (3.51, 5.58); [Placebo] 2.19 (1.27, 3.11)††	GBH groups, three mild events: 1 case of constipation; 1 case of dizzy; 1 case of menstrual period change. Placebo groups, two mild events: 1 case of coldness; 1 case of menstrual period change.
GBH, Gyejibokryeong-hwan; CI, confidence interval; CMSS, Cox menstrual symptom scale; DJS, danggwijagyak-san; MVRS, multi-dimensional verval rating scale; PGA, Patient’s global assessment; SAS, The self-rating anxiety scale; SDS, The self-rating depression scale; TCM, traditional Chinese medicine; VRS, verval rating scale modified from the one devised by Bibe roglu and Berhman; *, p < 0.05, vs. baseline; **, p < 0.01, vs. baseline; ## p < 0.01, vs 4 weeks; ††, p < 0.01;

Table 8. Clinical Study on Menopausal and Female Climacteric States Using Gyejibokryeong-hwan
Author /year /language	Diagnosis /sex /age	Drug type /dosage /period /control group	Main results	Adverse effects
Chen et al.22) /2003 /English	Post-menopausal with hot flashes symptom /Female, 8 /Age: 53.5 ± 0.58	GBH, extract granules (n = 8) /7.5 g/day /4 weeks /No control drug	1. Hot flush symptoms frequency: 5.25 ± 0.98 → 2.25 ± 0.16* 2. Calcitonin gene related peptide (pg/ml): 5.76 ± 1.52 → 2.88 ± 0.81 (p = 0.057)	-
Ushiroyama et al.23) /2005 /English	Post-menopausal with hot flashes symptom /Female, 131 /Mean age, 53.3; Mean menopausal age, 50.4	GBH, Extract granules /(n = 67) /7.5 g/day /1 months /Combined therapy: (HRT, PremarinR: 0.625 mg/day and ProveraR: 2.5 mg/day (n = 64)	1. Blood flow (mean ± S.D., k1∫ ωP(ω)dω/12) - Under the jaw: [GBH] 14.4 ± 7.04 → 6.01 ± 2.96***; [HRT] 15.8 ± 7.42 → 9.57 ± 5.88*** - Fingertip: [GBH] 45.3 ± 19.4 → 33.4 ± 12.7***; [HRT] 44.2 ± 10.0 → 40.5 ± 9.9*** - Toe tip: [GBH] 5.91 ± 3.77 → 8.12 ± 4.43**	-
Park et al.24) /2007 /Korean	Postmenopausal syndrome /female, 16 /Age: 40-60	- GBH extract granule (n = 11) / 9 g/day / 1 month administration and 1 month follow-up / Compared with DJS, 9 g/day (n = 5)/	1. Postmenopausal syndrome symptoms in [GBH]: - MENQOL, improved gradually** - Hot flush VAS, improved gradually** - Sweating VAS, improved gradually* - Palpitation VAS, improved gradually*** - MRS, improved gradually** - PGA, improved gradually** - Sleep disturbance VAS, tends to improvement gradually	-
Cho et al.25) /2011 /English	Hot flashes symptom /Male, 15; female, 22 /Age: 32.3 ± 10.3	GBH Extract granules (n = 37) /7.5g/day /128±103.2 days /No control drug	- VAS improvement for Hot flashes: 40.4 ± 28.5 % improvement - Assessment of treatment: Remarkable, 9 cases; More than effective, 10 cases; Effective, 11 cases; Not effective, 7 cases.	Itching and edema in 1 case ; dyspepsia and constipation in 1 case
Terauchi et al.26) /2011 /English	Hypertension in peri- or postmenopausal women /Female, 77 /Mean age: 52.14	GBH, Extract granules (n = 30) /7.5 g/day /182 ± 76 days / Control group (n = 47): no medication.	1. The systolic pressure (mmHg): 148.4 ± 2.6 → 134.8 ± 2.8*** 2. The diastolic pressure (mmHg): 89.7 ± 2.1 → 83.7 ± 1.9*** 3. The pulse rate (beats/min): 79.5 ± 1.7 → 73.5 ± 1.5*** 4. Resting energy expenditure (Kcal/day): 1552 ± 73 → 1373 ± 56* 5. Scores of menopausal symptoms: perspiration, 2.0 → 1.6*; difficulty sleeping, 1.1 → 0.8*; headaches/dizziness, 1.6 → 1.0*	-
Terauchi et al.27) /2011 /English	Sleep disturbances in peri- or postmenopausal women /Female, 151 /Mean age: 52.26	GBH, Extract granules (n = 16), DJS (n = 42) and GSS (n = 16) /7.5 g/day /144 ± 58 days / Control group (n = 77): no medication.	1. Subjective sleep disturbance score: [GBH] 2.8 (median value and 95% CI, 2.51-2.99) → 1.1 (95% CI, 0.80-1.46)***; [GSS] 2.3 (2.01–2.49) → 1.1 (0.80–1.46)** 2. Scores of menopausal symptoms (mean): [GBH] perspiration, 2.5 → 1.5**; [GSS] Headache/dizziness, 2.3 → 1.1*	-
Yasui et al.28) /2011 /English	Hot flashes symptom /Female, 116 /Mean age, 51.3(39.3～58.7)	Extract granules , GBH (n =38) and KSS (n = 39) /7.5 g/day /6 months / Control group: with no therapy (n = 39)	1. Hot flashes symptom improvement: [Control] 14 cases; [GBH] 28 cases; [KSS] 27 cases 2. Serum cytokine assay (median value and 10th-90th percentiles, pg/mL): [GBH] MCP-1, 49.7 (20.2-113.9) → 42.9 (21.2-76.5)**; [GSS] IL-6 1.68 (0.67-8.35) → 1.16 (0.55-5.26)*; MIP-1β, 236.7 (65.4-499.5) → 175.6 (80.9-351.7)*	- One case of abnormal feeling in the gastrointestinal tract in GBH - One case of oral bitterness and diarrhea
Plotnikoff et al.30) /2011 /English	Post-menopausal with hot flashes symptom /Female, 178 /Age: 53.3 ± 0.24	GBH, extract granules /7.5 g/day (n = 62) or 12.5 g/day (n = 57) /12 weeks /Control drug, placebo (n = 59)	1. Mayo hot flash symptom diary scoring system: no significant difference among 3 groups 2. Greene climacteric index: no significant difference among 3 groups 3. Pittsburgh Sleep Quality Scale: no significant difference among 3 groups	unanticipated diarrhea, 25 cases out of 119 GBH group patients
Saruwatari et al.31) /2012 /English	Healthy volunteers /Female, 31 /Age: 20-27	GBH, extract granules (n = 31) /7.5 g/day /7 days administration /No control drug	1. Phenotyping indices - CYP1A2 (mean ± S.D., Urinary molar ratio of (AAMU+1U+1X)/17U): 4.92 ± 5.45 → 4.11 ± 2.92* - XO, NAT2, CYP2D6, CYP3A: no significant changes.	-
Namiki et al.32) /2014 /english	Climacteric syndrome with estrogen β receptor polymorphism /Female, 34 /Age: 49.5 ± 4.69	GBH, extract granules (n = 34) /7.5 g/day /12 weeks administration /No control drug	Estrogen β receptor cytosine-adenine repeat: ≤21, defined as short (S), and >21, defined as long (L) 1. LL (n = 13): Kupperman vasomotor index, 10.46 ± 2.03 → 7.08 ± 4.05* 2. SL (n = 12): Kupperman melancholia index, 1.92 ± 0.90 → 1.25 ± 0.75*	-
Han et al.34) /2023 /English	Climacteric syndrome with blood stasis pattern /Female, 50 /Mean Age: 52.85 20-27	GBH, extract granules (n = 24) /2.66 g/day /4 weeks administration and follow-up after 4 weeks /Control group: placebo (n = 25)	1. Menopause rating scale change Week 5*: GBH, -9.25; Placebo, -6.88 Week 9: GBH, -6.88; Placebo, -6.04 2. Blood-stasis pattern questionnaire Week 5: GBH, -5.86; Placebo, -1.32	- GBH group: 1 case, climacteric symptom exacerbation; 1 case, dyspepsia - Placebo group: 1 case, abdominal distention; 1case, abnormal increase in ALP, γ-GTP, and hsCRP levels
ALP, alkaline phosphatase; CI, confidence interval; hsCRP, high sensitivity C-reavtive protein; CYP, cytochrome P450; DJS, danggwijagyak-san; GBH, Gyejibokryeong-hwan; GSS, gamisoyo-san; γ-GTP, gamma-glutamyl transpeptidase; HRT, hormone replacement therapy; IL, interleukin; MCP-1, monocyte chemotactic protein-1; MENQOL, The menopause-specific quality of life; MIP-1A, macrophage inflammatory protein-1A; MRS, menopause rating scale; NAT2, N-acetyltransferase 2; PGA, patient’s global assessment; VAS, visual analogue scale; XO, xanthine oxidase; *, p < 0.05; **, p < 0.01; ***, p < 0.001

Table 9. Systematic Reviews of Gyejibokryeong-hwan on Menopausal and Female Climacteric States
Author /year /language	Diagnosis /papers /patients	Main results
Li et al.33) /2019 /English	Post-menopausal with hot flashes symptom /RCT, 2; Parallel controlled study, 1; Case series 1	- GBH showed no significant changes in the frequency and severity of menopausal hot flushes - GBH could improve peripheral blood flow.
GBH, Gyejibokryeong-hwan; RCT, randomized controlled trials

Table 10. Clinical Study of the Endothelin-1 and Gyejibokryeong-hwan
Author /year /language	Diagnosis /sex /age	Drug type /dosage /period /control group	Main results	Adverse effects
Usuki et al.35) /1990 /english	Pregnant and non-pregnant women /Female, /Mean age: 27(21～39)	GBH or DJS, Extract granules /7.5 g/day / Control groups: no medication.	1. Endothelin-1 level during menstrual cycle: no significant difference 2. Endothelin-1 level during pregnancy, labor, and post-partum day: no significant difference	-
DJS, danggwijagyak-san; GBH, Gyejibokryeong-hwan