Dydrogesterone after 60 years: a glance at the safety profile

Figures & data

Figure 1. Preferred reporting items for systematic reviews and the meta-analyses (PRISMA) flow chart.

Table 1. Summary of reported safety outcomes in studies with dydrogesterone used in menopausal hormone therapy regimen.

Author	n	Mean age (years)	Interventions	Duration of treatment (exposure, weeks)	Key safety findings
Canonico M et al. [7]	549^#	54.0	Arm 1: Oral DYD/oral and transdermal 17-β estradiol (n = 91 including other pregnane derivatives) Arm 2: Oral micronized progesterone, pregnane derivatives^a, norpregnane derivatives^b, or nortestosterone derivatives/oral and transdermal 17-β estradiol (n = 229 excluding other and unknown treatment)	∼527	No significant association of VTE with 17-β estradiol + pregnane derivatives^a (HR = 1.3; 95% CI: 0.9–2.0) vs. 17-β estradiol + norpregnane derivatives^b(HR = 1.8; 95% CI: 1.2–2.7)
Stevenson et al. [8]	313	53.5	Arm 1: Oral DYD 2.5 mg/oral 17-β estradiol 0.5 mg (n = 124)	13	Breast discomfort/pain experienced by only 3–5% of the women
		54.0	Arm 2: Oral DYD 5 mg /oral 17-β estradiol 1 mg (n = 62)
		53.8	Arm 3: No MHT (Placebo) (n = 127)
Bergeron et al. [9]	446	53.5	Arm 1: Oral DYD 2.5 mg/oral 17-β estradiol 0.5 mg (n = 374 for endometrial analysis)	52	Breast discomfort and pain experienced by 0.9% and 1.6%, respectively
Kuba et al. [10]	123	56.5	Arm 1: Oral DYD 10 mg/percutaneous 17-β estradiol 1 mg (n = 41)	∼104 (12 days every 4 weeks)	No negative impact on metabolic profile
		55.2	Arm 2: Percutaneous 17-β estradiol alone 1 mg (n = 41)
		52.6	Arm 3: No MHT (n = 41)
Fournier et al. [11]	3678^$	67.0	Arm 1: Oral DYD/micronized progesterone/oral and transdermal 17-β estradiol (n = 638) Arm 2: Other progestins^c/oral and transdermal 17-β estradiol (n = 931) Arm 3: Oral and transdermal 17-β estradiol alone (n = 169) Arm 4: Tibolone alone (n = 71) Arm 5: Others (MHT containing an androgen) (n = 260)	≤260 (short-term) >260 (long-term)	Significantly reduced breast cancer risk with 17-β estradiol + DYD with ≤5 years of use (HR = 1.13; 95% CI: 0.99–1.29) vs. 17-β estradiol + other progestins^c (HR = 1.70; 95% CI: 1.50–1.91)
Fournier et al. [12]	301*	64.3	Arm 1: Oral DYD/systemic 17-β estradiol/CEE(n = 140) Arm 2: Estrogen alone (systemic estradiol or conjugated estrogens) (n = 140) Arm 3: Weak estrogen alone (orally or vaginally administered promestriene or estriol) (n = 31) Arm 4: Tibolone alone (n = 8) Arm 5: Oral micronized progesterone/systemic estradiol/CEE (n = 270) Arm 6: Oral progesterone derivative^d/systemic estradiol/CEE (n = 235) Arm 7: Oral norsteroid derivative^e/systemic estradiol/CEE (n = 68) Arm 8: Others (MHT containing androgen/ IM/patch containing progestogen (n = 25)	≤260(short-term) >260 (long-term)	17-β estradiol/CEE + DYD not associated with endometrial cancer risk with ≤5 years of use (HR = 0.87; 95% CI: 0.57–1.32) vs. systemic estrogen/CEE + oral NMP (HR = 1.39; 95% CI: 0.99–1.97)
Xue W et al. [13]	123	53.7	Arm 1: Oral DYD 10 mg/oral CEE 0.625 mg (n = 41)	52	No negative impact on metabolic profile
		53.1	Arm 2: Oral NMP 100 mg/oral CEE 0.3 mg (n = 41)
		53.4	Arm 3: Oral NMP 100 mg/oral CEE 0.625 mg (n = 41)
Piróg M et al. [14]	175	45–65	Arm 1: Oral DYD 5 mg/oral 17-β estradiol 1 mg (n = 58) Arm 2: Oral DYD 2.5 mg/oral 17 β-estradiol 0.5 mg (n = 59) Arm 3: No MHT (n = 58)	52	No impact on thrombin generation
Vinogradova Y et al. [15]	59,999 (QResearch) 38,612 (CPRD) n1 = 8860; estrogen only n2 = 24,843 estrogen-progesterone therapy	63.4	Arm 1: Oral DYD/oral and transdermal 17-β estradiol	≤260 (short-term) ≥260 (long- term)	Low risk of breast cancer with 17-β estradiol + DYD (OR = 1.24; 95% CI: 1.03–1.48) vs. 17-β estradiol + norethisterone (OR 1.88; 95% CI: 1.79–1.99) Lower risk of breast cancer with 17-β estradiol + DYD with ≥5 years of use (OR 1.24, 95% CI: 1.03–1.48)
		63.4	Arm 2: Oral norethisterone/oral and transdermal 17-β estradiol Arm 3: Oral medroxyprogesterone/oral and transdermal 17-β estradiol/oral CEE Arm 4: Levonorgestrel intrauterine system/oral and transdermal 17-β estradiol/oral CEE Arm 5: Estrogen alone (oral and transdermal 17-β estradiol/ oral CEE Arm 6: Tibolone alone
Song Y et al. [16]	132	45.7	Arm 1: Oral DYD 10 mg/oral 17-β estradiol 1 mg (n = 63)	25	Low incidence of AEs (breast pain, endometrial hyperplasia, uterine hemorrhage) with 17-β estradiol + DYD
		46.2	Arm 2: Oral DYD 10 mg/oral 17-β estradiol 0.5 mg (n = 69)
Tsiligiannis et al. [17]	682	NR	Arm 1: Oral DYD 2.5 mg/oral 17-β estradiol 0.5 mg (n = 682)	52 (long-term)	No breast malignancy; 1 case of endometrial hyperplasia

^#Including never users of MHT, past users of MHT, no progestogens users, micronized progesterone, pregnane derivatives, norpregnane derivatives, nortestosterone derivatives, other treatment and unknown treatment.

^$Total number of breast cancer cases exceeds 3678 since single woman could be exposed to several categories of MHT simultaneously (e.g. past use of estrogen-only therapy and current use of estrogen-micronized progesterone).

*Total number of endometrial cancer cases exceeds 301 since single woman could be exposed to several categories of MHT simultaneously (e.g. past use of estrogen-only therapy and current use of estrogen-micronized progesterone) AE, adverse event; CEE, conjugated equine estrogens; CI, confidence interval; CPRD, clinical practice research datalink, DYD, dydrogesterone; HR, hazard ratio; IM, intramuscular; MHT, menopausal hormone therapy; N, total sample size; n, total number of patients in a subset; NMP, natural micronized progesterone; NR, not reported; OR, odds ratio; VTE, venous thromboembolism.

^aChlormadinone acetate, cyproterone acetate dydrogesterone, medrogestone, and medroxyprogesterone acetate.

^bNomegestrol acetate and promegestone.

^cChlormadinone acetate, cyproterone acetate, demegestone, dienogest, drospirenone, ethynodiol acetate, gestodene, levonorgestrel, lynestrenol, medrogestone, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, norethisterone acetate, and promegestone.

^dChlormadinone acetate, cyproterone acetate, demegestone, medrogestone, medroxyprogesterone acetate, nomegestrol acetate, or promegestone.

^eDienogest, drospirenone, ethynodiol, gestodene, levonorgestrel, norethisterone acetate, or lynestrenol.

Table 2. Summary of reported safety outcomes in studies with dydrogesterone used as LPS in the context of ARTs, threatened abortion, menstrual disorders, endometriosis, and PMS.

Author	n	Mean age	Interventions	Duration of treatment (exposure, weeks)	Key safety findings
LPS in ART
Salehpour S et al. [18]	80	29.4	Arm 1: Oral DYD 10 mg QID (n = 40)	12 (starting from day of OR)	Higher AEs with DYD vs. MVP pessaries (vaginal bleeding 48% vs. 20%; nausea 25% vs. 0%; abdominal pain 15% vs.0%, respectively)
		31.8	Arm 2: MVP pessaries 400 mg BID (n = 40)
Gopinath PM et al. [19]	60	28.3	Arm 1: Oral DYD 10 mg BID (n = 30)	4 (subsequent to IUI procedure)	No drowsiness observed with DYD vs. oral NMP SR preparation
		28.3	Arm 2: Oral NMP SR preparation 400 mg OD (n = 30)
Tomic et al. [20]	853	34.1	Arm 1: Oral DYD 10 mg BID (n = 415)	12 (starting from day of OR)	Higher AEs with MVP gel vs. DYD (vaginal bleeding, vaginal discharge, and interference with coitus) (p < .05)
		32.6	Arm 2: MVP gel 90 mg OD (n = 416)
Malhotra J et al. [21]	78	30.1	Arm 1: Oral DYD 10 mg BID (n = 33)	8–12 (starting from day of hCG trigger)	Minimal AEs observed with DYD vs. oral NMP SR preparation (drowsiness, nausea)
		29.0	Arm 2: Oral NMP SR preparation 200/300 mg OD (n = 45)
Saharkhiz N et al. [22]	210	30.5	Arm 1: Oral DYD 20 mg BID (n = 96)	12 (starting from day of OR)	Similar AEs with DYD vs. MVP pessaries (vaginal bleeding 14% vs. 13%; breast fullness 5% vs. 4%, respectively; abdominal pain 8% vs. 6%; constipation 3% vs. 2%)
		30.9	Arm 2: MVP pessaries 400 mg BID (n = 114)
Nadarajah R et al. [23]	1050	35.0	Arm 1: Oral DYD 30 mg OD (n = 1050)	12 (starting from day of OR)	No evidence of elevated risk of congenital anomalies or miscarriage with DYD
Tournaye H et al. [24]	1031	32.5	Arm 1: Oral DYD 10 mg TID (n = 519)	12 (starting from day of OR)	Similar AEs with DYD vs. MVP capsules (vaginal bleeding 11.6% vs. 9.2%; spontaneous abortion 1.5% vs. 2%; missed abortions 1.4% vs. 1.4%; congenital anomalies 1.0% vs. 1.2%, respectively)
		32.5	Arm 2 MVP capsules 200 mg TID (n = 510)
Griesinger G et al. [25]	1034	31.8	Arm 1: Oral DYD 10 mg TID (n = 518)	12 (starting from day of OR)	Similar AEs with DYD vs. MVP gel (vaginal bleeding 9.8% vs. 7.2%; vaginal discharge 2.1% vs. 0.6%; missed abortion 2.3% vs. 0.4%; congenital anomalies 6.3% vs. 5.0%, respectively)
		31.6	Arm 2: MVP gel 90 mg OD (n = 512)
Huang J et al. [26]	3556	31.0	Arm 1: Oral DYD 20 mg OD (n = 1399 cycles)	12 (starting from day of ET)	No evidence of elevated risk of major congenital anomalies with dydrogesterone
		31.5	Arm 2: MVP capsules 400 mg OD (n = 2095 cycles)
Yang DZ et al. [27]	239	29.9	Arm 1: Oral DYD 30 mg OD (n = 119)	12 (starting from day of OR)	Similar AEs with DYD vs. MVP gel (vaginal bleeding 21.8% vs. 10.9%; congenital anomalies 6.3% vs. 5.0%, respectively)
		29.8	Arm 2: MVP gel 90 mg OD (n = 120)
Atzmon Y et al. [28]	599	34.3	Arm 1: Oral DYD 10 mg TID (n = 226)	6	Similar AEs with DYD vs. MVP gel and pessaries
		35.5	Arm 2: MVP gel 90 mg (n = 373)
Ozer G et al. [29]	134	31.8	Arm 1: Oral DYD 10 mg TID (n = 67)	12 (starting from 36 h after r-hCG trigger)	Higher AEs with MVP gel vs. DYD (vaginal irritation 1.6% vs. 44.6%; vaginal discharge 12.3% vs.76.9%; breast pain 36.9% vs. 4.6%; headache 13.8% vs. 0%; dizziness 9.4% vs. 0%; flatulence 32.8% vs. 12.3%, respectively)
		32.4	Arm 2: MVP gel 90 mg (n = 67)
Threatened abortion
Chan DMK et al. [30]	406	31.3	Arm 1: Oral DYD 40 mg OD followed by 10 mg TID (n = 203)	12 or until one week after cessation of vaginal bleeding	No increased incidences of maternal complications or congenital anomalies with dydrogesterone
		30.8	Arm 2: Conservative management (n = 203)
Siew JYS et al. [31]	141	30.2	Arm 1: Oral DYD 10 mg BID (n = 59)	2	Higher AE with NMP vs. DYD (drowsiness, 34% vs. 17%; p= .003, respectively)
		30.7	Arm 2: Oral NMP capsules 200 mg BID (n = 59)
Menstrual disorders
Hegde R et al. [32]	1000	29.2	Arm 1: Oral DYD 10 mg OD (n = N)	15 days for three menstrual cycles (From Day 11 to Day 25 of the menstrual cycle)	Minimal AEs with DYD (adenomyosis 0.1%, irregular menstruation 0.1%, respectively)
Pexman-Fieth C et al. [33]	986	28.3	Arm 1: Oral DYD 10 mg OD or BID (n = N)	15 days for three menstrual cycles (From Day 11 to Day 25 of the menstrual cycle)	Minimal AEs with DYD (metrorrhagia 0.41%)
Podzolkova N et al. [34]	986	28.3	Arm 1: Oral DYD 10 mg OD or BID (n = N)	15 days for three menstrual cycles (From Day 11 to Day 25 of the menstrual cycle)	Metrorrhagia was commonly reported (5 out of 19 total AEs (26.3%)
Trivedi N et al. [35]	1000	29.2	Arm 1: Oral DYD 10 mg BID (n = N)	15 days for one to six menstrual cycles (From Day 11 to Day 25 of the menstrual cycle)	Serious AEs with DYD (appendicitis, 0.4%) other AEs (adenomyosis and irregular menstruation with increased cycle duration)
Taniguchi F et al. [36]	44	31.6	Arm 1: Oral DYD 5 mg BID (n = N)	21 days for four menstrual cycles (From Day 5 to Day 25 of the menstrual cycle)	Metrorrhagia was commonly reported (29.5%)
Endometriosis
Qu et al. [37]	98	30.3	Arm 1: Oral DYD 10 mg/letrozole 2.5 mg (n = 49) Arm 2 : Oral calcium and vitamin D 500 / 200 mg (n=60) Arm 3: Placebo (n=60)	4	Similar AE with DYD + letrozole vs. dydrogesterone alone (vaginal bleeding 12.2% vs. 10.2%)
PMS
Khajehei M et al. [38]	180	20.8	Arm 1: Oral DYD 5 mg BID (n = 60) Arm 2: Oral calcium and vitamin D 500/200 mg (n = 60) Arm 3: Placebo (n = 60)	10 days for two menstrual cycles (Day 15 to Day 24 of the menstrual cycle)	Similar AEs with DYD vs. calcium and vitamin D vs. placebo (headache, nausea, constipation, and breast pain)

AE, adverse event; ART, assisted reproductive techniques; BID, two times daily; DYD, dydrogesterone; ET, embryo transfer; LPS, luteal phase support; IUI, intrauterine insemination; MVP, micronized vaginal progesterone; N, total sample size; n, total number of patients in a subset; NMP natural micronized progesterone; NR, not reported; OR, oocyte retrieval; OD, once-daily; PMS, premenstrual syndrome; QID, four times daily; rhCG, recombinant human chorionic gonadotropin; SR, sustained release; TID, three times daily.

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