Dydrogesterone after 60 years: a glance at the safety profile

Abstract

Objective

To provide an evidence-based safety and tolerability overview of dydrogesterone under various progesterone-deficient conditions as a commemoration of its role in managing women’s reproductive health over the past 60 years.

Methods

To identify relevant publications, we used a semi-systematic approach, which included performing a structured search through the PubMed and Cochrane central databases as well as an unstructured search for publications published in English from 2010 onward with human clinical data.

Results

A total of 32 relevant clinical studies were identified. Results were reported in the context of overall adverse events (AEs) and segregated according to various progesterone-deficient conditions. AEs concerning breasts (breast cancer risk), the endometrium (endometrial cancer risk), venous thromboembolism risk, and cardiovascular risk were found to be minimal when dydrogesterone was used as part of a menopausal hormone therapy regimen lasting ≤260 weeks. Vagina-related AEs, such as bleeding, discharge, irritation, and difficult coitus, occurred less frequently with dydrogesterone when used as luteal phase support in the context of assisted reproductive techniques (ARTs). However, other common AEs, such as headache, dizziness, abdominal pain, flatulence, and nausea, occurred more frequently with dydrogesterone. No maternal complications or congenital anomalies could be linked to dydrogesterone usage during ARTs or during early pregnancy to prevent recurrent miscarriages. Studies on dydrogesterone in endometriosis and premenstrual syndrome remain scarce.

Conclusions

Post-approval, dydrogesterone has displayed a favorable safety and tolerability profile during its 60-year use, which is reassuring, considering its important role in managing women’s reproductive health.

服用地屈孕酮60年的安全性概况 摘要

目的：提供基于证据的地屈孕酮在各种孕酮缺乏条件下的安全性和耐受性概述, 以回顾过去 60 年地屈孕酮在管理女性生殖健康方面的作用。

方法：为了识别相关出版物, 我们使用了一种半系统的方法, 其中包括PubMed 和 Cochrane 中央数据库进行结构化搜索以及非结构化搜索从 2010 年开始以英文发表的带有人类临床数据的出版物。

结果：共确定了 32 项相关的临床研究。结果以总体不良事件（AE）为背景进行报告, 并根据各种孕酮缺乏情况进行分类。研究发现, 当地屈孕酮被用作更年期激素治疗方案持续时间小于260周时, 乳房（乳腺癌风险）、子宫内膜（子宫内膜癌风险）、静脉血栓栓塞风险和心血管风险相关的不良事件极少。在辅助生殖技术（ART）中使用地屈孕酮黄体支持, 阴道相关的不良事件, 如出血、分泌物、刺激和性交困难发生率较低。然而, 使用地屈孕酮其他的不良事件, 如头痛、头晕、腹痛、胀气和恶心更常见。在抗逆转录病毒治疗期间或怀孕早期使用地屈孕酮防止反复流产, 没有出现孕产妇并发症或先天性异常。关于地屈孕酮在子宫内膜异位症和经前期综合征中的研究仍然很少。

结论：地屈孕酮批准上市后60年的使用中显示出良好的安全性和耐受性, 考虑到其在管理女性生殖健康方面的重要作用, 这是令人放心的。

Keywords:

• Assisted reproductive technology
• cycle regularization
• dydrogesterone
• endometriosis
• habitual abortion
• luteal phase support
• menopausal hormone therapy
• menstrual bleeding

Introduction

Dydrogesterone (Duphaston^®) is retro progesterone and is pharmacologically close to endogenous progesterone [1]. It is widely prescribed for correcting menstrual disorders, for supporting pregnancy following natural conception or artificial reproductive techniques (ARTs), and for providing healthy menopause (menopause hormone therapy [MHT]). The half-life of dydrogesterone and its active metabolite, 20α-hydroxydydrogesterone, is approximately 5–7 h and ∼14–17 h, respectively [2]. Dydrogesterone displays a higher oral bioavailability compared with micronized progesterone (MP; ∼28% vs. 5%). Additionally, compared with MP, a higher selectivity of dydrogesterone toward the progesterone receptor enables it to trigger endometrial transformation at doses that are 10–20 times lower [3,4].

Dydrogesterone does not display cross-activation of the steroid-hormone receptor and lacks any clinically relevant activity at the androgen, estrogen, glucocorticoid, and mineralocorticoid receptors [5]. Over the past 60 years, dydrogesterone has been used in more than 100 countries [3]. Recently, several evidence-based studies, investigator-initiated trials, randomized clinical trial (RCT) publications, and clinical and post-marketing studies involving dydrogesterone have supported the safety and tolerability profile of this drug [3,6]. This semi-systematic literature review (SLR) was performed to commemorate the contribution of dydrogesterone in managing women’s health over the past 60 years by consolidating recent evidence that underlines the long-term safety of dydrogesterone under various progesterone-deficient conditions.

Materials and methods

Study design

A combination of structured and unstructured searches was implemented to identify relevant studies pertaining to the safety and tolerability of dydrogesterone under various progesterone-deficient conditions. The SLR was designed using the following steps: (1) developing a detailed search strategy, (2) determining the inclusion and exclusion criteria, (3) screening and selecting studies, (4) data extraction, and (5) tabular summarization of the safety outcomes.

Search strategy

A structured search of the PubMed and Cochrane central databases was performed to identify studies reporting the safety and tolerability data for dydrogesterone under various progesterone-deficient conditions over a period of 11 years. To identify the studies not captured by structured search, an unstructured literature search was conducted in clinical trial registries, on Google, and by examining the reference list of the references used in this review. The search was performed to identify studies in the English language reporting human clinical data, with a search time limit from January 2010 until May 2021 to identify all the studies reporting safety and tolerability data pertaining to dydrogesterone under various progesterone-deficient conditions. The search terms used for study identification included ‘endometriosis,’ ‘premenstrual syndrome,’ ‘menstrual cycle regularization,’ ‘threatened abortion,’ ‘luteal phase deficiency,’ ‘assisted reproductive technology,’ ‘menopausal hormone therapy,’ ‘dydrogesterone,’ and ‘safety profile.’ The search terms were combined individually or in combination using the Boolean operators AND/OR to screen for appropriate studies, as mentioned in Supplementary Appendix 1.

Eligibility criteria

Studies identified from the aforementioned literature search were eligible for inclusion if they met the following criteria: RCTs, observational studies, cohort studies, or case-control studies (all with full-text articles published) reporting safety and tolerability data of dydrogesterone. Further, the included studies should have women with any of the following progesterone-deficient conditions: MHT; infertility due to luteal phase defect (LPD); threatened abortion and recurrent miscarriage; menstrual disorders; including dysfunctional uterine bleeding (DUB) and dysmenorrhea; endometriosis; and premenstrual syndrome (PMS).

Studies without any safety and tolerability data pertaining to dydrogesterone, published before 2010, non-English language studies, reviews, case reports, consensus statements, and study protocols were excluded. Other criteria, such as studies not involving dydrogesterone use; studies using dydrogesterone under non-progesterone deficient conditions, for example, Asherman syndrome, improper study design, duplicate studies, and without full text; and studies not meeting the inclusion criteria were also excluded.

Data extraction

An independent reviewer extracted data from both structured and unstructured searches using a semi-systematic approach. Titles and abstracts were filtered as per the eligibility criteria. The second independent reviewer assessed these study results based on study title, author name, study citation, year of publication, abstract, study design, and sample size, and excluded non-relevant studies. Any disagreements pertaining to the data were thoroughly discussed and mutually reconciled amongst both reviewers. The data from relevant studies were exported to Microsoft Excel (Microsoft 365) and were rechecked and verified by more than one reviewer for consistency and accuracy. Data such as sample size, treatment arms, treatment duration, and safety data were extracted from the included studies pertaining to the safety and tolerability of dydrogesterone under various progesterone-deficient conditions. A tabular summary of the outcomes was prepared and is presented in the following sections.

Results

Search results

A total of 338 studies were retrieved from the structured search (n = 329) and the unstructured search (n = 9). Of these, 259 studies from the structured search were excluded owing to their publication prior to 2010, non-availability of abstracts/full texts, or for not reporting human data and publication in non-English languages. Duplicates (n = 6) from the unstructured search were excluded. The remaining 73 studies (structured [n = 70], unstructured [n = 3]) were screened, of which 39 studies from the structured search were excluded due to the type of publication (n = 31, reviews, case reports, consensus statements, and study protocol) or because they did not use dydrogesterone in their study (n = 8). One study from the unstructured search was excluded as it used dydrogesterone for the non-progesterone deficiency condition (Asherman syndrome). Full texts for 33 studies (structured [n = 31], unstructured [n = 2]) were assessed, and one study from the structured search was excluded due to improper study design. Eventually, 32 studies (structured [n = 30], unstructured [n = 2]) were included. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flow chart is presented in Figure 1.

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

Overview of indications

Dydrogesterone is used under various progesterone-deficient conditions, for example, MHT; infertility due to LPD; threatened abortion and recurrent miscarriage; menstrual disorders, including DUB and dysmenorrhea; endometriosis, and PMS. The relevant findings from these studies are presented for each indication in the following sections.

Menopausal hormone therapy

The 11 studies pertaining to the role of dydrogesterone as MHT were considered for this review. The patient population included post-menopausal women with documented estrogen deficiency (<30–50 ng/L), high levels of follicle-stimulating hormone (FSH) (≥25 IU/L), vasomotor symptoms (moderate to severe hot flushes), and amenorrhea since ≥6–12 months [7–17]. The overall safety was comparable in the intervention groups. Breast-related adverse events (AEs) (e.g. mastitis, abnormal mammogram, breast cyst, breast discomfort, breast mass, breast pain, and fibrocystic breast disease) were lower with oral dydrogesterone combined with oral 17-β estradiol vs. placebo [8,9,14,16,17]. Breast cancer risk usually associated with the use of MHT was the lowest with oral dydrogesterone vs. medroxyprogesterone-, levonorgestrel-, and norethisterone-containing MHT regimens, both combined with oral or transdermal 17-β estradiol or oral conjugated equine estrogens (CEE), respectively, for both ≤260 weeks and ≥260 weeks [11,15]. Endometrium-related AEs (abnormalities of the endometrium, endometrial hyperplasia, metrorrhagia, uterine hemorrhage, and pelvic pain) were mild and infrequent with oral dydrogesterone combined with oral 17-β estradiol vs. placebo [8,9,14,17]. Endometrial cancer risk was lower with oral dydrogesterone vs. oral MP, both combined with oral 17-β estradiol and oral CEE, respectively, with ≤260 weeks of use [12]. No significant association of venous thromboembolism (VTE) with oral dydrogesterone vs. nomegestrol- and promegestone-containing MHT regimens, both combined with oral or transdermal 17-β estradiol, was observed [7]. No cardiovascular events were reported with oral dydrogesterone vs. oral MP, both combined with oral CEE [10]. Dydrogesterone has no negative impact on cardiovascular benefits exerted by17-β estradiol [10] (Table 1).

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.

Infertility due to luteal phase deficiency

The safety data of dydrogesterone in LPD were mentioned in 12 studies. Infertile women undergoing an ART procedure, for example, in vitro fertilization (IVF), intra-uterine insemination (IUI), intracytoplasmic sperm injections (ICSI), or frozen embryo transfer (FET) were included in the patient population. Luteal phase support (LPS) was started on the day of oocyte retrieval (OR) or embryo transfer (ET) or 36 h after recombinant human chorionic gonadotropin (rhCG) trigger, and it was continued until 8–12 gestational weeks in case the β-human chorionic gonadotropin (β-hCG) test was positive [18–29].

The overall safety profile was similar in the intervention groups. There was no notable difference with regards to maternal complications (spontaneous abortions, missed abortions, ovarian hyperstimulation syndrome) with oral dydrogesterone vs. micronized vaginal progesterone (MVP) capsules and gel [24,25,27,28].

Vagina-related AEs (bleeding, discharge, coitus interference) were infrequent and similar with oral dydrogesterone vs. MVP capsules and gel [22,24,25,27]. However, a couple of studies reported higher vagina-related AEs with MVP gel vs. oral dydrogesterone [20,29]. Only one study reported higher bleeding with oral dydrogesterone vs. MVP pessaries [18]. Fetal/neonatal complications (congenital anomalies, low birth weight, and neonatal death) were low and similar with oral dydrogesterone vs. MVP capsules and gel [23–27]. There was no significant difference in breast pain, breast fullness, or other commonly encountered AEs (headache, dizziness, abdominal pain, bloating, flatulence, constipation, nausea/vomiting) in oral dydrogesterone vs oral MP sustained release (SR) preparation, MVP capsules, gel, and pessaries [18,19,21,22,29]. However, one study showed a significantly higher incidence of headache, dizziness, abdominal pain, flatulence, nausea, and breast pain with oral dydrogesterone group vs. MVP pessaries [18] (Table 2).

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.

Threatened abortion or recurrent miscarriage

Two studies included pregnant women in their first trimester with threatened abortion or with a history of greater than three first-trimester pregnancy losses requiring hormonal support [30,31]. Overall, no significant differences in fetal/neonatal complications (congenital malformations, low birth weight at term, and intrauterine death) were observed with oral dydrogesterone vs. placebo [31]. There was no significant difference in maternal complications (antepartum hemorrhage, placenta previa, gestational hypertension, pre-eclampsia, preterm labor) with oral dydrogesterone vs. placebo [30]. Other routine AEs (nausea, vomiting, headache, dizziness, abdominal pain, bloating) were similar in oral dydrogesterone vs. oral MP or placebo [30,31] (Table 2).

Menstrual disorders and abnormalities

Five studies included women with irregular menstrual cycles (oligomenorrhea) for ≥3 months or dysmenorrhea requiring hormonal therapy [32–36]. Overall, the AEs reported were mild or moderate in nature. Metrorrhagia was the most commonly reported AE [33,34,36]. The other reported AEs (adenomyosis and irregular menstruation with increased cycle duration) were infrequent and confirmed to have improved or resolved [32–36] (Table 2).

Endometriosis and premenstrual syndrome

Only one study each, regarding women with endometriosis and PMS, respectively could be identified [37,38]. With regards to women with endometriosis, the incidence of vaginal bleeding was similar with oral dydrogesterone combined with letrozole vs. oral dydrogesterone alone [37]. In women with PMS, the AEs (headache, nausea, constipation, and breast pain.) were similar with dydrogesterone vs. calcium and vitamin D vs. placebo [38] (Table 2).

Discussion

Dydrogesterone has been used for almost 60 years, with over 20 European countries having at least one label for pregnancy [3]. The present SLR aimed at collating recent evidence to revalidate the safety and tolerability of this drug. Overall, 32 studies that included dydrogesterone as an intervention were reviewed, and the safety and tolerability profile of dydrogesterone was assessed. The review included studies with large sample size and varied progesterone-deficient conditions to synthesize evidence pertaining to the safety and tolerability of dydrogesterone.

As part of MHT regimens, dydrogesterone has an acceptable safety profile vs. oral MP and other progestins. Breast- and endometrium-related AEs were found to be lower with dydrogesterone vs. placebo. Dydrogesterone poses a lower risk of breast cancer vs. synthetic progestins such as medroxyprogesterone-, levonorgestrel-, and norethisterone-containing MHT regimens, especially with ≤260 weeks of use compared to never users of MHT. Long-term (≥260 weeks) use of dydrogesterone poses a lower risk of breast cancer vs. other progestins. Dydrogesterone is also superior to oral MP with regards to lower endometrial cancer risk with ≤260 weeks of use. The risk of VTE and cardiovascular events is also low with dydrogesterone-containing MHT regimens.

With regards to LPS, the safety of oral dydrogesterone was found to be similar compared with MVP gels, capsules, and pessaries. This could be clinically beneficial since both patients and physicians usually prefer oral over vaginal preparations in ARTs owing to the inconvenience of vaginal usage [39]. MVP gel was associated with increased vaginal symptoms in a few studies, while dydrogesterone was associated with increased vaginal bleeding in one study. Fetal/neonatal complications were low with oral dydrogesterone vs. MVP capsules and gel. AEs commonly seen with oral progesterone preparations, such as headache, dizziness, abdominal pain, flatulence, and nausea, occurred more frequently with the oral dydrogesterone group vs. MVP gel and pessaries.

In pregnancy-related conditions, such as threatened abortion and recurrent miscarriage, dydrogesterone poses no significant safety concerns in terms of pregnancy complications or congenital anomalies that could be attributed to a lack of androgenic effects on the fetus. No causal link between the use of oral dydrogesterone during pregnancy and congenital anomalies could be established.

For correcting menstrual irregularities, the safety of dydrogesterone was well established and was supported by the post-marketing safety data. However, dydrogesterone displays negligible anti-gonadotropic effects; therefore, recent evidence pertaining to the safety of dydrogesterone in endometriosis remains scarce. Similarly, insufficient data are available concerning the use of dydrogesterone in ameliorating PMS symptoms [40]. The main limitation of this review is the diverse nature of the studies and outcome measures. Hence, data pooling and quantitative analysis could not be performed.

Conclusions

For 60 years, dydrogesterone has been an important part of women’s lives, right from adolescence to post-menopause. The evidence presented in this review revalidates the well-established safety of dydrogesterone when it is particularly used as LPS in ART procedures, as hormonal support for preventing threatened abortion and recurrent miscarriages, for correcting menstrual irregularities, and in MHT regimens.

Acknowledgments

The authors would like to acknowledge Akshata Rao (Tata Consultancy Services, India) for providing writing assistance, and Gaurav Anand (Tata Consultancy Services, India), and Dr. Shanthakumar. V (Viatris) for additional editorial support toward the development of this article, which is funded by Viatris.

Disclosure statement

In accordance with Taylor & Francis policy and as an ethical obligation as a researcher, CE reports having served as a speaker at sponsored symposia for Mylan. CE discloses those interests fully to Taylor & Francis and has in place an approved plan for managing any potential conflicts arising from [that involvement].