Evaluation of the role of dydrogesterone in the real-world setting in women with recurrent pregnancy loss, endometriosis

Background: Dydrogesterone has been in use for over 60 years and has demon strated a favorable efficacy and safety balance across multiple obstetric and gynecologica l indications. Despite the extensive literature on dydrogesterone, studies on dydrogesterone utilizati on patterns are largely lacking in Indian patients Aim: To assess the dydrogesterone dosing patterns in Indian women with recurrent pregnancy loss, infertility due to luteal phase deficit, and gynecological conditions su ch as endometriosis in the real- world setting. Methodology: A rigorous literature search was performed by an information specialist c linician for relevant publications using databases. 63 Gynecologists from across India wit h at least 10 years of experience were invited to participate in the web-based survey.

65% experts opined that a 12-week treatment with dydrogesterone is optimal for achieving positive outcomes in women with recurrent pregnancy loss. Treatment till term was preferred by 28.57% of experts, reflecting a practice of continuing dydro gesterone SR therapy throughout pregnancy. In patients at risk of first-trimester abortion, the most preferre d regimen (46.03%) was a 40 mg oral loading dose of dydrogesterone followed by 10 mg orall y three times daily until 12 completed weeks of gestation or 1 week after bleeding stops, The 40 mg dydr ogesterone dose followed by 20 mg SR daily was preferred by 36.51% respondents. In endometriosis, the m ost preferred dosing regimen (39.68%) was 10 mg of dydrogesterone twice daily for six months, startin g from the 5th day of the menstrual cycle. The 20 mg SR per day dose was preferred by 66.67% for treating pe lvic pain in women with endometriosis. The 10 mg twice-per-day dose (53.9 7%) was widely regarded as effective for managing dysmenorrheal. The 20 mg SR regimen was the prefe rred dose by 61.90% of respondents in young women undergoing Progestin-Primed Ovarian Stimulation with dydrogesterone to suppress LH pulse surge under stimulation in an oocyte donor programme. 90.48% of respondents reported observing a dose-dependent improvement in outcomes in patients undergoing ART.

Oral dydrogesterone carries the least risk of miscarriage while treating threatened abortion and recurrent pregnancy loss as compared to other progesterone. Dyd rogesterone is now emerging as a preferred progesterone in both obstetric and gynecological disorders in the real-world setting in India.

Dydrogesterone, recurrent abortion, endometriosis, pregnancy, ART

Dydrogesterone has been in use for over 60 years and has dem onstrated a favorable efficacy and safety balance across multiple obstetric and gynecological indications [1, 2] . Amongst diverse progesterone-deficient obstetrical conditions such as recurrent pregnancy loss and infertility due to luteal phase deficit, Dydrogesterone has been proven to be effec tive and safe. In fact, dydrogesterone is the most commonly prescribed progesterone during pregnancy [3, 4, 5] . Dydrogesterone is also useful in the management of diverse gyneco logical conditions such as endometriosis, dysfunctional uterine bleeding, secondary amenorrhea, irregular menstrual cycles, and premenstrual syndrome [3, 4, 5]. Dydrogesterone is a stereoisomer of progesterone that is pharmacologically close to endogenous progesterone [6, 7, 8, 9]. It has high oral bioavailability and is more specific or more selective for progesterone receptors than micronized progesterone. Therefore, a 10-20 times lower oral dose than micronized progesterone is required to exert the pharmacological action International Journal of Obstetrics and Gynaecology 2025; 7(1): 57-62 ~ 58 ~ International Journal of Obstetrics and Gynaecology https://www.obstetricsjournals.com [6, 7, 8] . Several studies have shown that dydrogesterone directly stimulates progesterone receptors without affecting progesterone levels. Dydrogesterone also binds 50% more to the receptor than progesterone itself [7]. Oral dydrogesterone is associated with the lowest risk of miscarriage in women with threatened abortion and recurrent pregnancy loss as compared to other progesterones [3, 4, 5] . Oral micronized progesterone has limited use in clinical practice because it undergoes extensive first-pass metabolism and has a relatively low bioavailability [9]. The dosing of dydrogesterone varies depending upon the indication (Table 1). Table 1: Doses of dydrogesterone in some obstetrics and gynecology indications Indication Dose of dydrogesterone Endometriosis 1 to 3 tablets of Dydrogesterone (10 mg) from the 5th to the 25th day of the cycle or for the entire cycle. Dosages of 10 mg several times a day should be spread over the day. Treatment should start at the highest dose Dysmenorrhoea 1 to 2 tablets of Dydrogesterone (10 mg) to be given from the 5th to the 25th day of the cycle. Infertility as a result of corpus luteum insufficiency 1 tablet of Dydrogesterone (10 mg) every day from the 14th to the 25th day of the cycle. Treatment should be continued for at least 6 consecutive cycles. It is advisable to continue this treatment for the first months of any pregnancy at dosages as indicated for habitual abortion. Threatened abortion 4 tablets of Dydrogesterone at once, followed by 1 tablet of Dydrogesterone mg every 8 hours. Dosages of 10 mg several times a day should be spread over the day. It is recommended that treatment should start at the highest dose. If the symptoms persist or recur during the treatment, the dose should be increased by 1 tablet of Dydrogesterone every 8 hours. The effective dose should be maintained for one week after symptoms have ceased; it can then be gradually reduced. If the symptoms recur, the treatment should be resumed immediately at the effective dose. Habitual abortion 1 tablet of Dydrogesterone 10 mg per day up to the 20th week of pregnancy; the dose can then be gradually reduced. Treatment should preferably be started before conception. If the symptoms of threatened abortion occur during treatment, treatment should be continued as described for that indication. Despite the extensive literature on dydrogesterone, studies on dydrogesterone utilization patterns are largely lacking in Indian patients. Therefore, the present surveillance study was conducted with the objective of assessing the dydrogesterone dosing patterns in Indian women with conditions such as dysfunctional uterine bleeding, endometriosis, recurrent pregnancy loss, and assisted reproductive technology (ART) in the real-world setting. Aim To assess the dydrogesterone dosing patterns in Indian women with recurrent pregnancy loss, infertility due to luteal phase deficit, and gynecological conditions such as endometriosis in the real-world setting Methodology The expert opinions were elicited according to an a priori protocol, with the following steps: (1) Perform a systematic literature review, (2) Invite the expert gynecologists to answer a web-based questionnaire about the use of dydrogesterone, and (3) Analyze the opinions of the expert gynecologists and develop the report and manuscript for publication based on survey results. Literature Review for Framing the questionnaire for the web-based survey A rigorous literature search was performed by an information specialist clinician for relevant publications using databases in English, including PubMed, Web of Science, Scopus, and Google Scholar. The keywords included dydrogesterone, luteal phase support, threatened abortion recurrent abortion, assisted reproductive technology, and hormone replacement therapy. A structured questionnaire was prepared after the literature review Selection of experts 63 Gynecologists from across India with at least 10 years of experience were invited to participate in the web-based survey. Each gynecologist shared the experience of the past 10 patients they had treated with dydrogesterone. Collection of data and analysis The web-based survey forms were retrieved, and data was collated. Analysis of the cumulative data was used to prepare the report and subsequent manuscript for publication, the experts ratified the findings of the report and approved the final manuscript. Recurrent pregnancy loss

According to the European Society of Human Reproduction and Embryology (ESHRE) guidelines, recurrent pregnancy loss (RPL) is defined as the loss of two or more pregnancies. The American Society of Reproductive Medicine (ASRM) defines RPL as the loss of two or more clinical pregnancies. Neither of these definitions requires the pregnancies to be consecutive, although most women with RPL do experience a consecutive loss. About 5% of women experience RPL. Approximately 23 million pregnancy losses occur globally every year, which is estimated to account for 15-20% of all clinically recognized pregnancies. Progesterone plays a critical role in the maintenance of pregnancy, and progesterone supplementation is useful in reducing the risk of pregnancy loss [10]. Several mechanisms may explain the positive effect of dydrogesterone treatment in RPL patients. One of the most important explanations is the immunomodulatory effect [11] . Dydrogesterone significantly down-regulated the secretion of the Th1 cytokines IFN- α and TNF- γ and the Th17 cytokine IL -17A and IL-23 [12] . Compared to vaginal progesterone, oral dydrogesterone has been proven to be superior in preventing per vaginal bleeding and prolonging the viability of the pregnancy until the end of the second trimester [13] . Several studies have found positive effects of dydrogesterone treatment in RPL patients. A randomized controlled trial conducted by [14] reported that women who were treated with dydrogesterone had reduced chances of spontaneous abortion as compared to women in the control group, who received no additional treatment (13.4% vs. 29%, respectively; p-value ≤ 0.05 ) [14]. Dydrogesterone 40 mg stat dose followed by 10 mg twice a day for one week provides corpus luteal support and has ~ 59 ~ International Journal of Obstetrics and Gynaecology https://www.obstetricsjournals.com been shown to reduce the incidence of pregnancy loss in threatened abortion during the first trimester in women without a history of recurrent abortion [15]. Expert opinion on the preferred dosing regimen of dydrogesterone in patients with recurrent pregnancy loss to improve outcomes In order to prevent recurrent pregnancy loss, 50.79% of experts opined that the most preferred dosing regimen was a regular dose of 10 mg twice daily. The loading dose of 40 mg followed by 10 mg as a maintenance dose was preferred by 31.75% of experts. The lower-loading dose options (20 mg SR and 30 mg SR followed by 10 mg) were the least preferred dosing regimen (17.46%). Expert opinion on the duration of treatment with dydrogesterone for positive outcomes in women with recurrent pregnancy loss The majority of respondents (65.08%) indicated that a 12- week treatment duration is optimal for achieving positive outcomes in women with recurrent pregnancy loss. Treatment till term was preferred by 28.57% of experts, reflecting a practice of continuing dydrogesterone SR therapy throughout pregnancy in selected cases where ongoing progesterone support is deemed necessary. Shorter durations, such as 8 weeks and 10 weeks, were rarely chosen (both 3.17%), indicating that clinicians do not widely prefer stopping treatment before the first trimester is completed. Expert opinion regarding the dosing dydrogesterone regimen they follow in patients at risk of abortion in the first trimester In patients at risk of first-trimester abortion, the most preferred regimen (46.03%) was a 40 mg oral loading dose followed by 10 mg orally three times daily until 12 completed weeks of gestation or 1 week after bleeding stops, The 40 mg dose followed by 20 mg SR daily was preferred by 36.51% respondents indicating its growing acceptance among clinicians for convenience and sustained therapeutic effect. The 30 mg SR daily dose was preferred by 15.87% of respondents, while the 40 mg oral dose three times daily was accepted by just 1.59% of respondents. Endometriosis

Endometriosis is characterized by chronic - pelvic pain, dysmenorrhea, infe rtility associated with reduced ovarian reserve, diminished antral follicle count, and anti -Müllerian hormone levels. Endometriosis has a significant adverse impact on the health -related quality of life (HR -QoL) and psychological well -being of affected women [11]. Endometriosis is an estrogen -dependent condition [11]. Dydrogesterone can induce atrophy in ectopic endometrial tissue and inhibit the formation of de novo endometriotic tissue while leaving the endometrium unaffected. Dydrogesterone relieves. the symptoms of endometriosis. Dydrogesterone can be used in women who are attempting to become pregnant [11]. There are two regimens of dydrogesterone used for treating endometriosis: a prolonged cyclical regimen (between the 5th and the 25th days of the menstrual cycle) and a continuous regimen, with doses ranging from 10 to 30 mg daily Although dydrogesterone has been available for several years, it is unknown whether these regimens are comparable in terms of reducing the severity of endometriosis-related pelvic pain and improving associated HR-QoL parameters [11]. A prolonged cyclical regimen of dydrogesterone 20 or 30 mg daily taken between the 5th a nd the 25th days of the menstrual cycle and a continuous regimen of dydrogesterone 20 or 30 mg daily were effective and achieved a comparable reduction in chronic pelvic pain. A greater reduction of chronic pelvic pain in patients taking dydrogesterone 30 mg daily [11]. Expert opinion regarding the dosing regimen of dydrogesterone in women with mild endometriosis In endometriosis, the most preferred dosing regimen (39.68%) was 10 mg of dydrogesterone twice daily for six months, starting from the 5th day of the menstrual cycle, indicating that a longer treatment duration was favored for managing mild endometriosis effectively. Shorter-duration regimens such as 10 mg twice daily for three months (30.16%) and 20 mg SR for three months (30.16%) were equally preferred by a significant number of experts. Expert opinion on the dydrogesterone regimen they preferred in women with endometriosis The cyclical regimen was the most preferred regimen (53.97%), where dydrogesterone was administered from the 5th to the 25th day of the menstrual cycle. The continuous regimen was preferred by 46.03% respondents with daily doses of 10 mg to 30 mg SR. (Figure 1) A. A cyclical regimen, from the 5th to the 25th days of the menstrual cycle B. A continuous one, with daily doses ranging from 10mg to 30mg SR Fig 1: Dydrogesterone regimen preferred in women with endometriosis ~ 60 ~ International Journal of Obstetrics and Gynaecology https://www.obstetricsjournals.com Expert opinion on the dose of dydrogesterone that significantly reduced pelvic pain in women with endometriosis The 20 mg SR per day dose was preferred by 66.67% for treating pelvic pain in women with endometriosis. This suggests that the majority of clinicians find this dose to provide an optimal balance between efficacy and safety. The 30 mg SR per day dose was preferred by 30.16% of respondents as the second most preferred option to be used in patients who may require a higher dosage for more severe pain symptoms. The 40 mg per day dose was rarely used (3.17%) possibly due to concerns about side effects or lack of additional benefit over lower doses. Expert opinion on the dose of dydrogesterone useful in women with dysmenorrhea The 10 mg twice-per-day dose (53.97%) was widely regarded as effective for managing dysmenorrhea in clinical practice. The 20 mg SR per day dose was also highly preferred (46.03%), demonstrating its utility as a sustained- release option that simplifies dosing while providing comparable efficacy. (Figure 2) A. 10 mg per day twice per day for 21 days from the 5th to 25th day of each menstrual cycle. B. 20 mg SR per day for 21 days from the 5th to 25th day of each menstrual cycle. Fig 2: Dydrogesterone dose in women with dysmenorrhea Luteal phase support

The luteal phase is defined as the period between ovulation and the onset of menses following luteolysis. During the preovulatory peak of gonadotropins, luteinizing hormone (LH) allows the transformation of granulosa cells into large luteal cells, which ensures the production of progesterone. During the luteal phase, LH allows the maintenance of optimal secretion of progesterone. The subsequent secretory transformation of the endometrium opens a short window of implantation. The progesterone secreted by the corpus luteum allows maintenance of pregnancy during part of the first trimester. It has an immunomodulatory effect and regulates sub endometrial blood flow, and helps to maintain pregnancy by preventing embryo rejection. Dydrogesterone efficacy and safety has been evaluated in several clinical studies, and it has been demonstrated to be non-inferior to micronized vaginal progesterone (MVP). Oral dydrogesterone may potentially become a preferred drug for luteal phase support in millions of women undergoing In vitro fertilization (IVF) [16] . Oral dydrogesterone 10 mg three times daily may replace micronized vaginal progesterone as the standard of care for luteal phase support in IVF, owing to the oral route being more patient-friendly than intravaginal administration, as well as it being a well-tolerated and efficacious treatment [17]. In a meta-analysis, with daily administration of oral dydrogesterone (20 to 40 mg) versus MVP capsules (600 to 800 mg) or gel (90 mg), the pregnancy or live birth rates in women undergoing fresh cycle IV were compared. A higher pregnancy rate and live birth rate were observed in women receiving oral dydrogesterone versus MVP for luteal phase support [9]. Expert opinion regarding the dose of dydrogesterone given in young women undergoing Progestin-Primed Ovarian Stimulation with dydrogesterone to suppress LH pulse surge under stimulation in an oocyte donor programme. The 20 mg SR regimen was the preferred dose by 61.90% of respondents, indicating that clinicians favor the sustained- release option for its convenience, consistent efficacy, and ability to maintain steady hormone levels throughout the stimulation process. The 10 mg every 8 hours regimen (38.10%) is also a widely used alternative, reflecting its clinical utility in situations where immediate and consistent hormone suppression is needed, albeit with a more frequent dosing schedule. Expert opinion regarding preferred dose of dydrogesterone for luteal phase support in women undergoing ART The 10 mg bid dose (44.44%) was the most preferred regimen, indicating its widespread use and perceived efficacy for luteal phase support in women undergoing Assisted Reproductive Technology (ART). The 20 mg SR dose was preferred by 38.1% of experts, reflecting the advantages of convenience and consistent hormone levels. The 30 mg SR dose was preferred by just 17.46% of experts. Expert opinion regarding dose dependent improvement in outcomes in patients undergoing ART 90.48% of respondents reported observing a dose-dependent improvement in outcomes in patients undergoing ART, indicating a strong consensus that adjusting the dose of dydrogesterone positively influences treatment success rates. Only 9.52% opined that they did not observe dose- dependent improvements, which might be due to either ~ 61 ~ International Journal of Obstetrics and Gynaecology https://www.obstetricsjournals.com clinical variations, patient-specific factors, or alternative treatment approaches. Expert opinion on a dose-dependent change in tolerability profile and adherence to treatment with dydrogesterone in their patients undergoing art 69.84% of clinicians observed a dose-dependent change in tolerability and adherence, indicating that dosage adjustments directly impact patient experience and compliance with dydrogesterone treatment during ART. Expert opinion on dose-dependent risk of congenital anomalies in women treated with dydrogesterone in the first trimester for reducing the risk of abortion The majority of respondents (74.60%) opined that there is no dose-dependent risk of congenital anomalies associated with the use of dydrogesterone in the first trimester to reduce the risk of abortion. This reflects confidence in the safety profile of dydrogesterone when used appropriately during early pregnancy.

Dydrogesterone has been in use for over 60 years and has demonstrated a favorable efficacy, safety, and tolerability profile across multiple obstetric and gynecological indications. Dydrogesterone SR is the most commonly prescribed progesterone during pregnancy. Oral dydrogesterone carries the least risk of miscarriage while treating threatened abortion and recurrent pregnancy loss as compared to other progesterone. Various guidelines, such as FOGSI, the American College of Obstetricians and Gynecologists (ACOG) guidance, and ESHRE guidelines, have discussed the studies of dydrogesterone in endometriosis and recurrent pregnancy loss. In order to prevent recurrent pregnancy loss, the most preferred dosing regimen (50.79%) among respondents was a regular dose of 10 mg twice daily. The loading dose of 40 mg followed by 10 mg as a maintenance dose is the second most chosen option (31.75%). The majority of respondents (65.08%) indicated that a 12-week treatment duration is optimal for achieving positive outcomes in women with recurrent pregnancy loss. In patients at risk of first-trimester abortion, the most preferred regimen (46.03%) was a 40 mg oral loading dose followed by 10 mg orally three times daily until 12 completed weeks of gestation or 1 week after bleeding stops. In endometriosis, the most preferred dosing regimen (39.68%) was 10 mg of dydrogesterone twice daily for six months, starting from the 5th day of the menstrual cycle, indicating that a longer treatment duration was favored for managing mild endometriosis effectively. Shorter-duration regimens, such as 10 mg twice daily for three months (30.16%) and 20 mg SR for three months (30.16%), were equally preferred by a significant number of experts. The 20 mg SR per day dose was preferred by 66.67% for treating pelvic pain in women with endometriosis. The 10 mg twice-a-day dose of dydrogesterone was preferred by 44.44% of experts, indicating its widespread use and perceived efficacy for luteal phase support in women undergoing ART. The 20 mg SR dose was preferred by 38.1% experts owing to the advantages of convenience and consistent hormone levels. Dydrogesterone is now emerging as a preferred progesterone in both obstetric and gynecological disorders in the real-world setting in India. Conflict of Interest: All authors have no conflict of interest to declare. Funding: The study was supported by Aristo Pharmaceuticals Private Limited Mumbai. Acknowledgment: None.

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