The combination of dydrogesterone and micronized vaginal progesterone can render serum progesterone level measurements on the day of embryo transfer and rescue attempts unnecessary in an HRT FET cycle.

PURPOSE: To evaluate the role of serum progesterone (P4) on the day of embryo transfer (ET) when dydrogesterone (DYD) and micronized vaginal progesterone (MVP) are combined as luteal phase support (LPS) in a hormone replacement therapy (HRT) frozen ET (FET) cycles. METHODS: Retrospective study, including single euploid HRT FET cycles with DYD and MVP as LPS and P4 measurement on ET day. Initially, patients with P4 levels < 10 ng/ml increased MVP to 400 mg/day; this "rescue" was abandoned later. RESULTS: 560 cycles of 507 couples were included. In 275 women, serum P4 level was < 10 ng/ml on the ET day. Among those with low P4 levels, MVP dose remained unchanged in 65 women (11.6%) and was increased in 210 women (37.5%). Women with P4 levels ≥ 10 ng/ml continued LPS without modification. Overall pregnancy rates in these groups were 61.5% (40/65), 54.8% (115/210), and 48.4% (138/285), respectively (p = n.s.). Association of serum P4 levels with ongoing pregnancy rates was analyzed in women without any additional MVP regardless of serum P4 levels (n = 350); multivariable analysis (adjusted for age, BMI, embryo quality (EQ)) did not show a significant association of serum P4 levels with OPR (OR 0.96, 95% CI 0.90-1.02; p = 0.185). Using inverse probability treatment weights, regression analysis in the weighted sample showed no significant association between P4 treatment groups and OP. Compared to fair EQ, the transfer of good EQ increased (OR 1.61, 95% CI 1.22-2.15; p = 0.001) and the transfer of a poor EQ decreased the odds of OP (OR 0.73, 95% CI 0.55-0.97; p = 0.029). CONCLUSION: In HRT FET cycle, using LPS with 300 mg/day MVP and 30 mg/day DYD, it appears that serum P4 measurement and increase of MVP in patients with P4 < 10 ng/ml are not necessary.

Risk of breast cancer with HRT depends on therapy type and duration.

The studyVinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of breast cancer: nested case-control studies using the QResearch and CPRD databases. BMJ 2020;371:m3873. To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/risk-of-breast-cancer-with-hrt-depends-therapy-type-and-duration/.

Gongning granules plus low dose hormone in pubertal functional uterine hemorrhage: Analysis of hemodynamics and clinical efficacy.

To evaluate the clinical effect of Gongning granules combined with low-dose hormone therapy in pubertal dysfunctional uterine bleeding (PDUB) and its effect on uterine hemodynamics. A total of 164 PDUB patients who were treated in the gynecological outpatient department of our hospital from December 2018 to June 2020 were randomized into study group and control group, with 82 cases each. The control group received estrogen progesterone, and the study group received Gongning granules plus. The clinical efficacy and uterine arterial hemodynamics were compared. The clinical efficacy of the study group was superior to the control group (91.46% vs. 76.83%, P<0.05). The study group yielded shorter bleeding control time and complete hemostasis time than the control group (P<0.05). The amount of menstrual bleeding and duration of menstruation in both groups decreased significantly with time and the study group was significantly lower than the control group (all P<0.05). The endometrial thickness in the study group was significantly thinner than the control group, and the maximum follicle diameter was significantly longer than that in the control group (all P<0.05). After treatment, the platelet count, hemoglobin level of peripheral blood, uterine arterial blood flow and mean flow velocity in the study group were significantly higher than those in the control group (all P<0.05). In addition, there was no significant difference in adverse drug reaction (ADR) between the two groups (P>0.05). In PDUB patients, Gongning granules plus low-dose hormone can significantly relieve bleeding symptoms, improve hemodynamic status and has good safety.

Comparison of oral Dydrogesterone and 17-α hydroxyprogesterone caprate in the prevention of preterm birth.

BACKGROUND: Preterm birth (PTB) remains a significant problem in obstetric care. Progesterone supplements are believed to reduce the rate of preterm labor, but formulation, type of administration, and dosage varies in different studies. This study was performed to compare oral Dydrogesterone with intramuscular 17α-hydroxyprogesterone caproate (17α-OHPC) administration in prevention of PTB. METHODS: In this randomized clinical trial, we studied 150 women with singleton pregnancy in 28Th-34Th Gestational week, who had received tocolytic treatment for preterm labor. Participants were divided to receive 30 mg oral Dydrogesterone daily, 250 mg intramuscular 17α-OHPC weekly, or no intervention (control group). All treatments were continued until 37Th Week or delivery, whichever occurred earlier. Obstetric outcomes, including latency period, gestational age at delivery, birth weight, neonatal intensive care unit (NICU) admission, and neonatal mortality were recorded. All patients were monitored biweekly until delivery. RESULTS: Baseline gestational age was not significantly different between groups. Latency period was significantly longer in the progesterone group compared with Dydrogesterone and control groups (41.06 ± 17.29 vs. 29.44 ± 15.6 and 22.20 ± 4.51 days, respectively; P < 0.001). The progesterone group showed significantly better results compared with the other two groups, in terms of gestational age at delivery, birth weight, and Apgar score (P < 0.001). None of the participants showed severe complications, stillbirth, or gestational diabetes. CONCLUSION: Progesterone caproate can strongly prolong the latency period and improve neonatal outcomes and therefore, is superior to oral Dydrogesterone in the prevention of PTB.

Clinical efficacy of levonorgestrel intrauterine system (Mirena) combined with hysteroscopy in the treatment of perimenopausal AUB patients.

Perimenopausal abnormal uterine bleeding (AUB) is most common in ovulation dysfunction, which seriously compromises patients' health. This study aims to evaluate the efficacy of levonorgestrel intrauterine system (Mirena) plus hysteroscopy respectively in perimenopausal AUB. Sixty perimenopausal AUB patients treated with hysteroscopic electric resection in our hospital between January 2020 and December 2020 were enrolled and randomized to control group given dydrogesterone and study group treated with Mirena, with 30 cases in each group. The treatment efficacy, sex hormone level, hemoglobin (Hb) level, endometrial thickness and menstruation conditions were compared. The total efficacy was higher in the study group than that in the control group (P<0.05). The study group had lower follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2) levels and higher Hb levels compared with those of the control group (all P<0.05). Thinner endometrial thickness, lower pictorial blood loss assessment chart (PBAC) scores and shorter duration of menstruation were observed in the study group (all P<0.05). Both Mirena and dydrogesterone enhance the clinical efficacy of hysteroscopic treatment of perimenopausal AUB patients, with the advantages of Mirena being more promising.

Prolonged cyclical and continuous regimens of dydrogesterone are effective for reducing chronic pelvic pain in women with endometriosis: results of the ORCHIDEA study.

OBJECTIVE: To compare the effectiveness of two different treatment regimens of dydrogesterone in the management of endometriosis-related chronic pelvic pain. DESIGN: Observational, prospective cohort study over six months. SETTING: Twenty gynecology clinics in the Russian Federation. PATIENT(S): Three hundred fifty women from 18 to 45 years of age with endometriosis and chronic pelvic pain with or without dysmenorrhea. INTERVENTION(S): Dydrogesterone 10 mg 2 or 3 times daily, either between the 5th and 25th days of the menstrual cycle (prolonged cyclical treatment regimen) or continuously (continuous treatment regimen). For all patients, the data cutoff was at six months of treatment. MAIN OUTCOME MEASURE(S): Intensity of chronic pelvic pain on the 11-point numerical rating scale (after 6 months). RESULT(S): A marked reduction in chronic pelvic pain was observed with both the prolonged cyclical and continuous treatment regimens (mean ± standard deviation change from baseline -3.3 ± 2.2 and -3.0 ± 2.2, respectively), with no significant difference between the two groups. With both regimens, patients experienced significant improvements in the intensity of chronic pelvic pain, number of days in which analgesics were required, severity of dysmenorrhea, sexual well-being, and health-related quality-of-life parameters. A favorable safety profile of dydrogesterone was confirmed, and no serious adverse drug reactions were reported during the study. CONCLUSION(S): Prolonged cyclical and continuous treatment regimens of dydrogesterone therapy both demonstrated a pronounced and similar reduction in the severity of chronic pelvic pain and dysmenorrhea and led to marked improvements in all study parameters related to quality of life and sexual well-being. REGISTRATION NUMBER: NCT03690765.

Cytokines, Hormones and Cellular Regulatory Mechanisms Favoring Successful Reproduction.

Its semi-allogeneic nature renders the conceptus vulnerable to attack by the maternal immune system. Several protective mechanisms operate during gestation to correct the harmful effects of anti-fetal immunity and to support a healthy pregnancy outcome. Pregnancy is characterized by gross alterations in endocrine functions. Progesterone is indispensable for pregnancy and humans, and it affects immune functions both directly and via mediators. The progesterone-induced mediator - PIBF - acts in favor of Th2-type immunity, by increasing Th2 type cytokines production. Except for implantation and parturition, pregnancy is characterized by a Th2-dominant cytokine pattern. Progesterone and the orally-administered progestogen dydrogesterone upregulate the production of Th2-type cytokines and suppress the production of Th1 and Th17 cytokine production in vitro. This is particularly relevant to the fact that the Th1-type cytokines TNF-α and IFN-γ and the Th17 cytokine IL-17 have embryotoxic and anti-trophoblast activities. These cytokine-modulating effects and the PIBF-inducing capabilities of dydrogesterone may contribute to the demonstrated beneficial effects of dydrogesterone in recurrent spontaneous miscarriage and threatened miscarriage. IL-17 and IL-22 produced by T helper cells are involved in allograft rejection, and therefore could account for the rejection of paternal HLA-C-expressing trophoblast. Th17 cells (producing IL-17 and IL-22) and Th22 cells (producing IL-22) exhibit plasticity and could produce IL-22 and IL-17 in association with Th2-type cytokines or with Th1-type cytokines. IL-17 and IL-22 producing Th cells are not harmful for the conceptus, if they also produce IL-4. Another important protective mechanism is connected with the expansion and action of regulatory T cells, which play a major role in the induction of tolerance both in pregnant women and in tumour-bearing patients. Clonally-expanded Treg cells increase at the feto-maternal interface and in tumour-infiltrating regions. While in cancer patients, clonally-expanded Treg cells are present in peripheral blood, they are scarce in pregnancy blood, suggesting that fetal antigen-specific tolerance is restricted to the foeto-maternal interface. The significance of Treg cells in maintaining a normal materno-foetal interaction is underlined by the fact that miscarriage is characterized by a decreased number of total effector Treg cells, and the number of clonally-expanded effector Treg cells is markedly reduced in preeclampsia. In this review we present an overview of the above mechanisms, attempt to show how they are connected, how they operate during normal gestation and how their failure might lead to pregnancy pathologies.

Early-Pregnancy Dydrogesterone Supplementation Mimicking Luteal-Phase Support in ART Patients Did Not Provoke Major Reproductive Disorders in Pregnant Mice and Their Progeny.

Progestogens are frequently administered during early pregnancy to patients undergoing assisted reproductive techniques (ART) to overcome progesterone deficits following ART procedures. Orally administered dydrogesterone (DG) shows equal efficacy to other progestogens with a higher level of patient compliance. However, potential harmful effects of DG on critical pregnancy processes and on the health of the progeny are not yet completely ruled out. We treated pregnant mice with DG in the mode, duration, and doses comparable to ART patients. Subsequently, we studied DG effects on embryo implantation, placental and fetal growth, fetal-maternal circulation, fetal survival, and the uterine immune status. After birth of in utero DG-exposed progeny, we assessed their sex ratios, weight gain, and reproductive performance. Early-pregnancy DG administration did not interfere with placental and fetal development, fetal-maternal circulation, or fetal survival, and provoked only minor changes in the uterine immune compartment. DG-exposed offspring grew normally, were fertile, and showed no reproductive abnormalities with the exception of an altered spermiogram in male progeny. Notably, DG shifted the sex ratio in favor of female progeny. Even though our data may be reassuring for the use of DG in ART patients, the detrimental effects on spermatogenesis in mice warrants further investigations and may be a reason for caution for routine DG supplementation in early pregnancy.

Dydrogesterone primed luteal phase stimulation may be better than follicular phase stimulation in patients with diminished ovarian reserve.

OBJECTIVE: In this study, we aimed to compare the efficacy of luteal phase stimulation (LPS) and follicular phase stimulation (FPS) in two separate menstrual cycles (2-5 months intervals) of the same patient, utilizing LPS with dydrogesteron only. METHODS: This retrospective case control study was conducted with patients with diminished ovarian reserve (DOR) (Group 1) and infertile patients with Anti-Müllerian hormone >1.2 ng/mL (Group 2) undergoing two ovarian stimulations (FPS and LPS with dydrogesteron only) and two oocyte retrievals in two separate menstrual cycles (2-5 months intervals) in the Division of Reproductive Endocrinology and Infertility of Baskent University, Ankara, between April 2019 and December 2019. RESULTS: In group 1, the number of frozen embryos was significantly higher in LPS when compared to FPS; 1.71 vs. 0.54, (p < .001), respectively. In group 2, the number of frozen embryos was higher in LPS when compared to FPS (0.8 vs. 0.4) however the difference did not reach a statistical significance (p: 0.157). CONCLUSION: LPS may be beneficial especially in the patients with diminished ovarian reserve with follicular asynchronization in the menstrual onset. In addition, it should be kept in mind that dydrogesterone only may be used instead of gonadotropin-releasing hormone antagonist to prevent possible luteinizing hormone rise in LPS.

Effect of Oral versus Vaginal Administration of Estradiol and Dydrogesterone on the Proliferative and Secretory Transformation of Endometrium in Patients with Premature Ovarian Failure and Preparing for Assisted Reproductive Technology.

PURPOSE: This study aimed to assess the efficacy of vaginally versus orally administered estradiol (E2) and dydrogesterone (DG) on the proliferative and secretory transformation of endometrium in patients with premature ovarian failure (POF) and preparing for assisted reproductive technology. METHODS: Twenty patients with POF who were awaiting oocyte donation were included in the study; they were randomly assigned to two groups to receive E2 and DG either orally or vaginally. Treatment efficacy was compared between the two groups regarding blood E2 concentrations, endometrial thickness, histology using hematoxylin and eosin staining, immunohistochemical analysis of ER expression, and PR and pinopodes morphology using scanning electron microscopy. RESULTS: E2 concentrations differed significantly between oral and vaginal E2 and DG administration for 14 days (82.3 vs 1015.6 pg/mL; P < 0.001) and 21 days (85.0 vs 809.8 pg/mL; P < 0.001). Endometrial thickening was more pronounced in the vaginal treatment group, and also ER staining was stronger on days 14 and 21 in the vaginal treatment group. PR staining in the endometrium appeared more intense in the oral treatment group, which was, however, not significant. The abundance of developing pinopodes was higher in the vaginal treatment group (P = 0.04). CONCLUSION: Vaginal administration of E2 and DG is more effective than oral administration regarding proliferative and secretory transformation of the endometrium in POF patients and preparing for assisted reproductive technology.

Combination of Dydrogesterone and Antibiotic Versus Antibiotic Alone for Chronic Endometritis: a Randomized Controlled Trial Study.

To evaluate the impact of dydrogesterone in the treatment of chronic endometritis with antibiotic treatment in premenopausal women. A total of 188 chronic endometritis patients diagnosed by syndecan-1 (CD138) expression were enrolled in this randomized controlled trial study. Dydrogesterone and doxycycline were given in the treatment group, while single antibiotic was given in the control group. CD138, estrogen receptor, and progesterone receptor expression in samples of the endometrium was analyzed by immunohistochemistry. Comparison of chronic endometritis cure rate between groups was performed based on conversion of CD138 expression from positive to negative. The 188 cases included in the statistical analysis consisted of 93 cases in the treatment group and 95 cases in the control group. The cure rates of chronic endometritis in the dydrogesterone and antibiotic combination group and the single antibiotic group were 86.0% (80/93) and 72.6% (69/95), respectively, with an overall cure rate of 79.3% (149/188). The dydrogesterone and antibiotic combination group showed better effects regarding the cure rate of chronic endometritis (P<.05). Multivariate analysis showed that the cure rate of chronic endometritis was not affected by age, clinical diagnosis, hysteroscopic resection, estrogen receptor status, or progesterone receptor status (all P>.05). Addition of dydrogesterone was effective for the treatment of chronic endometritis with antibiotic treatment in premenopausal women. The study was retrospectively registered to Chinese Clinical Trial Registry (ChiCTR2000040227) in November 2020.

Oral dydrogesterone as an adjunctive therapy in the management of preterm labor: a randomized, double blinded, placebo-controlled trial.

BACKGROUND: Preterm birth is a major challenge in obstetric and perinatal care. It is the leading cause of neonatal death. The primary aim of this study was to evaluate the efficacy of oral dydrogesterone on latency period in managing preterm labor. The secondary aims were to evaluate the gestational age at delivery, percentage of preterm delivery before 34 weeks and 37 weeks, time to recurrent uterine contraction, pregnancy outcomes, neonatal outcomes, compliance and side effects. METHODS: This was a randomized, double blinded, placebo-controlled trial. Forty-eight pregnant women with preterm labor, singleton pregnancy, and gestational age of 24-34 weeks were enrolled into the study. The study group received 10 mg of oral dydrogesterone three times per day and the control group received placebo. All pregnant women received standard treatment with tocolytic and antenatal corticosteroids. RESULTS: The median latency periods were not significantly different between the dydrogesterone group (27.5 days) and placebo group (34 days, p = 0.45). Additionally, there were no differences in the gestational age at delivery, percentage of preterm delivery before 34 weeks and 37 weeks, pregnancy outcomes, neonatal outcomes, compliance and side effects. However, the time to the recurrence of uterine contractions in participants that had recurrent preterm labor was longer in the dydrogesterone group than in the placebo group (30.6 ± 12.3 vs 13.7 ± 5.0 days, p = 0.01). CONCLUSIONS: Adjunctive treatment with 30 mg of oral dydrogesterone could not prolong latency period in preterm labor when compared to placebo. TRIAL REGISTRATION: ClinicalTrials.gov (Clinical trials registration: NCT03935152 , registered on May 2,2019).

Additional luteal support might improve IVF outcomes in patients with low progesterone level in middle luteal phase following a GnRH agonist protocol.

AIM: The purpose of the study was to explore the efficacy of additional luteal support (ALS) for patients with low progesterone (P4) level in the middle luteal phase. METHODS: A retrospective study of 1401 women who underwent their first in vitro fertilization (IVF) treatment with a GnRH agonist protocol was analyzed. Patients were divided into five groups according to P4 level in the middle luteal phase (group I>40ng/mL, group II 31-40 ng/mL, group III 21-30 ng/mL, group IV 11-20 ng/mL and group V 0-10 ng/mL. Besides routine luteal support, the group V was offered with additional oral dydrogesterone 10 mg twice daily to HCG test (ALS group). RESULTS: After a multiple regression analysis, a similar higher hCG positive rate, clinic pregnancy rate and lower early pregnancy loss rate were achieved in group I and group V. In contrast to group I, group IV demonstrated significant lower HCG positive rate (OR = 0.65 [0.43; 0.99], p = .05), lower clinic pregnancy rate (OR = 0.60 [0.41; 0.88], p < .01) and significant higher early pregnancy loss rate (OR = 1.80 [1.08; 2.99], p = .02). The group III also resulted in significant lower clinic pregnancy rate (OR = 0.56 [0.36; 0.87], p = .01). The live birth rate tended to be higher in group I and group V but without a significant difference. CONCLUSION: Following agonist protocol, additional luteal support might improve IVF outcomes in patients with low serum P4 level in the middle luteal phase.

Oral dydrogesterone vs. micronized vaginal progesterone gel for luteal phase support in frozen-thawed single blastocyst transfer in good prognosis patients.

OBJECTIVE: To investigate the efficacy of oral dydrogesterone for luteal phase support (LPS) in modified natural cycle frozen-thawed embryo transfers (mNC-FET) compared to micronized vaginal progesterone (MVP) gel. METHODS: This was a randomized, single-center, parallel controlled trial conducted at an ART and Reproductive Genetics Centre within a private hospital between January and August 2019. A total of 134 women, aged below 38, were assigned randomly to receive oral dydrogesterone (n=67) or MVP (n=67) for LPS in mNC-FET. The primary outcome was ongoing pregnancy rate (OPR) and secondary outcomes were clinical pregnancy and miscarriage rates, patients' satisfaction and tolerability of oral and vaginal progesterone. A questionnaire was developed to compare patient satisfaction and side effect profiles. RESULTS: There was no significant difference in demographic features such as female age, body mass index, AMH levels and fresh cycle characteristics between two groups (p>0.05). When mNC-FET outcomes were compared, OPR was 68.7 % in MVP gel group and 71.6 % in the dydrogesterone group respectively percentage difference, -2.99; 95 % CI: -17.96, 13.10) Biochemical and clinical pregnancy rates and biochemical and clinical miscarriage rates were also similar between two groups. A significantly higher patient tolerability score was present in the dydrogesterone arm (4.09 ± 0.96 vs 3.36 ± 1.23, p=0.001). CONCLUSION: Our results suggest that oral dydrogesterone provides similar ongoing pregnancy rates compared to MVP gel as a LPS in mNC FET. Since dydrogesterone is an effective and easy-to-use option with fewer intolerable side effects including vaginal irritation, vaginal discharge, and preventing sexual intercourse, it can be used as LPS in mNC FET.

Comparable Outcomes Using Oral Dydrogesterone Vs. Micronized Vaginal Progesterone in Frozen Embryo Transfer: a Retrospective Cohort Study.

This retrospective study was conducted to determine whether using oral dydrogesterone (DYD) instead of micronized vaginal progesterone (MVP) in frozen embryo transfer (FET) cycles affects pregnancy outcomes. Women undergoing autologous FET in an academic fertility center were evaluated. Uses of 10 mg TID oral DYD or MVP for patients treated in FET cycles (artificial and ovulatory cycle, separately) were compared. The main outcome measure was live birth rates in each group. The study analyzed 599 cycles that occurred from January 2018 through December 2019. Chemical and clinical pregnancy rates were comparable between DYD vs. MVP groups (41.6% vs. 38.1%; P = 0.44 and 36.7% vs. 31.4%; P = 0.18, respectively). The ongoing pregnancy and delivery rates (29% vs. 22%, P = 0.06), as well as abortion rate (12.3% vs. 15.8%, P = 0.2), were comparable between the two groups. In a case-control sub-analysis of artificial FET cycles, we found comparable results between the two modes of luteal support. Similarly, results were comparable in ovulatory cycles using these medications for luteal support. Chemical and clinical pregnancy rates were comparable with DYD vs. MVP, in artificial FET (33.7% vs. 34.8%; P = 0.89 and 27.7% vs. 27.5%; P = 1), and in ovulatory FET (46.5% vs. 43.9%; P = 0.71 and 42.3% vs. 38.2%; P = 0.53), respectively. Our results indicate that in FET, pregnancy outcomes with oral DYD were not inferior to those with MVP.

El defecto inherente del endometrio causa fallo de implantación en Técnica de Reproducción Asistida / Inherent defect of the endometrium causes implantation failure in Assisted Reproductive Technique

Introduction. Implantation failure appears to be a significant factor in Assisted reproductive technique (ART) procedures. Even a mature endometrium may be non-receptive, preventing implantation or rejection of implanted embryo in early months of pregnancy, resulting in miscarriage or unexplained infertility with or without other associated factors. Objective. To investigate causes of failed implantation inspite of uneventful Grade I embryo transfer in ART procedure Material and Method. 90 women aged range between 25-40 yr old who visited Department of Reproductive Medicine at Calcutta Fertility Mission, over a period of 24 months(January 2017 to December 2019) , satisfying the inclusion criteria, were enrolled in this observational study. Endometrial aspirate histopathology was done along with ∞5ß3 integrin expression. They were treated with natural micronized progesterone (NMP) or oral dydrogesterone and results of endometrial changes were statistically analyzed. Results. 28.89% and 31.11% of women were seen to have mid-secretory changes of the endometrium after being treated with NMP and dydrogesterone respectively. Integrins were expressed in only 59.26% of women with mid-secretory endometrium and 5.41% of early secretory endometrium, which was statistically significant (p value <0.001). Conclusion. About 70% patients even after treatment with estrogen and progestin did not have adequate response in endometrial maturation. Not all patients with mid-secretory endometrium had integrin positive, when tested. NMP and oral Dydrogesterone have similar effect in endometrial maturation as well as in yielding successful pregnancy in some patients with previously failed In-vitro fertilization embryo transfer (IVF-ET).

Dydrogesterone as an oral alternative to vaginal progesterone for IVF luteal phase support: A systematic review and individual participant data meta-analysis.

The aim of this systematic review and meta-analysis was to conduct a comprehensive assessment of the evidence on the efficacy and safety of oral dydrogesterone versus micronized vaginal progesterone (MVP) for luteal phase support. Embase and MEDLINE were searched for studies that evaluated the effect of luteal phase support with daily administration of oral dydrogesterone (20 to 40 mg) versus MVP capsules (600 to 800 mg) or gel (90 mg) on pregnancy or live birth rates in women undergoing fresh-cycle IVF (protocol registered at PROSPERO [CRD42018105949]). Individual participant data (IPD) were extracted for the primary analysis where available and aggregate data were extracted for the secondary analysis. Nine studies were eligible for inclusion; two studies had suitable IPD (full analysis sample: n = 1957). In the meta-analysis of IPD, oral dydrogesterone was associated with a significantly higher chance of ongoing pregnancy at 12 weeks of gestation (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.08 to 1.61; P = 0.0075) and live birth (OR, 1.28; 95% CI, 1.04 to 1.57; P = 0.0214) compared to MVP. A meta-analysis combining IPD and aggregate data for all nine studies also demonstrated a statistically significant difference between oral dydrogesterone and MVP (pregnancy: OR, 1.16; 95% CI, 1.01 to 1.34; P = 0.04; live birth: OR, 1.19; 95% CI, 1.03 to 1.38; P = 0.02). Safety parameters were similar between the two groups. Collectively, this study indicates that a higher pregnancy rate and live birth rate may be obtained in women receiving oral dydrogesterone versus MVP for luteal phase support.

Novel approach using serum progesterone as a triage to guide management of patients with threatened miscarriage: a prospective cohort study.

Threatened miscarriage is a common gynaecological emergency, with up to 25% of women eventually progressing to spontaneous miscarriage. The uncertainty of pregnancy outcomes results in significant anxiety. However, there is currently no acceptable framework for triaging patients presenting with threatened miscarriage. We aim to evaluate the efficacy and safety of a novel clinical protocol using a single serum progesterone level to prognosticate and guide management of patients with threatened miscarriage. 1087 women presenting with threatened miscarriage were enrolled in the study. The primary outcome was spontaneous miscarriage by 16 weeks' gestation. Among the 77.9% (847/1087) of study participants with serum progesterone ≥ 35 nmol/L who were not treated with oral dydrogesterone, the miscarriage rate was 9.6% (81/847). This did not differ significantly from the 8.5% (31/364) miscarriage rate observed in our prior studies; p = 0.566. Among women with serum progesterone < 35 nmol/L who were treated with dydrogesterone, the miscarriage rate was 70.8% (170/240). Our novel clinical triage protocol using a single serum progesterone level allowed both effective risk stratification and a reduction in progestogen use with no significant adverse pregnancy outcomes. This protocol, based on a single serum progesterone cutoff, can be readily adapted for use in other healthcare institutions.

Characterization of early pregnancy placental progesterone production by use of dydrogesterone in programmed frozen-thawed embryo transfer cycles.

RESEARCH QUESTION: When and how does the gradual transition of the endocrine control of early pregnancy from the corpus luteum to the placenta, termed luteoplacental shift, take place? DESIGN: Prospective analysis of serum progesterone levels in pregnancies (n = 88) resulting from programmed frozen-thawed embryo transfer cycles in which ovulation was suppressed and no corpus luteum was present. Dydrogesterone, which does not cross-react with progesterone in immunoassay or spectrometric assay, was used for luteal phase and early pregnancy support. Progesterone, oestradiol and hCG were measured at regular intervals from before pregnancy achievement until +65 to 71 days after embryo transfer by Roche Elecsys electrochemiluminescence immunoassay (Elecsys ECLIA) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: Serum progesterone remained at baseline levels on first blood analysis +9 to 15 days after embryo transfer and increased only marginally independently from the type of pregnancy up to +16 to 22 days after embryo transfer. From +23 to 29 days after embryo transfer, progesterone increased non-linearly above 1.0 ng/ml and increased further throughout the first trimester with elevated levels in multiples. Oestradiol levels increased in parallel with progesterone; hCG plateaued around +37 to 43 days. Progesterone levels were significant predictors for pregnancy viability from +23 to 29 days after embryo transfer onwards with best accuracy +37 to 43 days after embryo transfer (receiver operator characteristic analysis area under the curve 0.98; 95% CI 0.94 to 1; P = 0.0009). CONCLUSIONS: The onset of substantial progesterone production is the 7th gestational week. Progesterone increase is non-linear, depends on chorionicity and zygosity, and may have predictive potential on the outcome of pregnancies originating from frozen embryo transfer cycles.

A Phase III randomized controlled trial of oral dydrogesterone versus intravaginal progesterone gel for luteal phase support in in vitro fertilization (Lotus II): results from the Chinese mainland subpopulation.

Lotus II, a randomized, open-label, multicenter, international study compared the efficacy and safety of oral dydrogesterone versus micronized vaginal progesterone (MVP) gel for luteal support in IVF. A prespecified subgroup analysis was performed on 239 Chinese mainland subjects from the overall study population (n = 1034), who were randomized to oral dydrogesterone 30 mg or 8% MVP gel 90 mg daily from the day of oocyte retrieval until 12 weeks of gestation. The aim was to demonstrate non-inferiority of oral dydrogesterone to MVP gel, assessed by the presence of a fetal heartbeat at 12 weeks of gestation. In the Chinese mainland subpopulation, there was a numerical difference of 9.4% in favor of oral dydrogesterone, with ongoing pregnancy rates at 12 weeks of gestation of 61.4% and 51.9% in the oral dydrogesterone and MVP gel groups, respectively (adjusted difference, 9.4%; 95% CI: -3.4 to 22.1); in the overall population, these were 38.7% and 35%, respectively (adjusted difference, 3.7%; 95% CI: -2.3 to 9.7). In both the Chinese mainland subpopulation and the overall population, dydrogesterone had similar efficacy and safety to MVP gel. With convenient oral administration, dydrogesterone has potential to transform luteal support treatment.