Medroxyprogesterone Acetate Research Articles

A framework for assessing interactions for risk stratification models: the example of ovarian cancer.

Generally, risk stratification models for cancer use effect estimates from risk/protective factor analyses that have not assessed potential interactions between these exposures. We have developed a 4-criterion framework for assessing interactions that includes statistical, qualitative, biological, and practical approaches. We present the application of this framework in an ovarian cancer setting because this is an important step in developing more accurate risk stratification models. Using data from 9 case-control studies in the Ovarian Cancer Association Consortium, we conducted a comprehensive analysis of interactions among 15 unequivocal risk and protective factors for ovarian cancer (including 14 non-genetic factors and a 36-variant polygenic score) with age and menopausal status. Pairwise interactions between the risk/protective factors were also assessed. We found that menopausal status modifies the association among endometriosis, first-degree family history of ovarian cancer, breastfeeding, and depot-medroxyprogesterone acetate use and disease risk, highlighting the importance of understanding multiplicative interactions when developing risk prediction models.

Dietary supplementation with different nano and organic selenium doses improves ovarian activity, fertility rate, and progesterone level in Ossimi ewes

This study aimed to investigate the effects of nano and organic selenium on ovarian activity, fertility rate, and progesterone hormone levels in Ossimi ewes. Thirty ewes were treated with intra-vaginal sponges impregnated with medroxyprogesterone acetate (40 mg) for 14 d and simultaneously assigned randomly to three groups. The 1st group ewe served as control (CG). Ewes in the 2nd and 3rd groups were treated orally with organic selenium 3 mg/ewe and Nano-selenium 0.2 mg/ewes during intra-vaginal sponges (IVS) treatment SeG and N-SeG, respectively. The ovarian activity was monitored using an ultrasonic device, and serum samples were harvested for progesterone measurement. The results revealed that ewes in SeG and N-SeG groups had a significantly (p < .05) higher number of small and large follicles after 48 h of IVS withdrawal than in the CG, respectively, on the left ovary. Also, the N-SeG group had a larger diameter of the Corpus luteum on both ovaries’ sides than CG, respectively, at the same time. However, the diameter of large follicles on both ovaries was significantly (p < .05) larger in the N-SeG after 72 h of IVS withdrawal than in SeG and CG. The ewes in N-SeG and SeG came in oestrus earlier (p < .05) than those in CG, and the oestrus durations were longer (p < .05) than that recorded in ewes of CG. The oestrus response and fertility rate were higher (p < .01) in N-SeG and SeG than in CG. Moreover, the progesterone concentrations were significantly higher (p < .05) in the N-SeG and SeG after 48 and 72 h of IVS withdrawal than in the CG. Also, the recorded serum progesterone concentrations in the included ewes non-significantly differed between groups during the first four months of pregnancy. It could be concluded that using nano and organic selenium can improve the quality of ovarian follicles and CL function and enhance the fertility rate in Ossimi ewes.

Effect of hCG administration on ovulation and estrus in Saanen goats subjected to short-term estrus synchronization protocol during the breeding season

This study aimed to compare the effect of hCG administered at 24 or 36 h following a short-term estrus synchronization treatment on the ovulation time and estrus parameters in non-lactating Saanen goats during the breeding season. The estrous cycles of does were synchronized with an intravaginal sponge containing 60 mg of medroxyprogesterone acetate (MAP) for six days, and an injection of 125 µg of d-cloprostenol at the time of sponge insertion in addition to an injection of 300 IU of eCG 24h before sponge removal. After removal of the sponges, does were injected intramuscularly either 1 ml physiological saline (0.9% NaCl) solution after 12 h (Group1/Control; n=10), 100 IU hCG after 24 h (Group2; n=9) or 100 IU hCG after 36 h (Group3; n=9). Estrus behavior after sponge removal was observed twice daily for 84 h using teaser bucks and transrectal ovarian ultrasonography was performed twice a day for seven days to determine small, medium and large follicle numbers, luteal development and the time of ovulation. Blood samples were collected on the same days to determine serum progesterone (P4) and estradiol (E2) concentrations. No significant differences were observed in terms of estrus parameters, ovarian structure and serum P4 and E2 concentrations between the hCG-treated groups and the control group. Average values observed for all groups: estrous response (53.57%), the interval from sponge removal to estrus and ovulation (35.2 h and 67.86 h, respectively), duration of estrus (18.4 h), the interval from estrus onset to ovulation (50.37 h), ovulation rate (96.43%), number of ovulations (1.36), ovulatory follicle diameter (6.86 mm), corpus luteum diameter (8.22 mm), follicle and luteal growth rate (1.17 and 0.68 mm/day, respectively). In conclusion, administration of hCG at 24 or 36 h following a short-term estrous synchronization protocol does not affect ovulation time, estrus parameters, and serum P4 and E2 concentrations in goats during the breeding season.

Genome-wide CRISPR screening reveals ADCK3 as a key regulator in sensitizing endometrial carcinoma cells to MPA therapy

BackgroundThe effectiveness of conservative treatment of endometrial carcinoma (EC) with oral progesterone therapy, such as medroxyprogesterone acetate (MPA), can be blunted due to primary or acquired resistance, but the underlying mechanisms remain incompletely defined.MethodsGenome-wide CRISPR screening was performed to identify potential regulators in response to MPA in Ishikawa cells. Crystal violet staining, RT–qPCR, western blotting, ChIP–qPCR and luciferase assays were employed to elucidate the p53-AarF domain-containing kinase 3 (ADCK3) regulatory axis and its roles in sensitizing EC cells to MPA treatment.ResultsADCK3 is identified as a previously unrecognized regulator in response to MPA in EC cells. Loss of ADCK3 in EC cells markedly alleviated MPA-induced cell death. Mechanistically, loss of ADCK3 primarily suppresses MPA-mediated ferroptosis by abrogating arachidonate 15-lipoxygenase (ALOX15) transcriptional activation. Moreover, we validated ADCK3 as a direct downstream target of the tumor suppressor p53 in EC cells. By stimulating the p53-ADCK3 axis, the small-molecule compound Nutlin3A synergized with MPA to efficiently inhibit EC cell growth.ConclusionsOur findings reveal ADCK3 as a key regulator of EC cells in response to MPA and shed light on a potential strategy for conservative EC treatment by activating the p53-ADCK3 axis to sensitize MPA-mediated cell death.

Implementation strategies to scale up self-administered depot medroxyprogesterone acetate subcutaneous injectable contraception: a scoping review

BackgroundSelf-administered depot medroxyprogesterone acetate subcutaneous injectable contraception (DMPA-SC) is registered in many countries. It shows great potential for improving contraceptive access, continuation, and autonomy. However, there are challenges in rolling out this new efficacious intervention, and major implementation problems have been encountered during scale-up.ObjectiveTo describe the implementation strategies to scale up self-administered DMPA-SC and the barriers, facilitators, and outcomes of these programs.MethodRecent guidelines, including the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews, were used to design and report this review. An article or report was eligible for inclusion if it reported interventions that could scale up self-administered DMPA-SC implementation or its facilitators, barriers, or outcomes. We searched six electronic databases and the grey literature for eligible articles and reports. Two reviewers independently screened the document titles, abstracts, and full texts to identify eligible documents. Data were extracted using structured forms. Using the Effective Practice and Organization of Care (EPOC) taxonomy of health systems framework for thematic analysis, data were presented in a narrative approach.ResultsOf the 755 retrieved documents, 34 were included in this review. Most of the documents included were multi-country reports (n = 14), and all documents were published within the last 5 years (2018–2021). This review identified documents that reported interventions in all EPOC domains. The most-reported interventions were: task-sharing amongst health workforce cadres, engaged leadership, encouraging policies, training and education, DMPA-SC demand generation, integration into existing programs, improved funding mechanisms, collaboration with development partners, and supply chain strengthening. The main barriers were suboptimal funding, inadequate human resources, and poor logistics supply of DMPA-SC. There was minimal evidence of scale-up outcomes.ConclusionThis scoping review reported a wide range of interventions employed by countries and programs to scale up DMPA-SC self-administration but minimal evidence of the scale-up outcomes. Evidence from this review can help design better programs that improves access to quality family planning services to achieve the Sustainable Development Goals (SDG) targets 3.7. However, efforts should focus on rigorous implementation research that assess scaled up self-administered DMPA-SC interventions and report their outcomes.RegistrationThe protocol for this review was registered in the protocols.io repository (https://www.protocols.io/view/a-protocol-for-a-scoping-review-of-implementation-x54v9yemmg3e/v1).

Mifepristone: effect on PBMC receptivity in healthy women and women with endometrial hyperplastic processes

In our previous study we found that peripheral blood mononuclear cells (PBMC) at women with endometrial proliferative processes increase their sensitivity to the suppressing action of sex steroid hormones. In order to reduce the receptivity of PBMC, it is possible to prescribe hormonal drugs. However, when studying the relative binding activity of the receptors, it was found that the affinity of medroxyprogesterone acetate, norethisterone acetate, in PBMC was 54% and 48% respectively. And research of selective modulators of progesterone receptors is promising.

Study of Old Relationship of Contraceptive Use of DMPA (Depomedroxy Progesterone Acetate) to Health Problems in Menopause

Depomedroxy Progesterone Acetate is a synthetic progesterone used in the injection method in the Family Planning program. This method is familiarly known as 3-month injection KB in the community. Injecting family planning services can be accessed at Independent Midwives' Practices, Doctor's Practices and Community Health Centers. Based on data for 2021, the most widely used method is injection, which is 33.1% (RI Ministry of Health, 2022). However, using it for a long time, this method will cause a hypoestrogen-like state like menopause. This causes health problems such as decreased libido and increased BMI (Body Mass Index). This research is a qualitative research that uses Chi-Square analysis to assess the relationship between the variables studied. The population in this study were 3-month injection acceptors at PMB Lia Sofa with a sampling technique using Acidental Sampling. This research was conducted from April to July 2022 using a questionnaire as a tool. From this study, it was found that there was a relationship between the duration of 3 months of injection injections with an increase in BMI and a decrease in libido

Cervical Os Marsupialization in the Initial Management of a Rare Case of Obstructive Uterine Didelphys with Ipsilateral Renal Agenesis

Introduction: Uterine didelphys is an uncommon Mullerian anomaly that often is associated with obstructive pathology. Without early intervention, obstruction can progress to potentially fatal complications including pyometra and sepsis. Due to the rarity and variability of this condition, treatment options have not been systematically studied. Case Description: In this case report, we discuss a 16-year-old female who presented with acute sepsis secondary to pyometra in the setting of chronic dysmenorrhea and purulent vaginal discharge. On imaging, she was found to have uterus didelphys with right renal agenesis and a hypoplastic right cervix along with a pelvic fluid collection. During exam under anesthesia, no obstructing hemivagina was found, however the right cervical os was identified with purulent material draining from it and identified as the site of obstruction. The right cervical os was extended and its edges marsupialized. The patient recovered well postoperatively with a course of antibiotics and continued to be followed in an outpatient setting, where she was started on Depo Provera for menstrual suppression. She remained asymptomatic for months, but after discontinuing the Depo for some time, began to experience pelvic pain and purulent vaginal discharge again. While she agreed to resume Depo treatment, definitive treatment with right hemihysterectomy was discussed and eventually undertaken. Discussion: Although hemihysterectomy may be required in many cases, the technique of marsupialization of a cervical os is unique and may be a new approach to patients with non-classic anatomic presentations of obstructive symptoms with uterine didelphys.

Enhanced ZBTB16 Levels by Progestin-Only Contraceptives Induces Decidualization and Inflammation.

Progestin-only long-acting reversible-contraceptive (pLARC)-exposed endometria displays decidualized human endometrial stromal cells (HESCs) and hyperdilated thin-walled fragile microvessels. The combination of fragile microvessels and enhanced tissue factor levels in decidualized HESCs generates excess thrombin, which contributes to abnormal uterine bleeding (AUB) by inducing inflammation, aberrant angiogenesis, and proteolysis. The- zinc finger and BTB domain containing 16 (ZBTB16) has been reported as an essential regulator of decidualization. Microarray studies have demonstrated that ZBTB16 levels are induced by medroxyprogesterone acetate (MPA) and etonogestrel (ETO) in cultured HESCs. We hypothesized that pLARC-induced ZBTB16 expression contributes to HESC decidualization, whereas prolonged enhancement of ZBTB16 levels triggers an inflammatory milieu by inducing pro-inflammatory gene expression and tissue-factor-mediated thrombin generation in decidualized HESCs. Thus, ZBTB16 immunostaining was performed in paired endometria from pre- and post-depo-MPA (DMPA)-administrated women and oophorectomized guinea pigs exposed to the vehicle, estradiol (E2), MPA, or E2 + MPA. The effect of progestins including MPA, ETO, and levonorgestrel (LNG) and estradiol + MPA + cyclic-AMP (E2 + MPA + cAMP) on ZBTB16 levels were measured in HESC cultures by qPCR and immunoblotting. The regulation of ZBTB16 levels by MPA was evaluated in glucocorticoid-receptor-silenced HESC cultures. ZBTB16 was overexpressed in cultured HESCs for 72 h followed by a ± 1 IU/mL thrombin treatment for 6 h. DMPA administration in women and MPA treatment in guinea pigs enhanced ZBTB16 immunostaining in endometrial stromal and glandular epithelial cells. The in vitro findings indicated that: (1) ZBTB16 levels were significantly elevated by all progestin treatments; (2) MPA exerted the greatest effect on ZBTB16 levels; (3) MPA-induced ZBTB16 expression was inhibited in glucocorticoid-receptor-silenced HESCs. Moreover, ZBTB16 overexpression in HESCs significantly enhanced prolactin (PRL), insulin-like growth factor binding protein 1 (IGFBP1), and tissue factor (F3) levels. Thrombin-induced interleukin 8 (IL-8) and prostaglandin-endoperoxide synthase 2 (PTGS2) mRNA levels in control-vector-transfected HESCs were further increased by ZBTB16 overexpression. In conclusion, these results supported that ZBTB16 is enhanced during decidualization, and long-term induction of ZBTB16 expression by pLARCs contributes to thrombin generation through enhancing tissue factor expression and inflammation by enhancing IL-8 and PTGS2 levels in decidualized HESCs.

P-598 Analysis of the oocyte yield and Ovarian Sensitivity Index with the use of two gonadotropins (FSHr/FSHu) and two pituitary suppression protocols (PPOS/GnRH-ant)

Abstract Study question Is there a difference, in terms of ovarian yield and sensitivity, comparing a progestin-primed protocols (PPOS) to a GnRH antagonist (GnRH-ant) and using different follitropin? Summary answer PPOS is an effective choice, with both follitropis. Nevertheless, could improve ovarian sensitivity to FSHu increasing the number of oocyte yield without compromising oocyte quality. What is known already The use of new ovarian stimulation protocols, starting during the luteal phase or randomly shows that endogenous progesterone alone is sufficient to block the LH surge and does not compromises oocyte competence and pregnancy outcomes. For these reasons, exogenous progesterone was utilized as an innovative model of pituitary suppression. Most studies have shown the effectiveness of the use of PPOS compared to the GnRH (antagonist or agonist) in IVF cycles. For oocyte donation only three studies were carried out analyzing the effect of PPOS with a recombinant FSH (FSHr) Study design, size, duration It is a retrospective, cohort, paired study. We analyzed egg donation cycles carried out in Next Fertility Valencia from January 2020 to May 2021. In total 93 donors were selected as eligible, each one undergoing both the PPOS and GnRH antagonist cycles for a total of 186 cycles, 54 received FSHr and 39 HP-FSHu. To attempt to eliminate possible bias due to interpersonal differences, every patient was her own control. Participants/materials, setting, methods All donors underwent two controlled ovarian stimulation cycles within 6 months, one using flexible GnRH antagonist (Ganirelix) and the other using medroxyprogesterone acetate (MPA), with FSHr or FSHu monotherapy and a GnRH-agonist triggering. The oocyte yield was analyzed focusing on: the number of oocytes retrieved, mature (MII) oocytes and useful oocytes (mature oocytes without morphological alterations). We also evaluated the Ovarian sensitivity index (OSI) calculating the oocyte number for each 1000 IU of gonadotropin used Main results and the role of chance Total gonadotropin consumption and duration of ovarian stimulation were similar in both models of pituitary suppression regardless the type of FSH. One less control is required with MPA than the GnRH-ant in both FSH groups. There were no premature ovulations in MPA or GnRH antagonist cycles regardless of the gonadotropin used. In the FSHr group no difference was observed in the oocyte yield and OSI between MPA and GnRHa. On the other hand, in the FSHu group a statistically significant improvement in the number of total oocytes retrieved (20,2 ± 8,5 vs 23,8 ± 10,9), total MII (18,0 ± 7,2 vs 21,2 ± 10,4) and OSI (6,4 ± 3,5 vs 7,7 ± 4,6) was observed in favor of the use of MPA. Also, the number of useful MII was higher with MPA (15,7 ± 6,5 vs 18,6 ± 10,4). No significant differences were detected in fertilization and blastocyst rate regardless the type of pituitary suppression and FSH used Limitations, reasons for caution The main limitation lies in the retrospective nature of the study. However, since each patient is her own control (Paired study), it gives an added value Wider implications of the findings The efficacy and efficiency of the MPA does not seem to be affected by the type of gonadotropin used, this further reassures about the possibility of using it with patients in case of fertility preservation cycles, PGT-A/M, "DuoStim" cycles Trial registration number Not applicable

A Pilot Study of Adolescent and Young Adult Experience with Subcutaneous Depot Medroxyprogesterone Acetate

Study ObjectiveTo describe satisfaction with and preference for subcutaneous depot medroxyprogesterone acetate (DMPA-SC), along with adherence and feasibility, in adolescents and young adults (AYAs) MethodsSurvey of a sample of AYA patients who received DMPA-SC prescription and injection ResultsOf 108 eligible patients, 34 completed the survey, and 29 respondents received at least 1 DMPA-SC injection. The mean age was 16.9 years. Seventy-nine point three percent used it for gynecologic reasons, 27.6% for gender dysphoria, and 20.7% for contraception (multiple responses allowed); 93.1% were satisfied with DMPA-SC; 78.6% gave DMPA-SC on time; 88.9% reported that giving the injection was easy; 89.7% reported no problems with administration; 89.3% reported no problems obtaining DMPA-SC; and 76.9% plan to continue using DMPA-SC. ConclusionIn this small sample of patients within a children's hospital, the overall experience with DMPA-SC was favorable. Clinicians caring for adolescents should consider including DMPA-SC in counseling when depot medroxyprogesterone acetate (DMPA) is indicated.

P-611 Progestin-Primed Ovarian Stimulation is a non-inferior alternative to the GnRH Antagonist Protocol in patients undergoing ovarian stimulation: a propensity score weighting analysis

Abstract Study question To evaluate the effectiveness of the progestin-primed ovarian stimulation (PPOS) protocol versus the gonadotropin-releasing hormone antagonist (GnRH-ant) protocol in ovarian stimulation. Summary answer The PPOS protocol with dydrogesterone provided similar embryo outcomes to the GnRH-ant protocol. The serum LH concentration during ovarian stimulation using PPOS was well-controlled. What is known already Since Yanping Kuang's proposal PPOS in 2015, several studies on the effectiveness of this treatment regimen have been published. Although it has been suggested that outcomes of the PPOS regimen were comparable to those of GnRH-ant regimen, the findings were limited due to differences in study design, patient characteristics, dosage and type of progestins. While medroxyprogesterone acetate is often used in PPOS studies, dydrogesterone has seen far less popularity. Additionally, dydrogesterone is a relatively weak LH inhibitor compared to MPA, leading to concern about the increased incidence of unexpected LH surge Study design, size, duration We conducted a retrospective study among women who underwent In Vitro Fertilization at the Assisted Reproduction Center, Tam Anh General Hospital, Vietnam from January 1st, 2022 to October 10th, 2022. Participants/materials, setting, methods We included 804 patients who underwent ovarian stimulation, among which 208 used the PPOS protocol with dydrogesterone (30 mg dydrogesteron per day from the beginning of stimulation until the trigger-day) and 598 women used the GnRH-ant protocol (cetrorelix 0.25 daily, from day 6 of ovarian stimulation until the trigger-day). In addition to unadjusted analysis, we used propensity score weighting to account for confounding that might possibly remain. Main results and the role of chance Baseline characteristics were comparable in both groups. In both unadjusted and adjusted analysis, the mean number of good cleavage embryos in PPOS (6.33) was non-inferior to GnRH-ant (6.44; unadjusted ratio of two means 1.02, 95%CI 0.92, 1.13). The trigger-day estradiol level in patients with PPOS was higher (4,420 vs 3,830 pmol/L in GnRH-ant) despite similar total follicle stimulating hormone dose and fewer days of ovarian stimulation. The overall number of oocytes retrieved, the number of MII oocytes, the number of cleavage embryos, the number of blastocysts, and the number of good blastocysts were comparable between the two protocols. None of the PPOS patients had an unexpected LH surge, and serum LH levels decreased slightly during ovarian stimulation. Limitations, reasons for caution Due to the nature of the retrospective study design, we did not record the progesterone level on the trigger-day in the PPOS regimen; therefore, identifying LH surge based on LH and progesterone levels is not feasible. Furthermore, we did not study the outcomes of embryo transfer. Wider implications of the findings These results supported the use of PPOS with dydrogesterone as a cheap and effective alternative for clinicians in clinical practice. In patients with an indication for freeze-all embryo, the PPOS protocol could be recommended. Trial registration number Not Applicable

P-640 No impact of Progestin Primed Ovarian Stimulation (PPOS) on euploid blastocyst rate per cohort of metaphase-II oocytes during PGT-A cycles: a case-control study

Abstract Study question Can progestins be used to prevent spontaneous LH surge during ovarian stimulation (OS) without affecting the euploid blastocyst rate (EBR) per metaphase-II (MII) oocytes? Summary answer Progestin Primed Ovarian Stimulation (PPOS) (conducted with norethisterone acetate) and conventional-OS with GnRH-antagonist show similar EBR per MII-oocytes What is known already PPOS is a novel OS protocol based exogenous progesterone to inhibit LH surge and spontaneous ovulation as an alternative to GnRH analogues. The rationale of its use is that multiple follicular waves arise during the ovarian cycle and no spontaneous ovulation occurs during the luteal phase. PPOS effectiveness and safety have been supported lately in the literature. A recent study reported similar number of euploid blastocysts after PPOS (conducted with medroxyprogesterone acetate) versus conventional-OS with GnRH-antagonist. Study design, size, duration Case-control study involving advanced-maternal-age women undergoing ICSI with PGT-A at two private IVF centers (May-2017 to February-2020). 80 PPOS women were matched with 160 control based on maternal-age and ovarian reserve markers. Patients with poor-ovarian-reserve (AFC&amp;lt;3), premature-ovarian-failure, III-IV stage endometriosis, ovarian cyst, severe-male-factor, PGT-SR or PGT-M were excluded. EBR per MII-oocytes was the primary outcome. All other embryological and clinical outcomes were reported. Participants/materials, setting, methods Both groups underwent recombinant-FSH OS with GnRH-agonist ovulation trigger; the only difference was that norethisterone acetate 10mg/day was administered orally to PPOS patients starting from the second day of the menstrual cycle until trigger. The control group, instead, underwent conventional antagonist protocol. The laboratory procedures were similar in both groups: ICSI, blastocyst culture, trophectoderm biopsy, comprehensive-chromosome-testing to report non-mosaic aneuploidies and vitrified-warmed euploid single-embryo-transfers (SETs). Main results and the role of chance The mean fertilization rate per MII-oocytes and blastulation rate per 2PN-zygotes were similar among PPOS and control (75.5%±21.8% versus 71.7±20.7%, p = 0.1; and 56.5%±27.7% versus 53.2%±27.5%, p = 0.4, respectively). No difference was reported for the EBR per MII-oocytes among PPOS and control (15.4%±19.8% versus 14.8%±18.2%, p = 0.9). No difference was reported among the biopsied blastocysts in terms of morphological quality and day of development. A total of 47 and 86 SETs were conducted in the two groups. There was no difference in the live-birth-rates (LBR) per SET in the two groups (N = 19/47, 40.4%, 95%CI 26.7-55.7 versus N = 35/86, 40.7%, 95%CI 30.4-51.8, p = 0.9), nor in the miscarriage rate per clinical pregnancy (N = 1/20, 5%, 95%CI 0.3-26.9 versus N = 3/36, 8.3%, 95%CI 2.2-25.6, p = 0.9). At last, the cumulative-LBR among concluded cycles (i.e., LB achieved or no transferable/all transferred euploid blastocysts) was also similar (N = 19/68, 27.9%, 95%CI 18.1-40.3 versus N = 31/132, 22.0%, 95%CI 15.4-30.2, p = 0.4). Limitations, reasons for caution The main limitation is the retrospective and non-randomized design. More data are required, especially for follicle recruitment, oocyte yield, gestational and perinatal outcomes. Wider implications of the findings Norethisterone acetate-based PPOS protocol has no impact on oocyte competence when compared to conventional GnRH-antagonist OS. These promising data support further investigation on PPOS, especially in view of its reduced cost, and putative increase in patient compliance and decrease in discomfort. Trial registration number none

P-662 Embryo ploidy rates following PPOS or GnRH antagonist protocol. A prospective study with repeated ovarian stimulation

Abstract Study question Is there any difference in embryo ploidy rates following progesterone primed ovarian stimulation (PPOS) using micronized progesterone or GnRH antagonist protocol? Summary answer Pituitary downregulation with a PPOS protocol with micronized progesterone results in a comparable number of euploid blastocysts with a GnRH antagonist protocol. What is known already Although the GnRH antagonist is consider by most the gold standard protocol for controlling the LH surge during ovarian stimulation for IVF/ICSI, progesterone-primed ovarian stimulation protocols (PPOS) are being increasing used in freeze-all protocols. Still, despite the promising results of PPOS protocols, an early randomized trial reported potentially lower live births in recipients of oocytes resulting following downregulation with medroxyprogesterone acetate as compared with a GnRH antagonist protocol. The scope of the current prospective study was to investigate whether PPOS with micronized progesterone results in equivalent blastocyst euploidy rates as compared with a GnRH antagonist protocol. Study design, size, duration In this prospective study, performed between September 2019 to January 2022, 44 women underwent two consecutive ovarian stimulation (OS) protocols within a period of 6 months in a GnRH antagonist protocol or in a PPOS protocol with oral micronized progesterone. Participants/materials, setting, methods Overall, 44 women underwent two OS cycles with identical fixed dose of rFSH (225 or 300 IU) in both cycles. Downregulation in the 1st cycles was performed with the use of a flexible GnRH antagonist protocol and consecutively, after a washout period of one month, control of LH surge was performed with oral micronized progesterone from stimulation day 1. After the completion of both cycles, all generated blastocysts underwent genetic analysis for aneuploidy screening (PGT-A). Main results and the role of chance Comparisons between cycles did not reveal differences between the duration of OS neither in the gonadotrophins dose. Hormonal profile on the day of trigger revealed statistically significant differences between cycles in all the tested hormones except for FSH: with significantly higher serum E2 levels, more elevated LH levels and higher Progesterone levels in PPOS cycles as compared with antagonist cycles, respectively. PPOS protocol resulted in a significantly higher number of oocytes (10.27± 5.84 versus 12.68± 8.09), (DBM -2.4 [95% CI -4.1; -0.73]), MIIs (7.34±4.15 versus 9.09± 6.12), (DBM -1.8 [95% CI -3.1; -0.43]), and 2PNs (5.66±3.35 versus 7.14± 4.99), (DBM -1.5 [95% CI -2.6.1; -0.32]) as compared with the GnRH antagonist protocol. Nevertheless, no differences were observed regarding the mean number of blastocysts (2.84±2.12 versus 2.91±2.11), (DBM -0.07 [95% CI -0.67; 0.53]) and the mean number of biopsied blastocysts (2.86±2.15 versus 2.93±2.16), (DBM -0.07 [95% CI -0.70; 0.56]). Finally, no difference was observed for the primary outcome, with a mean number of euploid embryos of 0.86 ± 0.90 vs. 1.00 ± 1.12 for the comparison of PPOS vs. GnRh antagonist. Limitations, reasons for caution The study was powered to detect differences in the mean number of euploid embryos and not in terms of pregnancy outcomes. Additionally, per protocol there was no randomisation, the first cycle was always a GnRH antagonist cycle and the 2nd a PPOS with one month of washout period in between. Wider implications of the findings The current study provides evidence that the PPOS may result in equivalent blastocyst euploidy rates compared with antagonist protocol. This may imply that in case of a freeze-all protocol, clinicians may safely consider PPOS to control the LH surge and patients could benefit from the advantages (cost and oral administration). Trial registration number NCT04108039

P-694 Desogestrel did not affect Follicular Output Rate (FORT) during controlled ovarian stimulation for oocyte vitrification: prospective cohort study

Abstract Study question Does desogestrel an option for LH suppression during controlled ovarian stimulation for oocyte vitrification? Summary answer This new option for LH suppression did not affect FORT and, consequently, the number of collected oocytes for vitrification. What is known already Traditionally, LH suppression is achieved by using a gonadotropin-releasing hormone (GnRH) analogue. However, improved cryopreservation techniques and freeze-all strategies are introducing new concepts, including the possibility of using progesterone instead of GnRH analogues. Progesterone compounds are currently wide-used during ovarian stimulation for oocyte freezing for LH suppression. The use of oral medroxyprogesterone was previously shown to effectively prevent the LH surge, without impacting embryo development or pregnancy rates after frozen embryo transfer. The use of dydrogesterone with the same purpose was also effective. Desogestrel is a progesterone broadly known and accepted, and has good tolerability and low cost. Study design, size, duration A prospective cohort study was performed during the period of 2019-2021 including 75 patients submitted to oocyte freezing and 173 women matched by age as the controls (patients submitted to IVF for the first time). Participants/materials, setting, methods Patients from the control group used a flexible GnRH antagonist for LH suppression, and patients in the desogestrel group utilized desogestrel 75 mcg oral twice a day (starting from the beginning of gonadotropin to hCG/agonist day). All patients received the same gonadotropin regimen (recombinant FSH). The final oocyte maturation was equal for both groups (recombinant hCG and GnRH analogue agonist). The primary endpoint was the antral follicle responsiveness to follicle-stimulating hormone, measured by FORT. Main results and the role of chance Age [control group= 36 years (median 28-45); desogestrel group= 36 years (median 23-43); p = 0.793; Mann Whitney U test], baseline antral follicle count [control group= 8 (2-23); desogestrel group= 9 (2-21); p = 0.741; Mann Whitney U test] and anti-Mullerian hormone [control group= 1.5 (0.05-7.95); desogestrel group= 1.00 (0.01-16.00); p = 0.540; Mann Whitney U test] were similar between both groups. However, the controlled ovarian stimulation length was shorter in the control group [10.4±1.6 vs. 11.0±1.6; p = 0.044; t-student test,] and those patients utilized less gonadotropin than the desogestrel group [2736 UI ± 745 vs. 2933 UI ± 785; p = 0.047; t-student test,]. Finally, Follicular Output Rate (FORT) [control group= 45%; desogestrel group= 52%; p = 0.217; t-student test], number of collected oocytes [control group= 6 (1-33); desogestrel group= 8 (1-20); p = 0.293; Mann Whitney U test] and MII [control group= 5 (1-27); desogestrel group= 6 (1-19); p = 0.156, Mann Whitney U test] were the same between both groups. Limitations, reasons for caution The small sample size and the absence of randomization are the main limitations of our study. Since the first results were encouraging, a randomized study should be performed. Wider implications of the findings Desogestrel is a cheap and easy option to be used during controlled ovarian stimulation for oocyte vitrification, since the final results are the same. This is the first scientific report showing the use of desogestrel did not affect FORT and, consequently, the number of collected oocytes for vitrification. Trial registration number Not applicable

Prognosis of patients with endometrial cancer or atypical endometrial hyperplasia after complete remission with fertility-sparing therapy

PurposeAlthough many patients with endometrial cancer (EC) or atypical endometrial hyperplasia (AEH) achieve complete remission (CR) after high-dose medroxyprogesterone acetate (MPA) treatment, no consensus has been reached on management after CR. Currently, patients receive estrogen-progestin maintenance therapy, but no recommendations exist regarding the duration of maintenance therapy or whether hysterectomy should be considered. This study aimed to provide insights into the management of EC/AEH after achieving CR.MethodsWe retrospectively investigated the prognosis of 50 patients with EC or AEH who achieved CR after MPA therapy. We assessed the association between disease recurrence and clinicopathological features and the pre- and post-operative histological diagnoses of patients who underwent hysterectomy.ResultsThe median follow-up duration was 34 months (range: 1–179 months). Recurrence was observed in 17 patients. Among the clinical characteristics investigated, only the primary disease was significantly associated with disease recurrence; patients with EC had a higher risk of recurrence than those with AEH (p = 0.037). During the observation period, 27 patients attempted pregnancy, and 14 pregnancies resulted in delivery. Patients who gave birth had significantly longer relapse-free survivals than those who did not (p = 0.031). Further, 16 patients underwent hysterectomies, and AEH was detected postoperatively in 4 of 11 patients (36.4%) with no preoperative abnormalities.ConclusionsWe identified several clinical features of patients with EC and AEH after CR. Given the high probability of endometrial abnormalities detected postoperatively, hysterectomy may be considered for patients who no longer want children.

The Acceptance of Postpartum Intrauterine Contraceptive Devices Among Women Who Receive Focused Family Planning Counseling in the Antenatal Period Compared to Those Who Receive Routine Counseling: A Randomized Controlled Trial.

Background and objective Unplanned pregnancies are very common in the postpartum period, and they often lead to negative outcomes such as abortion, low-birth-weight neonates, early delivery, postpartum bleeding, and fetal mortality. In the first 12 months after delivery, closely spaced and unintentional pregnancies can be prevented with postpartum contraception. The postpartum intrauterine contraceptive device(PPIUCD) is a method of family planning that may be used during the first few weeks after giving birth, and it is highly successful, reliable, affordable, non-hormonal, immediately reversible, long-acting, and does not interfere with lactation. Urban and educated women are largely aware of IUCD and its benefits, but the proportion of these women who use them is still small. In light of this, this study aimed to assess if providing focused antenatal counseling led to a greaterpostpartum IUCD acceptance ratewhen compared to routine counseling. Method We conducted arandomized controlled trial in the Department of Obstetrics and Gynaecology of a tertiary care center from January 2021 to December 2022. Based on the inclusion and exclusion criteria, 220 women were enrolled and were classified into two groups. Group A comprised 110 women (the focused counseling group) who received focused postpartum family planning (PPFP) counseling, and Group B consisted of the control group involving 110 women who received routine counseling. Results In both groups, the women who inserted IUCD were mostly gravida 2. Additionally, willingness to use IUCD was shown by 68% of women in the focused counseling group and 58% of women in the routine counseling group, and PPIUCD was accepted by 22% of women in the focused counseling group and 9% of women in the routine counseling group. Post-placental insertion was carried out in 18 (75%) cases in the focused counseling groupand seven (70%) cases in the routine counseling group. Extended postpartum insertion (insertion within one year of delivery) was carried out in six (25%) cases in the focused counseling group and three (30%) cases in the routine counseling group. The most common reasons for the refusal were a preference for tubal ligation (TL) and afear of side effects. When the patients were enquired about their contraceptive use over the past yearon telephone conversations after one year of delivery, it was observed that 21.81% inserted PPIUCD, 30% used injectable depot-medroxyprogesterone acetate (DMPA), 13.63% had undergone TL, 11.81% used barrier contraception, while 22.72% did not use any contraception in the focussed counseling group. In the routine counseling group, 16.36% of women inserted PPIUCD, 20% used injectable DMPA, 12.72% underwent TL, 18.18% used barrier contraception, and 32.72% did not use any contraception. Conclusion Although PPIUCD is a long-acting reversible contraceptive that is safe and reliable, only a few women choose it as a method of birth control. This may be due to ignorance, misconceptions, and worries/fears about potential difficulties/adverse effects associated with IUCD insertion. The IUCD stigma mostly results from misconceptions about the fear of complications. Hence, we recommend that proper IUCD counseling be provided during antenatal care visits to dispel misunderstandings and concerns regarding potential complications associated with PPIUCD insertion.

Progesterone receptor isoform ratios influence the transcriptional activity of progestins via the progesterone receptor

Progestins (synthetic progestogens) are progesterone receptor (PR) ligands used globally by women in both hormonal contraception and menopausal hormone therapy. Although four generations of unique progestins have been developed, studies seldom distinguish between the activities of progestins via the two functionally distinct PR isoforms, PR-A and PR-B. Moreover, not much is known about the action of progestins in breast cancer tumors where PR-A is mostly overexpressed relative to PR-B. Understanding progestin action in breast cancer is crucial since the clinical use of some progestins has been associated with an increased risk of developing breast cancer. This study directly compared the agonist activities of selected progestins from all four generations for transactivation and transrepression via either PR-A or PR-B, and when PR-A and PR-B were co-expressed at ratios comparable to those detected in breast cancer tumors. Comparative dose-response analysis showed that earlier generation progestins mostly displayed similar efficacies for transactivation on a minimal progesterone response element via the PR isoforms, while most of the 4th generation progestins, similar to the natural progestogen, progesterone (P4), were more efficacious via PR-B. Most of the progestogens were however more potent via PR-A. We are the first to show that the efficacies of the selected progestogens via the individual PR isoforms were generally decreased when PR-A and PR-B were co-expressed, irrespective of the ratio of PR-A:PR-B. While the potencies of most progestogens via PR-B were enhanced when the ratio of PR-A relative to PR-B was increased, those via PR-A were minimally influenced. This study is also the first to report that all progestogens evaluated, except 1st generation medroxyprogesterone acetate and 4th generation drospirenone, displayed similar agonist activity for transrepression via PR-A and PR-B on a minimal nuclear factor kappa B containing promoter. Moreover, we showed that the progestogen activity for transrepression was significantly increased when PR-A and PR-B were co-expressed. Taken together, our results highlight that PR agonists (progestogens) do not always display the same activity via PR-A and PR-B, or when PR-A and PR-B are co-expressed at ratios mimicking those found in breast cancer tumors. These results suggest that biological responses are progestogen- and PR isoform-dependent and may differ in target tissues expressing varying PR-A:PR-B ratios.

Endometrium-derived mesenchymal stem cells suppress progression of endometrial cancer via the DKK1-Wnt/β-catenin signaling pathway

BackgroundMesenchymal stem cell (MSC) therapy is an attractive treatment option for various cancers. Whether MSCs can be used to treat well-differentiated endometrial cancer (EC) remains unclear. The aim of this study is to explore the potential therapeutic effects of MSCs on EC and the underlying mechanisms.MethodsThe effects of adipose-derived MSCs (AD-MSCs), umbilical-cord-derived MSCs (UC-MSCs), and endometrium-derived MSCs (eMSCs) on the malignant behaviors of EC cells were explored via in vitro and in vivo experiments. Three EC models, including patient-derived EC organoid lines, EC cell lines, and EC xenograft model in female BALB/C nude mice, were used for this study. The effects of MSCs on EC cell proliferation, apoptosis, migration, and the growth of xenograft tumors were evaluated. The potential mechanisms by which eMSCs inhibit EC cell proliferation and stemness were explored by regulating DKK1 expression in eMSCs or Wnt signaling in EC cells.ResultsOur results showed that eMSCs had the highest inhibitory effect on EC cell viability, and EC xenograft tumor growth in mice compared to AD-MSCs and UC-MSCs. Conditioned medium (CM) obtained from eMSCs significantly suppressed the sphere-forming ability and stemness-related gene expression of EC cells. In comparison to AD-MSCs and UC-MSCs, eMSCs had the highest level of Dickkopf-related protein 1 (DKK1) secretion. Mechanistically, eMSCs inhibited Wnt/β-catenin signaling in EC cells via secretion of DKK1, and eMSCs suppressed EC cell viability and stemness through DKK1-Wnt/β-catenin signaling. Additionally, the combination of eMSCs and medroxyprogesterone acetate (MPA) significantly inhibited the viability of EC organoids and EC cells compared with eMSCs or MPA alone.ConclusionsThe eMSCs, but not AD-MSCs or UC-MSCs, could suppress the malignant behaviors of EC both in vivo and in vitro via inhibiting the Wnt/β-catenin signaling pathway by secreting DKK1. The combination of eMSCs and MPA effectively inhibited EC growth, indicating that eMSCs may potentially be a new therapeutic strategy for young EC patients desiring for fertility preservation.

EMAS at 25: meeting the challenges of WHI and beyond

EMAS has been founded 25 yrs ago to study Women's Health and to teach the management of the climacteric. Then, Hormone Therapy was used also to prevent chronic diseases, e.g. osteoporosis, cardiovascular diseases or dementia. In the US, the administration of oral CEE instead of oestradiol (E2), alone or combined with medroxy-progesterone-acetate (MPA), was standard and adopted for the Women's HeaIth Initiative (WHI) trial, a RCT. The mean age of its asymptomatic volunteers was 63 yrs at inclusion, beyond the "window of opportunity". To rely for guidelines only on RCTs performed in inappropriate populations induces in error if observational studies having a lower evidence but done in the population to be treated in real life are neglected, particularly studies with other ways of administration and metabolically better progestogens. Because of the strange information policy of the WHI steering committee in 2002, HT had been declared dangerous by the media. This led in the US to an estimated 58‘000 avoidable annual deaths in younger women (50-59 yrs). Europe resisted better to this one-sided view on HT. EMAS did teach after 2002 how to administer individualized HT using non-oral E2 with micronized progesterone or dydrogesterone. Today, it is accepted that the benefits of correctly indicated HT outweigh the risks. HT became a first-line therapy for the prevention and treatment of osteoporosis-related fractures. The decrease of CVD risk in HT users is an argument for its administration in presence of CVD risk factors although HT is not an independent indication for CVD prevention.Regional societies such as EMAS promote the best management of women's health adapted to its own culture and life style without the obligation of global societies to integrate other principals due to different ways of life, different cultures and different social structures, although such differences make the richness of our world.The mission of EMAS will always be to go beyond classical HT by analysing new therapeutic principals, hormonal or not, as long as they are based on solid evidence and aim at a better quality of life. The EMAS study planned in 2003 to give an answer to the questions raised by the WHI trial could not get the funding in the anti-HT climate of then. Perhaps the time has come now to perform the missing prospective clinical studies in the very European population we treat daily to validate the most appropriate forms of treatment of the climacteric for our patients.