Oral Progesterone Research Articles

A Protocol for Modifying Progesterone to Increase Postpartum Cigarette Smoking Abstinence and Reduce Secondhand Smoke Exposure in Infants

New interventions are necessary to increase postpartum abstinence from cigarette smoking. Sex hormones, specifically progesterone, have been found to be protective against drug-taking behaviors. Our pilot double-blind, randomized, controlled trial, although underpowered, suggested a trend toward a higher prevalence of smoking abstinence among postpartum participants receiving exogenous progesterone compared to those receiving placebo. This paper outlines the protocol used in our study to evaluate the efficacy of modifying progesterone to increase postpartum smoking abstinence and, subsequently, decrease secondhand smoke exposure in infants. In the intervention arm, participants will receive open-label exogenous oral progesterone (200 mg twice daily). Using a concurrent control group that does not receive progesterone treatment, we hypothesize that progesterone treatment will increase postpartum smoking abstinence as measured using a 7-day point prevalence at six months post-treatment allocation, as well as reduce smoking-related risk factors. Secondary objectives include examining the impact of this maternal smoking intervention on infant health. In addition to describing the protocol, we also discuss the protocol changes made due to the COVID-19 pandemic. Upon completion, this study will provide new information on how sex hormones may influence smoking cessation in postpartum populations, which can have broad public health implications. Clinical Trials Registration #NCT04783857

Comparison of Combined Oral Contraceptives and a Transdermal Estrogen Patch With Oral Progesterone: Treatment of Abnormal Uterine Bleeding in Adolescents

Comparison of Combined Oral Contraceptives and a Transdermal Estrogen Patch With Oral Progesterone: Treatment of Abnormal Uterine Bleeding in Adolescents

Oral Natural Micronized Progesterone: A Review of Its Implications in Obstetric Indications

Oral Natural Micronized Progesterone: A Review of Its Implications in Obstetric Indications

GnRH-a-based fertility-sparing treatment of atypical endometrial hyperplasia (AEH) and early endometrial carcinoma (EC) patients: a multicenter, open-label, randomized designed clinical trial protocol

BackgroundAround 4% of women receive an endometrial cancer diagnosis before turning 40, mainly those without prior childbirth experience and a strong desire to preserve their ability to conceive. Consequently, for young patients diagnosed with atypical endometrial hyperplasia (AEH) or early endometrial carcinoma (EC), a fertility-preserving approach employing high-dose oral progesterone has been adopted. However, previous research has shown a notable relapse rate. Furthermore, the extended use of substantial oral progesterone doses may hinder ovarian function and raise the risk of weight gain, liver issues, blood clotting, and breast cancer. We previously assessed the clinical effectiveness and pregnancy outcomes of gonadotropin-releasing hormone agonist (GnRH-a) based re-treatment for women with EC and AEH who did not respond to oral progestin therapy but achieved favorable treatment results and reproductive outcomes.MethodsThis study will be an open-label, two-armed, randomized, investigator-initiated multicenter trial evaluating the combination of GnRH-a with the levonorgestrel-releasing intrauterine system or the combination of GnRH-a with an aromatase inhibitor (comprising a subcutaneous GnRH-a injection every 4 weeks and daily oral letrozole 2.5 mg). A total of 226 participants will be randomly allocated to one of the two treatment groups in a 1:1 ratio. The primary objective is to determine the effectiveness of GnRH-a-based re-treatment in achieving a complete response (CR) at 24 weeks for patients with AEH or EC. Secondary objectives include assessing the pregnancy rate 12 weeks after treatment, as well as post-treatment pregnancy outcomes and the rate of recurrence.Ethics and disseminationThe protocol received approval from the Institutional Review Board of Peking Union Medical College Hospital and from boards at five other institutions. The trial will adhere to the principles outlined in the World Medical Association’s Declaration of Helsinki and follow Good Clinical Practice standards. The trial results will be disseminated through publication in a peer-reviewed journal.ConclusionsProspective evidence supporting conservative treatment for EC and AEH is limited. There is a need for new approaches that can achieve higher CR rates with fewer side effects. This trial will assess the effectiveness of GnRH-a-based fertility-sparing treatment in obese women and recurrent patients, offering a promising alternative for patients with EC and AEH.Trial registration numberChinese Clinical Trial Registry ChiCTR2200067099. Registered on December 27, 2022.

The Effects of Oral Progestagen Administration on the Fertility of Synchronized Goats During the Breeding Season

The objective of this study was to assess the impact of oral progesterone (altrenogest) administered after mating on fertility in goats synchronized during the breeding season. A total of 47 Hair goats were included in the study. A progesterone-impregnated intravaginal sponges were administered for 12 days. On day 10 of intravaginal sponge administration, 480 IU pregnant mare's serum gonadotropin (PMSG) and 0.075 mg cloprostenol were injected intramuscularly to the goats. Animals were exposed to bucks for 12 hours after detection of estrus by the foraging buck. The goats were randomly assigned to two distinct groups: Group 1 (G1, n=23) and Group 2 (G2, n=24). G1 goats were orally administrated 4.4 mg of altrenogest per day for 30 days after mating. G2 goats served as controls. Pregnancy examinations were performed by transrectal ultrasonography on the 30th and 42nd days after mating. Blood samples were taken from one day after mating to 30 days (3-day intervals). Statistical analysis comparing G1 and G2 revealed no significant differences between the groups regarding progesterone concentrations, conception rate, pregnancy rate, lambing rate, multiple birth rate, fecundity, and litter size (p>0.05). In conclusion, this study revealed that oral progesterone use had no impact on fertility parameters. Moreover, further research is warranted to explore the efficacy of various oral progesterone analogs.

Case Series: Severe meibomian gland loss in polycystic ovarian syndrome patients on estrogen-progesterone therapy: A case series

Purpose: To report the ocular surface and meibomian gland changes in polycystic ovarian syndrome (PCOS) women taking hormone supplementation. Methods: Case series. Results: Three women (27 ± 11 years) already diagnosed with PCOS presented with dry eye symptoms (mean OSDI, 37.5) for a mean duration of 13 months and were taking hormonal supplements for a mean duration of 60 ± 11 months. The hormonal supplements included oral estrogen (n=3), oral progesterone (n=3), antiandrogen cyproterone (n=1) and isotretinoin (n=1). Ocular surface evaluation revealed mean NIBUT of 9.9 ± 1.6 seconds and mean TMH of 0.27 ± 0.05 mm, assessed non-invasively using Oculus keratograph 5M (K5M). Meibography (K5M) showed near total loss of all meibomian glands (n=8/12 eyelids) with residual ghost glands in all four eyelids of two patients, and gland shortening alone in one patient. The gland morphology did not change following intense thermal pulsation treatment or cessation of hormonal therapy. Conclusions: Near-total irreversible meibomian gland loss was seen in two young PCOS women taking hormonal supplements. Collaboration between ophthalmologists and gynecologists is advisable for early detection and better understanding of dry eye disease (DED) progression in these patients.

P-585 Vaginal progesterone associated with oral dydrogesterone versus vaginal progesterone for luteal support in letrozole-hcg cycles for thawed embryo transfer: a non-inferiority prospective cohort study

Abstract Study question Does micronized vaginal progesterone (MVP) associated with oral dydrogesterone (DYG) an alternative for luteal support in Letrozole-hcg cycles for thawed embryo transfer? Summary answer The association of MVP and DYG is a non-inferior alternative to only MVP for luteal support in thawed embryo transfer in Letrozole-hcg cycles. What is known already Endometrial preparation is essential for thawed embryo transfer. Several protocols involving different luteal support with progesterones are available. Moreover, the presence of corpus luteum decreases the obstetrical morbidity mainly linked to hypertensive disorders. Letrozole-hcg administration is a good alternative for frozen embryo transfer (FET). However, the literature lacks information about the comparison among the different protocols for luteal support in Letrozole-hcg cycles. Dydrogesterone is an oral progesterone with some unique characteristics which could be utilized with some advantage for luteal support, including oral administration and some immunological activity. Study design, size, duration This is a prospective non-inferiority cohort study performed at an infertility clinic including patients performing the first FET cycle during 2023. Reproductive outcomes were compared between patients receiving 600 mg (3x200 mg) of MPV or 40 mg of DYG plus 400 mg of MVP after Letrozole-hcg administration. Participants/materials, setting, methods All patients (aged 23-39 years) undergoing their first FET cycle during 2023 were included in this study (n = 169), divided into two groups: MVP+DYG (n = 54) or MVP (n = 115) for luteal support after Letrozole-hcg. Letrozole was administered for 5 days (2,5 mg/bid) and hcg was done when a dominant follicle reached 18 mm with a follicular endometrium measuring at least 7 mm. Main results and the role of chance Both groups were equivalent in terms of age, infertility aetiology, BMI and AMH (P > 0.05). Moreover, the proportion of cleavage or blastocyst stage was also similar between both groups (57% blastocyst transfer for MVP+DYG and 50% blastocyst transfer for MVP group, P > 0.05). The number of transferred embryos was (mean ±SD) 1.6±0.5 for both groups, P > 0.05. Furthermore, the number of top-quality embryos (cleavage stage or blastocyst) was also similar, P > 0.05. Moreover, clinical pregnancy (> 12 weeks) was 42% in MVP+DYG group versus 31% in the MVP group (-0.22-1.27, P = 0.156) and the early pregnancy loss per positive hcg test did not differ (18% for MVP+DGY and 22% for MVP, P = 0.687). In addition, we performed a multivariable analysis controlling possible confounders for clinical pregnancy: BMI, age, AMH, embryo quality, infertility aetiology and embryo stage during the transfer, and only age (0.86; 95%CI -0.229 to -0.064, P = 0.001) was related to clinical pregnancy. Limitations, reasons for caution The main limitation is the cohort design of our study, with an inherent risk of bias (selection bias). Moreover, we calculated this study to achieve the power for a non-inferiority comparison, not superiority comparison. Wider implications of the findings This is the first study comparing MVP+DYG to only MVP in patients submitted to FET using the Letrozole-hcg protocol. We demonstrated in this non-inferiority study the usefulness of adding DYG. Moreover, our results were promising showing a trend towards better pregnancy rates after MVP+DYG. Trial registration number not applicable

P-286 Comparative study of frozen-thawed embryo transfer with modified natural cycle versus HRT cycle in previously cancelled true natural cycle patients

Abstract Study question Is there any difference in outcome of frozen embryo transfer(FET) between hormone replacement therapy(HRT) and modified natural cycle(MNC) in previously cancelled true natural cycle patients Summary answer In patients with previous history of cancelled true natural cycle, MNC results in higher clinical pregnancy rates after FET, when compared to HRT cycle What is known already Preparation of endometrium lays down the foundation for conception and subsequent successful pregnancy.There has been a plethora of endometrial preparation protocols described in the literature. The established protocols are true natural cycle,MNC with or without luteal phase support(LPS) and HRT cycle with or without gonadotrophin releasing hormone agonist(GnRha) suppression. Nevertheless,there is no consensus on protocol which may provide the best outcome in patients who have had cancelled true natural cycle.In such situations,HRT cycle may be considered as an easy option as the cancellation rate is low.However,HRT treatment is known for higher early pregnancy and obstetric complications,compared to MNC Study design, size, duration Prospective observational study,where 155 patients undergoing FET who had minimum one true natural cycle cancellation were recruited.They were divided into group A undergoing HRT cycle(n = 77) and group B for MNC cycle(n = 78).The study was conducted in a fertility unit over six months from June-November 2023.Primary outcome measures were serum betaHCG estimation and ultrasonographic documentation of intrauterine pregnancy.Results were analysed using statistical software SPSS version25 and p value of less than 0.05 was considered statistically significant Participants/materials, setting, methods HRT patients received injectable GnRha 3.75 mg on day21 of previous cycle.Oral estradiol valerate 6mg daily started on day2 of menses. When ET was minimum 7mm, luteal phase support(LPS) was started with daily oral and vaginal progesterone(30mg and 600mcg respectively),followed by FET. MNC patients received Letrozole 5mg daily from day 2-6 of menstruation.rhCG 250mcg was given subcutaneously,when ET was at least 7mm,dominant follicle 16-18mm and progesterone(P4) less than 1ng/ml.LPS(vaginal progesterone600mcg) was started 36hours after rHCG,followed by FET Main results and the role of chance Mean ET in MNC group was 8.92mm ± SD1.38, which was higher than HRT group (8.31 mm ± SD0.89). This difference was statistically significant with a p value of 0.014.Serum beta HCG estimation was done 2weeks after FET. In HRT group beta HCG was positive in 41 out of 77(53.25%) and in MNC group positivity was higher being 48 out of 78(61.54%). However, this difference was not statistically significant. Transvaginal ultrasonography(TVS) was done to confirm intrauterine pregnancy 2weeks after beta HCG assay. Clinical pregnancy rate(CPR) was higher in MNC group with 32 out of 78(41.03%),compared to 18 out of 77(23.38%) in HRT group. This difference is statistically significant with p value of 0.019 Limitations, reasons for caution Relatively small population in this study may be the reason for caution to interpret the statistical data. Study with higher numbers may bring about more robust conclusions Wider implications of the findings Patients with failed true natural cycles may be considered for modified natural cycle(MNC) stimulation for FET, without attempt of another true natural cycle stimulation Trial registration number NOT APPLICABLE

P-392 Luteal phase support for women trying to conceive by intrauterine insemination or sexual intercourse

Abstract Study question Is luteal phase support (LPS) necessary for intrauterine insemination or sexual intercourse? Summary answer Vaginal progesterone supplementation during luteal phase may increase live birth (LBR)/ongoing pregnancy rate (OPR), however, its effect on miscarriage per pregnancy (MPP) is uncertain. What is known already Ovulation induction may impact endometrial receptivity due to insufficient progesterone secretion. Low progesterone is associated with poor pregnancy outcomes. Study design, size, duration Systematic reviews and meta-analysis were conducted. We searched the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, LILACS, trial registries for ongoing trials, and reference lists of articles (from inception to 25 August 2021). Participants/materials, setting, methods Randomised controlled trials (RCTs) of LPS using progestogen, human chorionic gonadotropin (hCG), or gonadotropin-releasing hormone (GnRH) agonist supplementation in IUI or natural cycle. We used the standard methodological procedures expected by Cochrane. Main results and the role of chance We included 25 RCTs (5111 participants). Progesterone supplementation versus placebo or no treatment Vaginal progesterone does not significantly increase the LBR/ OPR (RR 1.10, 95% confidence interval (CI) 0.81 to 1.48; 7 RCTs; 1792 participants;) or decrease MPP (RR 0.70, 95% CI 0.40 to 1.25; 5 RCTs; 261 participants). Subgroup analysis revealed that progesterone may not increase LBR/OPR in women with gonadotropin stimulation (RR 1.24, 95% CI 0.80 to 1.92; 4 RCTs; 1054 participants) and oral stimulation (clomiphene citrate or letrozole) (RR 0.97, 95% CI 0.58 to 1.64; 2 RCTs; 485 participants). In addition, progesterone may not reduce MPP regardless of stimulation protocol (RR 0.68, 95% CI 0.24 to 1.91; 2 RCTs; 102 participants, with gonadotropin; RR 0.67, 95% CI 0.30 to 1.50; 2 RCTs; 123 participants, with gonadotropin plus oral stimulation; and RR 0.53, 95% CI 0.25 to 1.14; 2 RCTs; 119 participants, with oral stimulation). Different routes of progesterone administration versus vaginal route There is no difference in terms of LBR, OPR, and MPP when comparing intramuscular (IM), oral, or subcutaneous progesterone to vaginal progesterone. Very low-certainty evidence suggests that intramuscular progesterone may lead to a substantial increase in adverse events, particularly pain at the site of injection. Limitations, reasons for caution Most studies were at unclear or high risk of bias. The main limitations of the evidence were poor reporting and imprecision. Wider implications of the findings Vaginal progesterone does not significantly increase in LBR/OPR or decrease miscarriage rate. In comparison to vaginal progesterone, there is insufficient data to evaluate whether progesterone supplementation via an alternative route has an impact on pregnancy outcomes. Trial registration number PROSPERO2017 CRD42017055106

O-301 Progesterone Primed Ovarian Stimulation (PPOS) for DuoStim combined with PGT-A in poor prognosis patients: a valuable strategy

Abstract Study question Is PPOS rather than conventional GnRH-antagonist a valid strategy in DuoStim protocols? Summary answer PPOS-DuoStim and conventional-DuoStim showed similar mean euploid blastocyst rate (EBR) per inseminated metaphase-II (MII) oocytes. What is known already DuoStim (double stimulation in the same ovarian cycle) is an efficient strategy to increase the number of oocytes retrieved and embryos obtained in the shortest possible timeframe. PPOS is based on the use of exogenous oral progesterone to prevent LH surge during ovarian stimulation (OS). The effectiveness and safety of PPOS have been consistently reported across the last years, supporting it as a clinically-valuable OS protocol. To date, no evidence exists about PPOS application in DuoStim protocols and its association with oocyte competence, defined as EBR per MII-oocytes. Study design, size, duration Retrospective study involving 138 PPOS-DuoStim and 138 matched conventional-DuoStim patients treated at a single clinic between 2021 and 2022 and collecting ≥1 MII-oocyte after both stimulations. Matching was based on maternal age (40.3±2.7 years), number of oocytes collected after the I-stimulation (5.8±3.6 years), and sperm quality (66% normozoospermic). The primary outcome was the EBR per MII-oocytes. All intermediate embryological and clinical outcomes were also compared. Sub-analyses among I- and II-Stimulations were also conducted. Participants/materials, setting, methods DuoStim entailed the same protocol in I- and II-Stimulations with FSH 300IU/day+LH 150IU/day, 5 days spanning the two stimulations and GnRH-agonist to trigger ovulation. The only difference between PPOS-DuoStim and conventional-DuoStim was the administration of medrossiprogesterone acetate10mg/day orally from the first day of stimulation versus flexible GnRH-antagonist from the day the follicles reached a diameter of 13-14 mm. The same laboratory procedures were applied: ICSI, trophectoderm biopsy, comprehensive-chromosome-testing to report uniform aneuploidies and vitrified-warmed single-embryo-transfers. Main results and the role of chance The patients in the two groups were comparable for ovarian reserve markers, BMI, and duration of infertility. All data were comparable in conventional-DuoStim and PPOS-DuoStim (Mann-Whitney U tests were conducted): (i) overall fertilization rate per inseminated MII-oocytes were 73.1±23.2% versus 76.8±17.8% (p = 0.143), (ii) overall blastulation rate per 2PN-zygotes were 46.6±30.4% versus 45.7±25.1%(p = 0.797), (iii) overall euploidy rates per biopsied blastocysts were 24.1±30.9% versus 25.4±31.3%(p = 0.956), (iv) EBR per inseminated MII-oocytes were 9.6±17% versus 9.2±12.7% (p = 0.735). The data among only I- and II-stimulations were also similar. When comparing I- versus II-stimulations, paired t-tests highlighted longer II-stimulations (11±1.9 vs11.6±1.9 days, p = 0.001), resulting in larger cohorts of MII-oocytes (4.3±2.8 vs 5.2±3.3, p < 0.001) with comparable EBR per MII-oocytes (9.7±20.2% vs 11.6±16.2%, p = 0.233), thereby eliciting larger cohorts of euploid blastocysts (0.5±0.07 vs 0.7±0.09, p = 0.005). These data were confirmed also among conventional-DuoStim and PPOS-DuoStim study arms only. From a cycle perspective, among the 138 conventional-DuoStim couples, 31 (22%), 44 (32%) and 59 (43%) obtained ≥1 euploid blastocyst after I-stimulation, II-stimulation and overall, respectively. The same figures among the 138 PPOS-DuoStim were 36 (26%), 44 (32%) and 63 (46%), respectively. No statistical difference was reported (Fisher’s exact test=0.716). Limitations, reasons for caution Retrospective single center design. The current sample size should be doubled in order to reach a 80%-power with a 5%-α to exclude a 5% two-sided difference in the primary outcome. Patients’ compliance and discomfort, as well as clinical, gestational, and perinatal outcomes and cost-effectiveness analyses are needed. Wider implications of the findings PPOS is valuable in unconventional-OS protocols entailing freeze-all, like DuoStim with PGT-A. Future studies should assess if PPOS-DuoStim, by decreasing the number of injections and scans, may improve patient compliance and decrease OS discomfort. Any putative impact on follicular recruitment and oocyte yield should also be determined. Trial registration number not applicable

The Impact of Progesterone Administration Routes on Endometrial Receptivity and Clinical Outcomes in Assisted Reproductive Technology Cycles.

Introduction Assisted reproductive technologies (ART) rely on endometrial receptivity (ER) for successful embryo implantation. This study aimed to compare the impact of different progesterone administration routes on ERassessed using optimal time for endometrial receptivity analysis (OpERA)and clinical outcomes in ART cycles. Methods A retrospective cohort analysis was conducted on 281 infertile women who underwent in vitro fertilization(IVF). Patients were stratified based on progesterone administration routes: oral and vaginal progesterone (Group 1) vs. intramuscular progesterone (Group 2). OpERA was performed on 257 patients to assess ER. Clinical outcomes, including biochemical pregnancy rate (BPR), clinical pregnancy rate (CPR), implantation rate (IR), and abortion rate (AR), were compared between the groups. Results OpERA results showed no significant differences between Group 1 and Group 2 in receptive (51.2% vs. 52.0%, p = 0.857), pre-receptive (44.1% vs. 44.6%, p = 0.933), or post-receptive (4.7% vs. 3.1%, p = 0.496) states. Clinical outcomes, including BPR (59.9% vs. 60.9%, p = 0.903), CPR (50.0% vs. 56.5%, p = 0.463), IR (52.5% vs. 55.3%, p = 0.748), and AR (44.3% vs. 45.6%, p = 0.882), did not significantly differ between the groups. Conclusion Progesterone administration routes did not significantly affect ER or clinical outcomes,highlighting the need to prioritize understanding and enhancing ER instead of solely focusing on progesterone delivery methods.Identifying molecular pathways or biomarkers could improve receptivity and optimize ART, ultimately improving pregnancy outcomes.

A Case Report of 46 XY Partial Gonadal Dysgenesis with Dual Gonadal Tumours

46XY gonadal dysgenesis is known as a disorder of sex development (DSD) that occurs due to abnormality in gonadal development. There is a conflict between one’s genotype, phenotype, and gonadal development, which influences the wide range of presentation and clinical appearance of 46XY females. This was a case of a 46XY female who presented with primary amenorrhea with delayed puberty at the age of 18 years old. She had ambiguous genitalia. Her breast and pubic hair were at Tanner Stage 2. Transabdominal ultrasound found a small uterus with a vagina; however, the gonads were not seen. A magnetic resonance imaging (MRI) showed a 20mm right gonad located extra-pelvis near the right iliac vessels while the 9mm streak left gonad was at the usual location next to the sigmoid colon. All her tumour markers were normal except lactate dehydrogenase (LDH) was elevated. She was given estrogen therapy for pubertal induction and underwent laparoscopy prophylactic bilateral gonadectomy. The intraoperative findings were similar to the MRI findings, and the histopathology examination (HPE) results showed left gonadoblastoma and right dysgerminoma FIGO stage 1A. She continued taking estrogen therapy until she had withdrawal bleeding, and oral progesterone was added. 46XY-DSD has high risk of developing germ cell tumour and requires prophylactic gonadectomy as soon as the diagnosis is established. However, delay in presentation and surgery may affect the outcomes and prognosis.

Understanding the patient experience in nonsurgical management of endometrial cancer and complex atypical hyperplasia due to obesity: A qualitative analysis

ObjectivesPatients with class 3 obesity (BMI ≥ 40) and significant medical comorbidities with complex atypical hyperplasia (CAH) and early-stage endometrial cancer (EC) present challenges in standard surgical management. Progestin therapy is an alternative used for patient-centered reasons, including the desire for uterine preservation or because surgery is not a safe option. Our objective was to gain insights into the patient experience when undergoing this treatment approach. MethodsWe identified and recruited patients who received oral or IUD progesterone in the last 5 years for EC or CAH. We conducted semi-structured phone interviews regarding patients’ experience with non-surgical management as well as decision-making factors to start progesterone and weight loss. Interviews were audio-recorded and transcriptions were analyzed for common themes. ResultsA total of 20 interviews were performed. We enrolled nine patients with CAH, eight with grade 1 EC, and three with grade 2 EC. The majority of patients (18/20) were managed with IUD. We identified the following 5 common themes support in diagnostic workup and long-term outcomes, autonomy in care, thoroughness in counseling, emotional impact of diagnosis, and perception of obesity as a defining identity. ConclusionThe themes identified in the present study highlight the challenges and the stigma these patients face. It also demonstrates areas of opportunity in their counseling and care, which will help to build a more effective therapeutic relationship and ultimately lead to greater adherence in care.

Luteal phase support with oral progesterone improves live birth rate in intrauterine insemination cycles using letrozole

Does luteal phase support (LPS) with oral progesterone improve the live birth rate (LBR) in patients undergoing intrauterine insemination (IUI) cycles with letrozole? This retrospective cohort study included 1199 IUI cycles with letrozole between January 2017 and December 2021. A nearest neighbour random matching approach was employed to pair the LPS group and the control group in a 1:2 ratio. Eight variables were chosen for matching in the propensity score matching (PSM) model: age; body mass index; duration of infertility; cause(s) of infertility; antral follicle count; basal concentration of FSH; rank of IUI attempts; and leading follicle size. LBR was selected as the primary outcome. In total, 427 LPS cycles were matched with 772 non-LPS (control) cycles after PSM. The LBR was significantly higher in the LPS group compared with the control group (19.7% versus 14.5%; P = 0.0255). The clinical pregnancy rate (23.2% versus 17.6%; P = 0.0245) and ongoing pregnancy rate (20.6% versus 15.8%; P = 0.0437) were also significantly higher in the LPS group. The biochemical pregnancy rate, ectopic pregnancy rate and miscarriage rate were similar in the two groups (P > 0.05). The intergroup comparison revealed no significant variances in terms of gestational age, mode of delivery, ectopic pregnancy rate or abortion rate. Furthermore, there were no significant differences in birth weight or birth length between the two groups. Luteal support with oral progesterone significantly improved the LBR in IUI cycles with letrozole, but did not affect neonatal outcomes.

Abstract SS02-02: Hormone Replacement and Alternatives for Relief of Vasomotor Symptoms in Women at Increased Risk for Breast Cancer

Abstract 70% of women will experience vasomotor symptoms sufficient to impact their quality of life during menopause transition and the early menopause. These symptoms are thought result from neurotransmitter imbalances resulting from ovarian hormone reductions and hypersecretion of gonadotropins. Increases in gonadotropins result in neurotransmitter triggered stimulation of the neurokinin 3 (NK3) receptor and thermoregulatory imbalance. Estrogen deficiency also reduces serotonin which can also trigger increases in hot flashes, and sleep disturbances. Vasomotor symptoms last on the average for 7 years until acclimation to persistent low estrogen levels occurs. Estrogen +/- progestin replacement therapy is associated with the greatest likelihood of vasomotor symptom relief as it reduces gonadotropin and NK3 receptor signaling and increases serotonin. Progestins also increase the neuroinhibitory transmitter gamma-aminobutyric acid (GABA) which improves sleep quality. There continues to be confusion on the part of providers and patients regarding the excess risk of breast cancer and thromboembolic events as these risks are affected by type of agent, route of delivery, age, duration of treatment, and presence of obesity. The majority of placebo controlled randomized clinical trial data on hormone replacement with estrogen or estrogen + a progestin comes from the Women’s Health Initiative (WHI) for women 50-79 in which oral conjugated estrogen (CE) 0.625 mg was used as the estrogen for women without a uterus and medroxyprogesterone acetate (MPA) was added to CE for women with a uterus to protect against endometrial hyperplasia and cancer. The median age at entry to WHI that trial was 63 and a substantial proportion had previously taken hormones. Large longitudinal cohort studies have been helpful in assessing risks in women starting hormones at a more clinically relevant age (45-55) and with hormonal preparations other than oral CE and MPA. Five to seven years of estrogen alone results in minimal if any increased risk for breast cancer. However, combined estrogen+ progestin replacement for women over 50, necessary for women with a uterus, results in an ~ 30 % relative increased risk for breast cancer if taken for up to 5 years and a doubling of risk with 10 years of treatment. So called bioidentical hormones often compounded as oral troches of estradiol, progesterone, and testosterone, are also associated with increased breast cancer risk. Vaginal hormones have not been found to increase risk for breast cancer. Increased risk of thromboembolism is predominately observed in women over 50 using oral as opposed to transdermal preparations. Increased risk for stroke and dementia was observed in the WHI again with oral hormones in women over 65. In the WHI there was no increase in cancer related, cardiovascular or overall mortality with estrogen or estrogen and progestin. For high-risk peri and post-menopausal women with who would like to reduce/alleviate their vasomotor symptoms with no increase in risk for breast cancer there are several options: 1) the tissue selective estrogen complex bazedoxifene (BZA) combined with conjugated estrogen (CE) 2) the non-hormonal option of NK3 receptor antagonists such as fezolinetant ( 3) non-hormonal options of gabapentin, selective serotonin reuptake inhibitors (SSRI) and serotonin and norepinephrine uptake inhibitors (SNRI). BZA and CE and fezolinetant are reported to reduce hot flashes in 70% or more of individuals with paroxetine effectiveness reported as 50%. All three are FDA approved for reduction of vasomotor symptoms. The combination of BZA and CE is also being investigated for breast cancer risk reduction. These agents differ with respect to side effects with increased risk of blood clots for bazedoxifene and conjugated estrogen, increased risk of nausea, diarrhea, and liver dysfunction for fezolinetant and drowsiness and dry mouth for SSRIs. Drug costs may also dramatically affect insurance coverage and patient uptake of a particular strategy. A recent online perusal of a popular site for finding the lowest drug price suggested substantial differences in the cost of drugs for relief of vasomotor symptoms. The approximate cost for a 30- day supply of oral estradiol was $30, estradiol transdermal patches $35, oral progesterone $15, combined estradiol and levonorgestrel transdermal patches $240, oral CE $200, oral CE + medoxyprogesterone acetate $240, and for BZA+ CE $200. For non-hormonal therapies the cost of 30 days of gabapentin was $11, paroxetine $30 and fezolinetant $550. Crandall, Mehta, and Manson JAMA 2023 329:405-420 Collaborative Group on Hormonal Factors in Breast Cancer Lancet 2019 394: 1159-1168 Fabian et al Ca Prev Res 2019 10:711-720 Modi and Dhillo Neuroendocrinology 2019 109:242–248 Citation Format: C. Fabian. Hormone Replacement and Alternatives for Relief of Vasomotor Symptoms in Women at Increased Risk for Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr SS02-02.

Concurrent progestogen and cerclage to reduce preterm birth: a multicenter international retrospective cohort

Objective: We aimed to evaluate whether cerclage with progestogen therapy was superior to cerclage alone in the prevention of spontaneous preterm birth (sPTB) in singleton pregnancies Methods: This is an international retrospective cohort study of singleton pregnancies, without major anomaly or aneuploidy, and with cerclage placed at 10 different institutions in the United States and Colombia from June 2016-June 2020. Exclusion criteria were: lack of documentation regarding whether progestogen was or was not prescribed, delivery outcome unavailable, and pregnancy termination (spontaneous or induced) prior to 16 weeks’ gestation. Exposure of interest was progestogen use with cerclage placement, which included those who were continued on progestogen or who started progestogen after cerclage. Comparator was those without progestogen use after cerclage placement, which included those who had no progestogen use the whole pregnancy, or who initiated progestogen and then stopped it after cerclage placement. Progestogen type, cerclage indication, maternal baseline characteristics, and maternal/neonatal outcomes were collected. Primary outcome was sPTB <37 weeks. Secondary outcomes were sPTB <34 weeks, gestational age at delivery, composite neonatal outcome including ≥1 of the following: perinatal mortality, confirmed sepsis, Grade III or IV intraventricular hemorrhage, retinopathy of prematurity, respiratory distress syndrome, bronchopulmonary dysplasia. There was planned subgroup analyses by cerclage indication, progestogen type (vaginal progesterone vs 17-hydroxyprogesterone caproate (17-OHPC)), preterm birth history, and site.Continuous variables compared in adjusted analyses with ANCOVA and categorical variables compared with multivariable logistic regression adjusting for potential confounders with adjusted odds ratio (aOR). Cox regression survival curve was generated to compare latency to spontaneous delivery, censored after 37 weeks. Results: During the study period, a total of 699 singletons met inclusion, N=561 in the progestogen with cerclage group, and N=138 with cerclage alone. Baseline characteristics were similar, except those in the progestogen group were more likely to have had a prior sPTB (61% vs 41%, p<0.001). Within the progestogen group, 52% were on 17-OHPC weekly, 44% on vaginal progesterone daily, and 3% on oral progesterone daily. Progestogen with cerclage was associated with a significantly lower frequency of sPTB<37 (31% vs 39% aOR 0.59 (0.39 - 0.89), p=0.01) and <34 weeks (19% vs 27%, aOR 0.55 (0.35 - 0.87), p=0.01), increased latency to spontaneous delivery (Hazard ratio to sPTB <37wk, 0.66 (0.49-0.90), p=0.009), and lower frequency of perinatal death (7% vs 16%, aOR 0.37 (0.20-0.67), p=0.001). In planned subgroup analyses, association with reduced odds of preterm birth <37 weeks persisted in those on vaginal progesterone, those without a prior preterm birth, those with ultrasound or exam-indicated cerclage, those that started progestogen therapy prior to cerclage, and in sites restricted to the United States. Conclusion: Use of progestogen with cerclage was associated with reduced rates of sPTB and early sPTB compared to cerclage alone. Although not powered for subgroups, the strength of evidence for benefit appeared greatest for those with ultrasound or exam-indicated cerclage, and with vaginal progesterone.

Fabrication of controlled-release polymeric microneedles containing progesterone-loaded self-microemulsions for transdermal delivery

Progesterone (PG) has been approved for hormone replacement therapy to mitigate the risk of endometrial carcinoma. However, there has been a lack of success in oral PG due to its rapid degradation. Transdermal PG has advantages but lacks efficacy due to its poor solubility (Log p = 3.9). Therefore, this study aimed to evaluate how combining self-microemulsifying drug delivery systems (SMEDDS) and polymeric microneedles (MNs) could improve the transdermal delivery of PG in a controlled-release manner. Among PG-SMEDDS, PG–SME5 was selected for its desirable properties and stability. The two-layer polymeric MNs formulation incorporating PG–SME5 (PG-SMEDDS-tMNs) was formulated from aqueous blends of polymers as a first layer and 20% PCL as a second layer. It successfully penetrated neonatal porcine skin with the dissolution of the first layer observed within 15 min after application. In vitro skin permeation revealed that the percentage of PG which permeated the skin over 82 h using PG-SMEDDS-tMNs was higher than a PG-suspension and PG-SMEDDS. The Higuchi kinetic showed controlled release over 15 days of PG from PG-SMEDDS-tMNs. These studies suggested that incorporating PG-SMEDDS into controlled-release two-layer polymeric MNs could be a promising approach for improving the transdermal delivery of PG.

Spontaneous recurrent menstrual pneumothorax: a case report

Introduction and importance: Endometriosis is most commonly found in the pelvic area, ~12% of people have it in other areas or organs, which is known as extrapelvic endometriosis. Thoracic endometriosis, which is also classified as extrapelvic endometriosis, manifests with four distinct forms: catamenial pneumothorax, catamenial hemothorax, catamenial hemoptysis, or lung nodules. Catamenial pneumothorax is the most common clinical symptom of these; however, it is frequently neglected by clinicians and goes undiagnosed and untreated. As a result, it is critical to raise awareness of this medical condition among clinicians. Case presentation: The authors present a case report of a 34-year-old woman of reproductive age who had recurrent episodes of spontaneous pneumothorax during menstruation and underwent treatment with thoracoscopic surgery as well as gynaecological hormonal drugs including oral progesterone and dienogest throughout this time. Based on her symptoms, a catamenial pneumothorax caused by thoracic endometriosis was suspected. Clinical discussion: The clinical symptoms, pathogenesis, diagnosis, and treatment of Catamenial Pneumothorax are analyzed. Furthermore, the usage of gynaecological hormone medications in this condition has been discussed. The mechanisms of oral contraceptives and progestin-based medications are evaluated by comparing the patient’s treatment process, highlighting their pros and cons. Conclusions: Thoracoscopic surgery combined with postoperative gynaecological hormonal medications may be the most effective treatment for this issue. Several gynaecological hormonal medicines are available, each of which has its own set of pros and cons, and must be thoroughly evaluated as well as correctly tailored to the patient’s specific circumstances to have a positive therapeutic outcome.

Addition of progesterone to feminizing gender-affirming hormone therapy in transgender individuals for breast development: a randomized controlled trial

BackgroundFeminizing gender-affirming hormone therapy (GAHT) for transgender individuals traditionally includes estradiol and androgen deprivation. Research has demonstrated that breast size as a result of GAHT in transgender women is often limited. Therefore, transgender women often choose to undergo breast augmentation surgery. Progesterone is important for breast development in cisgender women during puberty. A potential role for progesterone in breast development in transgender women has not been investigated in a randomized controlled experimental set-up. The primary objective of this study is to explore the effects on breast volume of addition of oral progesterone to GAHT with estradiol in transgender women after vaginoplasty or orchiectomy. Secondary objectives include assessment of safety, satisfaction, mood, sleep and sexual pleasure.MethodsThis is a non-blinded, non-placebo, randomized controlled trial using a factorial design in adult transgender individuals assigned male sex at birth who have undergone GAHT for at least one year and underwent vaginoplasty or orchiectomy. The study design allows for rapid assessment of potential synergistic effects of various dose combinations of estradiol and progesterone on breast volume change: Ninety participants will be randomized into six groups of 15 subjects each, receiving either the baseline dose of estradiol, the baseline dose of estradiol and progesterone 200 mg daily, the baseline dose of estradiol and progesterone 400 mg daily, twice the baseline dose of estradiol, twice the baseline dose of estradiol and progesterone 200 mg daily or twice the baseline dose of estradiol and progesterone 400 mg daily, all for a duration of 12 months. The main study parameters include changes in breast volume as determined by 3D measurements. Participants will be followed-up with laboratory testing including serum progesterone concentrations as well as surveys for satisfaction, mood, sleep quality and sexual pleasure.DiscussionThis study will indicate whether progesterone is safe and of additional value with regard to breast volume change in transgender individuals receiving feminizing GAHT. The results of this study will be useful for innovation of feminizing GAHT.Trial registrationWHO International Clinical Trials Registry Platform: EUCTR2020-001952-16-NL; date of registration: 12 December 2020 https://trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2020-001952-16-NL.

SAT677 Use Of An Anti-obesity Medication In A Transgender Woman Pursuing Body Mass Index Requirements For Gender-affirming Surgery

Abstract Disclosure: J.M. Taormina: None. A.H. Gilden: None. S.J. Iwamoto: None. Introduction: Obesity prevalence is higher in transgender and gender diverse (TGD) adults compared to the general population. TGD people experience gender minority stress and disparities in lifestyle factors, socioeconomic status and medical comorbidities that likely contribute to excess weight. Gender-affirming hormone therapy (GAHT) has also been associated with increased body weight; oral estrogen with an antiandrogen is associated with increased fat mass and decreased lean mass. Many surgery centers enforce body mass index (BMI) requirements for gender-affirming surgeries (GAS) that limit access for TGD patients with obesity. The most effective and affirming weight management strategies for TGD patients have yet to be determined. Bariatric surgery has been identified as a treatment to address obesity prior to GAS; however, surgical weight loss can delay GAS for 3 years. While anti-obesity medications (AOMs) are effective, literature is needed supporting their use in TGD patients prior to GAS. Clinical Case: We report the case of a 40-year-old transgender woman with BMI 39.6 kg/m2, prediabetes, mixed hyperlipidemia, hypertension, non-alcoholic steatohepatitis (NASH) and congenital solitary kidney who presented for weight loss to qualify for gender-affirming bilateral breast augmentation. Her surgeon required a presurgical BMI &amp;lt;35.0 kg/m2. She had no prior GAS or bariatric procedures. She was taking intramuscular estradiol valerate, oral progesterone, spironolactone, and omeprazole without a history of prior AOM use. She was counseled on lifestyle modification, including recommendations for a reduced calorie diet, regular aerobic and resistance physical activity and sleep hygiene. Given history of prediabetes and NASH and superior mean weight loss with semaglutide compared to other FDA-approved AOMs, she was started on semaglutide 0.25 mg subcutaneously weekly with monthly dose escalation. In 3 months, she lost 17.7 kg or 13.9% total body weight with BMI 34.1 kg/m2. Complications addressed during treatment included acute kidney injury from poor water intake as a potential medication side effect; medication supply issues; limited engagement in physical activity due to lack of social safety, body dysmorphia and wish to limit upper body muscle mass for her desired body contour. Clinical Lessons: This case highlights (1) the need for increased access to affirming weight management services for TGD patients with obesity pursuing GAS and (2) the potential role of AOMs in assisting TGD patients in reaching presurgical BMI targets. Whether BMI requirements for GAS lead to improved surgical outcomes needs additional research. Perspectives on and the impacts of BMI requirements for GAS deserve exploration. Further studies are also needed to evaluate the needs of TGD patients in weight loss interventions and the effects of weight loss and AOMs on GAHT management. Presentation: Saturday, June 17, 2023