Low Serum Progesterone Levels Research Articles

P-662 Effect of rescue-dose progesterone in patients with low serum progesterone levels on the day of embryo transfer in frozen embryo transfer cycles

Abstract Study question What is the effect of rescue-dose progesterone in patients with low serum progesterone on the day of embryo transfer in frozen embryo transfer cycles? Summary answer In patients with low serum progesterone on the day of embryo transfer, rescue dose progesterone results in significantly higher clinical pregnancy rates. What is known already Frozen embryo transfer (FET) has become more common lately with many centers utilizing hormone replacement therapy (HRT) to electively plan embryo transfer with improved compliance rates. Serum progesterone level on the day of embryo transfer is a very simple, useful investigation which can be used as a predictor of clinical outcomes. Patients with lower progesterone levels (<5ng/ml) are associated with lower clinical pregnancy and ongoing pregnancy rates. Progesterone levels of > 10ng/ml are considered optimal by various studies. There is limited data on the efficacy of progesterone supplementation in patients with low progesterone levels. Study design, size, duration This study was conducted to assess the effect of rescue dose progesterone in patients with low serum progesterone levels on the day of embryo transfer in patients with HRT-FET cycles. This was a retrospective study and data was collected from prospectively maintained records of patients undergoing treatment at Miracles IVF and fertility center, Gurgaon, India between December, 2021 to November, 2023. Participants/materials, setting, methods All were HRT-FET cycles with vaginal progesterone supplementation of 800 mg/day. Serum progesterone levels were done on day of embryo transfer and if 5-10 ng/ml, rescue dose progesterone (100 mg intramuscular) was given. Single blastocyst embryo transfer was done. Inclusion criteria: 1.Age 25-35 years, 2.Endometrial thickness >7.5mm on day of start of progesterone. Exclusion criteria: 1.Transfer day progesterone <5ng/ml, 2. BMI > 30, 3. Previously failed embryo transfer The primary outcome was clinical pregnancy rate. Main results and the role of chance A total of 121 patients underwent 165 cycles during the study period with 93 patients included in the study after fulfilling the inclusion and exclusion criteria. 35 patients (37.6%) received rescue dose progesterone (RD group) and remaining 58 patients (62.4%) received no rescue dose (NRD group) as per their serum progesterone levels. All these patients were followed as per protocol and serum bhcg was done after 14 days of embryo transfer. Patients with positive values were monitored till positive clinical pregnancy. Biochemical pregnancy rates were 20 out of 35 (57.1%), 35 out of 58 ( 60.3%) and 55 out of 93 ( 59.1%) in RD group, NRD group and overall respectively. Clinical pregnancy rates were 18 out of 35 (51.4%), 34 out of 58 ( 58.6%) and 52 out of 93 ( 55.9%) in RD group, NRD group and overall respectively. RD group had significantly improved outcomes in terms of clinical pregnancy rates which were comparable to NRD group Limitations, reasons for caution Limitations, reasons for caution: Ours was a single center retrospective study with limited sample size. Though, our study revealed comparable outcome between the two groups but large volume multicenter studies are needed for making conclusive recommendations. Wider implications of the findings This study provides an insight into the role of serum progesterone levels on the day of embryo transfer. Rescue progesterone dosage for patients with sub-optimal serum progesterone levels may help in achieving similar clinical pregnancy rates and improving overall outcomes. Trial registration number not applicable

P-297 Intensive luteal phase support regimens for endometriosis and adenomyosis patients in hormone replacement therapy frozen embryo transfer cycles – subcutaneous or intramuscular progesterone treatment?

Abstract Study question Does subcutaneous (SC) progesterone treatment provide progesterone levels comparable to intramuscular (IM) progesterone when using a cut-off level of 118nmol/l(37.1ng/ml) during intensive luteal phase support? Summary answer As part of an intensive luteal phase support regimen SC progesterone provides higher P4 levels compared to the use of IM progesterone. What is known already Low serum progesterone (P4) levels in HRT-FET cycles negatively impact reproductive outcomes. This effect is particularly pronounced in patients with endometriosis and adenomyosis, due to reduced progesterone actions and progesterone resistance at the receptor level. Therefore, higher serum P4 levels are required to maintain an optimal reproductive outcome during HRT-FET. A P4 cut-off of 118nmol/l (37.1ng/ml) or above has been suggested, a level four times higher than that of the non-endometriosis patient. To achieve high P4 levels, intensive luteal phase support (LPS) regimen has been suggested. This includes vaginal progesterone administration and additional treatment via IM, SC or rectal administration. Study design, size, duration This cohort study includes 380 HRT-FET cycles in endometriosis/adenomyosis patients. Patients were treated from January 2016 until August 2019 with one type of intensive LPS regimen (n = 262) and from January 2000 to January 2023 with two different LPS regimens depending on whether serum P4 levels were lower or higher than 118nmol/l on the day of blastocyst transfer (BT) (n = 118). P4 was measured in a standardised manner. Participants/materials, setting, methods Patients received treatment in a public university affiliated fertility clinic. Endometrial priming involved the use of estradiol followed by vaginal progesterone. From the fourth day of progesterone, one of the following intensive LPS regimens were added: A) 50mg IM progesterone, B) 25mg SC progesterone BD, or C) 25mg SC progesterone BD plus 400mg rectal rescue progesterone BD if P4<118nmol/l. Blastocyst transfer (BT) and P4 measurement were performed on the sixth day of progesterone administration. Main results and the role of chance The overall pregnancy rate, live birth rate (LBR) and total pregnancy loss rates for the whole cohort were 63%, 41% and 36%, respectively. For the three groups A, B and C the mean serum P4 levels on the day of BT were 103.1 ±44.4nmol/l, 170.5 ±62.9nmol/l and 90.1 ±21.5nmol/l. In Group A (IM) 67% of patients (176/262) had P4 levels <118 nmol/l whereas only 36% (43/118; p < 0.001) had P4 <118 nmol/l in the groups of patients treated with SC progesterone (Group B and C). The unadjusted LBR was not significantly different between groups, 39%, 39%, 51%, (p = 0.32). However, a sub-group analysis showed that comparing patients with serum P4 levels <118nmol/l on the BT day in Group A with patients with P4 levels <118nmol/l in Group C a significantly higher LBR was found if intensive LPS included both SC and rectally administered progesterone compared to IM progesterone, only: 51% (44/86) vs 34% (59/176), p = 0.03. The adjusted odds ratio for live birth was 2.04 (95% CI [1.00, 4.16], p = 0.05) after adjusting for age, vitrification day 5 or 6, blastocyst quality and numbers of blastocysts transferred, if intensive LPS included SC and rectal rescue compared to IM, only in patients with P4 levels <118nmol/l. Limitations, reasons for caution This cohort study was conducted over two different time periods. Single embryo transfer was performed only during the later period. The bio-pharmacological profiles of SC and IM progesterone differ, which can influence serum P4 levels. However, in the present study, all blood samples were collected in a standardised manner. Wider implications of the findings This study is the first to report reproductive outcomes following different intensive LPS regimens in a cohort of endometriosis/adenomyosis patients. To increase reproductive outcomes, individualisation of the HRT-FET cycle may be beneficial and, importantly, rectal progesterone administration can be used as a rescue regimen in addition to SC progesterone. Trial registration number Due to the retrospective study design no ethical approval was needed.

P-437 Are serum progesterone levels predictive for reproductive outcomes in artificial cycles if individualized luteal phase support is only administered when progesterone is below 5 ng/ml?

Abstract Study question Do serum progesterone levels predict reproductive outcomes in artificial cycles when individualized luteal phase support is administered only if progesterone falls below 5 ng/ml? Summary answer The low 5 ng/ml progesterone threshold appears to be sufficient for the patient not to require additional progesterone injections when progesterone is above 5 ng/ml. What is known already Serum progesterone (P4) level is negatively associated with ongoing pregnancy rate (OPR) and miscarriage rate in artificially prepared frozen embryo transfer (FET) cycles using standard micronized vaginal progesterone (MVP) for luteal phase support. Individualized luteal support is considered a successful rescue strategy in cycles with low serum progesterone levels eliminating the effect of P4 levels on outcome. Cut-off levels for this rescue strategy range from 8.8 to 10 ng/ml. Study design, size, duration A retrospective single-centre cohort study including a total of 1,016 vitrified-warmed single blastocyst transfers performed at a tertiary fertility centre between October 2021 and December 2022. Blastocysts of ≥ 3CC Gardner score were eligible for vitrification on day 5 or day 6 (Vit-kit or Vit-kit NX, FuijiFilm). Embryos were warmed and subsequently transferred on the same day which was day 5 in the cycle, regardless if the embryo was vitrified on day 5 or day 6. Participants/materials, setting, methods We included 595 patients undergoing an artificially prepared embryo transfer (ET) cycle using MVP 800mg BID for luteal phase support. Serum P4 levels were determined on the day of ET with the initiation of additional injections of subcutaneous P4 from the day after ET in patients with P4 < 5ng/ml. Primary endpoint was OPR. Multivariable logistic regression was performed to correct for confounders. Generalized estimating equations (GEE) models were fitted for primary and secondary outcomes. Main results and the role of chance OPR was comparable for the 3 groups: 9/40 (22.5%) for patients with P4 <5ng/ml, 64/275 (23.3%) for patients with P4 5-10 ng/ml and 181/701 (25.8%) for patients with P4 >10ng/ml (p = 0.377). No significant association between P4 category and likelihood for OPR was found after adjusting for confounders. Early clinical miscarriage rate was significantly different between the 3 groups: 5/40 (12.5%) in patients with P4 <5ng/ml, 26/275 (9.5%) with P4 5-10ng/ml and 37/701 (5.3%) with P4 >10ng/ml (P = 0.005). Limitations, reasons for caution Higher clinical miscarriage rate in cycles with a P4 level under 10 ng/ml questions the efficacy of rescue progesterone in cycles with a low P4. The patient population also exists of a subgroup of PGT-a tested cycles which was not included as a potential confounder in this analysis. Wider implications of the findings The 5 ng/ml P4 threshold appears to be sufficient for the patient not to require additional P4 injections when P4 is above 5 ng/ml. Consequently, a significantly lower proportion of cycles would need to be supplemented with rescue progesterone; 3.8% versus 31.3% for the 10 ng/mL cut off. Trial registration number ONZ-2023-0223

#129 : The Ratio of Luteal Phase Serum Progesterone and Estradiol Can be Used to Predict Pregnancy in Frozen Embryo Transfer Cycles

Background and Aims: Low serum progesterone (P) levels on day of embryo transfer (ET) and luteal phase have been associated with poorer pregnancy outcome. This study aimed to know if serum estradiol (E2) and P levels during mid and late luteal phase are related with ongoing pregnancy. Method: The serum E2 and P levels from mid luteal phase (5 days after ET) to the day of the [Formula: see text]-hCG check (11 days after ET) in both fresh and frozen embryo transfer (FET) cycles was investigated between January 2019 and December 2021. Eligible patients were reproductive aged women with a normal uterus. Single blastocyst transfer cycles were included. Estradiol valerate (2 mg/bid) was started from day 3 of cycle as hormone replacement and vaginal micronized P (400 mg/bid) was started 5 days before ET in all FET cycles. The 2-degree polynomial fitted data were analysed and logistic linear model and ROC analysis were performed to assess E2 and P4 polynomial coefficients as a predictive test for ongoing pregnancy. Results: A total of 388 patients were included. The overall pregnancy rate was 43.8% and 31.3% for FET and fresh ET, respectively. On day 5 post ET, the serum P levels correlated significantly with ongoing pregnancy and live birth rates, especially in FET cycles. The ROC curve showed that there is a significant day 5 post ET predictive value of serum P4/E2 levels for pregnancy rate, being the AUC (95% CI) = 0.596 (0.539–0.653) for the combination of both fresh and FET cycles; and 0.611 (0.548–0.674) for FET cycles, with best cut-off values of 0.079 and 0.077, respectively. Conclusion: Serum P levels in mid and late luteal phase days are associated with pregnancy outcome both in fresh and frozen ET cycles. Ongoing pregnancies can be predicted using the day 5 post ET serum P4/E2 levels.

Effect of different levels of serum progesterone on day of frozen ET on clinical outcome

BackgroundProgesterone (P4) plays a critical role in a natural menstrual cycle. It is an essential hormone to have successful embryo implantation into the endometrium.ObjectiveIn the current study, we compared the clinical outcomes of patients with different levels of P4 on embryo transfer day and aimed to determine the optimum threshold for P4 in the luteal phase.Material and methodsWe performed a prospective cohort study on 100 patients who were referred to the Taleqani Infertility Treatment Institute to undergo frozen embryo transfer (FET). Endometrial preparation was programmed using an estrogen (E2) and progesterone supplement. FET was carried out 3 days after administration of the first dosage of progesterone. We measured serum progesterone levels on embryo transfer day. Clinical pregnancy was the main investigated outcome. We used a parametric receiver operating characteristic curve (ROC) to determine the best-cut points of P4 on embryo transfer day.ResultsOverall, the average endometrial thickness was 7.9 ± 0.2 mm. We observed no association between endometrial thickness and clinical pregnancy (P value = 0.719). The mean number of the transferred embryos in all investigated cycles was 1.5 ± 0.5, and 80.0% of the transferred embryos were high quality (high and medium level). The average progesterone level in cycles with clinical pregnancy was 17.2 ± 3.3 ng/mL. It was only 13.4 ± 9.4 in patients without clinical pregnancy. The observed difference was statistically significant (P value = 0.032). The estimated AUC for the drawn ROC curve was 0.71 indicating a high predictive value.ConclusionThe current study demonstrated that high and low serum progesterone (P4) levels on embryo transfer day were associated with reduced clinical outcomes following blastocyst transfer during IVF/ICSI. However, more studies with large sizes are required in this regard.

P-330 Is 17 alpha hydroxyprogesterone caproate an adequate alternative to improve reproductive outcomes in artificially prepared frozen embryo transfer cycles (FET)?

Abstract Study question Is 17 alpha-hydroxyprogesterone caproate an adequate option to improve reproductive outcomes in patients with low serum progesterone (P4) level the day of frozen embryo transfer? Summary answer Patients with serum P4<10ng/ml may benefit with the addition of intramuscular 17alpha-hydroxyprogesterone caproate injections, and have similar ongoing pregnancy rates than patients with serum P4≥10ng/ml. What is known already Indications of embryo cryopreservation have expanded in the last years. Recently published papers highlight that low serum progesterone levels before frozen embryo transfers decrease pregnancy and live birth rates and increase miscarriage rates, even in cases of euploid embryos transfers. Other studies have published a beneficial effect with the addition of daily subcutaneous progesterone injections in patients with low serum progesterone levels around the time of embryo transfers. In Argentina subcutaneous progesterone has been available since October 2022, not before. 17alpha-hydroxyprogesterone caproate is a synthetic progestin used for luteal phase support and approved for the prevention of preterm birth. Study design, size, duration This prospective cohort study was performed between May 2021 and August 2022 in 114 patients undergoing 138 FET cycles after an artificial endometrial preparation with estradiol valerate 4mg daily and micronized vaginal progesterone 200mg, three times daily. Participants/materials, setting, methods Patients <50 years old with triple-layer endometrium ≥7mm underwent frozen embryo transfer. Progesterone was measured immediately before the embryo transfer. Group 1 (N = 47): P4>10ng/ml; Group 2 (N = 46): P4<10ng/ml with addition of 17 alpha-hydroxyprogesterone caproate after embryo transfer; Group 3 (N = 46): P4<10ng/ml without addition of 17 alpha-hydroxyprogesterone. Primary endpoint was to compare ongoing pregnancy rate beyond week 12 between the three groups. Secondary endpoints were pregnancy rate and miscarriage rate. Main results and the role of chance Parameters were comparable between the groups in terms of age, body mass index, estradiol, P4 levels at the beginning of endometrial preparation and number of embryos transferred. Ongoing pregnancy rate was: Group 1 = 38.3% (18/47); Group 2 = 39.1% (18/46); Group 3 = 28.3% (13/46) (p = 0,337). Pregnancy rate was: Group 1 = 48,9% (23/47); Group 2 = 50% (23/46); Group 3 = 50% (23/46) (p>0,05). Miscarriage rate was: Group 1 = 21.73% (5/23), Group 2 = 26.1% (6/23) and Group 3 = 43.47% (10/23) (p = 0,208). Although there were no significant differences between the groups, both, Group 1 and Group 2, had higher ongoing pregnancy rates and lower miscarriage rates than group 3. This is probably due to the limited sample size. Limitations, reasons for caution The main limitation of our study is the sample size and the fact that most of the embryos were not genetically evaluated before being transferred, which would eliminate a variable that could interfere with the results obtained. Only micronized progesterone and 17alpha-hydroxyprogesterone caproate were studied. Wider implications of the findings The addition of exogenous 17alpha-hydroxyprogesterone caproate on the embryo transfer day may improve ongoing pregnancy rates in cases of low serum progesterone levels, being a simple and safe strategy to individualize luteal phase support when no other form of progesterone administration is available. Trial registration number NOT APPLICABLE

P-500 Relationship of midluteal serum progesterone levels and pregnancy outcomes after day-3 embryo-transfer(ET) in hormonal replacement therapy (HRT) cycles with intramuscular progesterone: a prospective cohort study

Abstract Study question Does midluteal(day-9 of progesterone) serum progesterone level in HRT cycles with intramuscular progesterone affect the clinical pregnancy rate (CPR)/early miscarriage rate(MR) and live birth rate(LBR)? Summary answer Midluteal serum progesterone between 32.2-43.7ng/ml results in significantly greater CPR versus that with lower/higher levels and significantly greater LBR compared to that with lower levels. What is known already Evidence points to low serum progesterone levels at the time of FET being associated with lower ongoing pregnancy rates. Recently, the relation of midluteal serum progesterone levels in HRT cycles with vaginal progesterone as luteal phase support (LPS) has been elaborated indicating better pregnancy outcomes with an optimum range of serum progesterone/higher levels. There is no data establishing the association of pregnancy outcomes with midluteal serum progesterone levels when intramuscular progesterone is used as LPS in HRT cycles. Study design, size, duration A prospective cohort study conducted between December 2019-March 2022 at a tertiary centre with 196 patients(204 cycles), both-autologus(AO)-56.3% and donor oocytes(DO)- 43.6%: fresh ET-16.6% and frozen ET(FET)-83.3% with similar ICSI, vitrification and ET protocols(2/3 Grade A day-3 embryos). CPR, early MR (≤13 weeks miscarriage/clinical pregnancy) and LBR (≥28 weeks, LBs/ETs) were compared. Serum progesterone was measured on the morning of day-5 post-ET(day 9th from the start of progesterone). Most patients delivered at the same institute. Participants/materials, setting, methods Patients were non-smokers with normal hysteroscopy. Oral estradiol 6-8mg was initiated from Day 1-2 (for 10-17 days). When ET ≥ 7mm and serum progesterone <1ng/ml, intramuscular progesterone 100mg/day was started (daily till day-4 post-ET, then every 3rd day till week 8). Vaginal progesterone gel was added from day 5 post-ET till week 10. Serum progesterone levels were categorized in tertiles. Chi-square, t-tests and multiple regression analysis was used for statistical analysis. Two-tailed P<.05 indicated statistical significance. Main results and the role of chance Mean age was 34.76±5.36 years with a mean BMI 26.4±4.38kg/m2 Overall, CPR was 106/204(51.9%), LBR 78/204(38.2%) and early MR 28/106(26.4%) Midluteal serum progesterone levels ranged from 11.1-261ng/ml and were divided into tertiles(T) T1<32.0ng/ml(n = 68),T2 32.2-43.7ng/ml(n = 68),T3 >43.7ng/ml (n = 68) Median progesterone levels of T1,T2,T3 were 27.7ng/ml(Interquartile range [IQR] 7.0), 38.4ng/ml (IQR 5.0) and 51.2ng/ml (IQR 12.6) respectively. Mean age and mean BMI was not significantly different across the tertiles P=.27, P=.20 respectively CPR was significantly different across T1 32/68(47%),T2 45/68(66.1%)and T3 29/68(42.6%) P=.014. CPR was significantly more in T2 versus T1 and T3, (OR:2.2, 95%CI:1.1-4.4 P =.02) and (OR:2.6,95%CI:1.3-5.3, P=.006), respectively. T3 versus T1, P =.60 LBR was also significantly different across the tertiles [T1 20/68(29.4%), T2 34/68(50%),T3 24/68(35.3%) P=.03] LBR in T2 was significantly more than in T1(OR: 2.4,95% CI:1.2-4.9, P=.02). There was no significant difference betweenT3 versus T1 and T2 versus T3, P=.46, P=.08, respectively. Early MR wasn’t significantly different across T1 12/32(37.5%), T2 11/45(24.4%) and T3 5/29(17.2%), P=.18 Serum progesterone levels were not significantly affected by age r = 0.0257, P=.71 or BMI r = 0.0097, P=.89 Multivariate logistic regression showed that age affected CPR after adjusting for BMI, midluteal serum progesterone levels, origin of oocytes, fresh ET/FET(AOR 0.92: 95% CI:0.86-0.98, P=.01). Limitations, reasons for caution This is a single centre study with limited sample size. Including the measurement of serum progesterone at the time of ET would have given a better perspective of the patient specific behavior of progesterone as LPS. Larger studies with different LPS protocols are needed to validate the results. Wider implications of the findings In HRT cycles with intramuscular progesterone, an optimum midluteal serum progesterone level is related to better pregnancy outcomes. Factors causing the wide variation of progesterone levels need to be evaluated so as to individualize the dose. Identifying the appropriate time frame for optimising the midluteal progesterone levels should be explored. Trial registration number not applicable

Cytokine and hormone status of women of reproductive age with pulmonary tuberculosis

Objective. To study the levels of cytokines (γ-interferon, tumor necrosis factor α (TNF-α)) and hormones (cortisol, prolactin, estradiol, progesterone, testosterone) in blood serum of women of reproductive age with pulmonary tuberculosis (TB).Materials and methods. We studied the serum levels of γ-interferon, tumor necrosis factor α, cortisol, prolactin, estradiol, progesterone, testosterone in women 18-45 years old with newly diagnosed pulmonary TB (n = 47) compared with the same indices in women without TB and with no previous TB (n = 35).Results. Women with pulmonary TB had higher levels of cortisol (cutoff point, 196.1 nmol/L, AUC 0.75, Se 85.1 %, Sp 70.6 %) and prolactin (cutoff point, 486, 1 mEU/L, AUC 0.69, Se 59.6%, Sp 73.5%) and lower serum progesterone levels (cutoff point 3.9 nmol/L, AUC 0.71, Se 73.9%, Sp 64.7%) than women without TB. The study of the levels of γ-interferon and TNF-α showed less diagnostic significance of the parameters, and there was a slight increase in the levels of both cytokines in women with pulmonary TB.Conclusion. Changes in cytokine-hormone status in women with TB can both reflect mechanisms of anti-infective defense and be a consequence of the development of the disease.

Individualized luteal phase support based on serum progesterone levels in frozen-thawed embryo transfer cycles maximizes reproductive outcomes in a cohort undergoing preimplantation genetic testing.

Low serum progesterone concentration on frozen embryo transfer (FET) day in hormone replacement therapy (HRT) cycles results in lower reproductive outcomes. Recent studies showed the efficiency of a "rescue protocol'' to restore reproductive outcomes in these patients. Here, we compared reproductive outcomes in HRT FET cycles in women with low serum progesterone levels who received individualized luteal phase support (iLPS) and in women with adequate serum progesterone levels who underwent in vitro fertilization for pre-implantation genetic testing for structural rearrangements or monogenic disorders. This retrospective cohort study included women (18-43 years of age) undergoing HRT FET cycles with pre-implantation genetic testing at Montpellier University Hospital between June 2020 and May 2022.A standard HRT was used: vaginal micronized estradiol (6mg/day) followed by vaginal micronized progesterone (VMP; 800 mg/day). Serum progesterone was measured after four doses of VMP: if <11ng/ml, 25mg/day subcutaneous progesterone or 30mg/day oral dydrogesterone was introduced. 125 HRT FET cycles were performed in 111 patients. Oral/subcutaneous progesterone supplementation concerned 39 cycles (n=20 with subcutaneous progesterone and n=19 with oral dydrogesterone). Clinical and laboratory parameters of the cycles were comparable between groups. The ongoing pregnancy rate (OPR) was 41.03% in the supplemented group and 18.60% in the non-supplemented group (p= 0.008). The biochemical pregnancy rate and miscarriages rate tended to be higher in the non-supplemented group versus the supplemented group: 13.95% versus 5.13% and 38.46% versus 15.79% (p=0.147 and 0.182 respectively). Multivariate logistic regression analysis found that progesterone supplementation was significantly associated with higher OPR ​​ (adjusted OR = 3.25, 95% CI [1.38 - 7.68], p=0.007). In HRT FET cycles, progesterone supplementation in patients with serum progesterone concentration <11 ng/mL after four doses of VMP significantly increases the OPR.

VERY HIGH SERUM PROGESTERONE LEVELS ON THE DAY OF EMBRYO TRANSFER DO NOT HAVE AN IMPACT ON OUTCOMES IN ARTIFICIALLY PREPARED FROZEN EMBRYO TRANSFER CYCLES

Low serum progesterone (P4) levels on the day of embryo transfer (ET) decrease the ongoing pregnancy rates in artificial cycles for frozen embryo transfer (FRET). It is not known whether very high P4 levels may be inducing any effect on clinical outcomes. Objective of this study is to determine whether there is an upper limit for serum P4 levels on the day of ET above which clinical outcomes are affected in artificially prepared FRET cycles.

Polycystic ovarian syndrome with endometrial hyperplasia and uterine fibroids treated with homoeopathy: A case report

Introduction: Any circumstance that alters the balance of oestrogen and progesterone leads to excessive, prolonged estrogenic stimulation, or preventing the counteracting effects of progesterone causing various pathological conditions in the reproductive system, as a result. Women with polycystic ovarian syndrome (PCOS) have mostly anovulatory cycles and low serum progesterone levels. Endometrial hyperplasia is most often due to excess oestrogen without progesterone. The clinical significance of chronic oestrogen secretion is an increased risk of endometrial hyperplasia. A striking feature of uterine fibroids (UFs) is their dependency on the ovarian oestrogen and progesterone. Existing treatments are mostly directed at the symptoms but not at the syndrome itself. Case Summary: A patient suffering from PCOS, with Endometrial Hyperplasia and multiple UFs, was successfully treated with the homoeopathic medicine Pulsatilla nigricans. Repeat ultrasonography showed normal endometrial thickness, no hyperechoic or hypoechoic lesions in uterus and no ovarian PCOS morphology after treatment. Thus, the usefulness of homeopathic medicines for the treatment of multi-morbid pathologies related to reproductive system of women is demonstrated.

Endometriosis patients benefit from high serum progesterone in hormone replacement therapy–frozen embryo transfer cycles: a cohort study

Research questionWhat is the optimal serum progesterone cut-off level in patients with endometriosis undergoing hormone replacement therapy frozen embryo transfer (HRT-FET) with intensive progesterone luteal phase support? DesignA cohort study, including 262 HRT-FET cycles in 179 patients all diagnosed with endometriosis either by laparoscopy or by ultrasound in patients with visible endometriomas. Pre-treatment consisted of 42 days of oral contraceptive pills and 5 days’ wash-out, followed by 6 mg oral oestrogen daily. Exogenous progesterone supplementation with vaginal progesterone gel 90 mg/12h commenced when the endometrium was 7 mm or thicker. From the fourth day of vaginal progesterone supplementation, patients also received intramuscular progesterone 50 mg daily. Blastocyst transfer was scheduled for the sixth day of progesterone supplementation. ResultsThe overall positive HCG, live birth (LBR) and total pregnancy loss rates were 60%, 39% and 34%, respectively. The optimal progesterone cut-off level was 118 nmol/l (37.1 ng/ml) defined as the maximum of the Youden index. The unadjusted LBR was significantly higher in patients with progesterone measuring 118 nmol/l or above compared with patients with progesterone measuring less than 118 nmol/l (51% [44/86] versus 34% [59/176], P = 0.01), whereas the adjusted odds ratio for a live birth was 2.1 (95% CI 1.2 to 3.7) after adjusting for age, body mass index, blastocyst score, blastocyst age, quality and number of blastocysts transferred. ConclusionsSerum progesterone levels above 118 nmol/l (37.1ng/ml) resulted in significantly higher LBR compared with lower serum progesterone levels, suggesting that a threshold for optimal serum progesterone exists.

P-579 The effect of serum progesterone level on ET Day and the efficacy of rescue progesterone treatment on ongoing pregnancy rates with artificial FET cycles

Abstract Study question To evaluate serum progesteron level on ET day during FET cycles with a vaginal progesterone tablet plus weekly twice IM progesteron; to determine the efficacy of resque sc progesteron treatment Summary answer Resque daily sc progesterone treatment can improve PRs. The measurement of progesterone on ET day may create a chance to resque treatment on ET day. What is known already Successful implantation requires a suitable decidualized endometrium combined with a good quality embryo. The secretory phase of endometrium induced by progesterone is one of the most crucial steps for a proper implantation process and continuation of pregnancy. Recently, with improved cryopreservation techniques, Frozen–thawed embryo transfer (FET) has commonly used all over the world due to several reasons. Programmed- artificial FET cycles are different in terms of luteal phase because endogenous corpus luteum is absent. Therefore, programmed- artificial FET require hormone replacement treatment including estradiol and progesterone. Study design, size, duration We prospectively designed this multi-centric cohort study (NCT04769401) and carried out this study at IVF center of Acibadem Health Group and Bezmialem University Hospital and between February 2021 and September 2021. A total of 238 programmed-artificial FETs, carried out by two expert gynecologists (P.O. and C.F.) were evaluated. Participants/materials, setting, methods Estrofem was orally started. At 14 days of estrofem, Progesterone was started (100 mg vaginal progesterone tablet two times per day and 250 mg IM hydroxyprogesterone caproate weekly twice). Serum progesterone level were analysed at ET day and two days later. 25 mg/d of SC progesterone daily was given to patients with low serum progesterone levels at ET day and ET was performed on the same day. Main results and the role of chance Of all transfers, 77.2% (127/222) resulted in CP. Although there was no statistically significant difference with regard to CPR, OPR and miscarriage between groups (55,4% vs 61,5%, P = 0.4; 78,2% vs 72,5%, P = 0.5; 21,8/% vs 27,5%, P = 0.5; respectively progesterone levels on ET day ≥10 ng/ml and &amp;lt;10 ng/ml) ongoing PR was higher and misscarriage was lower in patients with serum progesterone levels on ET day ≥10 ng/ml. 84% (n = 54) of patients with low serum progesterone level on ET day reached adequate progesterone level with resque sc progesterone treatment (≥10 ng/ ml). 90% (36/40) of PRs in patient with serum progesterone levels &amp;lt;10 ng/ml on ET day was in patient with reaching adequate serum progesterone level with resque daily sc progesterone treatment. Age, number of previous IVF attempts and the embryo flash position at 1 minutes after ET were significantly lower in patients who conceived (p = 0.002, p = 0.016, p = 0.025, respectively). Limitations, reasons for caution The limitation of our study is not to present live birth rate. Wider implications of the findings The study demonstrated that adequate progesterone level on ET day is reached in 70,7% with the combination of vaginal progesterone tablet plus 250 mg of IM hydroxyprogesterone caproate. Patients with low progesterone level can achieve similar PR when adequate progesterone level was reached with resque sc progesterone treatment. Trial registration number NCT04769401

P-640 Impact of adding oral dydrogesterone (OD) in patients with low serum progesterone (P) levels in artificially prepared frozen embryo transfer cycles (FET-HRT)

Abstract Study question In case of low serum P on the day of FET (PFET), does the addition of OD to micronized vaginal progesterone (MVP) normalise reproductive outcomes? Summary answer In case of low serum PFET, adding OD results in ongoing pregnancy rates (OPR) comparable to those of patients who had normal serum PFET. What is known already Low serum PFET is associated with increased rates of early pregnancy loss (EPL) and reduced live birth rates in FET HRT cycles. While adding subcutaneous P injections to vaginal progesterone has been shown to normalize clinical outcomes in case of low serum PFET, it is unknown whether adding OD has a similar effect. Study design, size, duration This is a retrospective, single-centre cohort study in a tertiary IVF-clinic. 694 unique patients who had a single blastocyst transfer in an HRT cycle were included. As soon as an endometrial thickness of ≥ 6.5mm was reached following estradiol valerate priming, MVP (400mg,twice daily) was started, followed by FET on the 6thday of MVP. All patients underwent serum P measurement just prior to FET. Serum PFET was analysed using a validated electrochemiluminescence immunoassay (Cobas 6000®,Roche). Participants/materials, setting, methods Clinical outcomes of patients with normal serum PFET(≥8,8ng/dl) following the routine MVPsupplementation were compared with those of patients with low serum PFET(&amp;lt;8,8ng/dl) in whom OD(30mg TID) was added from FET onwards. Primary outcome was OPR, defined as a vital intra-uterine pregnancy at 8 weeks. EPL was defined as biochemical pregnancy loss or early miscarriage. A multivariate regression model was developed adjusting for age, BMI, endometrial thickness, embryo quality and estradiol level. Main results and the role of chance Mean age in the MVP-only versus the MVP+OD group was 34.6(±4.2) and 33.6(±4.3) years, respectively (p = 0.01). No other statistically significant differences were seen among both groups for BMI, endometrial thickness nor embryo quality. A normal serum PFET level was observed in 547/694 (78.8%) of patients, who continued MVP as planned, whereas a low serum PFET level was detected in 147/694 (21.2%) patients who received additional OD supplementation next to MVP from the day following FET onwards. The mean serum PFET level was 14.6 (±5.8) ng/ml in the MVP-only group and 7.0(±1.8) ng/ml in the MVP+OD group. The OPR was comparable between both groups: 40.8% for MVP only versus 40.0% for MVP+OD (p = 0.86). The biochemical pregnancy rates were 55.0% and 60.5% (p = 0.23) and the EPL rates were 14.4% and 21.1% (p = 0.05) in the MVP-only group vs. the MVP+OD group, respectively. Multivariate logistic regression analysis indicated that OPR was not associated with the investigated approaches (OR 0.92, SD 0.18, CI 0.63-1.35, p = 0.68). Only embryo quality was significantly associated with OPR (OR 3.03, SD 1.11, CI 1.48-6.21, p = 0.002). Limitations, reasons for caution The main limitation is the retrospective nature of this study with the risk of unmeasured confounder bias. While OPR is a less robust outcome parameter compared to LBR, LBR data will be presented once available. Wider implications of the findings Additional OD supplementation in patients with low P gives rise to comparable OPRs as observed in patients with normal P. Prospective studies are required to identify the individualized luteal phase support strategy that combines optimal LBR and low EPL rates. Trial registration number Not Applicable

O-245 Clinical factors associated with low serum progesterone on the day of frozen blastocyst transfer in hormonal replacement therapy cycles

Abstract Study question Which factors are associated with low serum progesterone (P) levels on the day of frozen embryo transfer (FET), in hormonal replacement therapy (HRT) cycles? Summary answer Body Mass Index (BMI), parity, and non-European geographic origin are factors associated with low serum P levels on the day of FET in HRT cycles. What is known already While the detrimental impact of low serum P concentrations on HRT-FET outcomes is unanimously recognized, the factors accounting for P levels disparities among patients receiving the same luteal phase support treatment remain to be elucidated, in order to help clinicians predicting which subgroups of patients would benefit from a tailored P supplementation. Study design, size, duration Observational cohort study with 915 patients undergoing HRT-FET at a tertiary care university hospital, between January 2019 and March 2020. Participants/materials, setting, methods Patients undergoing single autologous blastocyst FET under HRT using exogenous estradiol and vaginal micronized progesterone for endometrial preparation. Women were only included once during the study period. The serum progesterone level was measured in the morning of the FET, in a single laboratory. Independent factors associated with low serum P levels (defined as ≤ 9.8 ng/mL, according to a previous published study) were analyzed using univariate and multivariate logistic regression models. Main results and the role of chance The live birth rate was 31.5% (288/915) in the overall population. Two hundred and twenty-six patients (24.7%) had a low serum P level, on the day of the FET. Univariate analysis showed that BMI (p &amp;lt; 0.001), parity (p = 0.001), non-European geographic origin (p = 0.001), and the duration of infertility (p = 0.018) were significantly associated with low serum P levels. Moreover, the proportion of active smokers was significantly lower in the “low P concentrations” group (p = 0.002). After multivariate analysis, BMI (OR 1.06 95%CI [1.02-1.11], p = 0.002), parity (OR 1.31 95%CI [1.04-1.65], p = 0.024), non-European geographic origin (OR 1.67 95%CI [1.19-2.35], p = 0.003), and active smoking (OR 0.43 95%CI [0.21-0.85], p = 0.016) remained independent factors associated with serum P levels ≤ 9.8 ng/mL. Limitations, reasons for caution The main limitation of our study is linked to its observational design. Extrapolation of our results to other laboratories, or other routes and/or doses of administering progesterone also needs to be validated. Wider implications of the findings There is urgent need for future research on clinical factors affecting P concentrations to help clinicians predicting which subgroups of patients would benefit from individualized luteal phase support. More data are also needed on the underlying mechanisms explaining the relationship between patients’ characteristics and serum P levels in HRT-cycles. Trial registration number NA

P-669 The impact of luteal phase support on pregnancy outcomes in relation to serum progesterone levels on the day of frozen embryo transfer in natural cycles

Abstract Study question Is luteal phase support (LPS) beneficial in low and normal serum progesterone (P) levels the day of frozen embryo transfer (FET) in natural cycles (NC)? Summary answer LPS in case of low serum P on the day of NC-FET results in similar pregnancy rates as compared to patients with normal P levels. What is known already The use of FET cycles has increased exponentially in recent years. Endometrial preparation in FET cycles can be achieved either in a natural cycle, a stimulated cycle or in an artificial cycle (AC). There is increasing evidence that proper serum P levels around the time of FET are important in AC and NC. Recent studies in AC have shown that enhanced progesterone supplementation in case of low serum P levels could reduce early pregnancy loss rates and normalize live birth rates. Whether this rescue strategy could also be beneficial in NC-FET has not been investigated in detail. Study design, size, duration A retrospective study was conducted at a tertiary university-based referral hospital encompassing 459 unique patients who had a NC-FET with or without hCG trigger from November 2020 onwards. Only patients who had an in-house validated serum P measurement (Cobas 6000®,Roche) on the day of FET were included. Blastocyst transfer was performed 6 days after a spontaneous luteinizing hormone (LH) peak or 7 days after hCG administration. Ongoing pregnancy rate (OPR) was the primary outcome. Participants/materials, setting, methods Outcomes were compared in patients with low serum P (&amp;lt;10ng/dl) levels, who received LPS from the day of FET onwards (group 1) and patients with normal serum P (≥10ng/dl) levels (group 2). Group 2 was subdivided into patients who did not received LPS (group 2a) and patients who did (group 2b), as by practitioner’s choice. Multivariable regression analysis was performed adjusting for age, BMI, endometrial thickness, rank of FET, embryo quality and indication for treatment. Main results and the role of chance Mean ages were 31.8 years (group 1) and 33.3 years (group 2, p = 0.004). BMI was significantly lower in group 2 (23.7 kg/m2) compared to group 1 (26.7 kg/m2, p &amp;lt; 0.001). Indication for treatment, menstrual cycle length, anti-Mullerian hormone (AMH) levels and parity were comparable between both groups. An hCG ovulation trigger was administered in 26.0% of the cycles in group 1 and 20.4% in group 2 (p = 0.28). Endometrial thickness was equal in both groups (8.3mm, p = 0.84). In group 1, 40.3% of the patients had a transfer of a top quality embryo as compared to 46.3% in group 2 (p = 0.33). Positive hCG rate (54.6%, 64.0% and 65.0% for group 1, 2a and 2b respectively, p = 0.26) and miscarriage rate per positive hCG (2.4%, 9.2% and 6.7% for group 1,2a and 2b respectively, p = 0.37) were comparable between groups. OPR per started cycle was similar between groups (46.8%, 55.4% and 55.6% for group 1, 2a and 2b respectively, p = 0.37). Multivariable logistic regression analysis showed no relationship between OPR and the three different groups (p = 0.13). A significant association was observed between OPR and patient age at embryo cryopreservation. Limitations, reasons for caution Although only patients were included who had serum P levels on the day of FET measured by a standardized in-house assay, the results of the study are limited by the retrospective nature and its associated bias. Confirmation of the results should be obtained in prospective studies. Wider implications of the findings Luteal phase deficiency was observed in only 16.8% of patients in our study population. Administration of LPS in patients with low serum P levels on the day of FET could rescue pregnancy outcomes. However, starting LPS when serum P levels are normal appears to have no added value. Trial registration number not applicable

O-217 Associations between endometrial stem cells quantities, serum levels of progesterone and estradiol and expression of their respective receptors in endometrial tissue during the mid-luteal phase

Abstract Study question Is the percentage of endometrial stem cells linked to serum progesterone, serum estradiol, and their receptors expression in human endometrium during the mid-luteal phase? Summary answer We found an association between CD117+ endometrial stem cells and serum progesterone, estradiol, as well as with the expression of their receptors in the endometrium. What is known already Various types of stem cells including NOTCH1+ and CD117+ stromal cells have been found in the endometrium. Their quantities have been hypothesised to fluctuate with the menstrual cycle and to have a link with endometrial receptivity. It has been well established that progesterone and estradiol play a crucial role in the preparation of the endometrium for implantation and the expression of their receptors also varies with the menstrual cycle. Nonetheless, the relationship between stem cells and other established markers of endometrial receptivity, such as the sex hormones signaling system, constitutes a novel field of research. Study design, size, duration The present observational study included 87 women aged 26-56 (mean 39.5 years old) undergoing in-vitro fertilisation and for whom a peripheral blood sample and an endometrial biopsy were obtained during the mid-luteal phase (LH + 7) of a natural cycle. Immunohistochemical (IHC) markers for NOTCH1 (E-AB-12815, Elabscience), CD117 (CD117/c-Kit/SCF-Receptor RB-9038-RQ, Epredia), progesterone (PR) and estrogen receptors (ER) (1-PR026-07, 1-ES006-07, Quartett) were used to stain endometrial tissue. The investigation was carried out between March 2020 and January 2022. Participants/materials, setting, methods Serum progesterone and estradiol were measured via electrochemiluminescence using Cobas e411 analyser (Roche Diagnostics, Germany) on the day of obtaining the endometrial biopsy. Stem cells (count and percentage) and the expression of hormone receptors (6-point scale) were determined using ImageJ. Stem cells percentage was compared between groups with high and low progesterone (analogously for estradiol) using Wilcoxon signed-rank test. To assess the link between stem cell percentages and receptor expression, Spearman correlation was used. Main results and the role of chance The mean percentage of positively stained NOTCH1 endometrial stromal stem cells was 0.13 ± 0.29% and CD117+ cells was 0.034 ± 0.039%. The hormone serum levels ranged from 0.2 to 60 ng/mL (median of 14.9 ng/mL) for progesterone and from 12 to 1985 pg/mL (median of 135.6 pg/mL) for estradiol. While the quantities of the two stem cell types demonstrated a positive correlation with each other (R = 0.379, p &amp;lt; 0.001), the percentage of NOTCH1+ stem cells showed no difference between the studied serum hormone levels (p &amp;gt; 0.05), nor revealed a relationship with the expression of their receptors (p &amp;gt; 0.05). In contrast, the amount of CD117+ cells differed significantly between patients with high and low serum progesterone (cutoff 14.9 ng/mL, p = 0.001) and estradiol levels (cutoff 135.6 pg/mL, p = 0.019). Furthermore, the quantity of stem cells positive for CD117 correlated positively with the two hormone receptor levels in the endometrium – PR (R = 0.277, p = 0.019) and ER (R = 0.318, p = 0.007). Limitations, reasons for caution A limitation of the study was the sample size. These findings should be confirmed using a larger population. In addition, confounding variables such as the immunological profile of the tissue should also be taken into account. Wider implications of the findings This study shows that certain endometrial stem cell types (CD117+) but not others (NOTCH1+) are associated with sex hormone signaling during the mid-luteal phase. This relationship highlights the role these cells play in preparing the endometrium for embryo implantation and their quantity might be an indirect indicator of endometrial receptivity. Trial registration number not applicable

Female sex hormones and symptoms of obstructive sleep apnea in European women of a population-based cohort.

BackgroundThe prevalence of obstructive sleep apnea is higher in women after menopause. This is suggested to be a result of an altered sex hormone balance but has so far not been confirmed in a population-based study.ObjectiveTo investigate whether serum concentration of estrogens and progesterone are associated with the prevalence of sleep apnea symptoms in middle-aged women of the general population.MethodsWe analyzed data from 774 women (40–67 years) from 15 study centers in seven countries participating in the second follow-up of the European Community Respiratory Health Survey (2010–2012). Multiple logistic regression models were fitted with self-reported symptoms of sleep apnea as outcomes and serum concentrations of various estrogens and progesterone as predictors. All analyses were adjusted for relevant covariates including age, BMI, education, study center, smoking habits, and reproductive age.ResultsAmong all included women, a doubling of serum concentrations of estrone and progesterone was associated with 19% respectively 9% decreased odds of snoring. Among snorers, a doubling of the concentrations of 17β-estradiol, estrone and estrone 3-sulfate was associated with 18%, 23% and 17% decreased odds of breathing irregularly, and a doubling of the progesterone concentration was further associated with 12% decreased odds of waking up suddenly with a chocking sensation. Other evaluated associations were not statistically significant.ConclusionsMiddle-aged women with low serum estrogen and progesterone levels are more likely to snore and report symptoms of obstructive sleep apnea.

Low Luteal Serum Progesterone Levels Are Associated With Lower Ongoing Pregnancy and Live Birth Rates in ART: Systematic Review and Meta-Analyses.

Progesterone plays a key role in implantation. Several studies reported that lower luteal progesterone levels might be related to decreased chances of pregnancy. This systematic review was conducted using appropriate key words, on MEDLINE, EMBASE, and the Cochrane Library, from 1990 up to March 2021 to assess if luteal serum progesterone levels are associated with ongoing pregnancy (OP) and live birth (LB) rates (primary outcomes) and miscarriage rate (secondary outcome), according to the number of corpora lutea (CLs). Overall 2,632 non-duplicate records were identified, of which 32 relevant studies were available for quantitative analysis. In artificial cycles with no CL, OP and LB rates were significantly decreased when the luteal progesterone level falls below a certain threshold (risk ratio [RR] 0.72; 95% confidence interval [CI] 0.62–0.84 and 0.73; 95% CI 0.59–0.90, respectively), while the miscarriage rate was increased (RR 1.48; 95% CI 1.17–1.86). In stimulated cycles with several CLs, the mean luteal progesterone level in the no OP and no LB groups was significantly lower than in the OP and LB groups [difference in means 68.8 (95% CI 45.6–92.0) and 272.4 (95% CI 10.8–533.9), ng/ml, respectively]. Monitoring luteal serum progesterone levels could help in individualizing progesterone administration to enhance OP and LB rates, especially in cycles without corpus luteum.Systematic Review Registration https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=139019, identifier 139019.

Influence of serum progesterone levels on the inflammatory response of female dogs with visceral leishmaniosis

The aim of this study was to evaluate the histopathological changes to the mammary gland that occur in female dogs with visceral leishmaniosis and to correlate the findings with the parasite load, inflammatory cell profile in mammary tissue and serum progesterone levels. For this, 20 adult female dogs that were naturally infected with Leishmania infantum, not spayed, not pregnant and free from mammary tumors were used. They were divided into two groups: G1 (n = 9) with high serum progesterone levels and G2 (n = 11) with low serum progesterone levels. The parasite load and the immunophenotype of leukocytes infiltrated into the mammary tissue (CD3, CD4, CD8 and MCA874) were evaluated using the immunohistochemical technique. In the mammary gland, chronic inflammatory infiltrate was mainly found in G1, sometimes associated with granulomatous inflammation, higher parasite load and higher density of cells immunolabeled for CD3, CD4, CD8 and MCA874. A significant positive correlation (p < 0.05) was observed between the parasite load and the immunolabeled leukocytes. The influence of the serum progesterone level in the mammary gland of infected female dogs can contribute to the maintenance of an immunosuppressive cell profile and favor the persistence of the parasite in this site.