Should the trigger to oocyte retrieval interval be different in progestin-primed ovarian stimulation cycles?

RESEARCH QUESTION: Does the trigger to oocyte retrieval interval (TORI) affect oocyte maturation rates differently in progestin-primed ovarian stimulation (PPOS) and gonadotrophin-releasing hormone (GnRH) antagonist cycles? DESIGN: This was a retrospective cohort study. The interaction between the stimulation protocol and TORI was assessed in a linear mixed effects multivariable regression analysis with oocyte maturation rate as the dependent variable, and stimulation protocol (GnRH antagonist or PPOS), age (continuous), gonadotrophin type (FSH or human menopausal gonadotrophin), trigger (human chorionic gonadotrophin [HCG] or GnRH agonist), TORI (continuous) and days of stimulation (continuous) as the independent variables. Oocyte maturation rate was defined as number of metaphase II oocytes/number of cumulus-oocyte complexes retrieved. The maturation rate was calculated per cycle and treated as a continuous variable. RESULTS: A total of 473 GnRH antagonist and 205 PPOS cycles (121 conventional PPOS and 84 flexible PPOS) were analysed. The median (quartiles) female age was 36 (32-40) years. Of these cycles, 493 were triggered with HCG and 185 with a GnRH agonist. The TORI ranged between 33.6 and 39.1 h, with a median (quartiles) of 36.2 (36-36.4) hours. Maturation rates were similar between fixed PPOS, flexible PPOS and antagonist cycles (median 80%, 75% and 75%, respectively, P = 0.15). There was no significant interaction between the stimulation protocols and TORI for oocyte maturation. CONCLUSIONS: PPOS cycles do not seem to require a longer TORI than GnRH antagonist cycles.

Endometriosis and adenomyosis: shared pathophysiology.

Endometriosis and adenomyosis are closely related disorders. Their pathophysiologies are extremely similar. Both tissues originate from the eutopically located intracavitary endometrium. Oligoclones of endometrial glandular epithelial cells with somatic mutations and attached stromal cells may give rise to endometriosis if they travel to peritoneal surfaces or the ovary via retrograde menstruation and/or may be entrapped in the myometrium to give rise to adenomyosis. In both instances, the endometrial cell populations possess survival and growth capabilities conferred by somatic epithelial mutations and epigenetic abnormalities in stromal cells. Activating mutations of KRAS are the most commonly found genetic variant in endometriotic epithelial cells, whereas the adenomyotic epithelial cells almost exclusively bear KRAS mutations. Epigenetic abnormalities in the stromal cells of endometriosis and adenomyosis are very similar and involve an abnormal expression pattern of nuclear receptors, including the steroid receptors. These epigenetic defects give rise to excessive local estrogen biosynthesis by aromatase and abnormal estrogen action via estrogen receptor-ß. Deficient progesterone receptor expression results in progesterone resistance in both endometriosis and adenomyosis.

Adenomyosis: single-cell transcriptomic analysis reveals a paracrine mesenchymal-epithelial interaction involving the WNT/SFRP pathway.

OBJECTIVE: To assess the cellular and molecular landscape of adenomyosis. DESIGN: Single-cell analysis of genome-wide messenger RNA (mRNA) expression (single-cell RNA sequencing) of matched tissues of endometrium, adenomyosis, and myometrium using relatively large numbers of viable cells. SETTING: Not applicable. PATIENT(S): Patients (n = 3, age range 40-44 years) undergoing hysterectomy for diffuse adenomyosis. MAIN OUTCOME MEASURE(S): Definition of the molecular landscape of matched adenomyotic, endometrial and myometrial tissues from the same uterus using single-cell RNA sequencing and comparison of distinct cell types in these tissues to identify disease-specific cell populations, abnormal gene expression and pathway activation, and mesenchymal-epithelial interactions. RESULT(S): The largest cell population in the endometrium was composed of closely clustered fibroblast groups, which comprise 36% of all cells and seem to originate from pericyte progenitors differentiating to estrogen/progesterone receptor-expressing endometrial stromal- cells. In contrast, the entire fibroblast population in adenomyosis comprised a larger (50%) portion of all cells and was not linked to any pericyte progenitors. Adenomyotic fibroblasts eventually differentiate into extracellular matrix protein-expressing fibroblasts and smooth muscle cells. Hierarchical clustering of mRNA expression revealed a unique adenomyotic fibroblast population that clustered transcriptomically with endometrial fibroblasts, suggestive of an endometrial stromal cell population serving as progenitors of adenomyosis. Four other adenomyotic fibroblast clusters with disease-specific transcriptomes were distinct from those of endometrial or myometrial fibroblasts. The mRNA levels of the natural WNT inhibitors, named, secreted frizzled-related proteins 1, 2, and 4, were higher in these 4 adenomyotic fibroblast clusters than in endometrial fibroblast clusters. Moreover, we found that multiple WNTs, which originate from fibroblasts and target ciliated and unciliated epithelial cells and endothelial cells, constitute a critical paracrine signaling network in adenomyotic tissue. Compared with endometrial tissue, unciliated and ciliated epithelial cells in adenomyosis comprised a significantly smaller portion of this tissue and exhibited molecular evidence of progesterone resistance and diminished regulation of estrogen signaling. CONCLUSION(S): We found a high degree of heterogeneity in fibroblast-like cells in the adenomyotic uterus. The WNT signaling involving differential expression of secreted frizzled-related proteins, which act as decoy receptors for WNTs, in adenomyotic fibroblasts may have a key role in the pathophysiology of this disease.

Breast cancer treatment and ovarian function.

The aim of this study was to provide an update on ovarian function and the mechanisms of gonadal damage after exposure to chemotherapy in breast cancer survivors. The alkylating agents are toxic to both primordial and growing follicles. However, anti-metabolite drugs are more likely to destroy preantral and antral follicles. Younger patients are more likely to have a higher ovarian reserve, and therefore, more likely to retain some residual ovarian function after exposure to gonadotoxic regimens. However, there can be significant variability in ovarian reserve among patients of the same age. Furthermore, patients with critically diminished ovarian reserve may continue to menstruate regularly. Therefore age and menstrual status are not reliable indicators of good ovarian reserve and might give a false sense of security and result in an adverse outcome if the patient is consulted without considering more reliable quantitative markers of ovarian reserve (antral follicle count and anti-Müllerian hormone) and fertility preservation is not pursued. In contrast to well-documented ovarian toxicity of older chemotherapy regimens, data for newer taxane-containing protocols have only accumulated in the last decade and data are still very limited regarding the impact of targeted therapies on ovarian function.

Role and effectiveness of progestins in pituitary suppression during ovarian stimulation for assisted reproductive technology: a systematic review and a meta-analysis.

INTRODUCTION: Despite the many unknowns about its exact mechanism, progesterone and progestins are being successfully used to prevent luteinizing hormone (LH) surge during ovarian stimulation for assisted reproductive technology (ART). We will review progestin primed ovarian stimulation (PPOS) protocols in comparison with gonadotropin releasing hormone (GnRH) analogues and each other. EVIDENCE ACQUISITION: MEDLINE via PubMed; Cochrane Central Register of Controlled Trials (CENTRAL); Scopus; Web of Science were screened with keywords related to assisted reproductive technology, ovarian stimulation progesterone, GnRH analogue and progesterone in several combinations. Search period was from the date of inception of each database until 20 May 2022. EVIDENCE SYNTHESIS: Live birth or ongoing pregnancy rate per embryo transfer (ET) was similar in PPOS and GnRH antagonist cycles (RR=1.16, 95% CI: 0.93-1.44). Clinical pregnancy rate per ET was likewise similar (RR=1.12, 95% CI: 0.92-1.37). Miscarriage rate per pregnancy was similar with PPOS and GnRH antagonists in autologous cycles (RR=1.01, 95% CI: 0.65-1.55). Pooled analyses showed similar live birth rate between progestins and short GnRH agonist protocols (RR=1.01, 95% CI: 0.49-2.09), however, clinical pregnancy rates per ET were significantly higher with progestins (RR=1.31, 95% CI: 1.06-1.62). Miscarriage rate per pregnancy was similar with progestins (RR=0.82, 95% CI: 0.55-1.21). CONCLUSIONS: Progestins seem to be an efficient option for pituitary suppression during ovarian suppression, providing similar outcomes for stimulation and pregnancy. They can be especially beneficial for women for whom fresh ET is not considered.

Ischemic-Modified Albumin in Neonates with Congenital Heart Defects.

OBJECTIVES: Ischemia-modified albumin (IMA) is a new biochemical marker of ischemia. We aimed to search blood IMA levels in neonates with congenital heart defects. STUDY DESIGN: During the study period, patients diagnosed with congenital heart disease and newborns with a diagnosis of hyperbilirubinemia as a control group were included in the study. IMA level was analyzed using the IMA absorbance unit (ABSU) method. RESULTS: In total, 57 newborns with congenital heart disease requiring cardiac operation for the study group and 38 newborns for the control group were included. There was no difference between the two groups in terms of gender, mode of delivery, and weeks of gestation. The average IMA values in the control group were 0.19 ± 0.09 ABSU. The prepostoperative mean IMA values of the patient group were 0.22 ± 0.07 and 0.23 ± 0.07 ABSU, respectively. Comparison of the postoperative IMA with the mean of the control group was statistically significant. Preoperative and postoperative IMA values of patients who have died due to primary heart disease and surgical complications were 0.21 ± 0.07 (0.08-0.32) ABSU and 0.25 ± 0.06 (0.12-0.36) ABSU, respectively. IMA levels were not statistically different between the two groups. CONCLUSION: Hypoxia and ischemia in congenital heart disease in the newborn period both preoperatively and postoperatively were important in prognosis. IMA was higher in the postoperative group. Many comprehensive studies are important in terms of preventing complications and decreasing mortality and morbidity by commenting on prognosis. KEY POINTS: · IMA is a new biochemical marker of ischemia.. · In the literature, there are no reports about the relation between congenital heart defects and IM.. · The exposure of CHD patients to hypoxia/asphyxia in the preintra and postoperative periods cause neurologic deficits.

Outcomes of a GnRH Agonist Trigger Following a GnRH Antagonist or Flexible Progestin-Primed Ovarian Stimulation Cycle.

A suggested explanation for the pituitary-suppressive effects of progestin-primed ovarian stimulation cycles (PPOS) is pituitary luteinizing hormone (LH) depletion with progestin exposure during the follicular phase. The GnRH agonist (GnRHa) trigger releases endogenous LH from the pituitary, and if the LH depletion theory is correct, the response to the agonist trigger would be dampened in PPOS cycles. In this study, we compared the performance of the GnRHa trigger after PPOS and GnRH antagonist ovarian stimulation cycles. All women who underwent ovarian stimulation with the GnRH antagonist or flexible PPOS (fPPOS) and received a GnRH agonist trigger were eligible for inclusion. Outcomes included number of metaphase-II (MII) oocytes retrieved per cycle, rates of empty follicle syndrome, maturation, fertilization, blastulation, and cumulative clinical pregnancy per stimulation cycle. During the screening period, there were 166 antagonists and 58 fPPOS cycles triggered with a GnRH agonist. Groups were matched for potential confounders using propensity score matching. Progestin-downregulated cycles had 19% high mature oocyte yield (median: 14 vs. 19 MII oocytes, P = 0.03). Cumulative ongoing pregnancy or live birth rates were estimated after matching for transferred embryo count, and rates were similar between GnRH antagonist and fPPOS group (57.0% vs. 62.1%, P = 0.68). However, the number of remaining blastocysts was higher in the fPPOS group (median: 5.0 vs. 6.0, P < 0.001). LH levels were higher in fPPOS cycles compared to GnRH antagonist cycles up to the trigger day (P < 0.001). After the GnRHa trigger, fPPOS cycles were associated with a steeper LH surge compared with antagonist cycles (P = 0.02). Higher endogenous gonadotropin levels through the stimulation period and an LH surge of higher magnitude following a GnRHa trigger suggest a milder pituitary suppression by fPPOS, which needs to be confirmed in larger samples. It appears that progestins do not deplete pituitary LH reserves and a GnRHa trigger is usable after PPOS in women with high ovarian reserve.

Epidermal growth factor receptor-mutated lung adenocarcinoma diagnosed from endometrial polyp metastasis: A case report and literature review.

Endometrial metastasis from the lung primary remains is rare. Moreover, the literature only contains case reports of endometrial metastasis from the primary lung cancer. An 83-year-old female patient presented with postmenopausal uterine bleeding and anemia. Endometrial thickening was detected using transvaginal ultrasound and endometrial curettage was performed. Histopathology revealed adenocarcinoma infiltration on an endometrial polyp surface. On histologic examination, high-grade serous carcinoma and clear cell carcinoma diagnoses were initially considered. The tumor cells were immunohistochemically negative for Wilms' tumor 1 and wild-type for p53 expression; however, it was positive for Napsin A. Primary lung adenocarcinoma (LUAD) metastasis was also included in the differential diagnosis. Thyroid transcription factor 1 was positive, whereas paired box gene 8 (Pax8) was negative in tumor cells. Primary LUAD metastasis was diagnosed since a lung mass was radiologically confirmed. Furthermore, epidermal growth factor receptor-exon 19 mutation was detected by molecular analysis. In addition to the clinical and morphological features, this case report emphasizes the importance of multiple immunohistochemical panel applications for the correct diagnosis.

Effectiveness of the flexible progestin primed ovarian stimulation protocol compared to the flexible GnRH antagonist protocol in women with decreased ovarian reserve.

The aim of this retrospective cohort study was to compare the effectiveness of the new flexible progestin primed ovarian stimulation (fPPOS) protocol with the flexible gonadotropin-releasing-hormone antagonist (GnRH-ant) protocol in women with decreased ovarian reserve (DOR). Twenty-seven women who underwent fPPOS and 54 age-matched women who received GnRH-ant for pituitary suppression were included in the study. All women had DOR and underwent oocyte cryopreservation. Three-hundred IU/day FSH was started on cycle day 2-3 and 0.25 mg/day GnRH-ant or 10 mg/day medroxyprogesterone acetate was started when the leading follicle reached 14 mm or serum oestradiol level was ≥200 ng/mL. The median duration of stimulation, day of commencing pituitary suppression and duration of suppression were similar in both groups, with 8, 5, and 5 days, respectively. The median number of cumulus-oophorous complexes (4.0 vs 5.5), metaphase-two oocytes (3 vs 4), the total number of oocytes cryopreserved (3.0 vs 4.5), and oocyte maturation rates (0.67 vs 0.70) were similar between the fPPOS and GnRH-ant groups, respectively. There was one case of premature ovulation in the fPPOS group and none in the GnRH-ant group (p = 0.91). In conclusion, fPPOS may be used in women with DOR without compromising the number of oocytes retrieved and seems a viable alternative to the flexible GnRH-ant protocol.

Dual Trigger Compared with Human Chorionic Gonadotropin Alone and Effects on Clinical Outcome of Intracytoplasmic Sperm Injection.

BACKGROUND: This study compared outcomes of the standard 6000 IU human chorionic gonadotropin (hCG) trigger with a dual trigger comprised of 6000 IU hCG and 1 mg leuprolide acetate for final oocyte maturation in an intracytoplasmic sperm injection (ICSI) cycle. By convention, ICSI was performed in most cases at the clinic. MATERIALS AND METHODS: In this retrospective study, a total of 50 women were included in each arm. Participants were matched for age, indication and number of prior assisted reproduction technology (ART) cycles. Women at risk for ovarian hyperstimulation syndrome (OHSS) were excluded. A flexible gonadotropin releasing hormone (GnRH) antagonist protocol was used and final oocyte maturation was triggered when two leading follicles were >17 mm. Distribution of variables was evaluated visually with histograms. Continuous variables were defined by mean (standard deviation) or median (25th-75th percentile) depending on distribution characteristics. Categorical variables were defined by numbers and percentages. Continuous variables were compared between the groups with the t test or Mann-Whitney U test as appropriate. Categorical variables were compared by the chi-square test and its derivatives as appropriate. A two-sided P<0.05 indicated statistical significance. RESULTS: Both groups had similar antral follicle counts, median parity (0) and number of previous failed cycles (0). The median number of oocytes (8 vs. 7), metaphase-two oocytes (6 vs. 5.5), blastocysts (1 vs. 1), clinical pregnancy rates (CPR) (28% vs. 22%), ongoing pregnancy rates (OPR) (22% vs. 20%) and pregnancy rate per transfer (53.3% vs 53.8%) were similar between the dual trigger and hCG only groups, respectively. CONCLUSION: Dual trigger for oocyte maturation stimulation failed to improve the ICSI outcome.

Do live birth rate and obstetric outcomes vary between immediate and delayed embryo transfers following freeze-all cycles?

RESEARCH QUESTION: Do live birth rates (LBR), obstetric and perinatal outcomes vary between women who underwent frozen embryo transfer (ET) in the immediately subsequent menstrual cycle, and with those who underwent delayed frozen ET. DESIGN: Retrospective cohort study (n = 198) consisting of 119 women who underwent immediate transfer within 30 days of oocyte retrieval (OR) and 79 women who underwent delayed transfer which was performed after >30 days following OR. Either flexible antagonist or flexible progestin-primed ovarian stimulation protocols were started after a baseline ultrasonography on the second or third day of menstrual cycle. Only freeze all cycles were included in the study and all transfers were with hormonal endometrial preparation. Main outcome measures were LBR, birth weight, gestational day at birth and pregnancy complications. RESULTS: Peak estradiol level on trigger day (2746 vs 2081 pg/ml) and number of metaphase-two oocytes (13 vs 10) were significantly higher in the immediate transfer group. Clinical pregnancy rate per ET was similar between the groups (50.4% vs 44.3%). However, miscarriage rate per positive pregnancy was significantly higher (12.3% vs 31.1%) while LBR per ET was significantly lower (42.9% vs 26.6%) in the delayed transfer group. Median gestational age at delivery were 267.5 and 268 days in the immediate and delayed transfer groups. Median birthweight was significantly higher in the delayed transfer group (3520 vs 3195 g). Adjusted analyses also suggest similar LBR with immediate and delayed transfer. CONCLUSION(S): Frozen ET in the immediate menstrual cycle and delayed ET, after a freeze all strategy did not show significant difference in terms of LBR after adjustment. Obstetric and perinatal outcomes of frozen ET in the immediate menstrual cycle appear reassuring.

Adenomyosis pathogenesis: insights from next-generation sequencing.

BACKGROUND: Adenomyosis, characterized by the presence of islands of endometrial tissue surrounded by hypertrophic smooth muscle cells within the myometrium, is one of the most challenging uterine disorders in terms of diagnosis and management. Adenomyosis presents with pelvic pain, excessive uterine bleeding, anemia and infertility. The relative contributions of abnormal endometrial tissue and myometrial smooth muscle cells to the development and growth of adenomyosis are not well understood. Moreover, there is continuing debate on the origins of adenomyosis; two competing theories describe the invagination of basal endometrium into the myometrium or the metaplastic differentiation of remnant endometrial stem/progenitor cells within the myometrium. OBJECTIVE AND RATIONALE: A recent series of next-generation sequencing (NGS) studies have provided the best scientific evidence thus far regarding the cellular origins of adenomyosis and the contributions of new signaling pathways to its pathogenesis, survival, and growth. These seminal studies on endometrium, adenomyosis and endometriosis demonstrate or support the following key points. (i) Mutations of KRAS map to both intracavitary endometrial tissue and proximally located adenomyotic samples, supporting the invagination theory of pathogenesis. Driver mutations found in smooth muscle cells of uterine fibroids are absent in adenomyosis. (ii) KRAS and other less frequent mutations are limited to endometrial-type epithelial cells. They are also observed in endometriosis, indicating that the disease process in adenomyosis is similar to that in endometriosis and distinct from that of uterine fibroids. (iii) Activating mutations of KRAS stimulate specific pathways to increase cell survival and proliferation and are associated with progesterone resistance in adenomyosis. Together, these findings suggest that distinct cell populations in eutopic endometrial tissue play key roles in the etiology of adenomyosis. Dependence on ovarian steroids and ovulatory cycles for disease severity is a unique feature of adenomyosis. In this context, common patterns of aberrant gene expression have been reported both in adenomyosis and endometriosis. These include pathways that favor increased estrogen biosynthesis, decreased estradiol metabolism, a unique estrogen receptor beta (ESR2)-driven inflammatory process, and progesterone resistance due to decreased progesterone receptor expression. Since adenomyosis exhibits a uniquely estrogen-driven inflammatory process and progesterone resistance, we discuss the interactions between these molecular characteristics and signaling pathways induced by the newly discovered KRAS mutations. SEARCH METHODS: We conducted a comprehensive search using PubMed for human and animal studies published until 2020 in the following areas: adenomyosis, endometriosis, endometrium, NGS, whole-exome sequencing, whole-genome sequencing, RNA sequencing, targeted deep sequencing, epigenetics, driver mutation, KRAS, progesterone resistance, estrogen action and steroid production. OUTCOMES: Targeted deep sequencing analyses of epithelial cells in adenomyosis and adjacent basalis endometrial glands demonstrated recurring KRAS mutations in both cell types. This finding suggests that adenomyosis originates from basalis endometrium. Epithelial cells of the endometrium, adjacent adenomyosis and co-occurring endometriosis also share identical KRAS mutations. These findings suggest both adenomyosis and endometriosis are oligoclonal tissues that arise from endometrial cell populations carrying a specific driver mutation that most commonly affects the KRAS gene. WIDER IMPLICATIONS: Adenomyosis usually follows an event such as pregnancy that has disrupted the integrity of the endometrial-myometrial junction followed by repetitious menstrual episodes that increase the likelihood of the entrapment of the basalis endometrium within the myometrium. Glandular epithelial cells carrying KRAS mutations and located within the deep crypts of basalis endometrium may become entrapped and invade myometrial tissue to give rise to adenomyosis. Evidence suggests that KRAS mutations may be responsible, in part, for previously observed phenomena such as prolonged cell survival and progesterone resistance in adenomyosis.

Endometrial thickness is not predictive for live birth after embryo transfer, even without a cutoff.

OBJECTIVE: To investigate the predictive value of endometrial thickness (EMT) for live birth when a lower threshold of EMT is not employed for embryo transfer (ET). DESIGN: Retrospective study SETTING: Academic assisted reproduction center PATIENT(S): All women who underwent fresh or frozen-thawed ET at the Koç University Hospital Assisted Reproduction Unit between October 2016 and August 2019 INTERVENTION(S): After ruling out endometrial pathology, blastocyst transfer was planned regardless of the EMT in the absence of increased serum progesterone level on the trigger day in fresh embryo transfer cycles or before commencing progesterone treatment in artificially prepared frozen-thawed ET cycles. MAIN OUTCOME MEASURE(S): The primary outcome was live birth. Live birth and miscarriage rates per ET were stratified according to fresh and frozen-thawed ET cycles for each millimeter of endometrial thickness. Receiver operator characteristic curve analyses were performed to evaluate the predictive value of EMT for live birth. RESULT(S): A total of 560 ET cycles, 273 fresh and 287 frozen-thawed, were included in the study. Relevant patient characteristics as well as EMTs were similar between women who achieved a live birth and those who did not after fresh or frozen-thawed ET. There was no linear association between EMT and live birth or miscarriage rates. Area under the curve values for EMT to predict live birth after fresh, frozen-thawed, and all ETs were 0.56, 0.47, and 0.52, respectively. CONCLUSION(S): Our results showed that the EMT was not predictive for live birth in either fresh or frozen-thawed ET cycles. Once intracavitary pathology and inadvertent progesterone exposure were excluded, women with thinner EMTs should not be denied their potential for live birth because it is comparable to that of those with thicker EMT.

The Comparison of Fixed and Flexible Progestin Primed Ovarian Stimulation on Mature Oocyte Yield in Women at Risk of Premature Ovarian Insufficiency.

While gonadotrophin releasing hormone (GnRH) antagonists have been the standard of pituitary suppression during ovarian stimulation for ART, progestin primed ovarian stimulation (PPOS) has emerged as an alternative. Progestins can be started simultaneously with gonadotrophins (fixed PPOS) or later in the cycle depending on follicle growth (flexible PPOS). However, the flexible and fixed PPOS regimens have not been directly compared as of yet. This was a retrospective cohort study including women with diminished ovarian reserve who underwent oocyte cryopreservation. All women underwent ovarian stimulation with a fixed 300 IU daily dose of FSH. The primary outcome was the number of MII oocyte retrieved per cycle. Secondary outcome measures included the incidence of premature LH surge (>10ng/mL) and number of follicles larger than 14mm on the day of maturation trigger. During the screening period 2 out of 97 cycles were cancelled before oocyte retrieval, one in each group yielding an overall cancelation rate of 2%. Among women who had oocyte retrieval, 65 underwent flexible and 30 fixed PPOS. At baseline women on fixed and flexible PPOS had similar age (mean difference: -2.17 years, 95% CI: -4.46 to 0.11) and serum AMH levels (mean difference: 0.10 ng/mL, 95% CI: -0.24 to 0.47). Slight imbalances between the groups were rectified with propensity score matching using age and AMH levels. The incidence of premature LH surge (RR: 1.47, 95% CI: 0.51 - 5.27, p = 0.50), follicle count larger than 14mm on hCG day (RR: 1.14, 95% CI: 0.93 - 1.42, p = 0.22), number of MII oocytes retrieved (RR: 0.95, 95% CI: 0.79 - 1.15, p = 0.61) were similar between flexible and fixed PPOS. The rate of no oocyte retrieval was same between the groups (0.0% both) but no formal estimation was possible. Flexible and fixed PPOS regimens had no appreciable differences regarding MII oocyte yield and the incidence of premature LH surges. Cycles without oocyte retrieval were rare in both groups and ultrasonographic parameters of gonadotropin response were similar. Our study suggests the performances of either progestin regimen are comparable in this group of women.

Progestins for pituitary suppression during ovarian stimulation for ART: a comprehensive and systematic review including meta-analyses.

BACKGROUND: Progestins are capable of suppressing endogenous LH secretion from the pituitary. Progestins can be used orally and are less expensive than GnRH analogues. However, early endometrial exposure to progestin precludes a fresh embryo transfer (ET), but the advent of vitrification and increasing number of oocyte cryopreservation cycles allow more opportunities for using progestins for pituitary suppression. OBJECTIVE AND RATIONALE: This review summarizes: the mechanism of pituitary suppression by progestins; the effectiveness of progestins when compared with GnRH analogues and with each other; the effect of progestins on oocyte and embryo developmental potential and euploidy status; and the cost-effectiveness aspects of progestin primed stimulation. Future research priorities are also identified. SEARCH METHODS: The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE via PubMed, the Web of Science and Scopus were screened with a combination of keywords related to ART, progesterone, GnRH analogue and ovarian stimulation, in various combinations. The search period was from the date of inception of each database until 1 April 2020. Only full text papers published in English were included. OUTCOMES: Overall, the duration of stimulation, gonadotrophin consumption and oocyte yield were similar with progestins and GnRH analogues. However, sensitivity analyses suggested that progestins were associated with significantly lower gonadotrophin consumption than the long GnRH agonist protocol (mean difference (MD) = -648, 95% CI = -746 to -550 IU) and significantly higher gonadotrophin consumption than the short GnRH agonist protocol (MD = 433, 95% CI = 311 to 555 IU). Overall, live birth, ongoing and clinical pregnancy rates per ET were similar with progestins and GnRH analogues. However, when progestins were compared with GnRH agonists, sensitivity analyses including women with polycystic ovary syndrome (risk ratio (RR) = 1.27, 95% CI = 1.06 to 1.53) and short GnRH agonist protocols (RR = 1.14, 95% CI = 1.02 to 1.28) showed significantly higher clinical pregnancy rates with progestins. However, the quality of evidence is low. Studies comparing medroxyprogesterone acetate, dydrogesterone and micronized progesterone suggested similar ovarian response and pregnancy outcomes. The euploidy status of embryos from progestin primed cycles was similar to that of embryos from conventional stimulation cycles. Available information is reassuring regarding obstetric and neonatal outcomes with the use of progestins. Despite the lower cost of progestins than GnRH analogues, the mandatory cryopreservation of all embryos followed by a deferred transfer may increase cost per live birth with progestins as compared to an ART cycle culminating in a fresh ET. WIDER IMPLICATIONS: Progestins can present an effective option for women who do not contemplate a fresh ET, e.g. fertility preservation, anticipated hyper responders, preimplantation genetic testing, oocyte donors, double stimulation cycles.

The impact of dysmenorrhea and premenstrual syndrome on academic performance of college students, and their willingness to seek help.

OBJECTIVE: To reveal the characteristics and prevalence of dysmenorrhea and Premenstrual syndrome (PMS) among college students and to investigate their impact on their academic performance. MATERIALS AND METHODS: This cross-sectional study was conducted between December 2017 and January 2018 at Koç University, Turkey. An online survey that included multiple-choice and short paragraph questions was prepared. Female students aged between 18 and 27 years were invited with an email to provide online informed consent to proceed to the survey. RESULTS: The final analysis included 352 students. The prevalence of dysmenorrhea was found as 90.1%. Fifty-six percent of the participants reported lower academic performance during menstruation. However, only 32.8% of the students with dysmenorrhea presented to the gynecology clinic. The prevalence of PMS alone and with dysmenorrhea was 71.3% and 65.9%, respectively. The most common symptom among those who reported affected academic performance was depression (prevalence of 27.5%). However, only 19.9% of students with PMS consulted a healthcare professional. CONCLUSION: Symptoms of dysmenorrhea and PMS are generally neglected by students. Quality of life can be affected more than estimated. Considering the reluctance to disclose menstrual disorders, health care providers should be aware of them and ask women about their symptoms during routine visits.

There is a cycle to cycle variation in ovarian response and pre-hCG serum progesterone level: an analysis of 244 consecutive IVF cycles.

We aimed to answer one key question, that was not previously addressed as to whether serum progesterone (P4-hCG day) and its co-variates (estradiol (E2-hCG day) and the number of retrieved oocytes) of a given cycle can be predictive of the subsequent cycle when both cycles are consecutive and comparable for the stimulation protocol, gonadotropin dose and duration of stimulation. We analyzed such 244 consecutive (< 6 months) IVF cycles in 122 patients with GnRH agonist long protocol and found that P4, E2 and the number of retrieved oocytes significantly vary between the two cycles. Although P4 increased (ranging from 4.7 to 266.7%) in the 2nd cycle in 61 patients, E2 and the number of retrieved oocytes, which are normally positively correlated with P4 paradoxically decreased in the 41% and 37.7% respectively, of these same 61 patients. When a similar analysis was done in the 54 out of 122 patients (44.3%) in whom serum P4 was decreased in the 2nd cycle, the mean decrease in P4 was - 34.1 ± 23.3% ranging from - 5.26 to - 90.1%. E2 and the number of retrieved oocytes paradoxically increased in the 42.3% and 40.7% of these 54 patients respectively. P4 remained the same only in the 7 (5.7%) of these 122 patients. These findings indicate that late follicular phase serum P4 may change unpredictably in the subsequent IVF cycle. The changes are not always necessarily proportional with ovarian response of previous cycle suggesting that growth characteristics and steroidogenic activities of antral cohorts may exhibit considerable cycle to cycle variations.

Subcutaneous versus vaginal progesterone for vitrified-warmed blastocyst transfer in artificial cycles.

RESEARCH QUESTION: Does subcutaneous progesterone provide similar live birth or ongoing pregnancy rates as vaginal progesterone in frozen embryo transfer (FET) cycles? DESIGN: Retrospective cohort study (n = 214 women), consisting of 107 women who received subcutaneous progesterone for FET in artificial cycles and 107 women receiving vaginal progesterone who were matched for age and treatment cycle rank acted as controls. All embryos were transferred in an artificial cycle with 6 mg per day oral oestradiol valerate starting on the second or third day of the menstrual cycle. Patients underwent transvaginal ultrasound on the 10th day of priming, and subcutaneous progesterone (50 mg/day) or vaginal progesterone (180 mg/day) was started if the endometrium had a trilinear pattern regardless of its thickness. Embryo transfer was carried out on the sixth day of progesterone administration. Oestradiol and progesterone were continued until a negative pregnancy test, 10 days after the transfer, or until the completion of 10th gestational week. Main outcome measures were live birth or ongoing pregnancy rates. RESULTS: Baseline characteristics were similar between the groups. Positive pregnancy test rates (64.5% versus 58.9%; P = 0.40; RR 1.1; 95% CI 0.89 to 1.35), live birth or ongoing pregnancy rates (39.3% versus 35.5%; P = 0.57; RR 1.11; 95% CI 0.78 to 1.56) and miscarriage rates (29% versus 25.5%; P = 0.68; RR 1.08; 95% CI 0.76 to 1.55) were similar in the subcutaneous progesterone and vaginal progesterone groups, respectively. CONCLUSIONS: Subcutaneous progesterone seems to be an effective alternative to vaginal progesterone in patients undergoing FET. Randomized controlled trials comparing it with different progesterone preparations, routes and protocols are needed to better define its role.

Impact of the sexual abstinence period on the production of seminal reactive oxygen species in patients undergoing intrauterine insemination: A randomized trial.

AIM: To evaluate whether the duration of sexual abstinence has impact on oxidative stress in semen samples. METHODS: Oxidative reaction was tested for different levels of reactive oxygen species (ROS) by nitro blue tetrazolium assay in 90 patients with the diagnosis of unexplained or male factor infertility that were grouped into 3 groups as 0-2 (group 1), 3-4 (group 2) and >4 days (group 3) of duration of sexual abstinence. Subsequently, the remaining semen was prepared by gradient method for ovarian stimulation and intrauterine insemination (IUI) cycles to compare pregnancy rates in terms of different levels of ROS and different abstinence periods. RESULTS: Increased staining pigment intensity was related to higher level of ROS in >4 days' group as compared to groups 0-2 and 3-4 days (70% vs 43.3% and 50%, P = 0.013 and P = 0.014, respectively). Pregnancy rates significantly decrease with prolonged abstinence period (26.7%, 16.7% and 6.7% in groups 1, 2 and 3, respectively, P = 0.039). Progressive motile sperm count after gradient method of sperm preparation for IUI was highest in 3-4 days of abstinence period than shorter and longer abstinence groups. CONCLUSION: Longer duration of sexual abstinence causes higher oxidative stress and decreases pregnancy rates in IUI cycles.