Effect of intraovarian platelet-rich plasma injection on IVF outcomes in women with poor ovarian response: the PROVA randomized controlled trial.

STUDY QUESTION: Does intraovarian platelet-rich plasma (PRP) injection increase the number of mature oocytes obtained after controlled ovarian stimulation (COS) in young women with poor ovarian response (POR) undergoing IVF? SUMMARY ANSWER: Intraovarian PRP injection procedure does not improve mature oocyte yield after COS in women less than 38 years old with an established IVF history of POR. WHAT IS KNOWN ALREADY: POR is frequently encountered among the infertile population and the number of women seeking infertility treatment related to POR is increasing. Effective treatment options for this patient population to conceive with autologous oocytes are lacking. Case series and cohort studies suggest that intraovarian PRP injection may improve follicular recruitment in women with premature ovarian insufficiency (POI) and POR, yet robust randomized studies have not been performed to date to determine the clinical utility of this intervention. STUDY DESIGN, SIZE, DURATION: This was a multi-center randomized controlled trial (RCT) conducted at university-affiliated reproductive centers in the USA and Turkey, between January 2020 and November 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients who met inclusion criteria (<38 years old, two or more prior cycles with <3 oocytes retrieved; and without single gene disorders, prior ovarian surgery, endometriomas, BMI >35 kg/m2, or severe male factor infertility) were randomized to either the PRP or control group. Patients in both groups subsequently underwent COS, oocyte retrieval, ICSI, preimplantation genetic testing for aneuploidy (PGT-A), and single euploid embryo transfer. Number of metaphase II (MII) oocytes obtained was the primary outcome. Secondary outcomes included ovarian reserve tests (antral follicle count [AFC] and anti-Müllerian hormone [AMH]), blastocyst and euploid blastocyst yields, and sustained implantation. The study was powered to detect a difference of one mature oocyte obtained at oocyte retrieval. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 83 patients met inclusion criteria and were randomized to receive autologous intraovarian PRP injection (n = 41) or to no intervention (n = 42). No significant differences were observed in number of MII oocytes retrieved per cycle (2.8 ± 2.4 vs 3.1 ± 3.3 in PRP vs control, respectively; P = 0.9), blastocysts (1.0 ± 1.3 vs 1.3 ± 2.1, P = 0.8), or euploid blastocysts (0.8 ± 1.1 vs 0.9 ± 1.6; P = 0.5). Similarly, no differences were observed in the likelihood of obtaining at least one euploid blastocyst (45% vs 37%, P = 0.4; relative risk [RR], 95% CI = 0.9, 0.6-1.2) or the rate of sustained implantation (31% vs 29%, P = 0.9; RR 1.0, 0.7-1.3). Posttreatment AFC (7.9 ± 4.5 vs 6.8 ± 4.8, P = 0.3) and AMH (0.99 ± 0.98 vs 0.7 ± 0.6, P = 0.2) were also not different between the groups. LIMITATIONS, REASONS FOR CAUTION: Results from this RCT may not be generalizable to other PRP preparations owing to heterogeneity and lack of standardization. The control groups did not undergo a sham ovarian injection, which would have been relevant had the results shown benefit of PRP injection. Only patients with POR were included in this study, and these results may not be generalizable to more severe diminution of ovarian reserve, as seen with POI. WIDER IMPLICATIONS OF THE FINDINGS: The intraovarian PRP injection procedure does not improve mature oocyte yield or other parameters of IVF outcome in women less than 38 years old with an established IVF history of POR. The results from this study do not support the use of intraovarian PRP injection in this population. STUDY FUNDING/COMPETING INTEREST(S): Departmental funds were used and no external funding was requested for this study. ES is a consultant for and receives grant funding from the Foundation for Embryonic Competence. All other authors have no conflict of interest to declare. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov Registry Identifier: NCT04163640. TRIAL REGISTRATION DATE: 15 November 2019. DATE OF FIRST PATIENT'S ENROLMENT: 24 February 2020.

Effects of Non-Cavity-Distorting Intramural Fibroids on IVF Outcomes in Patients with Recurrent IVF Failure: Does Myomectomy Change IVF Outcomes ?

Background: Uterine fibroids are the most common benign smooth muscle tumors of the uterus. However, there is no consensus on whether myomectomy improves IVF success in women with non-cavity-distorting intramural fibroids. The aim of this study was to compare the IVF and pregnancy outcomes of women who had non-cavity-distorting intramural fibroids and underwent myomectomy vs women who had intramural fibroids, but did not undergo myomectomy. Methods: A retrospective cohort study at Acibadem Maslak Hospital, IVF Center, between 2019 and 2020. Data of 128 women aged between 25 and 43 years who have at least 2 intramural non-cavity-distorting fibroids of 2-6 cm in size were used. All patients had at least two IVF failure. The intervention group comprised women who decided to proceed to myomectomy before IVF (Group 1, n = 56). The control group was established women with intramural fibroids who reject myomectomy (Group 2, n = 71). Results: In regard to IVF result parameters and perinatal outcomes, there was no statistically significant difference between the two groups. Between study groups, there were no statistically significant differences in the perinatal outcomes. Myomectomy surgery did not increase miscarriage and biochemical pregnancy rate (odds ratio (OR) 0.9; 95% confidence interval (CI) 2.8-3.7). Conclusion: Myomectomy does not impact on pregnancy or live birth rates substantially, according to the results of this study.

Treatment options for endometrial hypoproliferation.

PURPOSE OF REVIEW: Endometrial hypoproliferation refers to the failure of the endometrium to reach optimal thickness during fresh or frozen embryo transfer cycles in women undergoing infertility treatment with in-vitro fertilization (IVF). This review discusses the treatment options for endometrial hypoproliferation. RECENT FINDINGS: Apart from factors related to the embryo quality, ultrasonographic findings associated with the endometrium, such as endometrial thickness, endometrial pattern and subendometrial blood flow, are considered key factors associated with the outcome of assisted reproductive treatment. To date, a consensus has not been reached regarding the definition of thin endometrium, while thresholds of 6, 7 or 8 mm have been used in the literature. Strategies to increase endometrial thickness can be reviewed in three groups: endocrine approaches, vitamins & supplements, and new experimental therapeutic interventions. Some of the recently introduced experimental therapeutic interventions such as platelet-rich plasma injection, stem cell treatment and tissue bioengineering are exciting potential therapies that need to be further studied. SUMMARY: Despite a large number of publications on the topic, diagnosing and treating endometrial hypoproliferation remains a challenge. Well designed studies are needed to establish a widely accepted endometrial thickness cut-off value below which endometrial hypoproliferation is diagnosed and to generate meaningful data that would allow an evidence-based discussion of available therapeutic options with patients.

Distress response in granulosa cells of women affected by PCOS with or without insulin resistance.

PURPOSE: In this study, we investigated whether metabolic dysfunction in women with Polycystic ovarian syndrome (PCOS) induces granulosa cell (GC) stress and activates in the endoplamatic reticulum and the mitochondria (UPRer and UPRmt, respectively). METHODS: Women who were diagnosed with PCOS (based on the Rotterdam criteria), were divided into two groups, PCOS with insulin resistance (PCOS-IR; n = 20) and PCOS with no insulin resistance (PCOS-nIR; n = 20), and compared to healthy oocyte donors (CONT; n = 20). Insulin resistance (IR) was assessed on the results of homeostasis model assessment (HOMA) that determines IR using the concentration of fasting plasma glucose and fasting insuline. Expression of UPRer genes (i.e., IRE1, ATF4, ATF6, XBP1, BIP, and CHOP), and UPRmt genes (i.e., HSP60, HSP10, CLPP, and HSP40) was assessed in cumulus GCs by qRT-PCR. RESULTS: We found that several genes involved in UPRer and UPRmt were overexpressed in the GCs of PCOS-IR and PCOS-nIR compared to CONT. IRE1, ATF4 and XBP1, that are activated by ER stress, were significantly overexpressed in PCOS-IR compared to CONT. BIP and CHOP were overexpressed in PCOS groups compared to CONT. HSP10 and HSP40 were upregulated in PCOS-IR and PCOS-nIR groups compared to the CONT. HSP60 and CLPP showed no statistical different expression in PCOS-IR and PCOS-nIR compared to CONT group. CONCLUSION: Our findings suggest that the GCs of women with PCOS (with or without IR) are metabolically distressed and upregulate UPRer and UPRmt genes. Our study contributes to the understanding of the molecular mechanisms underlying the pathological changes that occur in the follicular microenvironment of women with PCOS.

What should be the strategy in case of a big follicle at the start of the cycle? Shall we start the stimulation or postpone it to the next cycle?

Objective: This study facilitates decision-making when an antral follicle diameter >15 mm is detected at the beginning of the menstrual cycle in poor responder (POR) patients. Materials and Methods: Eighty-three POR patients with at least one leading follicle with a diameter of 15 to 24 mm on the 2nd-4th days of the menstrual cycle were assessed. Results: The mean age of females was 40.1±4.8 (26-45), and the mean partners' age was 42.1±7.8 (26-65). Fifty-one (61.4%) women underwent an oocyte pick-up procedure 36 h after the first ultrasonographic examination on the 2nd-4th days of the menstrual cycle. Gonadotrophin stimulation was initiated in 32 (38.6%) patients. Among women in whom oocyte retrieval was performed, an oocyte was obtained in 49 (59.75%) patients. In 13 of 49 patients (26.5%), no mature oocytes were obtained. Fertilized 2pn embryos were obtained in 18 of 33 patients (54.5%). Among the fertilized embryos, 12 were good, six were moderate, and two were of poor quality. Following the frozen embryo transfer procedure, one of the two patients experienced a clinical pregnancy. Conclusion: Patients with POR are still difficult to manage both clinically and therapeutically. Since every oocyte is valuable and important, patients should be carefully followed up. Our research will be directed by the need to rule out a physiological ovarian cyst when large antral follicles appear at the beginning of the cycle. The clinician should give them a chance.

Determining diagnostic criteria and cause of recurrent implantation failure.

PURPOSE OF REVIEW: Recurrent implantation failure (RIF) refers to the absence of implantation after repeated transfer of good embryos into a normal uterus. This review discusses the diagnostic criteria and cause of RIF. RECENT FINDINGS: Regardless of the advancements in IVF practice, RIF is still a challenge that has to be solved. Exact definition of RIF is lacking today. For the initial evaluation, a rigorous algorithmic evaluation should be compromised with an individualized principle. Factors that might affect the number and quality of the oocyte and sperm cells should be investigated in order to obtain a good-quality embryo. Embryo assessment should be performed under ideal laboratory circumstances. The uterine environment should be carefully evaluated and the embryo should be transferred into the uterus at the most receptive time. Some of the newly introduced diseases and empirical treatment strategies, such as chronic endometritis, vaginal microbiota, immunologic profile and immunomodulator treatments, can be discussed with the couple under the light of adequate evidence-based information. SUMMARY: New diagnostic and treatment modalities are needed to be introduced, which would be safe, efficient and efficacious after well-designed randomized controlled trials.

Germline cells in ovarian surface epithelium of mammalians: a promising notion.

It is a long held doctrine in reproductive biology that women are born with a finite number of oocytes and there is no oogenesis during the postnatal period. However, recent evidence challenges this by showing the presence of germ line stem cells in the human ovarian surface epithelium (OSE), which can serve as a source of germ cells, and differentiate into oocyte like structures. Postnatal renewal of oocytes may have enormous therapeutic potential especially in women facing the risk of premature ovarian failure idiopathically or iatrogenically after exposure to gonadotoxic chemotherapy and radiation for cancer therapy.This article reviews current knowledge on germ line stem cells in human OSE.

Management of endometrial polyps diagnosed before or during ICSI cycles.

This retrospective study aimed to shed light on the management options of endometrial polyps diagnosed before or during intracytoplasmic sperm injection (ICSI) treatment. The study included all fresh ICSI cycles performed in the Anatolia IVF Center between July 2005 and January 2009. Group 1 consisted of 47 patients who were diagnosed with an endometrial polyp before their ICSI cycle. All patients diagnosed with an endometrial polyp by transvaginal ultrasonography before the ICSI cycle underwent hysteroscopic polyp resection. Group 1 was compared with 47 matched control patients without endometrial polyps who underwent standard ICSI cycles (group 2). Group 3 included 128 patients diagnosed with an endometrial polyp during stimulation in their ICSI cycles. Group 3 was compared with 128 matched control patients without endometrial polyps who underwent standard ICSI cycles (group 4). Patients diagnosed with an endometrial polyp before ICSI cycles were similar to their controls with regard to clinical pregnancy (29.8% versus 38.3%) and live-birth (25.5% versus 31.9%) rates per transfer, as were patients diagnosed with an endometrial polyp during ovarian stimulation (clinical pregnancy rates 45.3% versus 46.9%; live-birth rates 40.6% versus 39.8%). In conclusion, further studies are required to identify the most appropriate management of endometrial polyps.

Comparison of diagnostic accuracy of saline infusion sonohysterography, transvaginal sonography and hysteroscopy in postmenopausal bleeding.

OBJECTIVE: To compare the diagnostic accuracy of transvaginal sonography (TVS), saline infusion sonohysterography (SIS) and hysteroscopy (HS) with respect to pathological diagnosis in the detection of uterine cavity abnormalities associated with abnormal uterine bleeding among postmenopausal women. METHODS: Being a prospective, investigator-blind trial, the present study was conducted on 137 postmenopausal women, with abnormal uterine bleeding, admitted to the Department of Obstetrics and Gynecology of Istanbul Bilim University, Florence Nightingale Hospital and Fertigyn Woman Health and IVF Center. After TVS, all patients underwent SIS using Cook Soft 500 IVF transfer catheter and HS, consecutively. Sensitivity, specificity, and positive and negative predictive values (PPV and NPV) were calculated to compare the diagnostic accuracy of TVS, SIS and HS. RESULTS: Most commonly encountered endometrial lesions were polypoid lesion (38.0%) and hyperplasia (28.4%) among our study population consisting of 137 women (mean age 61.6 ± 9.6 years) in their postmenopausal stage. Overall sensitivity rates were 70.0% for TVS, 89.6% for SIS and 92.3% for HS, while the overall specificity rates were 50.0, 77.3 and 80.7%, respectively. HS had PPV of 96.2% and NPV of 65.3%, whereas PPV was determined to be 80.9 versus 95.3% and NPV was 35.4 versus 58.3% for TVS and SIS, respectively. CONCLUSIONS: As an easy to perform, safe and well-tolerated procedure yielding high diagnostic accuracy, saline infusion SIS via this catheter seems to be superior to TVS and very close to HS. It may be used as the primary method for the detection of uterine abnormalities among postmenopausal women with abnormal uterine bleeding.

Effects of hormone replacement therapy on glucose and lipid profiles and on cardiovascular risk parameters in postmenopausal women.

OBJECTIVES: The aim of this study was to evaluate the effects of hormone replacement therapy (HRT) on carbohydrate and lipid metabolisms and cardiovascular risk parameters in healthy postmenopausal women. METHODS: Forty women receiving and 38 women not receiving HRT were included and baseline and sixth month blood pressure, weight, body mass index, waist/hip ratio, blood lipid profile, inflammatory markers (homocysteine, C-reactive protein (CRP) and fibrinogen), hemoglobin A1c (HbA1c) and insulin, and oral glucose tolerance test (OGTT) results were evaluated. RESULTS: The mean age was 52.6+/-4.9 and 52.2+/-5.0 years in the HRT and Control Groups, respectively. Whereas there was no change in the Controls, the weight, waist/hip ratio, and BMI increased and diastolic blood pressure decreased in the HRT patients. LDL-c, VLDL-c and lipoprotein (a) levels were significantly higher in the HRT Group in the sixth month; however, total cholesterol and LDL-c increased in the Controls but VLDL-c and lipoprotein (a) did not. CRP and homocysteine significantly increased and fibrinogen decreased, whereas in the Control Group no significant change was detected. A significant improvement in HbA1c and OGTT was found in both the groups, whereas a significant reduction was measured only in the HRT Group. CONCLUSIONS: In response to 6 months of HRT, there was an increase in weight, BMI, and waist/hip ratio as known cardiovascular risk factors, but no significant impact on lipid profile and glucose metabolism could have been clearly demonstrated. A mixed effect profile of HRT on the state of inflammation (increase in CRP and homocysteine, decrease in fibrinogen) was observed.

TESE-ICSI in patients with non-mosaic Klinefelter syndrome: a comparative study.

There are limited data in the literature on the performance of testicular sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI) treatment in patients with Klinefelter syndrome. The current study compared TESE-ICSI treatment in patients with non-mosaic Klinefelter syndrome with controls having non-obstructive azoospermia and normal karyotype. Thirty-three consecutive patients (39 TESE-ICSI cycles) with Klinefelter syndrome (study group) and 113 consecutive patients (130 TESE-ICSI cycles) with non-obstructive azoospermia and normal karyotype (control group) were recruited in a private IVF setting. In the two groups, the mean ages of the men at the time of TESE were 32.0 +/- 6.4 and 34.3 +/- 5.8 years respectively (P < 0.05) and the successful sperm recovery rates per total TESE attempts were 56 (22/39) and 44% (57/130) respectively. Similarly, fertilization rates were comparable between the two groups. In the Klinefelter syndrome group, following biopsy and fluorescence in-situ hybridization, a normal karyotype was obtained in 42 of the 71 embryos (59%). The clinical pregnancy and implantation rates in the study and control groups were similar (39, 23 and 33, 26% respectively). In conclusion, patients with non-mosaic Klinefelter syndrome have sperm recovery and pregnancy rates comparable with patients having non-obstructive azoospermia and normal karyotype.

ICSI outcome following conservative fertility sparing management of endometrial cancer.

Approximately 5% of cases of endometrial cancer occur in women aged 40 years or younger. In the presence of early staged endometrial cancer, fertility sparing management may be considered in selected patients. Following high dose progestin therapy and confirmation of the regression of cancer, the patient might attempt to conceive spontaneously. However, assisted reproduction techniques might increase the likelihood of pregnancy and decrease the time interval to conception. In this report, the authors present four patients with endometrial cancer who were treated conservatively with high dose progestin. In all of the cases, the endo-myometrial junctional zone was intact with no evidence of extra-uterine spread on pelvic imaging. A total of seven intracytoplasmic sperm injection and embryo transfer cycles were performed in four patients; five healthy infants were delivered. Two additional spontaneous pregnancies occurred in two patients. During the follow-up period, no recurrence was noted. Although there are limited data, fertility sparing with high dose progestin therapy may be offered to patients with early stage disease and subsequently assisted reproductive techniques may be employed to achieve immediate pregnancy.

Antagonist/letrozole protocol in poor ovarian responders for intracytoplasmic sperm injection: a comparative study with the microdose flare-up protocol.

OBJECTIVE: To compare the effect of the GnRH antagonist/letrozole protocol (AL) with the microdose GnRH agonist flare-up (MF) protocol in poor ovarian responders for intracytoplasmic sperm injection (ICSI). DESIGN: Retrospective, case-control study. SETTING: Anatolia Women and IVF Center. PATIENT(S): Eight hundred eighty-five consecutive patients (1383 cycles) predicted to have or with a history of poor ovarian response who were undergoing ICSI were enrolled. The MF protocol was used in 673 patients (1026 cycles), and the AL protocol was used in the remaining 212 patients (357 cycles). INTERVENTION(S): Controlled ovarian hyperstimulation and ICSI. MAIN OUTCOME MEASUREMENT(S): Cycle cancellation rate, number of oocytes retrieved, fertilization rate, embryo quality, clinical pregnancy, and implantation rates. RESULT(S): The total gonadotropin consumption, duration of stimulation, E(2) level on the day of hCG administration, and number of oocytes retrieved were significantly lower with the AL protocol compared with the MF protocol. However, the fertilization rate and the rate of at least one top-quality embryo transferred were higher with the AL compared with the MF protocol. The clinical pregnancy rates were comparable between the two groups. The implantation rates with the MF and AL protocols were 9.8% and 14.5%, respectively. CONCLUSION(S): The GnRH AL protocol is an effective protocol that may be used in poor ovarian responders for ICSI.

The effects of rosiglitazone and metformin on menstrual cyclicity and hirsutism in polycystic ovary syndrome.

OBJECTIVE: The aim of the present study was to assess the effects of metformin and rosiglitazone on menstrual cyclicity and hirsutism in patients with polycystic ovary syndrome (PCOS). MATERIALS AND METHODS: Ninety-six patients were included in the study. Serum sex steroids, serum fasting glucose and insulin levels, and insulin response to a 75-g oral glucose tolerance test were assessed in all patients. Menstrual cyclicity, with recording of menses in the 6-month periods before the study and during treatment, was evaluated in each patient. Patients were divided into two groups: one was treated with metformin (MET group, n = 48), while the other received rosiglitazone (ROSI group, n = 48). At baseline and after 24 weeks of treatment all patients underwent hormonal and clinical assessments, including body mass index (BMI), waist and hip measurements and Ferriman - Gallwey (FG) scores. RESULTS: Of the 96 patients included in the study, 88 (91.7%) were able to complete it and yielded data for analyses. After the 24-week treatment period, fasting insulin levels and area under the curve for serum insulin decreased significantly, while the glucose/insulin ratio increased in both groups. The degree of reduction in serum free testosterone and androstenedione levels was similar in the two groups. The decreases in luteinizing hormone/follicle-stimulating hormone ratio and serum dehydroepiandrosterone sulfate levels were significantly greater in the ROSI group compared with the MET group. BMI increased in the ROSI group, while it decreased in the MET group. In patients with menstrual disturbance treated with rosiglitazone, menstrual cycles became regular in 87.8%, while improvement occurred in 79.3% of the patients treated with metformin. FG score decreased in both ROSI and MET groups, but the degree of decrease was significantly greater in the ROSI group than in the MET group. CONCLUSION: Our data show that both metformin and rosiglitazone improve ovarian function and hirsutism in patients with PCOS. Rosiglitazone appears better than metformin in the treatment of hirsutism and has better patient tolerance.

Assisted reproduction in the treatment of polycystic ovarian syndrome.

Treatment of patients with polycystic ovary syndrome (PCOS) with assisted reproductive techniques is a great challenge for the infertility specialist. Patients with PCOS demonstrate many problems, such as excessive body weight and hyperinsulinaemia, that render management more complex. Prior to treatment with IVF, the PCOS patient should be thoroughly evaluated for disclosure of endometrial neoplasia, hyperinsulinaemia, and other general health related problems. Ovarian stimulation for IVF carries the risks of overstimulation and severe hyperstimulation, which should be avoidable in most cases with preventive measures. The outcome in terms of pregnancy and implantation rates is similar for patients with PCOS when compared with patients undergoing IVF for other indications. There are some questions regarding oocyte and embryo quality in women with PCOS. This manifests itself in lower fertilization rate and decreased embryo quality in some studies. However, increased numbers of oocytes available for insemination or ICSI compensate for decreased fertilization rates and embryo quality. More recent studies suggest higher cumulative conception rates in women with PCOS when compared with controls. In-vitro maturation (IVM) of oocytes retrieved from non-stimulated or minimally stimulated cycles represents a viable option that should be considered seriously when assisted conception is attempted. Results of IVM, however, should be improved further and generalized before the technique can be advocated as the initial treatment approach in these patients.

Acquired pelvic anomaly preventing sexual intercourse in a female patient.

This report describes a patient with dyspareunia related to an acquired pelvic anomaly that was treated surgically.