What are the most common controversial clinical issues in fertility preservation? A content analysis of a collaborative professional online consultation group.

RESEARCH QUESTION: Clinicians involved in fertility preservation (FP) are often required to make prompt and consequential decisions despite the absence of evidence-based data. We established a collaborative professional online consultation group for fertility preservation issues. We sought to determine the main controversial clinical issues in FP as raised by participants of this group. DESIGN: Content analysis of a dedicated community of practice interacting via a messaging application (WhatsApp) and a survey of group participants. RESULTS: Between January 2019 and July 2022, group members posed 39 clinical questions which were discussed and debated by the group. Common themes included management of oncofertility cases (33%), potential gonadotoxicity of various therapies (23%), fertility preservation in women and girls with premature ovarian insufficiency (POI) (18%), and technical aspects of ovarian tissue cryopreservation (10%). All but one query received prompt response (mean time for first response for 95% of queries 7.1 ± 9.0 min) from a mean of 5.4 ± 3.2 members. An anonymous online survey of group members was conducted during August 2022 (n = 31, response rate 94%). The majority of respondents stated they gained knowledge and assistance in clinical decision making from participation in the discussion group (90% and 58% of respondents, respectively). CONCLUSIONS: Management of clinical oncofertility cases, potential gonadotoxic effect of therapeutics and fertility preservation in women and girls with POI were the most common controversial issues in our fertility preservation community of practice. Intra-professional collaborative communication via a messaging application can aid in clinical management of fertility preservation and augment clinician's knowledge.

Clinical outcome of planned oocyte cryopreservation at advanced age.

PURPOSE: To report outcome of planned oocyte cryopreservation (POC) in the first 8 years of this treatment in our center. METHODS: A retrospective study in a university-affiliated medical center. RESULTS: A total of 446 women underwent POC during 2011-2018. Fifty-seven (13%) women presented to use these oocytes during the study period (until June 2021). POC was performed at a mean age of 37.9 ± 2.0 (range 33-41). Age at thawing was 43.3 ± 2.1 (range 38-49). A total of 34 (60%) women transferred their oocytes for thawing at other units. Oocyte survival after thawing was significantly higher at our center than following shipping to ancillary sites (78 vs. 63%, p = 0.047). Forty-nine women completed their treatment, either depleting their cryopreserved oocytes without conceiving (36) or attaining a live birth (13)-27% live birth rate per woman. Only one of eleven women who cryopreserved oocytes aged 40 and older had a live birth using thawed oocytes. CONCLUSION: Women should be advised to complete planned oocyte cryopreservation before age 40, given low success rates in women who underwent cryopreservation at advanced reproductive age. In this study, oocyte shipping was associated with lower survival rate. These findings may be relevant for women considering POC and utilization of cryopreserved oocytes.

Live birth of twins after performing early hCG administration as a modification of natural cycle in vitro fertilization, in a women with decreased ovarian reserve.

PURPOSE: This case reports the first twin live births achieved in a woman with a serum FSH of such magnitude -80 IU/L, after following early hCG administration in natural cycle in vitro fertilization (IVF). METHOD: Case report. RESULTS: A 27-year-old with 2 years of primary infertility presented with regular menses since menarche. FSH following clomiphene citrate challenge test was 80 IU/L. Antral follicle count was 1. After failing two IVF cycles, natural cycle IVF with early hCG administration was attempted. Ovulation with 10,000 IU hCG was triggered when the dominant follicle was 10 mm in mean diameter. Two smaller follicles were also present. Oocyte collection was performed 38 h after hCG injection. Three mature oocytes were retrieved. Two oocytes fertilized normally. Two good-quality embryos were transferred on day 2. Bichorionic biamniotic pregnancy was achieved and healthy twins were delivered at term. CONCLUSIONS: This case suggests that natural cycles with early hCG administration should be investigated further as an option for poor responders to retrieve more than one mature oocyte, and prevent premature ovulation. We believe this case to represent the patient with the highest serum FSH level, reflective of ovarian reserve at the time of treatment, to achieve a live birth. It is also the first case report to describe this modification on the traditional natural cycle.

Does optimal follicular size in IUI cycles vary between clomiphene citrate and gonadotrophins treatments?

OBJECTIVE: To evaluate pregnancy-related leading follicles during ovulation induction and superovulation with clomiphene citrate (CC) or gonadotropin. DESIGN: Retrospective cohort. PATIENTS: Five hundred and forty-two women who underwent a total of 615 treatment cycles with CC or gonadotropin. INTERVENTION: We evaluated the effects of CC and gonadotropin on the leading follicles, clinical pregnancy rates and miscarriage rate. RESULTS: The number of follicles larger than 15 mm in the different protocols was comparable. In those treated with CC, the diameter of the dominant follicles before human chorionic gonadotropins (hCG) trigger in the conception cycles (20.4 ± 1.2 mm) was significantly larger than in the non-conception cycles (18.8 ± 1.9 mm). In women treated with gonadotropin, the diameter of the leading follicle in the conception cycles (18.5 ± 1.7 mm) was comparable to that in the non-conception cycles (18.2 ± 1.7 mm). The pregnancy-related diameter of the leading follicle in CC cycles (20.4 ± 1.2 mm) was significantly larger than that in gonadotropin cycles (18.8 ± 1.9 mm; p = 0.001; 95% CI, -2.2 to -0.9). CONCLUSION: Pregnancy-related diameter of the leading follicle in CC cycles is significantly larger than that in gonadotropin cycles and the best time for hCG trigger in the CC cycle is when the leading follicle reaches 20 mm.

Planned oocyte cryopreservation: a systematic review and meta-regression analysis.

BACKGROUND: Awareness of the age-related decline in fertility potential has increased the popularity of planned oocyte cryopreservation (POC). However, data regarding outcomes of POC, including rates of women returning to thaw oocytes, as well as pregnancy and live birth rates, are scarce and based mostly on small case series. OBJECTIVE AND RATIONALE: POC was defined as cryopreservation exclusively for prevention of future age-related fertility loss. The primary outcome was live birth rate per patient. The secondary outcomes included the return to thaw rate and laboratory outcomes. A meta-regression analysis examining the association between live birth and age above 40 or below 35 was conducted. SEARCH METHODS: We conducted a systematic database search from inception to August 2022. The search included PubMed (MEDLINE) and EMBASE. Our search strategies employed a combination of index terms (Mesh) and free text words to compile relevant concepts. The systematic review and meta-regression were undertaken following registration of systematic review (PROSPERO registration number CRD42022361791) and were reported following guidelines of Preferred Reporting Items for Systematic Review and Meta-Analyses 2020 (PRISMA 2020). OUTCOMES: The database search yielded 3847 records. After the selection process, 10 studies, conducted from 1999 to 2020, were included. Overall, 8750 women underwent POC, with a mean cryopreservation age of 37.2 (±0.8). Of those, 1517 women returned to use their oocytes with a return rate of 11.1% (± 4.7%). The mean age at the time of cryopreservation for women who returned to use their oocytes was 38.1 (±0.4), with an average of 12.6 (±3.6) cryopreserved oocytes per woman. In a meta-analysis, the oocyte survival rate was 78.5% with a 95% CI of 0.74-0.83 (I2 = 93%). The live birth rate per patient was 28% with a 95% CI of 0.24-0.33 (I2 = 92%). Overall, 447 live births were reported. In a sub-group analysis, women who underwent cryopreservation at age ≥40 achieved a live birth rate per patient of 19% (95% CI 0.13-0.29, I2 = 6%), while women aged ≤35 years old or younger had a higher live birth rate per patient of 52% (95% CI 0.41-0.63, I2 = 7%). WIDER IMPLICATIONS: POC emerges as a feasible option for women aiming to improve their chances of conceiving at a later reproductive age. Nonetheless, it must be acknowledged that the overall success rates of POC are limited and that the likelihood of successful live birth declines as the age at cryopreservation rises. With increasing interest in POC, the collation of comprehensive and high-quality data is imperative to clearly define the outcomes for various age groups. REGISTRATION NUMBER: CRD42022361791.

Age-related normogram for antral follicle count in women with polycystic ovary syndrome.

Antral follicle count (AFC) has been shown to be a reliable marker for ovarian reserve. The aims of this study were to create an age-related normogram for AFC in infertile women with polycystic ovary syndrome (PCOS) and to compare age-related decline in AFC between infertile women with and without PCOS. A retrospective cohort study was conducted. Of a total of 4956 women, 619 women fit criteria for PCOS. In those with PCOS, there were large variations in the AFC between the 10th and 90th percentiles in all age groups. The rate of decline in AFC among women with PCOS was linear, while in those with non-PCOS, it was exponential until 30 years of age, and then became similar to that of PCOS. The rate of follicle loss per year was significantly slower in PCOS women compared with that in non-PCOS women. In both groups, the fastest period of follicle loss was between the ages of 18 and 30. The average follicle loss was 0.8 follicles/year in PCOS women and 1.7 follicles/year in those without PCOS (P<0.001). This study concludes that age-related decline in AFC among women with PCOS is slower than in those without PCOS. Antral follicle count (AFC) has been shown to be a reliable marker for ovarian reserve. The aims of this study were to create an age-related normogram for AFC in women with polycystic ovary syndrome (PCOS), and to compare age-related decline in AFC between women with and without PCOS. A retrospective cohort study was conducted. All patients underwent a baseline transvaginal ultrasound that was performed on day 2-4 of the menstrual cycle. The total number of antral follicles of 2-9mm in diameter was recorded. Of total 4956 women, 619 women fit criteria for PCOS. In those with PCOS, there were large variations in the AFC between the 10th 90th percentiles in all age groups. The rate of decline in AFC among women with PCOS was linear; while in those with non-PCOS, it was exponential until 30 years of age, and then became similar to that of PCOS. The rate of follicle loss per year was significantly slower in PCOS women compared with that in non-PCOS women. In both groups, the fastest period of follicle loss was between the ages 18-30 years. The average follicle loss was 0.8 follicles/year in PCOS women and 1.7 follicles/year in those without PCOS (P<0.001). We have concluded that age-related decline in AFC among women with PCOS is slower than in those without PCOS. Further studies are needed to determine if the AFC normogram in women with PCOS could be clinically relevant to select the optimal gonadotrophin dose for ovulation induction.

Effect of high LH/FSH ratio on women with polycystic ovary syndrome undergoing in vitro maturation treatment.

OBJECTIVE: To determine whether high luteinizing hormone/follicle-stimulating hormone (LH/FSH) ratios have a clinical impact on women with polycystic ovary syndrome (PCOS) undergoing in vitro maturation (IVM) treatment. STUDY DESIGN: Women with PCOS who underwent IVM treatment were divided into those with LH/FSH ratio > 1.5 and LH/FSH 0.5-1.5. We analyzed baseline characteristics of the patients, number of oocytes retrieved, number of mature oocytes, and pregnancy rates. RESULTS: Women with LH/FSH ratio of > 1.5 had higher basal serum testosterone (2.2 vs. 1.4, p < 0.005, CI 0.1-1.0) and estradiol (188.7 +/- 16.2 vs. 143.7 +/- 6.9, p < 0.01, CI 23-96). The antral follicle count (AFC) was also higher in the patients with high LH/FSH (46.2 +/- 3.5 vs. 32.9 +/- 1.3, p < 0.001, CI 7-21). The total number of retrieved oocytes and number of mature oocytes was also significantly higher in women with LH/FSH ratio of > 1.5 than in those with a lower ratio. However, the pregnancy rate in women with LH/FSH ratio of > 1.5 (16.7%) was significantly lower than in those with a ratio of 0.5-1.5 (40.4%), p < 0.05, odds ratio 0.32. CONCLUSION: PCOS patients with LH/FSH ratio of > 1.5 had higher basal testosterone, E2, and AFC but decreased pregnancy rate. This could be due to the deleterious effect of LH on folliculogenesis and endometrial receptivity.

Primary amelanotic melanoma of the vagina.

BACKGROUND: Primary malignant melanoma of the vagina is extremely rare, accounting for 0.3-0.8% of all malignant melanomas. True amelanotic vaginal melanoma showing no melanin on histological examination is exceedingly rare, accounting for only 2% of all vaginal melanomas. CASE REPORT: We describe a 31-year-old female patient who presented with locally advanced amelanotic melanoma of the vagina, with no evidence of metastatic spread on the computerized tomography (CT) scan, but who was subsequently diagnosed as suffering from metastatic disease by positron emission tomography (PET)-CT performed a few weeks following posterior pelvic exenteration. CONCLUSION: Specific immunohistochemical staining with melanoma markers should be performed to confirm or exclude a diagnosis of amelanotic melanoma in all patients presenting with a vaginal mass composed of undifferentiated epithelioid malignant cells. Fluorodeoxyglucose (FDG)-PET-CT should be performed as part of the preoperative evaluation, to identify the presence or absence of metastatic disease in all patients with vaginal melanoma.

Preimplantation genetic diagnosis as a strategy to prevent having a child born with an heritable eye disease.

BACKGROUND: In developed countries, genetically inherited eye diseases are responsible for a high percentage of childhood visual impairment. We aim to report our experience using preimplantation genetic diagnostics (PGD) in order to avoid transmitting a genetic form of eye disease associated with childhood visual impairment and ocular cancer. MATERIAL AND METHODS: Retrospective case series of women who underwent in vitro fertilization (IVF) and PGD due to a familial history of inherited eye disease and/or ocular cancer, in order to avoid having a child affected with the known familial disease. Each family underwent genetic testing in order to identify the underlying disease-causing mutation. IVF and PGD treatment were performed; unaffected embryos were implanted in their respective mothers. RESULTS: Thirty-five unrelated mothers underwent PGD, and the following hereditary conditions were identified in their families: albinism (10 families); retinitis pigmentosa (7 families); retinoblastoma (4 families); blue cone monochromatism, achromatopsia, and aniridia (2 families each); and Hermansky-Pudlak syndrome, Leber congenital amaurosis, Norrie disease, papillorenal syndrome, primary congenital cataract, congenital glaucoma, Usher syndrome type 1F, and microphthalmia with coloboma (1 family each). Following a total of 88 PGD cycles, 18 healthy (i.e., unaffected) children were born. CONCLUSIONS: Our findings underscore the importance an ophthalmologist plays in informing patients regarding the options now available for using prenatal and preimplantation genetic diagnosis to avoid having a child with a potentially devastating genetic form of eye disease or ocular cancer. This strategy is highly relevant, particularly given the limited options currently available for treating these conditions.

Transvaginal ultrasound to guide embryo transfer: a randomized controlled trial.

OBJECTIVE: To compare sonographic visualization and patient pain in conventional transabdominal ultrasound (TAUS) with transvaginal ultrasound (TVUS) sonographic-guided embryo transfer (ET). DESIGN: Prospective, randomized, controlled study. SETTING: Tertiary medical center, in vitro fertilization (IVF) unit. PATIENT(S): One hundred and twenty patients younger than 40 years old scheduled for ET. INTERVENTION(S): Patients (32.9 ± 4.5 years old) undergoing fresh cleavage-stage ET were randomly assigned to the study group (TVUS; n = 60) or control group (TAUS; n = 60). After ET each patient filled out a questionnaire based on a visual analogue scale (VAS) to evaluate pain and discomfort before, during, and after the procedure. The physician assessed the quality of sonographic visualization. The follow-up observation lasted 12 months and included pregnancy rates. MAIN OUTCOME MEASURE(S): Visualization of the uterus and ET location and pain before, during, and after the ET procedure. RESULT(S): Visualization of the uterus and the ET location by the physician was statistically significantly better in the TVUS than in the TAUS group (9.57 vs. 8.42 and 9.58 vs. 8.82, respectively). Pain sensation assessed by a visual analogue scale (VAS) before, during, and after the procedure was statistically significantly lower in the study group compared with the control group (5.45 vs. 1.48, 5.03 vs. 2.42 and 2.97 vs. 1.52). The implantation and live-birth rates did not differ between the two groups (32.9% vs. 23.4%, OR 1.61; 95% CI, 0.85-3.07; 31.6% vs. 25.0%, OR 1.39; 95% CI, 0.63-3.09, respectively). CONCLUSION(S): TVUS guidance to facilitate ET is superior to TAUS in visualization of ET location and in lessening the pain and discomfort of the patients. CLINICAL TRIAL REGISTRATION NUMBER: NCT008263312.

Fertility preservation options after gonadotoxic chemotherapy.

Chemotherapy has the potential to deplete and destroy a woman's reproductive potential. Although many oncologists are referring women for fertility preservation before chemotherapy, in many cases there is limited time for fertility preservation. This review provides an overview of the impact of cancer and chemotherapy on the ovarian reserve, a summary of methods of fertility preservation prior to chemotherapy, and current knowledge of fertility preservation techniques after gonadotoxic chemotherapy.

DHEA supplementation may improve IVF outcome in poor responders: a proposed mechanism.

OBJECTIVE: Dehydroepiandrosterone (DHEA) supplementation for poor responders may improve ovarian response and IVF treatment outcome. This study aimed to determine the mechanism of action of DHEA, and specifically, the stage of folliculogenesis influenced by DHEA. STUDY DESIGN: This is a prospective, self-controlled study of poor responders to IVF treatment, comparing day 3 biochemical (anti-Mullerian hormone (AMH), inhibin B and FSH) and ultrasound (antral follicle count (AFC)) ovarian reserve markers and IVF treatment outcome before and after DHEA supplementation of at least 3 months duration. RESULTS: Thirty-two women were included. Following DHEA, there was a significant increase in AFC (P=0.0003) without significant changes in the baseline biochemical parameters AMH, inhibin B, or FSH. The enhanced response comprised increased peak estradiol levels (P=0.0005), number of follicles >15 mm, oocytes, MII oocytes and embryos (P=0.004, P=0.00001, P=0.0004 and P=0.0006, respectively) and oocytes number/total FSH dose (P=0.0009). The proportion of cancelled cycles due to very poor response decreased significantly (P=0.02). CONCLUSIONS: DHEA does not appear to exert influence via recruitment of pre-antral or very small antral follicles (no change in AMH and inhibin B) but rather by rescue from atresia of small antral follicles (increased AFC).

Does estrogen directly modulate anti-müllerian hormone secretion in women?

OBJECTIVE: To investigate whether estrogen may modulate anti-müllerian hormone (AMH) expression in women. DESIGN: Prospective analysis. SETTING: Fertility clinic of tertiary university hospital. PATIENT(S): Cycling infertile women. INTERVENTION(S): Blood samples were taken at the early, middle, and late follicular phase in five groups: spontaneous cycle (n=10), ovulation induction with clomiphene-citrate (n=15) or gonadotropins (n=9), controlled ovarian hyperstimulation for IVF (COH-IVF; n=10) and in women who were treated with exogenous E2 for frozen-thawed embryo-transfer (FET) with no follicular development (n=20). MAIN OUTCOME MEASURE(S): AMH and E2 serum levels. RESULT(S): Basal serum AMH and E2 levels were similar in all groups. AMH levels were stable in all women during the follicular phase except for significant reduction in the COH-IVF group. In women in the FET group with high E2 levels, comparable to the COH-IVF group, AMH levels remained stable. CONCLUSION(S): In women, estrogen does not appear to have a direct role in AMH regulation.

Ovarian hemorrhage after transvaginal ultrasonographically guided oocyte aspiration: a potentially catastrophic and not so rare complication among lean patients with polycystic ovary syndrome.

OBJECTIVE: To report the first case series of ovarian hemorrhage after transvaginal ultrasonographically guided oocyte aspiration (TVOA). DESIGN: Retrospective analysis. SETTING: In vitro fertilization unit of a tertiary university hospital. PATIENT(S): Patients who underwent TVOA during a 6-year period. INTERVENTION(S): Surgical intervention due to active bleeding from the ovary. MAIN OUTCOME MEASURE(S): Prevalence and risk factors. RESULT(S): Among 3,241 patients undergoing TVOA, 7 were diagnosed as having ovarian hemorrhage afterward. All patients were thin, with a body mass index of 19-21 kg/m(2), and 4 had polycystic ovary syndrome (PCOS). The prevalence of ovarian bleeding among lean patients with PCOS was 4.5%. The odds ratio for bleeding in lean patients with PCOS vs. all other patients was 50 (95% confidence interval 11-250). The interval between the TVOA and surgical intervention ranged from 5 to 18 hours (mean +/- SD, 11.4 +/- 5 hours). The Delta decrease in hemoglobin levels was 3.2-9 g/dL (mean 6.1 +/- 1.8). In 6 of the 7 patients, laparoscopically guided electrocoagulation was sufficient to achieve hemorrhagic control. CONCLUSION(S): Although acute hemorrhage is a rare event after TVOA, lean patients with PCOS specifically are at much higher risk for this complication.

Peri-implantation pelvic inflammatory disease with normal pregnancy outcome.

OBJECTIVE: To report on the presentation, diagnostic assessment, treatment, and outcome of a case of peri-implantation pelvic inflammatory disease. DESIGN: Case report. SETTING: Emergency department and gynecology ward of a tertiary university hospital. PATIENT(S): A 25-year-old multiparous woman in her 1st month of pregnancy. INTERVENTION(S): Diagnostic laparoscopy, antibiotic therapy, and pregnancy surveillance. MAIN OUTCOME MEASURE(S): Surveillance and outcome of pregnancy. RESULT(S): The patient presented with abdominal pain and fever 26 days after her last menstrual period. Examination revealed peritoneal irritation and cervical tenderness, with free fluid in the pelvis. Diagnostic laparoscopy was performed, with no evidence of ectopic pregnancy. A significant quantity of yellow purulent fluid was drained from the pelvis, which cultured for Escherichia coli. Antibiotic therapy yielded excellent response. The pregnancy continued, with no complications, to healthy term delivery. CONCLUSION(S): This rare diagnosis of peri-implantation pelvic inflammatory disease should be considered in the differential diagnosis of abdominal pain in early pregnancy. Timely, rational treatment, including early pelvic drainage and appropriate antibiotic therapy, may save the pregnancy.