Fertility preservation in patients undergoing gonadotoxic treatments: a Canadian Fertility and Andrology Society clinical practice guideline.

The management of young patients with cancer presents several unique challenges. In general, these patients are ill prepared for the diagnosis and the impact on their fertility. With the improved survival for all tumour types and stages, the need for adequate fertility counselling and a multidisciplinary approach in the reproductive care of these patients is paramount. Recent advances in cryopreservation techniques allow for the banking of spermatozoa, oocytes, embryos and ovarian tissue without compromising survival. This Canadian Fertility and Andrology Society (CFAS) guideline outlines the current understanding of social and medical issues associated with oncofertility, and the medical and surgical technologies available to optimize future fertility.

Surgeon and Patient Reports of Fertility Preservation Referral and Uptake in a Prospective, Pan-Canadian Study of Young Women with Breast Cancer.

BACKGROUND: Prompt referral by their surgeon enables fertility preservation (FP) by young women with breast cancer (YWBC) without treatment delay. Following a FP knowledge intervention, we evaluated surgeon and patient reports of fertility discussion, FP referral offer and uptake, and FP choices and reasons for declining FP among patients enrolled in the Reducing Breast Cancer in Young Women, prospective pan-Canadian study. METHODS: Between September 2015 and December 2020, 1271 patients were enrolled at 31 sites. For each patient, surgeons were sent a questionnaire inquiring whether: (1) fertility discussion was initiated by the surgical team; (2) FP referral was offered; (3) referral was accepted; a reason was requested for any "no" response. Patients were surveyed about prediagnosis fertility plans and postdiagnosis oncofertility management. RESULTS: Surgeon questionnaires were completed for 1068 (84%) cases. Fertility was discussed with 828 (84%) and FP consultation offered to 461 (47%) of the 990 YWBC with invasive disease. Among the 906 responding YWBC, referral was offered to 220 (82%) of the 283 (33%) with invasive disease who stated that they had definitely/probably not completed childbearing prediagnosis. Of these, 133 (47%) underwent FP. The two most common reasons for not choosing FP were cost and unwillingness to delay treatment. CONCLUSIONS: Although the rates of surgeon fertility discussion and FP referral was higher than most reports, likely due to our previous intervention, further improvement is desirable. FP should be offered to all YWBC at diagnosis, regardless of perceived childbearing intent. Cost remains an important barrier to FP uptake.

COVID-19 and assisted reproductive technology services: repercussions for patients and proposal for individualized clinical management.

The prolonged lockdown of health services providing high-complexity fertility treatments -as currently recommended by many reproductive medicine entities- is detrimental for society as a whole, and infertility patients in particular. Globally, approximately 0.3% of all infants born every year are conceived using assisted reproductive technology (ART) treatments. By contrast, the total number of COVID-19 deaths reported so far represents approximately 1.0% of the total deaths expected to occur worldwide over the first three months of the current year. It seems, therefore, that the number of infants expected to be conceived and born -but who will not be so due to the lockdown of infertility services- might be as significant as the total number of deaths attributed to the COVID-19 pandemic. We herein propose remedies that include a prognostic-stratification of more vulnerable infertility cases in order to plan a progressive restart of worldwide fertility treatments. At a time when preventing complications and limiting burdens for national health systems represent relevant issues, our viewpoint might help competent authorities and health care providers to identify patients who should be prioritized for the continuation of fertility care in a safe environment.

Effect of a Knowledge-Translation Intervention on Breast Surgeons' Oncofertility Attitudes and Practices.

BACKGROUND: The breast surgeon, generally the first oncology specialist consulted, is ideally suited to offer fertility preservation (FP) referral to young women with breast cancer (YWBC). In the authors' 2015 survey of 84 surgeons participating in the pan-Canadian RUBY study of YWBC, oncofertility knowledge and rates of FP referral were suboptimal. The authors designed an oncofertility knowledge-translation intervention for surgeons. METHODS: A customized oncofertility toolbox was created including a seminar/webinar, an option grid, a three-question FP survey sent upon registration of each RUBY patient, and a management checklist. In 2018, the 28 site lead surgeons were re-invited to participate in a follow-up telephone interview, and 85 non-site lead surgeons were invited to complete a follow-up online questionnaire. RESULTS: A total of 27 site lead surgeons consented to be re-interviewed. After the intervention, 85% indicated that they "routinely" initiated a fertility discussion compared with 54% at baseline (p < 0.005), with 56% stating that the toolbox had been helpful for making positive changes in their practice regarding oncofertility, and 44% stating that they found it easier to initiate a fertility discussion. Among the 55 non-site lead surgeons who completed the questionnaire, a significant improvement in oncofertility knowledge was found. The percentage reporting "rarely" or "never" discussing FP options decreased from 41 to 14% (p < 0.005), and 84% stated that they referred patients who had not completed their families and were at risk for infertility to FP consultation compared with 32% before the intervention (p < 0.001). CONCLUSIONS: A multi-pronged but simple knowledge-translation intervention improved the attitudes, knowledge, and FP practice of Canadian breast surgeons.

Mapping the human DC lineage through the integration of high-dimensional techniques.

Dendritic cells (DC) are professional antigen-presenting cells that orchestrate immune responses. The human DC population comprises two main functionally specialized lineages, whose origins and differentiation pathways remain incompletely defined. Here, we combine two high-dimensional technologies-single-cell messenger RNA sequencing (scmRNAseq) and cytometry by time-of-flight (CyTOF)-to identify human blood CD123+CD33+CD45RA+ DC precursors (pre-DC). Pre-DC share surface markers with plasmacytoid DC (pDC) but have distinct functional properties that were previously attributed to pDC. Tracing the differentiation of DC from the bone marrow to the peripheral blood revealed that the pre-DC compartment contains distinct lineage-committed subpopulations, including one early uncommitted CD123high pre-DC subset and two CD45RA+CD123low lineage-committed subsets exhibiting functional differences. The discovery of multiple committed pre-DC populations opens promising new avenues for the therapeutic exploitation of DC subset-specific targeting.

Oncofertility Knowledge, Attitudes, and Practices of Canadian Breast Surgeons.

BACKGROUND: Guidelines recommend that oncologists discuss treatment-related fertility issues with young cancer patients as early as possible after diagnosis and, if appropriate, expedite referral for fertility preservation (FP). This study sought to determine the attitudes and practices of Canadian breast surgeons regarding fertility issues, as well as barriers to and facilitators of fertility discussion and referrals. METHODS: Semistructured telephone interviews were conducted with 28 site lead surgeons (SLSs) at 28 (97 %) of 29 centers (25 % cancer centers, 64 % teaching hospitals) across Canada participating in RUBY, a pan-Canadian research program for young women with breast cancer. In addition, 56 (65 %) of 86 of their surgical colleagues (non-site lead surgeons [NSLSs]) completed an online survey of their oncofertility knowledge, attitudes, and practices. RESULTS: Of the 28 SLSs (43 % male, 36 % in practice <10 years), 46 % had inadequate oncofertility knowledge, 25 % discussed fertility only if mentioned by the patient, 21 % believed fertility discussion and referral were the mandate of the medical oncologist, and 45 % did not know of an FP center in their area. More than 80 % of the NSLSs (54 % male, 30 % in practice <10 years) were unfamiliar with oocyte or embryo cryopreservation; 36 % never or rarely discussed fertility issues; and 51 % thought referral to a fertility specialist was not their responsibility. CONCLUSIONS: Oncofertility knowledge was low among the SLSs, especially the NSLSs, and barriers to referral were identified. An oncofertility knowledge translation intervention specifically for breast surgeons is being developed to increase surgeon knowledge and awareness of oncofertility issues and referral.

Improved pregnancy rates with luteinizing hormone supplementation in patients undergoing ovarian stimulation for IVF.

INTRODUCTION: Luteinizing hormone (LH) is believed to play a role in follicle maturation during the natural cycle. However, the need for co-treatment with recombinant LH (rLH) for controlled ovarian stimulation is controversial. PURPOSE: The primary objective of our study was to determine if pregnancy rates are improved when rLH is used in addition to rFSH for ovarian stimulation. Secondary outcomes were fertilization rate, implantation rate and live birth rate. METHODS: A retrospective cohort study was performed of 1565 IVF or ICSI cycles. Outcomes were compared between ovarian stimulation cycles from 2007 when rLH and rFSH was used (n = 765) to 2006 when rFSH only was used (n-800). RESULTS: Improved outcomes were found for rLH + rFSH versus rFSH alone for; pregnancy rate (61% and 54% respectively, p = 0.006), live birth rate (49% and 42% respectively, P = 0.01), fertilization rate (74% versus 72% respectively, p = 0.04 and implantation rate (41% versus 37% respectively, p = 0.03). CONCLUSIONS: Our large retrospective cohort study showed an improved pregnancy rate and live birth rate with rLH supplementation. This was associated with an improved fertilization and implantation rate and therefore may reflect an improvement in oocyte quality and/or uterine receptivity.

A prospective randomized trial of conventional in vitro fertilization versus intracytoplasmic sperm injection in unexplained infertility.

PURPOSE: To compare outcomes in patients with unexplained infertility undergoing conventional in vitro fertilization (IVF) versus intracytoplasmic sperm injection (ICSI). METHODS: Sixty women with unexplained infertility in a Canadian tertiary-level clinic were randomized to IVF or ICSI. Subjects underwent downregulation with gonadotropin-releasing hormone agonist prior to initiation of recombinant human follicle-stimulating hormone. The primary outcome measure was fertilization rate. Secondary outcomes included implantation rate, embryo quality, clinical pregnancy rate, and live birth rate. RESULTS: There was no statistically significant difference in fertilization rate (77.2% IVF vs. 82.4% ICSI), implantation rate (38.2% IVF vs. 44.4% ICSI), clinical pregnancy rate (50% in each group), or live birth rate (46.7% IVF vs. 50% ICSI). There were two cases of failed fertilization in the IVF group. There was no significant difference in embryo quality between groups. CONCLUSIONS: There were no differences in clinical outcomes associated with IVF versus ICSI in the treatment of unexplained infertility.

Follicle luteinization in hyperandrogenic follicles of polycystic ovary syndrome patients undergoing gonadotropin therapy for in vitro fertilization.

CONTEXT: Polycystic ovary syndrome (PCOS) is a reproductive disorder of ovarian hyperandrogenism and insulin resistance characterized by abnormal luteinization of small follicles. After exposure to GnRH analog/FSH stimulation for in vitro fertilization (IVF), however, it is unclear whether such PCOS follicles remain abnormally luteinized during the resumption of oocyte maturation in vivo. OBJECTIVE: The aim of this study was to determine whether PCOS follicles exposed to GnRH analog/FSH stimulation for IVF show abnormal luteinization. DESIGN: This study was a prospective cohort. SETTING: The setting was an institutional practice. PATIENTS: Eleven PCOS and 30 normoandrogenic ovulatory women were included. INTERVENTION(S): All subjects received GnRH analog/FSH therapy after basal serum hormone determinations. MAIN OUTCOME MEASURE(S): Follicle fluid aspirated at oocyte retrieval from the first follicle of each ovary was assayed for gonadotropins, steroids, insulin, and glucose. LH receptor mRNA expression was determined in granulosa cells of the same follicle. RESULTS: In PCOS patients with basal hyperandrogenemia and hyperinsulinemia, total oocyte number was increased and follicle diameter was decreased, despite normal maximal serum estradiol levels. Within PCOS follicles, progesterone levels were reduced (P < 0.01), despite comparable bioactive LH and insulin levels and granulosa cell LH receptor mRNA expression; estradiol levels were normal, despite diminished FSH availability (P < 0.004). Elevated androstenedione (P < 0.01), testosterone (P < 0.001), and glucose (P < 0.01) levels also occurred. In PCOS follicles containing mature oocytes, however, elevated androgen levels were accompanied by both normal progesterone concentrations and a normal inverse relationship between glucose depletion and lactate accumulation. CONCLUSION: Hyperandrogenic follicles with mature oocytes from PCOS women receiving GnRH analog/recombinant human FSH therapy for IVF show sufficient glucose utilization for normal luteinization.

Diagnosis of polycystic ovaries by three-dimensional transvaginal ultrasound.

OBJECTIVE: To study diagnostic thresholds for polycystic ovary (PCO). DESIGN: Retrospective cohort study. SETTING: Academic hospital. PATIENT(S): Normoandrogenic ovulatory women and patients with polycystic ovary syndrome (PCOS). INTERVENTION(S): Two-dimensional (2D) and three-dimensional (3D) transvaginal ultrasound. MAIN OUTCOME MEASURE(S): The mean follicle number per ovary (FNPO) of both ovaries and the maximum number follicles in a single sonographic plane (FSSP) of either ovary were determined using 3D transvaginal ultrasound. Ovarian volume was determined using 2D transvaginal ultrasound. RESULT(S): Twenty-nine normoandrogenic ovulatory women were compared with 10 patients with PCOS. Diagnostic thresholds for PCO with 100% specificity as determined by receiver operator characteristic (ROC) curves were > or =20 for mean FNPO, > or =10 for maximum FSSP, and > or =13 cm3 for ovarian volume. Both 2D and 3D transvaginal ultrasound were highly accurate in the diagnosis of PCO as determined by areas under the curve (AUC) that were >90% for all three measures. CONCLUSION(S): Mean FNPO and maximum FSSP by 3D transvaginal ultrasound have comparable high accuracy for diagnosis of PCO. The diagnostic threshold with 100% specificity for mean FNPO is > or =20, which is greater than suggested by the Rotterdam Consensus Workshop in 2003. Use of the consensus standard, consequently, may result in overdiagnosis of PCO. A threshold of > or =20 mean FNPO using 3D transvaginal ultrasound may be appropriate to minimize false-positive diagnoses of PCO.

Diminished intrafollicular estradiol levels in in vitro fertilization cycles from women with reduced ovarian response to recombinant human follicle-stimulating hormone.

OBJECTIVE: To correlate serum and intrafollicular E(2) levels in women receiving GnRH agonist and recombinant human (h)FSH for IVF. DESIGN: Prospective study. SETTING: Academic IVF center. PATIENT(S): Twenty-three nonhirsute ovulatory women. INTERVENTION(S): In vitro fertilization cycles were classified as high- or low-normal response, according to whether the amount of recombinant hFSH administered was below or above, respectively, the mean recombinant hFSH given to all women combined. Serum bioactive LH and immunoreactive FSH were measured during pituitary desensitization preceding recombinant hFSH and repeated at oocyte retrieval. The first mature follicle aspirated from either ovary had a mean diameter >15 mm. MAIN OUTCOME MEASURE(S): Serum and follicular fluid (FF) insulin, bioactive LH, immunoreactive FSH, and steroid levels. RESULT(S): Basal serum gonadotropin levels were comparable between female groups. Serum immunoreactive FSH levels, but not bioactive LH levels, at oocyte retrieval were greater in cycles of low-normal vs. high-normal response, whereas maximum serum E2 levels and total oocyte counts were similar between both groups. Despite elevated FF immunoreactive FSH levels, FF E2 was decreased in low-normal response cycles. Intrafollicular T and P also were decreased and increased, respectively, in cycles of low-normal response, although FF bioactive LH levels were comparable in both groups. CONCLUSION(S): Intrafollicular E2 is decreased in cycles of reduced ovarian responsiveness to GnRH agonist and recombinant hFSH and is not predicted by maximal serum E2 or number of oocytes retrieved.

Nonhuman primates contribute unique understanding to anovulatory infertility in women.

Anovulatory infertility affects a large proportion of reproductive-aged women. Major improvements in successful clinical treatment of this prevalent disorder in women's health have been made possible because of biomedical research employing nonhuman primates. Experiments on female rhesus monkeys were the first to demonstrate that the key hypothalamic neurotransmitter, gonadotropin-releasing hormone, involved in stimulating pituitary gonadotropin synthesis, storage, and release was bioactive only when released in approximately hourly bursts. This breakthrough in understanding gonadotropin regulation enabled identification of hypogonadotropic, apparently normogonadotropic, and hypergonadotropic forms of anovulatory infertility, and development of appropriate stimulatory or inhibitory gonadotropin therapies. Treatments to overcome anovulatory infertility represent one of the major advances in clinical reproductive endocrinology during the last 25 yr. The future promise of nonhuman primate models for human ovulatory dysfunction, however, may be based on an increased understanding of molecular and physiological mechanisms responsible for fetal programming of adult metabolic and reproductive defects and for obesity-related, hyperinsulinemic impairment of oocyte development.

Eclampsia in Southern Alberta: is there a role for seizure prophylaxis in all women with gestational hypertension?

OBJECTIVE: To evaluate the predictability of eclampsia and explore the role for seizure prophylaxis in a population with a low frequency of seizure prophylaxis. METHODS: A retrospective review was conducted of all women with eclampsia registered at the Foothills Hospital in Calgary, Alberta, between 1991 and 2000. The data collected included timing of seizure in relation to diagnosis of gestational hypertension (GHTN) and delivery, method of seizure prophylaxis (if any), and maternal characteristics. RESULTS: During the study period, 3075 of 38,577 women (8.0%) were diagnosed with GHTN, with or without proteinuria or adverse conditions. Three percent had received magnesium sulfate for seizure prophylaxis. Of these 3075 women, 17 (0.6%) developed eclampsia, none of whom was receiving magnesium sulfate for seizure prophylaxis at the time. Of these, 10 women (59%) exhibited GHTN prior to their first seizure, including 6 women with GHTN with adverse conditions, 3 with GHTN with proteinuria but without adverse conditions, and 1 with GHTN without proteinuria or adverse conditions. Five of the 17 women had seizures that occurred prior to labour, 6 were intrapartum, and 6 were postpartum. Nine (53%) of the 17 women with eclampsia had their initial seizure after the diagnosis of GHTN and before 24 hours postpartum. CONCLUSION: Seizure prophylaxis for all the women with GHTN, from the time of diagnosis through 24 hours postpartum, may have been able to prevent as many as 53% of eclamptic episodes. Three hundred and seven women with GTHN would have to receive seizure prophylaxis to prevent one seizure.