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.

State insurance mandates and racial and ethnic inequities in assisted reproductive technology utilization.

OBJECTIVE: To examine whether the (1) scope of state-mandated insurance coverage for assisted reproductive technology (ART) and (2) proportion of the population eligible for this coverage are associated with reductions in racial/ethnic inequities in ART utilization. DESIGN: National cross-sectional, ecologic study. SUBJECTS: We employed estimates from the US Census Bureau of all women 20-44 years of age living in the US in 2018. Data on the number of women who initiated an ART cycle during that year that were reported to the US Centers for Disease Control and Prevention were obtained from the National ART Surveillance System. EXPOSURE: State mandates were classified according to the scope of required coverage for fertility services: Comprehensive, Limited, and No Mandate. MAIN OUTCOME MEASURES: Race and ethnic-specific ART utilization rates, defined as the number of women undergoing ≥1 ART cycles per 10,000 women, were the primary outcomes. As state mandates do not apply to all insurance plans, Comprehensive Mandate utilization rates were recalculated using denominators corrected for the estimated proportions of populations eligible for coverage. RESULTS: Across all mandate categories, Non-Hispanic (NH) Asian and NH White populations had the highest ART utilization rates, whereas the lowest rates were among Hispanic, NH Black, and NH Other/Multiple Races populations. Compared with the NH Asian reference group, the NH Black population had smaller inequities in the Comprehensive Mandate group than the No Mandate group (rate ratio [RR 0.33 [0.28-0.38] vs. RR 0.23 [0.22-0.24]). Using the Comprehensive Mandate group for each race/ethnicity as the reference, the NH Black and NH Other/Multiple Races populations showed the largest relative differences in utilization between the No Mandate and Comprehensive Mandate groups (RR 0.39 [0.37-0.41] and 0.33 [0.28-0.38], respectively). Within the Comprehensive Mandate group, the disparities in the Hispanic and NH Black populations moved toward the null after correcting for state-mandated insurance eligibility. CONCLUSIONS: Racial/ethnic inequities in ART utilization were reduced in states with comprehensive infertility coverage mandates. Inequities were further attenuated after correcting for mandate eligibility. Mandates alone, however, were not sufficient to eliminate disparities. These findings can inform future strategies aimed at improving ART access under a social justice framework.

From oocytes to a live birth: Are we improving the biological efficiency?

OBJECTIVE(S): The objectives of our study were to investigate the live birth rate (LBR) per oocyte retrieved during in vitro fertilization, in patients who had used all their embryos and to extrapolate the LBR in patients with remaining frozen embryos by calculating the expected LBR from these embryos. DESIGN: A retrospective cohort study. SETTING: A single academically affiliated fertility clinic. PATIENT(S): Autologous in vitro fertilization cycles from January 2014 to December 2020. Data on the number of oocytes retrieved, number of embryos obtained and transferred (at cleavage or blastocyst-stage), use of preimplantation genetic testing for aneuploidy (PGT-A), and number of live births were obtained. The expected LBR was estimated in patients with remaining frozen embryos according to nationally reported Society for Assisted Reproductive Technology LBR data. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Live birth rate per oocyte retrieved. RESULT(S): A total of 12,717 patients met the inclusion criteria and underwent a total of 20,677 oocyte retrievals which yielded a total of 248,004 oocytes and 57,268 embryos (fresh and frozen). In patients who had fully utilized all their embryos the LBR per oocyte was 2.82% (ranging from 11.3% aged <35 years to 1.2% aged >42 years). Stratification of the population based on PGT-A utilization yielded similar results (with PGT-A: 2.88% and without PGT-A: 2.79%). When stratified by the Society for Assisted Reproductive Technology age groups, the addition of PGT-A in patients aged 35-37 and 38-40 years yielded higher LBR per oocyte compared with patients who did not add PGT-A (P<.05). In patients with remaining frozen embryos who had added PGT-A, the projected LBR per oocyte was 8.34%. Use of PGT-A in patients aged <35 and 35-37 years decreased LBR per oocyte (P<.001 and P=.03, respectively) but improved LBR per oocyte in patients aged 38-40 and 41-42 years (P=.006 and P=.005, respectively). Poisson regression analysis demonstrated an age threshold of 38.5, below which PGT-A lowers LBR per oocyte compared with no PGT-A. CONCLUSION(S): Despite clinical and scientific advances in Assisted Reproductive Technology, with the current protocols of ovarian stimulation, the LBR per oocyte remains low reflecting a biological barrier that has yet to be overcome. Overall, the addition of PGT-A did not demonstrate improved outcomes.

The Clinical Significance of Embryonic Chromosomal Errors in Recurrent Pregnancy Loss: an Analysis of 1107 Miscarriages.

The objective of this study was to characterize the relationship between embryonic chromosomal errors in the products of conception (POC) and maternal age, gestational age (GA) of pregnancy loss, and findings on routine recurrent pregnancy loss (RPL) workup. This is a retrospective cohort study of women with a history of ≥ 2 pregnancy losses and who underwent cytogenetic testing on the POC of a subsequent pregnancy loss at an academic tertiary RPL referral center. The association between the odds of embryonic chromosomal errors in POC and maternal age, GA of pregnancy loss, as well as RPL work up findings was investigated. A total of 1107 miscarriages were analyzed from 741 women. There was an overall linear relationship between embryonic chromosomal errors and maternal age, with a nearly twofold increase in the odds of chromosomal error with every 5-year increase in maternal age (P < 0.0001). The association between chromosomal errors and GA was also linear (P = 0.0001), with most losses having no chromosomal errors after 13 weeks' gestation. Women with ≥ 1 positive findings on routine RPL diagnostic workup had lower odds of embryonic chromosomal errors compared to those with a normal workup [OR 0.57 (95% CI = 0.41-0.80)]. Notably, the estimated prevalence of chromosomal error remained high (> 60%) in women ≥ 35 years old irrespective of findings on routine evaluation. While embryonic chromosomal errors were associated with advanced maternal age, early GA of loss, and a negative routine RPL evaluation, the prevalence of chromosomal errors remained high in all subpopulations. These findings suggest that primary cytogenetic testing on POCs should be offered at the time of second and subsequent pregnancy losses in all RPL patients.

Simulation-based training for embryo transfer for clinicians with differing levels of expertise: an application of the American Society for Reproductive Medicine Embryo Transfer Simulator.

Objective: To compare the learning curve of clinicians with different levels of embryo transfer (ET) experience using the American Society for Reproductive Medicine (ASRM) Embryo Transfer Simulator. Design: Prospective cohort study. Setting: Single large university-affiliated in vitro fertilization center. Patients: Participants with 3 levels of expertise with ET were recruited: "group 1" (Reproductive Endocrinology and Infertility attendings), "group 2" (Reproductive Endocrinology and Infertility nurses, advance practice providers, or medical assistants), and "group 3" (Obstetrics and Gynecology resident physicians). Interventions: All participants completed ET simulation training using uterine cases A, B, and C (easiest to most difficult) of the ASRM ET Simulator. Participants completed each case 5 times for a total of 15 repetitions. Main Outcome Measures: The primary outcome was ET simulation scores analyzed at each attempt for each uterine case, with a maximum score of 155. Secondary outcomes included self-assessed comfort levels before and after the completion of the simulation and total duration of ET. Comfort was assessed using a 5-point Likert scale. Results: Twenty-seven participants with 3 different levels of expertise with ET were recruited from December 2020 to February 2021. For cases A and B, median total scores were not significantly different between groups 1 and 3 at first or last attempts. Group 2 did not perform as well as group 3 at the beginning of case A or group 1 at the end of case B. All groups demonstrated a decrease in total time from the first attempt to the last attempt for both cases. For case C, the "difficult" uterus, groups 2 and 3 exhibited the greatest improvement in total median score: from 0 to 75 from the first to last attempt. Group 1 scored equally well from first through last attempts. Although no one from group 2 or 3 achieved a passing score with the first attempt (80% of the max score), approximately 30% had passing scores at the last attempt. Groups 1 and 3 showed a significant decrease in total time across attempts for case C. Following simulation, 100% of groups 2 and 3 reported perceived improvement in their skills. Group 3 showed significant improvement in comfort scores with Likert scores of 1.71 ± 0.76 and 1.0 ± 0.0 for the "Easy" and "Difficult" cases, respectively, before simulation and 4.57 ± 0.53 and 2.4 ± 1.1 after simulation. Conclusions: The ASRM ET Simulator was effective in improving both technical skill and comfort level, particularly for those with little to no ET experience and was most marked when training on a difficult clinical case.

The effect of interpregnancy interval on preterm birth and low birth weight in singleton pregnancies conceived without assistance or by infertility treatments.

OBJECTIVE: To determine the association of interpregnancy interval on perinatal outcomes and whether this was influenced by mode of conception. DESIGN: Retrospective cohort. SETTING: Centers for Disease Control and Prevention's natality national database. PATIENT(S): Patients who had an index singleton live birth with a preceding live birth. Index pregnancies from 2016 to 2019 were conceived with in vitro fertilization (IVF) (n = 32,829) or ovulation induction/intrauterine insemination (OI/IUI) (n = 23,016) or without assistance (n = 7,564,042). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The primary outcomes evaluated were preterm birth (<37 weeks) and low birth weight (<2,500 g). Multivariable logistic regression was performed to evaluate the association of interpregnancy intervals with perinatal outcomes stratified by mode of conception. Adjusted odds ratios and 95% confidence intervals (CIs) were presented. RESULT(S): Compared with the interpregnancy interval reference group of 12 to <18 months, a <12 month interpregnancy interval was associated with an increase in preterm birth (<37 weeks) for pregnancies conceived with OI/IUI or without assistance (aOR, 1.42; 95% CI, 1.16-1.74, and aOR, 1.14; 95% CI, 1.13-1.15, respectively), whereas IVF was not associated with an increase (aOR, 0.90; 95% CI, 0.77-1.04). A <12 month interpregnancy interval was associated with an increase in low birth weight for pregnancies conceived with IVF or OI/IUI or without assistance (aOR, 1.34; 95% CI, 1.09-1.64; aOR, 1.33; 95% CI, 1.01-1.76; and aOR, 1.26; 95% CI, 1.24-1.27, respectively). CONCLUSION(S): An interpregnancy interval of at least 12 months reduces adverse perinatal outcomes for pregnancies conceived with and without infertility treatment.

Endometrial compaction does not predict live birth in single euploid frozen embryo transfers: a prospective study.

STUDY QUESTION: Is there a relationship between endometrial compaction and live birth in euploid frozen embryo transfer (FET) cycles? SUMMARY ANSWER: Live birth rates (LBRs) were similar in both patients that demonstrated endometrial compaction or no compaction in single euploid FETs. WHAT IS KNOWN ALREADY: There has been increasing interest in the correlation between endometrial compaction and clinical outcomes but there has been conflicting evidence from prior investigations. STUDY DESIGN, SIZE, DURATION: This was a prospective observational study from 1 September 2020 to 9 April 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study was performed at a single, academically affiliated fertility center in which patients who had an autologous single euploid FET using a programmed or modified natural cycle protocol were included. All embryos had trophectoderm biopsy for preimplantation genetic testing for aneuploidy followed by vitrification at the blastocyst stage. Two ultrasound measurements of endometrial thickness (EMT) were obtained. The first measurement (T1) was measured transvaginally within 1 day of initiation of progesterone or ovulation trigger injection, and a second EMT (T2) was measured transabdominally at the time of embryo transfer (ET). The primary outcome (LBR) was based on the presence and proportion of compaction (percentage difference in EMT between T1 and T2). MAIN RESULTS AND THE ROLE OF CHANCE: Of the 186 participants included, 54%, 45%, 35%, 28% and 21% of women exhibited >0%, ≥5%, ≥10%, ≥15% and ≥20% endometrial compaction, respectively. Endometrial compaction was not predictive of live birth at any of the defined cutoffs. A sub-analysis stratified by FET protocol type (n = 89 programmed; n = 97 modified natural) showed similar results. LIMITATIONS, REASONS FOR CAUTION: There was the potential for measurement error in the recorded EMTs. The T2 measurement was performed transabdominally, which may cause potential measurement error, as it is generally accepted that transvaginal measurements of EMT are more accurate, though, any bias is expected to be non-differential. The sub-analysis performed looking at FET protocol type was underpowered and should be interpreted with caution. Our study, however, represents a pragmatic approach, as it allowed patients to avoid having to come in for an extra transvaginal ultrasound the day before or on the day of ET. WIDER IMPLICATIONS OF THE FINDINGS: Assessing endometrial compaction may lead to unnecessary cycle cancellation. However, further studies are needed to determine if routine screening for endometrial compaction would improve clinical outcomes. STUDY FUNDING/COMPETING INTEREST(S): No authors report conflicts of interest or disclosures. There was no study funding. TRIAL REGISTRATION NUMBER: NCT04330066.

Higher blastocyst implantation in frozen versus fresh embryo transfers in good prognosis patients.

BACKGROUND: There is emerging evidence that frozen embryo transfers provide a more favorable environment for implantation as compared to fresh embryo transfers. Our objective was to determine if there is a clinical benefit to frozen versus fresh blastocyst transfers in good prognosis patients. METHODS: Subjects undergoing their first or second IVF/ICSI cycle <38 years of age in an OCP pretreated GnRH antagonist stimulation protocol with supernumerary embryos available for blastocyst cryopreservation were eligible for analysis. Primary transfer was exclusively blastocyst transfer. Exclusion criteria consisted of rescue ICSI, preimplantation genetic testing, donor oocytes, and surrogacy. The cohort was divided into two groups based on whether they underwent a fresh vs. frozen primary transfer. The implantation rates were compared using mixed-effects logistic regression. The clinical pregnancy and live birth rates were compared using logistic regression adjusted for number of oocytes retrieved and number of embryos transferred. All models included age, reason for treatment, and number of prior births as covariates. RESULTS: A total of 615 subjects were included in the study. There were no differences in the two groups with respect to age, BMI, baseline ovarian reserve testing, total gonadotropin dosage, and duration of stimulation. The implantation rate was higher in the frozen-embryo group as compared to the fresh-embryo group (59% and 48% respectively; OR 1.58; 95% CI 1.02-2.44). There was a trend towards higher clinical pregnancy and live birth rates in the frozen-embryo group. These differences persisted in the adjusted analysis. CONCLUSIONS: Among good prognosis patients undergoing IVF, frozen embryo transfer was associated with improved implantation rates. Consideration should be given to primary frozen blastocyst transfer in this population.

Clinical outcomes and utilization from over a decade of planned oocyte cryopreservation.

RESEARCH QUESTION: What is the clinical experience of patients who have undergone planned oocyte cryopreservation and oocyte thawing and warming? DESIGN: Retrospective observational cohort study. All women who completed planned oocyte cryopreservation at a single large university-affiliated fertility centre between June 2006 and October 2020 were identified, including the subset who returned to use their oocytes. Patients who underwent oocyte cryopreservation for medical reasons were excluded. Baseline demographics, oocyte cryopreservation and thawing-warming cycle parameters, and clinical outcomes, were extracted from the electronic medical record. The primary outcome was cumulative live birth rate (LBR), and secondary outcomes were cumulative clinical pregnancy rate (CPR), and CPR and LBR per transfer. Results were stratified by age at time of cryopreservation (<38 and ≥38 years). RESULTS: Of 921 patients who underwent planned oocyte cryopreservation, 68 (7.4%) returned to use their oocytes. Forty-six patients (67.6%) completed at least one embryo transfer. The CPR per transfer was 47.5% and LBR was 39.3%. The cumulative LBR per patient who initiated thawing-warming was 32.4%. Cycle outcomes were not significantly different in patients aged younger than 38 years and those aged 38 years or over. No patient aged 40 years or older (n = 6) was successful with their cryopreserved oocytes. Ten patients (14.7%) who were unsuccessful with their cryopreserved oocytes achieved a live birth using donor oocytes, with most (7/10) of these patients aged 38 years and older. CONCLUSION: Only a small percentage of patients returned to use their oocytes, and 32% of those were able to achieve a live birth.

Perinatal outcomes in singleton pregnancies after in vitro fertilization cycles over 24 years.

OBJECTIVE: To determine how a shift in clinical practice along with laboratory changes has impacted singleton perinatal outcomes after autologous in vitro fertilization (IVF) cycles. DESIGN: Retrospective cohort. SETTING: Single academic fertility clinic. PATIENT(S): Singleton live births resulting from all IVF cycles (n = 14,424) from August 1, 1995 to October 31, 2019. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Live birth weight, large for gestational age (GA), small for GA, and preterm birth. RESULT(S): The entire cohort consisted of 9,280 fresh and 5,144 frozen IVF cycles. Maternal age, parity, body mass index, neonatal sex, and GA at delivery were similar in both groups. There was a decrease in adjusted birth weight per year over the study period for the entire cohort of IVF cycles (-4.42g, 95% confidence interval [CI]: -6.63g to -2.22g). Rates of large for GA newborns decreased by 1.7% (95% CI: 2.9% to 0.6%) annually across the entire cohort of IVF cycles. Furthermore, there was a decrease in annual rates of preterm birth before 32 weeks by 3.2% (95% CI: 5.9% to 0.5%) across the entire cohort of IVF cycles. Trends were also seen in annual reduction of rates of preterm birth before 37 and 28 weeks. CONCLUSION(S): With the gradual evolution of clinical and IVF laboratory practices, there has been a decrease in birth weight over 24 years for the entire cohort of IVF cycles. Concurrently, noteworthy practice changes have resulted in an improvement in IVF outcomes with decreased rates of large for GA newborns and preterm birth before 32 weeks for the entire cohort of IVF cycles.

Modest Increase in Fertility Consultations in Female Adolescents and Young Adults with Lymphoma: A Population-Based Study.

While survival after hematological malignancies in adolescent and young adult patients is improving, patients report poor oncofertility care. This population-based, retrospective, cohort study used data from the Ontario Cancer Registry and billing codes to identify fertility consultations for lymphoma patients between 2000 and 2018. Consultation trends across time and different patient and physician characteristics were analyzed. We identified 2088 patients and a consultation rate of 3.4% (increasing from 1% in 2000-2006 to 8% in 2014-2018). Patient parity and regional deprivation scores decreased rates. Despite mild improvement, there is ample missed opportunity for fertility discussions.

Anti-Müllerian hormone and embryo quality as determined by time-lapse imaging.

BACKGROUND: There is conflicting evidence as to whether serum anti-Mullerian hormone (AMH) is a biomarker of oocyte quality in addition to its known role in assessing ovarian reserve. This study aims to examine the relationship between AMH and embryo potential as assessed by time-lapse imaging (TLI). METHODS: A total of 106 embryos from 67 patients were included in the study. All subjects were women with recorded pre-treatment AMH levels who underwent in vitro fertilization using a TLI embryo incubator. Exclusion criteria included cases of donor oocytes, rescue-ICSI, and >2 embryos transferred. Individual time measures, presence of multinucleation (MN), and composite TLI score were analyzed in relation to patient AMH. Linear regression was used to model AMH among embryo TLI parameters while controlling for age as a continuous covariate. RESULTS: There was no statistically significant difference in the mean AMH levels between patients in the normal and abnormal time frames for CC2, S2, and T5. Similarly, there was no significant difference in AMH levels based on composite TLI score or presence/absence of multinucleation. The lack of association between AMH levels and embryo TLI variables persisted after controlling for age (Grade P=0.19, CC2 P=0.47, S2 P=0.52, t5 P=0.34, MN P=0.92). CONCLUSIONS: Serum AMH is not predictive of embryo quality as assessed by TLI standardized time intervals, composite score, and presence of MN. From a clinical perspective, these findings suggest that diminished ovarian reserve alone does not imply poorer quality of individual embryos.

Patterns of Referral for Fertility Preservation Among Female Adolescents and Young Adults with Breast Cancer: A Population-Based Study.

PURPOSE: To assess the fertility preservation (FP) referral rates and patterns of newly diagnosed breast cancer in female adolescent and young adult (AYA) patients. METHODS: Women aged 15-39 years with newly diagnosed breast cancer in Ontario from 2000 to 2017 were identified using the Ontario Cancer Registry. Exclusion criteria included prior sterilizing procedure, health insurance ineligibility, and prior infertility or cancer diagnosis. Women with a gynecology consult between cancer diagnosis and chemotherapy commencement with the billed infertility diagnostic code (ICD-9 628) were used as a surrogate for FP referral. The effect of age, parity, year of cancer diagnosis, staging, income, region, neighborhood marginalization, and rurality on referral status was investigated. RESULTS: A total of 4452 patients aged 15-39 with newly diagnosed breast cancer met the inclusion criteria. Of these women, 178 (4.0%) were referred to a gynecologist with a billing code of infertility between cancer diagnosis and initiation of chemotherapy. Older patients, prior parity, and advanced disease were inversely correlated with referrals. Referral rates also varied regionally: patients treated in the south-east and south-west Local Health Integration Networks (LHINs) had the highest probability of referral, and patients covered by north LHINs had the lowest (central LHIN as reference). General surgeons accounted for 36.5% of all referrals, the highest percentage of all specialists. Referral rates significantly increased over time from 0.4% in 2000 to 10.7% in 2016. CONCLUSION: FP referral rates remain low and continue to be influenced by patient demographics and prognosis. These findings highlight the need for further interdisciplinary coordination in addressing the fertility concerns of AYA with newly diagnosed breast cancers.

Testosterone in Women: Measurement and Therapeutic Use.

Androgens, both in excessive and depleted states, have been implicated in female reproductive health disorders. As such, serum testosterone measurements are frequently ordered by physicians in cases of sexual dysfunction and in women presenting with hirsutism. Commercially available androgen assays have significant limitations in the female population. Furthermore, the measurements themselves are not always informative in patient diagnosis, treatment, or prognosis. This article reviews the limitations of serum androgen measurements in women suspected to have elevated or reduced androgen action. Finally, we consider when therapeutic use of androgen replacement may be appropriate for women with sexual interest/arousal disorders.

Outcomes of a Decade of Routine Cervical Screening in a Canadian Adolescent Obstetrics Clinic.

OBJECTIVE: New recommendations from the Ontario Cervical Cancer Screening Program indicate that initiation of screening should be delayed to age 21. However, there is sparse evidence pertaining to pregnant adolescents. Our objective was to determine whether early cervical cancer screening in pregnant adolescents confers an advantage over delayed screening in the prevention of cervical carcinoma. METHODS: We conducted a retrospective cohort study of cervical cancer screening in all pregnant adolescents receiving antenatal care through an obstetrics clinic for adolescents between 2000 and 2010. Clinic attendees had an antenatal and/or postpartum Pap smear, with follow-up according to standard recommendations. Results were recorded together with information on regression, persistence, or progression of abnormal cytology, colposcopy referrals, and cervical biopsies. There is a single regional colposcopy clinic. RESULTS: At least one Pap smear result was documented in 365 of the 388 patients. Of these 365 smears, 88 had abnormal cytology, 76 (86.4%) of which were reported as atypical cells of undetermined significance/low-grade squamous intraepithelial lesion, 11 (12.5%) high-grade squamous intraepithelial lesion (HSIL), and one atypical glandular cells (1.1%). Follow-up cytology was available for 78 patients. No patient lost to follow-up had subsequent referrals for colposcopic assessment in the region. Overall, cytologic abnormalities regressed in 75 (96.1%), persisted in two (2.6%), and progressed in one patient (1.3%). Twenty-three patients (of 365) required a total of 68 colposcopy visits and 17 biopsies, but ultimately only three loop electrosurgical excision procedures (LEEPs) and one laser vaporization were performed. Only one LEEP in a 20-year-old demonstrated HSIL. CONCLUSION: This population of pregnant adolescents had a high incidence of low-grade cervical abnormalities with a high rate of regression. Routinely screening these pregnant adolescents resulted in numerous repeat visits, repeat Pap smears, and colposcopy referrals, and led to patient anxiety and systemic costs. Not a single case of cervical cancer was prevented that would not otherwise have been identified by adherence to the new guidelines.

Sortilin mediates the lysosomal targeting of cathepsins D and H.

Delivery of soluble lysosomal proteins to the lysosomes is dependent primarily on the mannose 6-phosphate receptor (M6PR). However, in I-cell disease (ICD), in which the M6PR pathway is non-functional, some soluble lysosomal proteins continue to traffic to the lysosomes. In this paper, we tested the hypothesis that cathepsins D and H, two soluble proteases that exhibit M6PR-independent trafficking, are targeted to the lysosomes by sortilin. Using a dominant-negative sortilin construct and small interfering RNA (siRNA) we demonstrated that while cathepsin D transport is partially dependent upon sortilin, cathepsin H requires exclusively sortilin for its transport to the lysosomes. Our results suggest that sortilin functions as an alternative sorting receptor to the M6PR for these soluble hydrolases.