Fertility in Young Adults Who Did (Not) Store Testicular Tissue Before a Treatment Leading to Fertility Problems.

Fertility in Young Adults Who Did (Not) Store Testicular Tissue Before a Treatment Leading to Fertility Problems.

Follow-up of Fertility in Young Adults Who Did or Did Not Store Testicular Tissue Before Gonadotoxic Treatment for Fertility Preservation.

This study is a prospective comparative interventional cohort study. The study population consists of young adults (≥18 years) cured of childhood cancer or hematological disorders for which they received high-risk gonadotoxic treatment (with an ≥80% risk of later fertility problems) during childhood. In order to preserve their fertility, these patients were proposed to store their testicular tissue at a young age. These young adults will be invited by e-mail/letter/telephone to evaluate their fertility status (Tanner stage, testicular volume, hormones, semen analysis) at adult age and at least one year after the last received gonadotoxic treatment. A prospective analysis of data on their fertility status will be performed in order to identify differences between young adults who underwent a testicular tissue biopsy procedure (which is performed to harvest testicular tissue) at a young age and those who did not. The results of this prospective analysis will also be compared to the reproductive health of spontaneously conceived young adults.

Cancer patients and patients suffering from hematological disorders require gonadotoxic treatments (like chemo- and radiotherapy) and/or total body irradiation as a conditioning therapy before bone marrow transplantation. One of the possible side effects of these therapies is life-long sterility or subfertility. Currently, the only option for pre- and peripubertal boys (who do not yet produce mature spermatozoa) is to bank testicular tissue before gonadotoxic treatment, followed by auto-transplantation at adulthood. While evidence shows that immediate surgical complications of such a biopsy procedure are rare (2-3%), only limited data is available on the potential long-term adverse events. Hence, it is important to assess these patients' fertility status at adult age to ensure that there are no late effects related to the biopsy procedure. Therefore, this prospective comparative interventional cohort study was designed to investigate the effects of a testicular tissue biopsy at a young age on the future fertility. The study population for this project consists of young adult (≥18 years) patients who were diagnosed with cancer or hematological disorders during childhood for which they received high-risk gonadotoxic treatment (with ≥80% risk of facing fertility problems in adult life). These patients were offered to undergo a testicular tissue biopsy at a young age in the context of fertility preservation. Both patients who did and those who did not undergo the biopsy procedure will be included in this study. A prospective analysis of data on their fertility status will be performed to identify differences between the young adults who underwent a testicular tissue biopsy procedure at a young age and those who did not. At adult age and at least one year after the last received gonadotoxic treatment, the patients will be invited by e-mail, by letter, or by telephone to evaluate their fertility status. The results will be discussed during a consultation with a fertility specialist and a psychologist (if necessary). Only in case of infertility (azoospermia) or subfertility (oligo-, astheno- or teratozoospermia), the semen analysis will be repeated one year later as the recovery of spermatogenesis with the return of sperm production may occur several years after oncological treatment. To assess the patient's fertility status, the following examinations and procedures will be performed: A physical examination where the patient's age, weight, height, body mass index, blood pressure, testes volumes using a Prader orchidometer, and Tanner stage (to score the patient's pubertal maturation) will be determined. The start, duration, and the prescribed dose of hormonal substitution treatment will also be noted if applicable. A scrotal ultrasound to measure the patient's testes volumes and to identify potential abnormalities in the testicular parenchyma. A morning blood sample will be collected to evaluate the serum levels of LH, FSH, IGF1, TSH, FT4, PRL, T, E2, cortisol, ACTH, and INHB. A semen analysis after a 48 hours' abstinence period (according to the WHO criteria) to evaluate the ejaculate volumes, sperm concentration, sperm motility, and sperm morphology. An anti-sperm antibody test: (in)direct mixed anti-globulin reaction testing. A sperm DNA fragmentation test: sperm chromatin dispersion test. For this study, the following data will be collected from the patient's medical records: The patient's diagnosis and age at that moment, the type of treatment received, and the cumulative dose (chemotherapy, radiotherapy, total body irradiation, bone marrow transplantation, type and frequency of surgery, …), and the time since the last received gonadotoxic treatment. Whether or not a testicular tissue biopsy procedure was performed at a young age, specifying the biopsy size (orchiectomy, hemi-orchiectomy, or smaller portion) and location (left or right), the patient's age at the time of biopsy, and why the patient and his parents accepted or refused the testicular tissue banking. The collected data will be compared between the young adult patients who did and those who did not undergo the testicular tissue biopsy procedure at a young age. In addition, these results will be compared to the WHO reference values and published data from a control group, consisting of spontaneously conceived young adults from previous ICSI offspring follow-up studies conducted at the UZ Brussel. In this way, a possible association between the biopsy procedure and the patient's fertility could be identified.

Male fertility preservation, Testicular tissue biopsy, Male fertility status, Tanner stage, Testicular volume, Hormones, Semen analysis

This study is a prospective comparative interventional cohort study. The fertility status of young adults (≥18 years) cured of childhood cancer or hematological disorders for which they received high-risk gonadotoxic treatment (with an ≥80% risk of later fertility problems) during childhood will be compared between patients who did and those who did not undergo a testicular tissue biopsy procedure at a young age as a fertility preservation strategy in order to identify a possible association between the biopsy procedure (which is performed to harvest testicular tissue) and the later fertility outcome. Their fertility status will also be compared to the reproductive health of spontaneously conceived young adults that has already been published (Belva F et al., 2016/2017/2019).

Young adults (≥18 years) cured of childhood cancer or hematological disorders for which they received high-risk gonadotoxic treatment (with an ≥80% risk of later fertility problems) during childhood and who have chosen to undergo a testicular tissue biopsy procedure at a young age as a fertility preservation strategy.

Young adults (≥18 years) cured of childhood cancer or hematological disorders for which they received high-risk gonadotoxic treatment (with an ≥80% risk of later fertility problems) during childhood and who have refused to undergo a testicular tissue biopsy procedure at a young age as a fertility preservation strategy.

Spontaneously conceived young adults whose data on reproductive health have already been published (Belva F et al., 2016/2017/2019).

A physical examination to measure the patients' weight, height, body mass index, blood pressure and testicular volume using a Prader orchidometer and to determine the patients' Tanner stage (secondary sexual development).

A scrotum ultrasound to measure the patients' testicular volume and to investigate potential abnormalities in the testicular parenchyma.

A morning blood sample to evaluate the serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T), estradiol (E2), inhibin B (INHB), thyroid-stimulating hormone (TSH), free thyroxine (FT4), insulin-like growth factor 1 (IGF1), prolactin (PRL), cortisol and adrenocorticotropic hormone (ACTH). Upon approval by the patient himself, a spare blood sample will be collected and retained for 5 years for subsequent research purposes limited to the context of the present study.

A semen analysis to evaluate the ejaculate volumes, sperm concentration, sperm motility and sperm morphology. If sperm is found in the semen sample, an antisperm antibody test ((in)direct mixed anti-globulin reaction test) and a sperm DNA fragmentation test (sperm chromatin dispersion test) will be performed. Upon approval by the patient himself, the surplus of the semen sample will be retained for 5 years for subsequent research purposes limited to the context of the present study.

The patients' fertility status (Tanner stage, testicular volume, hormones, semen analysis) will be evaluated once a year. Only in case of infertility (azoospermia) or subfertility (oligo-, astheno- or teratozoospermia), the different interventions will be repeated one year later as the recovery of spermatogenesis with return of sperm production may occur several years after gonadotoxic treatment.

Impact of high-risk gonadotoxic treatment (with an ≥80% risk of later fertility problems) received during childhood on fertility restoration.

The patients' spermatogenesis (with return of sperm production) will be evaluated through semen analysis once a year after cessation of gonadotoxic treatment.

Inclusion Criteria: Young adults (≥18 years). Diagnosis of cancer or hematological disorder during childhood (<18 years). High-risk gonadotoxic treatment (with an ≥80% risk of later fertility problems) during childhood. At least one year after the last received gonadotoxic treatment. Did or did not undergo a testicular tissue biopsy procedure at a young age as a fertility preservation strategy. Exclusion Criteria: Prepubertal patients and adolescents (<18 years).

Belva F, Bonduelle M, Roelants M, Michielsen D, Van Steirteghem A, Verheyen G, Tournaye H. Semen quality of young adult ICSI offspring: the first results. Hum Reprod. 2016 Dec;31(12):2811-2820. doi: 10.1093/humrep/dew245. Epub 2016 Oct 5.

Belva F, Roelants M, De Schepper J, Van Steirteghem A, Tournaye H, Bonduelle M. Reproductive hormones of ICSI-conceived young adult men: the first results. Hum Reprod. 2017 Feb;32(2):439-446. doi: 10.1093/humrep/dew324. Epub 2016 Dec 21.

Belva F, Bonduelle M, Tournaye H. Endocrine and reproductive profile of boys and young adults conceived after ICSI. Curr Opin Obstet Gynecol. 2019 Jun;31(3):163-169. doi: 10.1097/GCO.0000000000000538.