Thomson, Angela B.

2018-01-31T11:38:53Z

2018-01-31T11:38:53Z

2003

The successful treatment of childhood cancer with chemotherapy and radiotherapy may be associated with testicular damage resulting in impaired spermatogenesis and temporary or permanent infertility in adulthood. In this study testicular function and semen quality was investigated in 33 survivors of childhood cancer. Treatment of childhood cancer was associated with a significant risk of impaired spermatogenesis, with 30.3% of this population being azoospermic and 18.2% being oligozoospermic. Moreover, in those men who do have surviving spermatogenesis after treatment, it is commonly compromised, with reductions being observed in ejaculate volume, sperm concentration, sperm motility and the proportion of morphologically normal sperm. Only 33.3% of this group of 33 male childhood cancer survivors had completely normal semen quality by conventional criteria. However, the sperm produced do not appear to carry a greater burden of damaged DNA compared with the healthy population, suggesting that assisted conception treatment is a safe option for these men.

Detection of gonadal damage in the prepubertal male is hampered by lack of a sensitive marker. The role of inhibin B as a marker of early gonadotoxic effects of chemotherapy in prepubertal children treated for cancer was investigated. In prepubertal boys, chemotherapy had little immediate effect on Sertoli cell production of inhibin B during and immediately after treatment stopped, although one boy showed a delayed deleterious effect. Inhibin B changed earlier and appeared to be a more sensitive marker of gonadal damage than FSH or LH. Prospective studies are underway combining inhibin B with FSH, LH and sex hormone measurements, to assess the impact of cancer therapy on gonadal function in children, particularly as they approach and progress through puberty.

For prepubertal boys fertility preservation through semen cryopreservation is not an option and consequently, attention is focusing on the development of techniques that might preserve or restore fertility potential in boys being subjected to gonadotoxic cancer therapy. In rats, it has been shown that some germ cells survive cytotoxic therapy and that the resulting azoospermia is a consequence of the inability of those spermatogonia that are present to proliferate and differentiate. Suppression of the hypothalamic-pituitary-gonadal (H-P-G) axis facilitates recovery of spermatogenesis following such cytotoxic treatment. Investigation of whether suppression of the H-PG axis in men rendered azoospermic by treatment for childhood cancer might restore spermatogenesis was undertaken, using both semen analysis and testicular biopsy as end points. In men treated with sterilising radiotherapy and chemotherapy for childhood cancer, effective gonadotrophin suppression with medroxyprogesterone acetate for at least 3 months did not result in restoration of spermatogenesis. The absence of histological evidence of spermatogonial stem cells in testicular biopsies from these men before and after suppression suggests complete ablation of the germinal epithelium and irreversible infertility.

Understanding the vulnerability of the prepubertal human testis to cytotoxic damage is compounded by the dearth of data describing normal testicular development in the prepubertal human. Based on immunohistochemical studies in marmosets, a primate that exhibits a similar developmental profile to the human male, it has been shown that significant testicular development occurs during childhood long before the clinical onset of puberty. If we can establish that cell activity does occur in the 'quiescent' testis in boys and is comparable to changes shown in the marmoset, it will validate use of the marmoset as a model for the human in this instance and give encouragement to the possibility of using this primate model to develop a method of protecting spermatogenesis in boys undergoing cancer therapy prior to puberty. Preliminary studies to investigate the development of the prepubertal human testis confirmed testicular cell activity in the foetal and neonatal periods and infancy comparable to that shown in the marmoset. However, to date development during mid childhood and early puberty has proved to be somewhat discordant with the marmoset studies. It is too premature to definitively conclude that marmoset and human testicular development are dissimilar, as a number of explanations have been proffered to explain the discrepancies, including suboptimal tissue fixation and antigen preservation in the human tissues.

http://hdl.handle.net/1842/27532

The University of Edinburgh

Annexe Thesis Digitisation Project 2017 Block 16

Already catalogued

Male fertility in survivors of childhood cancer

Thesis or Dissertation

MD Doctor of Medicine