Male Fertility Issues After HSCT
Normal Testicular Function
The normal function of the male reproductive tract is twofold: to produce spermatozoa and male sex hormones, necessary for sexual development. Testicular function is regulated by the anterior pituitary hormones FSH and LH, which are under the controlling influence of hypothalamic gonadotropin-releasing hormone. Testosterone, essential for spermatogenesis, is synthesized and secreted by the Leydig cells in response to stimulation by LH. FSH and testosterone act synergistically on Sertoli cells to promote Sertoli cell function and to support spermatogenesis. During spermatogenesis, germ cell spermatogonia undergo proliferation and differentiation into mature spermatozoa. The time necessary to the production of mature spermatozoa is about 74 days.[37] Spermatogenesis begins in the prepubertal male. Spermarche (release of spermatozoa) occurs during puberty. Once the sperm present, sperm quality does not seem to be affected by the patient age.
Approximately 15% of couples are unable to conceive after one year of unprotected intercourse. A male factor is solely responsible in about 20% of infertile couples and contributory in another 30−40%.[38]
Male Fertility After Cancer Treatment & HSCT
In the male, the Leydig cells are less vulnerable to chemotherapy and radiotherapy than the Sertoli cells and germ cells; as a reflection of this, after HSCT, serum LH levels are typically in the normal range for age, while serum FSH levels are increased. The risk of Leydig cell dysfunction after radiotherapy is inversely related to age and directly correlated with the radiation dose to the testes: patients receiving doses of <12 Gy will usually not require testosterone replacement therapy, but doses of >20 Gy will cause Leydig cell failure in most prepubertal males and doses >30 Gy in most pubertal boys and young adults.[39,40] In contrast, radiation doses as low as 1 Gy can impair spermatogenesis, with doses >4 Gy causing persisting azoospermia. Germinal epithelium of the testis is also very sensitive to the detrimental effects of chemotherapy, irrespective of the patient's pubertal status at time of treatment. Therefore, male cancer patients may be rendered oligospermic or azoospermic before they undergo HSCT. In patients with Hodgkin's lymphoma treated with chemotherapy alone, alkylating agents have been shown to be mostly related with damage of the sperm production.[41]
Sperm concentration does not decrease immediately after gonadotoxic treatment. During the first 4−8 weeks after chemotherapy or radiotherapy has been administered, sperm counts may remain normal. The reason for this is, that spermatogenic stem cells are more sensitive to chemotherapy and radiation than later stage germ cells, which will continue to mature into spermatozoids. Recovery of spermatogenesis therefore depends on the degree of destruction of the early sperm stem cells.[42]
Absence of spermatozoa is a frequent finding in male long-term survivors of HSCT as a result of chemoradiotherapy given before transplantation or as conditioning for HSCT.[43] TBI is the main cause of azoospermia in patients treated with HSCT. Patients conditioned with a total TBI dose of 7.5 Gy or more are at highest risk for prolonged or definitive infertility.[44] In a large retrospective analysis from the European Group for Blood and Marrow Transplantation (EBMT), 81% of the patients receiving TBI presented with azoospermia and only 1% had normal sperm counts in the follow-up sperm analysis.[45] Azoospermia is less frequent in patients conditioned with busulphan and cyclophosphamide (50%) and uncommon in those treated with cyclophosphamide alone.[46] However, with increased follow-up, male recipients surviving more than 10 years, younger than 25 years of age at HSCT, and apparently without chronic GVHD have a reasonable likelihood of spermatogenesis, even when conditioned with standard dose of TBI.[47] Recovery of normal spermatogenesis as defined by WHO guidelines remains unlikely, however.
It is possible that the strong impact of TBI on infertility, masks other potential risk factors, such as chronic GVHD. In the aforementioned recent publication from the EBMT on sperm analyses, the subgroup of patients not conditioned with TBI presented ongoing chronic GVHD as main adverse factor for sperm recovery (RR: 3.11; 95% CI: 1.02−9.47; p = 0.045).[45] The impact of GVHD affecting fertility has already been described in a study on long-term survivors treated for severe aplastic anemia and conditioned with cyclophosphamide alone: overall, the probability for a male patient to father a child was 50%; it was 29% for those with GVHD and 62% for patients without GVHD.[48] So far, it is not clear whether this sterilizing effect of chronic GVHD is due to a graft versus testis effect, or simply the consequence of chronic disease.
Screening for Infertility & Fertility Preservation
The condition of male fertility is most easily provided by semen analysis, assessing sperm concentration, motility and morphology. Infertility can occur temporary after HSCT; an azoospermic seminal fluid specimen does not exclude that sperm production will be restored at a later point in time. Therefore, repetitive sperm analysis may be indicated. As for females, the definitive proof of recovered fertility is provided by successful fatherhood following naturally induced pregnancy of the survivor's partner. Tests such as FSH, LH and testosterone are necessary for gonadal function, particularly in prepubertal boys but are not very useful to determine fertility condition. In adult long-term HSCT survivors, FSH is usually increased, and testosterone and LH are normal.[49]
Fertility preservation options for males treated with HSCT are summarized in Table 1. An algorithm for fertility preservation options according to the pubertal age of male patients at time of HSCT is presented in Figure 1B. Sex hormone replacement is usually not necessary in most of the patients treated with HSCT, despite spermatogenesis is reduced or absent. Furthermore, such hormonal treatment does not restore spermatogenesis. Gonadal shielding during the radiation therapy to reduce radiation damage, may preserve fertility, but is not appropriate for transplantation of most of the hematological malignancies because of the risk of residual neoplastic cells in the testis. In the transplant setting gonadal shielding has been rarely used for irradiation in non-malignant diseases.[50] Due to the high probability of infertility after transplantation, the possibility of semen cryopreservation should be addressed before treatment commences in any case. Semen cryopreservation is an established and successful technique for the adult male and postpubertal boys, but is more challenging to perform in adolescents. Semen cryopreservation is a readily available option than can be offered in practically every fertility center and can be performed with hardly any delay in the treatment.
If a young patient with sperm production is unable to provide a semen sample, electroejaculation or surgical sperm extraction can be performed. Penile vibratory stimulation and electroejaculation is currently used in case of ejaculatory dysfunction due to spinal cord injury. It has been successfully applied in the HSCT setting, to induce ejaculation in pubertal boys who failed to obtain ejaculation by masturbation.[37,51] For prepubertal boys, the situation is more complicate. There are no established option, to date. No effective gonadoprotective drug is yet available for in vivo spermatogonial stem cell protection in humans. The cryopreservation of immature testicular tissue including spermatogonial stem cells with the aim of retransplanting them after cure is currently investigated.[52–54]
After HSCT, there is a need for prolonged banking of cryopreserved sperm. In single center study of the UK, the median time to attempt pregnancy after transplantation was 8 years, with wide range extending to 22 years. As third of the survivors using stored sperm did so after more than 10 years.[34] This need of prolonged sperm storage for this group of patients is of importance, since in some reproductive center, the median storage time is only 3 years.
Despite infertility being common in males after HSCT, late recovery of spermatogenesis may occur in some patients. Therefore counseling in relation to contraception is recommended for long-term survivors. Periodic analysis of sperm should be undertaken to evaluate fertility recovery, particularly in patients who have received less gonadotoxic regimens. Even if the post-HSCT sperm count is low or there is poor sperm quality, paternity may still be possible using assisted reproductive technology. Protection against sexually transmitted infections independent of fertility status is strongly recommended.
Expert Rev Hematol. 2013;6(4):375-388. © 2013 Expert Reviews Ltd.
