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Effects of cytotoxic agents on gonadal function in adult men

Effects of cytotoxic agents on gonadal function in adult men
Literature review current through: Jan 2024.
This topic last updated: Apr 28, 2023.

INTRODUCTION — Significant advances have been made in the treatment of a number of malignancies in men. Increasing interest has therefore been focused on the late toxicities of cancer chemotherapy in long-term survivors. One of the most common long-term side effects of cytotoxic agents in men is gonadal dysfunction [1-4]. The following general rules apply to the gonadal toxicity of chemotherapy in the male.

Spermatogenesis is much more likely to be disrupted than is testosterone production, because the germinal epithelium of the testis is more sensitive to damage from cytotoxic drugs than the Leydig cells.

The degree of damage to the germinal epithelium is influenced by the stage of sexual maturation of the testis. In general, the postpubertal testis appears to be more susceptible to damage than the prepubertal testis [5].

The magnitude of the effect on sperm production is both drug-specific and dose-dependent [1,3,6-11].

MECHANISM OF DRUG-INDUCED INFERTILITY — The mechanism of action of most cytotoxic chemotherapeutic agents is interference with obligatory cell processes, such as DNA synthesis, in the rapidly dividing cancer cells. However, all cells that undergo rapid division are susceptible to the toxic effects of chemotherapy, and this would include cells involved in spermatogenesis.

Impact on the germinal epithelium — In the testis, the cells within the seminiferous tubules of the germinal epithelium have the highest mitotic and meiotic indices, and are thus most vulnerable to the toxic effects of chemotherapy [1,7]. While sperm counts begin to decline within a few weeks of chemotherapy, it typically takes two to three months for azoospermia to occur, in keeping with the known kinetics of spermatogenesis [12,13]. Because antineoplastic agents act on the sperm cells during cell division, they are most toxic to the rapidly proliferating type B spermatogonia, which can be reproduced from the germinal stem cell layer. However, the severity and duration of gonadal damage induced by cytotoxic agents correlates best with the number of stem cells (type A spermatogonia) that are destroyed [14]. If the stem cells within the tubules remain intact, spermatogenesis may begin to show recovery approximately 12 weeks after treatment. Therefore, drugs that damage the stem cells are likely to cause permanent infertility. The typical histological pattern on testicular biopsy of patients who have received cytotoxic agents is atrophic tubules containing Sertoli cells lining the lumen, a few scattered spermatogonia and spermatids, and peritubular fibrosis [1].

Subtle effects on Sertoli cell function, including changes in cytokeratin expression and inhibin/follicle stimulating hormone (FSH) ratios, have also been reported in adult men who underwent chemotherapy during adolescence [15,16].

Impact on Leydig cells — Less commonly, chemotherapy can damage Leydig cells, the site of testosterone production within the testis [1,3,4,17,18]. However, Leydig cell dysfunction in this setting is typically subclinical, characterized by testosterone levels that are at the lower end of the normal range in association with elevated luteinizing hormone (LH) levels [17]. The clinical significance of this state of "compensated hypogonadism" is still unclear. However, one randomized, placebo-controlled trial of testosterone replacement in 35 men with evidence of mild Leydig cell damage following treatment with cytotoxic chemotherapy for malignancy showed no beneficial impact of 12 months of supplemental testosterone on bone mineral density (BMD), body composition, lipids, or quality of life [19]. In patients with testosterone levels that are clearly hypogonadal, however, testosterone replacement is a reasonable and safe strategy.

IMPACT OF CANCER ON GONADAL FUNCTION — It is important to bear in mind that certain tumors may also be associated with pretreatment abnormalities in testicular function [3,20], particularly Hodgkin lymphoma [21-23], and germ cell tumors [11,12,24-27].

Hodgkin lymphoma — Abnormalities in pretreatment semen analysis are common in male patients with Hodgkin lymphoma [3,20-23]. Of 92 men with Hodgkin lymphoma studied prior to therapy, 67 percent had an abnormal semen sample in terms of sperm count (34 percent), motility (68 percent), or morphology (71 percent) [23]. In another study of 33 men with Hodgkin lymphoma, 12 (36 percent) had abnormalities in sperm count or motility prior to treatment [21]. However, eight of nine patients (89 percent) who consented to testicular biopsy had histological evidence of damage to the seminiferous epithelium [21]. Elevation of basal follicle-stimulating hormone (FSH) levels occurred in 15 percent and luteinizing hormone (LH) in 19 percent [21].

As a result of these pretreatment abnormalities, only 20 to 30 percent of men with Hodgkin lymphoma meet traditional criteria for sperm cryopreservation for intrauterine insemination [28,29] (see 'Semen cryopreservation' below). The precise pathophysiology of the gonadal damage in these patients is not clear, but no correlation has been observed either with the stage of disease or age at presentation. (See "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma".)

Testicular cancer — Up to 50 percent of men with testicular germ cell cancer (TGCC) have evidence of impaired spermatogenesis before any treatment [3,11,20,24-26] or after orchiectomy but before chemotherapy [30] (see "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors", section on 'Cryopreservation of sperm'). In a review of 10 series of men with TGCC who were evaluated prior to chemotherapy, over one-half had oligospermia, 13 percent were azoospermic, and 30 percent had significant elevation in FSH levels [12].

In a second series of 63 men with TGCC evaluated prior to orchiectomy, mean sperm concentrations were significantly lower than those of normal controls, 15 x 106/mL versus 146 x 106/mL, p<0.001 [26]. Although a history of cryptorchidism was four times more common in patients with TGCC than in the controls (22 versus 5 percent), sperm counts remained significantly lower in men with testicular cancer even when those with cryptorchidism were excluded from the analysis (see "Epidemiology and risk factors for testicular cancer", section on 'Cryptorchidism'). This preexisting suppression of spermatogenesis could not be explained by a general effect related to having a malignancy, as higher sperm counts were observed in a control group of men with lymphoma [26].

The mechanism of association between altered spermatogenesis and testicular cancer remains unclear. Histologically, suppression of spermatogenesis can be demonstrated in both the tumor-bearing [31] and the contralateral testis [30]. It has been proposed that factors secreted by the tumor, eg, human chorionic gonadotropin (hCG) or interleukins, may be implicated in the disruption of normal sperm production [32,33]. However, an association between infertility and tumor gonadotropin production has not been shown by others [27]. It is also possible that the germ cell defect in these patients is related to a defect in maturation of both testes that could predispose to cancer in one or both.

Acute leukemia — Although not as well documented as testicular cancer and Hodgkin lymphoma, men with acute leukemia may have poor pretreatment semen quality relative to healthy sperm donors [34].

CHEMOTHERAPEUTIC AGENTS ASSOCIATED WITH INFERTILITY — The primary source of information concerning the impact of cytotoxic drugs on fertility has been studies of patients receiving single agent chemotherapy, often for non-malignant conditions (eg, nephrotic syndrome or autoimmune diseases) (see "Treatment of idiopathic nephrotic syndrome in children", section on 'Alkylating agents'). The chemotherapeutic agents with the most deleterious effect on male fertility are the alkylating agents, including cyclophosphamide, chlorambucil, cisplatin, and busulfan. These drugs all have cumulative dose ranges above which most patients will be rendered permanently infertile [1-4]. The risk of alkylating agent-related infertility is dose-, age-, and gender-dependent. (See "General toxicity of cyclophosphamide in rheumatic diseases", section on 'Gonadal toxicity'.)

Cyclophosphamide — The approximate minimum total dose at which gonadal toxicity begins to become a problem with cyclophosphamide is 200 to 300 mg/kg in prepubertal males, and as little as 100 mg/kg in mature males [5,35]. In one analysis of 116 men who had received cyclophosphamide as a single agent for renal disease (mean total dose 395 mg/kg), the incidence of gonadal dysfunction was 80 percent in men who received cumulative doses in excess of 300 mg/kg [5].

Cumulative cyclophosphamide doses of 6 to 10 g are likely to result in irreversible azoospermia [13]. In a study designed to determine the threshold dose of cyclophosphamide that results in long-term infertility, semen analyses were performed before, during, and after cyclophosphamide-containing combination chemotherapy in men with advanced soft tissue sarcoma [36]. Recovery of normal spermatogenesis was significantly more likely in men who received a cumulative dose of less than 7.5 g/m2 compared with those receiving higher cumulative doses (70 versus 10 percent) [36].

Ifosfamide — The impact of the related drug ifosfamide on long-term fertility is uncertain. In one report of 164 patients undergoing combination chemotherapy with or without ifosfamide for nonmetastatic extremity sarcoma, 10 of 12 men who were tested following treatment were azoospermic; nine had also received ifosfamide and etoposide [37].

However, in a nonrandomized study of adolescents with sarcoma and non-Hodgkin lymphoma (NHL, median age 11.2 years) ifosfamide was associated with a lower risk of gonadal damage than cyclophosphamide [38]. After a median follow up of 10.7 years, follicle-stimulating hormone (FSH) levels were elevated in 47.5 percent of patients who had received cyclophosphamide versus 6 percent of those treated with ifosfamide.

Chlorambucil — In men treated with chlorambucil, cumulative doses up to 400 mg are associated with progressive but reversible oligospermia, while doses in excess of this result in irreversible damage [6].

Cisplatin — Cumulative cisplatin doses >400 mg/m2 result in permanent infertility in approximately 50 percent of men, while doses less than this are less likely to result in long-term impaired fertility [11]. (See 'Multiagent regimens associated with infertility' below.)

Procarbazine — Procarbazine is rarely used as a single agent in the treatment of cancer, except perhaps in the setting of high-grade brain tumors (see "Initial treatment and prognosis of IDH-wildtype glioblastoma in adults"). Data from non-human primates indicate that it is extremely toxic to the germinal epithelium [39]. As deduced from its effects when used in combination therapy for Hodgkin lymphoma (see 'Hodgkin lymphoma' above), procarbazine is also very gonadotoxic in the human [40].

Other agents — Other nonalkylating cytotoxic agents that have a modest but reversible effect on sperm production include methotrexate [41], doxorubicin [42], fluorouracil, fludarabine [43], and the taxanes [2,3]. The effect of chemotherapeutic agents on sperm production is dependent on when sperm counts are assessed. Even cytotoxic agents that have not been shown to affect long-term fertility, such as vinblastine, bleomycin, or etoposide [44], can suppress spermatogenesis in the short term. There is also a report of hydroxyurea negatively affecting sperm counts and motility that did not recover in every patient even after cessation of the agent [45].

Newer targeted therapies such as antibodies (including immune checkpoint inhibitors) and tyrosine kinase inhibitors (TKIs) would be expected to have relatively minimal effect on fertility. However, there are reports of oligospermia in a patient treated with imatinib [46] even though this agent did not affect spermatogenesis in an animal model [47]. Sperm production is dependent on signal transduction pathways that might be inhibited by TKIs, but their effect would be expected to be reversible and that recovery of sperm production would be expected. In addition, rapid but reversible reduction in serum testosterone concentrations has been observed in one study of men treated with crizotinib for non-small cell lung cancer, although in this case the mechanism appears to be central suppression of luteinizing hormone (LH) secretion as opposed to direct toxicity to the Leydig cells [48]. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer".)

Hormonal therapies used to treat prostate cancer are not cytotoxic in the same sense as are chemotherapeutic agents. However, these agents can have dramatic effects of fertility and erectile function by affecting testosterone levels or androgen signaling pathways. (See "Side effects of androgen deprivation therapy".)

MULTIAGENT REGIMENS ASSOCIATED WITH INFERTILITY — Of the chemotherapeutic regimens known to cause infertility in men, the best studied are those used for the treatment of testicular cancer and Hodgkin lymphoma, malignancies that often affect young men, for whom fertility is an important issue. When evaluating the effects of combination therapy in men with these malignancies, it is important to bear in mind that a significant number have a preexisting reduction in sperm counts prior to any therapy. (See 'Impact of cancer on gonadal function' above.)

Cisplatin and testicular cancer — In addition to the high frequency of gonadal dysfunction prior to any treatment, men who receive chemotherapy for testicular cancer usually undergo further deterioration in testicular function compared with those treated with orchiectomy alone [11,49]. The number of chemotherapy courses is an important variable. Men who receive more than four cycles of platinum-based chemotherapy (ie, greater than 400 mg/m2 or a cumulative dose >850 mg of cisplatin) have a 50 percent chance of irreversible impairment of spermatogenesis and infertility [11].

Another important issue is the age of the patient when receiving chemotherapy. In one study, patients treated with a high-dose salvage regimen that included carboplatin, etoposide, and ifosfamide had a significantly different outcome with respect to potential fertility issues based on their age at treatment [50]. Non-azoospermic patients averaged 28.2 years old and azoospermic patients averaged 36.2 years old. (See "Treatment-related toxicity in testicular germ cell tumors", section on 'Spermatogenesis' and "Management of stage I nonseminomatous germ cell tumors", section on 'Adjuvant chemotherapy'.)

Hodgkin lymphoma — In men treated for Hodgkin lymphoma, administration of six or more courses of mechlorethamine, vincristine, procarbazine, and prednisolone (MOPP); or mechlorethamine, vinblastine, procarbazine, and prednisolone (MVPP); results in azoospermia in more than 90 percent of cases [51-55]. In contrast, the alternative ABVD regimen (doxorubicin, bleomycin, vinblastine, and dacarbazine) is significantly less gonadotoxic [53-56]. In one study, as an example, azoospermia and oligospermia developed in 36 and 20 percent of men treated with ABVD, respectively, and all recovered to normal values [53]. In contrast, 97 percent of men treated with MOPP became azoospermic, with recovery of spermatogenesis in only three of 21 men retested during follow-up. This difference in long-term fertility outcome is one of the reasons why ABVD is usually chosen over MOPP as initial therapy for advanced Hodgkin lymphoma. (See "Initial treatment of advanced (stage III-IV) classic Hodgkin lymphoma".)

The addition of rituximab to this regimen would not be expected to negatively affect the effects of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) on sperm production.

Non-Hodgkin lymphoma — In general, chemotherapy regimens used for the treatment of non-Hodgkin lymphoma (NHL) tend to be less gonadotoxic than those used for Hodgkin lymphoma. In a study of 71 men with NHL who received CHOP chemotherapy, all became azoospermic during therapy [10]. By five years following chemotherapy, sperm counts had returned to normal or to the oligospermic range in 67 and 5 percent of men, respectively. (See "Initial treatment of advanced stage diffuse large B cell lymphoma" and "Initial treatment of peripheral T cell lymphoma".)

Much of the reduction in long-term gonadal toxicity in men treated for NHL has been attributed to the avoidance of procarbazine. In one study that compared the incidence of long-term gonadal toxicity in relapse-free survivors of high-grade NHL with those treated for Hodgkin lymphoma, gonadal dysfunction (as assessed by elevated follicle-stimulating hormone [FSH] levels) was twice as frequent in men with Hodgkin lymphoma (65 versus 32 percent) [40]. A comparison of the chemotherapy regimens used in the two groups demonstrated comparable cumulative doses of cyclophosphamide, vincristine, and doxorubicin, but men treated for Hodgkin lymphoma received a median cumulative procarbazine dose of 13.3 g per patient.

This hypothesis is further supported by the fact that other chemotherapy regimens for NHL that do not include procarbazine, eg, VAPEC-B (vincristine, doxorubicin, prednisolone, etoposide, cyclophosphamide, and bleomycin) [57] or MACOP-B (methotrexate, doxorubicin, prednisone, vincristine, cyclophosphamide, and bleomycin) [58], also tend to be less gonadotoxic. Spermatogenesis recovers in almost all patients treated with these regimens.

Leukemia — Despite the greater degree of myelosuppression, the chemotherapeutic regimens that are used to treat acute leukemia appear to be associated with less long-term gonadal toxicity than those used to treat lymphoma, even when prolonged maintenance therapy is administered [59-61]. This was illustrated in a study of 10 men with acute lymphoblastic or undifferentiated leukemia, in whom azoospermia and elevated FSH levels were observed in all after completion of induction and consolidation therapy [59]. However, in all subjects, recovery of spermatogenesis (as indicated by normalization of FSH levels and sperm counts) occurred in the second year of maintenance therapy.

There are other reports of patients being treated with acute myeloid leukemia (AML) regimens who have had long term abnormalities in sperm count or motility; however, in this study the two affected patients were 55 and 59 years old, and therefore the impact on possible infertility is likely to be minimal [62].

Hematopoietic stem cell transplantation (HSCT) — Gonadal damage is an invariable consequence of the high-dose myeloablative chemotherapy used for autologous or allogeneic hematopoietic cell transplantation [63,64]. Such patients are at a higher risk for long-term infertility than those receiving chemotherapy alone [65]. One study of 106 boys who underwent HSCT at a mean age of 8 years showed that those conditioned with busulfan-based regimens or regimens containing only cyclophosphamide had higher adult testicular volumes and lower FSH levels compared with those conditioned with total body irradiation [66]. While the majority of women undergoing high-dose chemotherapy with hematopoietic cell transplantation are rendered permanently infertile, particularly if treated after the age of 25 years, recovery of gonadal function tends to occur more often in men [67-70]. Ongoing graft-versus-host disease is a risk factor for azoospermia after allogenic HSCT [71].

ASSESSMENT OF DRUG-INDUCED INFERTILITY — Evaluation of gonadal function in a male patient who has received cytotoxic chemotherapy should include a physical examination, semen analysis, and hormonal evaluation.

Clinical evaluation — Measurement of testicular size using a Prader orchidometer is key to assessing gonadal function; in normal men, it ranges from 15 to 25 mL. Given that approximately three-quarters of the volume of the testis is made up of seminiferous tubules, physical examination of men who have received gonadotoxic chemotherapy will typically demonstrate a significant decrease in testicular volume. One study demonstrated that adult testicular volume predicted spermatogenetic recovery after childhood stem cell transplant [66]. Regression of secondary sexual characteristics or symptoms of sexual dysfunction (such as decreased libido and potency) are rare given the low incidence of subnormal serum testosterone concentrations.

Semen analysis — A semen analysis is the simplest and most reliable method of assessing the impact of chemotherapy on fertility. In an effort to standardize the procedure for semen collection and analysis, the World Health Organization (WHO) published the Laboratory Manual for the Examination of Human Semen and Semen-Cervical Mucus interaction, which was last revised in 2010 [72]. Semen analysis is very sensitive to the duration of abstinence prior to collection. Therefore, it is recommended that a sample be collected after a minimum of 48 hours and not longer than seven days abstinence.

The lower reference limits for normal sperm concentration used to be >20 x 106/mL [73]. Current reference limits for semen analyses [72], as revised and published by the WHO, include: (See "Approach to the male with infertility".)

Semen volume – 1.5 mL (95% CI 1.4-1.7)

Sperm concentration – 15 million spermatozoa/mL (95% CI 12-16)

Total sperm number – 39 million spermatozoa per ejaculate (95% CI 33-46)

Morphology – 4 percent normal forms (95% CI 3-4), using "strict" Tygerberg method [74]

Vitality – 58 percent live (95% CI 55-63)

Progressive motility – 32 percent (95% CI 31-34)

Total (progressive + nonprogressive motility) – 40 percent (95% CI 38-42)

Sperm concentration has traditionally been accepted as the most important determinant of fertility. However, because of the large intersample variability in sperm concentration [75], a diagnosis of male infertility should never be based on a single sample. If the first sample gives an abnormal result, two more samples should be obtained several weeks apart to permit adequate interpretation. When assessing fertility potential in men who have received chemotherapy, it is important to keep in mind that recovery of spermatogenesis may continue for up to five years after completing treatment [76].

Hormonal evaluation — Laboratory assessment should include measurement of serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone levels. (See "Clinical features and diagnosis of male hypogonadism", section on 'Initial evaluation'.)

FSH and inhibin B levels — FSH is a very sensitive hormonal indicator of seminiferous tubular damage; the serum FSH concentration may be increased five to 10-fold in men who have received cytotoxic chemotherapy. The mechanism of the increase is a decrease in the peptide hormone, inhibin B, which is secreted by Sertoli cells and inhibits FSH secretion [77-80]. In a prospective study of 12 men with hematologic malignancies treated with combination chemotherapy, inhibin B levels fell to 20 percent of baseline and FSH rose fivefold over baseline within four months of beginning treatment [81].

Inhibin B may be superior to FSH as a marker for spermatogenesis in survivors of childhood cancer. In a study of 56 males who had received combination chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) or EBVD (epirubicin, bleomycin, vinblastine and dacarbazine) with or without MOPP (mechlorethamine, vincristine, procarbazine, and prednisolone) for non-Hodgkin lymphoma (NHL), patients who received MOPP had higher FSH levels (16.8 versus 3.0 U/L), lower inhibin B levels (17.5 versus 143 ng/L), and lower sperm counts (1.1 versus 49.5 x 106/mL) than those treated without MOPP [82]. However, only inhibin B showed an independent correlation with sperm concentration.

LH — In vivo, LH secretion is pulsatile, so a single LH measurement may be misleading and should always be interpreted in the context of a concomitant serum testosterone level. LH levels are typically normal or slightly elevated following cytotoxic chemotherapy, while testosterone levels tend to remain in the lower end of the normal range.

Total testosterone — Total, rather than free, testosterone should be measured, since chemotherapy does not affect levels of the binding protein for testosterone, sex hormone-binding globulin (SHBG).

Testicular biopsy — There is no role for a diagnostic testicular biopsy in the evaluation of gonadal dysfunction secondary to cytotoxic agents. However, if no sperm are present in the ejaculate, and fertility is desired, it may be possible to retrieve sperm by testicular aspiration or biopsy, which can then be used for intracytoplasmic sperm injection (ICSI). Although successful pregnancies have been reported in men with chemotherapy-induced azoospermia using this technique, a diagnostic biopsy was of only limited value in predicting the outcome of sperm retrieval [83]. (See "Treatments for male infertility" and 'Semen cryopreservation' below.)

An increased frequency of aneuploidy in sperm has been reported in some [84,85] but not all studies [86] following chemotherapy. However, to date there has been no reported increase in genetically-mediated birth defects in children fathered by men who have had cytotoxic chemotherapy, perhaps due to selection bias against genetically abnormal sperm [87]. However, ICSI may overcome nature's barrier to transmitting genetic diseases, in that by manipulating gametes, the natural sperm selection process is entirely overridden.

PREVENTION OF GONADAL TOXICITY — As treatment for cancer has become more successful during the last few decades, increasing attention must now be focused on improving quality of life in these patients. Sexual function and fertility have been reported to be the major lifestyle concerns in more than 80 percent of men who are long-term survivors of cancer chemotherapy [88]. Given the deleterious effects of chemotherapy on the testis, a number of strategies have been explored to preserve fertility in men scheduled to receive cytotoxic chemotherapy [89].

Semen cryopreservation — The simplest strategy for preserving fertility is to obtain a semen sample for cryostorage prior to initiating therapy [90]. However, this approach has a number of limitations. First, pretreatment semen parameters are abnormal in a significant number of patients (see 'Impact of cancer on gonadal function' above). Second, the process of freeze-thawing has an additional negative impact on sperm function causing a further decrease in sperm motility, although this effect is no worse in cancer patients than in healthy men [91]. Third, cryopreservation is not typically pursued for patients who are still prepubertal. Although testicular biopsy samples from prepubertal boys have been performed successfully, this procedure is considered experimental and its clinical utility has not been established. Fourth, most insurance companies will not cover the monthly cost of maintaining the specimen.

Most men are able to obtain their semen samples by ejaculation. The optimal number of samples for future fertility and number of days of abstinence between samples varies based upon baseline semen analysis and the urgency of starting the chemotherapy or radiotherapy [92]. For men who are too ill or weak to collect samples through ejaculation, other options include electroejaculation, percutaneous epididymal sperm aspiration, or needle testicular sperm extraction or aspiration (TESE or TESA). (See "Treatments for male infertility".)

Prior to the development of assisted reproductive technologies such as in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), semen cryopreservation was generally not offered to men with poor baseline semen parameters, ie, sperm counts <20 x 106/mL and/or <40 percent motile sperm [93,94], as it was presumed that such counts would be too low for conception to occur using artificial insemination. However, with the advent of IVF, viable pregnancies have been reported with as few as 0.6 x 106 motile spermatozoa [95-97]. Therefore, semen cryopreservation should now be offered to all patients as long as there are some spermatozoa present in the ejaculate [98,99]. (See "Treatments for male infertility".)

All men scheduled for potentially gonadotoxic chemotherapy who are interested in future paternity should be informed about the risk of infertility and referred for sperm banking. However, only 50 percent are offered sperm banking, and even fewer result in cryopreserved sperm [100], in spite of current guidelines from the American Society of Clinical Oncology [101] and the American Society of Reproductive Medicine [92]. The common reasons given for not discussing the option with patients include lack of time, lack of local facilities for semen collection, and the high costs of sample storage [92].

In the past, men who developed azoospermia after chemotherapy were considered to be sterile. Now, many of these men (approximately 37 percent in one study) [102] are able to undergo successful testicular sperm extraction and intracytoplasmic sperm injection. (See "Treatments for male infertility".)

Hormonal manipulation — The demonstration that the prepubertal testis appears to be less susceptible to the gonadotoxic effects of chemotherapy than the mature adult testis [5] led to the hypothesis that suppression of testicular function in adult men undergoing chemotherapy might preserve their fertility. While studies in a variety of animal models, including the rat [103,104] and mouse [105], have yielded encouraging results, the experience to date in the human has been disappointing. In rats treated with procarbazine, administration of the gonadotropin-releasing hormone (GnRH) agonist, leuprolide acetate, for 10 weeks prevented loss of spermatogenic cells. In this study, the percentage of seminiferous tubules with differentiating germs cells was 98 percent in the group treated with leuprolide acetate versus 20 percent in controls [104]. A similar beneficial effect on fertility in the rat has been reported with use of testosterone alone [106] and following treatment with a GnRH antagonist [107].

In contrast to rodent models, data on the efficacy of GnRH analogs in adult men with Hodgkin lymphoma and germ cell tumors have been disappointing. Studies using a variety of GnRH analogs to reversibly suppress steroidogenesis demonstrated no benefit in either preserving spermatogenesis or accelerating its recovery [108-111]. These studies generally involved small numbers of patients [108,110], and one was not placebo-controlled [108].

One potential explanation for the discrepancy between the results of animal and human studies is that the mechanism of chemotherapy-induced infertility is not the same in these two models. In men who receive combination chemotherapy, it is possible that the gonadal toxicity observed is greater than that seen after administration of a single agent in the rat; complete ablation of the germinal epithelium in this setting would preclude any possibility of recovery of spermatogenesis.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Male infertility or hypogonadism".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Preserving fertility after cancer treatment in men (The Basics)")

SUMMARY AND RECOMMENDATIONS — As treatment for cancer has become more successful during the last few decades, increasing attention must now be focused on improving quality of life in these patients. Sexual function and fertility have been reported to be the major lifestyle concerns in more than 80 percent of men who are long-term survivors of cancer chemotherapy. We recommend the following for these patients:

Where possible, chemotherapeutic regimens that include agents known to cause permanent gonadal dysfunction, eg, procarbazine, should be avoided in patients wanting to preserve fertility whenever agents with at least equal efficacy but less gonadotoxicity are available. (See 'Chemotherapeutic agents associated with infertility' above.)

All men scheduled for potentially gonadotoxic chemotherapy who are interested in future paternity should be informed about the risk of infertility and referred for sperm banking. (See 'Semen cryopreservation' above.)

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Topic 7455 Version 18.0

References

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