Hematopoietic cell transplantation (HCT) has matured from a daring intervention into routine practice for many hematologic disorders. Survival curves have climbed; clinic rosters have filled with long-term survivors. Now comes the part less suited to heroics and more to discipline: recognizing and managing male-specific late effects. These are not boutique complaints. Genital chronic graft-versus-host disease (cGVHD), hypogonadism, sexual dysfunction, impaired fertility, and subsequent malignancies can overlap, amplify each other, and quietly erode quality of life—often without being mentioned in the room. Our job is to bring them into the light, ask on purpose, examine on purpose, and treat on purpose. This guide distills a comprehensive, multi-disciplinary systematic review into practical moves for everyday care.
Late effects are common precisely because HCT is successful. With more men living longer after transplant, complications that once hid in small case series are now visible at scale. The epidemiology is heterogeneous across centers and regimens, but several themes hold: genital cGVHD in roughly 5%–20% of men (depending on how hard you look), hypogonadism with a prevalence that swings widely with definitions, high rates of sexual difficulties, frequent infertility after myeloablative conditioning, and a male-skewed burden of certain subsequent solid tumors, especially squamous cell cancers of skin and oral cavity. None of these is trivial; all of them are modifiable if we bother to look.
The following sections lay out what to recognize, what to measure, and what to do—without drama, and with a dash of honest pragmatism. If a touch of dry irony slips in, take it as a reminder that medicine is often simple in principle and stubborn in practice.
Genital Chronic GVHD: Under-Asked, Under-Found, Under-Treated
Genital involvement is a recognized organ site in the National Institutes of Health (NIH) cGVHD criteria (updated 2014), and yet it is chronically underreported in trials and underexamined in clinics. When teams ask directly and examine routinely, the signal emerges: cross-sectional studies identify male genital lesions in the low double digits, often coupled with oral, ocular, or cutaneous cGVHD elsewhere. Typical onset is not early noise; most series report presentation two or more years after transplantation—amply late to be missed if follow-up is casual.
Clinically, the glans, foreskin, meatus, and urethra may be affected. Men describe burning, dysesthesia, or dyspareunia; partners sometimes report the problem first. On exam, look for noninfectious balanoposthitis; lichen planus-like or lichen sclerosus-like changes; shiny plaques; phimosis; and meatal or urethral scarring. Distinctive but non-diagnostic features (erosions, fissures, ulcers) should prompt broader cGVHD evaluation. Histopathology is helpful—parakeratosis, lichenoid infiltrate, epidermal atrophy, dermal fibrosis—but not mandatory if the clinical picture is classic. Keep Peyronie’s disease on the radar as a fibrotic fellow traveler, even if not yet folded into formal scoring.
The cure for invisibility is habit. Ask about symptoms at every visit; perform a focused genital exam yearly; and lower the threshold for multidisciplinary input (urology, dermatology) when findings are present or symptoms persist. Treatment aligns with severity: high-potency topical corticosteroids or topical calcineurin inhibitors for inflammatory phenotypes; systemic immunosuppression when genital disease tracks with active multisystem cGVHD; and surgical solutions such as circumcision for complete phimosis or urologic intervention for meatal stenosis. Evidence quality is limited, but the directional guidance is sensible—treat the inflammation you see and the scarring you can fix. Meanwhile, educate patients on self-inspection and the (rare but real) link between chronic inflammatory dermatoses and squamous cell carcinoma.
Hypogonadism and Bone Health: Measure What Matters, Treat What Helps
Hypogonadism in male HCT survivors is common, variably defined, and frequently symptomatic. Mechanistically, Leydig cells are sturdier than the germinal epithelium, so one can see azoospermia with normal testosterone; but many men do drift into compensated or overt hypogonadism—elevated luteinizing hormone (LH) with normal testosterone, or elevated LH with low testosterone. Steroids, calcineurin inhibitors, iron overload, and active GVHD compound the risk by suppressing the hypothalamic–pituitary–gonadal axis. The clinical picture ranges from the obvious (loss of body hair, small testes, erectile dysfunction) to the nonspecific (fatigue, low mood, sarcopenia, increased fat mass). Bone loss is a parallel threat, driven by hypogonadism, glucocorticoids, cGVHD, and transplant-related catabolism.
Screen with intent, not reflex. A man with low libido, ED, or compatible symptoms deserves a fasting morning total testosterone; if low, repeat it before labeling. Free testosterone is useful for borderline cases or when sex hormone–binding globulin (SHBG) is altered (think glucocorticoids); use equilibrium dialysis where available, or a validated calculation from total testosterone, SHBG, and albumin. There is no single universal numerical cut-off; use your lab’s reference ranges and clinical context. Expect recovery in some men within a year post-HCT, so time since transplant matters when interpreting a single number.
Therapy follows general principles: offer testosterone replacement to symptomatic hypogonadal men after shared decision-making about benefits (libido, erectile function, body composition, mood, bone density improvements in the general population) and risks (polycythemia, suppression of spermatogenesis, potential prostate concerns). Avoid or defer in men with prostate cancer, worrisome prostate exams, or at high prostate cancer risk until appropriately evaluated. Monitor hematocrit and prostate parameters as per endocrine/urologic guidelines. Parallel bone health care is not optional: vitamin D and calcium as indicated, weight-bearing exercise, and dual-energy X-ray absorptiometry (DEXA) at one year after allogeneic HCT (earlier if no baseline or prolonged high-dose steroids), with bisphosphonates or other agents for those meeting treatment thresholds. Testosterone is helpful, but it does not single-handedly prevent osteoporotic fractures; do the bone work.
Sexual Health: Beyond Testosterone, Back to the Whole Person
Sexual dysfunction after HCT is common, persistent, and multifactorial. Men report decreased sexual interest, erectile difficulties, trouble with ejaculation or orgasm, and diminished enjoyment of sex. Depending on the domain measured, prevalence ranges widely, but the theme is consistent: compared with matched controls or non-transplanted peers with similar diseases, HCT survivors report lower sexual function and greater distress—often still evident years after transplant. Some studies link dysfunction with cGVHD; others fail to show a strong association in men. Either way, the problem is not rare, and it is not solely hormonal. Body image, fatigue, mood, relationship dynamics, and the slow recalibration of identity after intensive therapy all weigh in.
The gap is not just biological; it is conversational. Most clinicians do not ask about sexual health unless prompted, and most patients do not volunteer unless asked—an equilibrium that rewards avoidance. Gentle, direct screening at routine follow-up is a low-cost, high-yield intervention. When men are invited to talk, they do; when they receive information and practical options, activity and satisfaction improve. A multimodal survivorship clinic model—identify contributors; normalize the topic; correct hormonal deficits; offer erectile aids; and refer to sexual health specialists when appropriate—has improved multiple domains of sexual function and mood in transplant survivors of both sexes. That is not a miracle; it is structured attention.
Pharmacologic options are familiar. Sildenafil works for erectile function across organic and psychogenic contributors, though it will not fix low desire alone. Escalation follows standard pathways: vacuum erection devices, intraurethral alprostadil, intracavernosal injections, and, in selected men, prostheses. Couple-centered psychological support can address the human factors medicine often pretends are optional. The formal evidence base is still lean; the clinical logic is not. Screen routinely, tailor interventions to what the patient wants to improve, and revisit.
Fertility: Risk, Recovery, and the Discipline of Planning Ahead
Impaired fertility after HCT is common and regimen-dependent. Conditioning intensity, cumulative chemotherapy and radiation exposure, age at transplant, time since transplant, and GVHD all shape the odds. As a rough sketch: recovery of spermatogenesis has been reported in most men conditioned with cyclophosphamide alone, in about half with busulfan- or thiotepa-based combinations, and in a minority with total body irradiation (TBI)–containing regimens. Azoospermia after busulfan plus cyclophosphamide is the rule at one year; TBI drives non-obstructive azoospermia rates up to the mid-80% range in some cohorts. The likelihood of recovery rises with longer follow-up and younger age at transplant.
Paternity is the endpoint that matters to many men, and it is achievable—but not as often as the desire would predict. Despite substantial interest in fatherhood, reported rates of successful conception are low across mixed HCT cohorts, with better outcomes in settings like aplastic anemia (where pre-transplant cytotoxic exposures are lighter) and where assisted reproductive technologies are available. Among reported conceptions after HCT, pregnancies are generally uncomplicated, without excess miscarriage or congenital anomaly rates attributable to the father’s transplant history. That is reassuring, but it does not erase the need to plan.
The most effective “treatment” for post-HCT infertility is pre-HCT fertility preservation. Offer sperm banking to every adult man headed toward transplantation—ideally before any gonadotoxic therapy begins. Barriers are depressingly predictable: perceived lack of time, low clinician awareness, underestimation of future parenthood goals, and insurance hurdles. For men rendered azoospermic or for adolescents who cannot provide an ejaculate, micro-TESE (microsurgical testicular sperm extraction) with cryopreservation is an option. Post-HCT, discuss desires, obtain semen analysis when appropriate, and refer early to reproductive specialists. And please do the mundane work of contraception counseling for men who remain fertile or whose fertility status is unknown; many unplanned pregnancies occur precisely because nobody thought to ask.
Subsequent Malignancies: Focus Where Risk Runs Highest
Long-term HCT survivors carry heightened risks for some solid tumors, and several of these risks skew male. The aggregate 10-year incidence of subsequent solid malignancy sits in the low single digits, but the distribution matters: squamous cell carcinomas (SCC) of skin and oral cavity are recurring offenders, with male sex repeatedly flagged as a risk factor in cohort analyses. Melanoma risk appears elevated after autologous HCT in men in some series. Donor–recipient sex mismatch (female donor to male recipient) has surfaced as a risk signal for subsequent solid cancers independent of GVHD in at least one study, a reminder that immunobiology does not stand still once engraftment is complete.
Conversely, strictly male-organ cancers tell a calmer story. Across large datasets, risks of prostate, testicular, and penile cancers do not appear significantly increased compared with the general population, though case reports do exist (including penile SCC in the context of genital lichen sclerosus). Prostate cancer–specific mortality does not seem uniformly higher in HCT survivors, and overall survival after prostate cancer mirrors population figures in available series. This is not license to ignore; it is guidance to follow general population screening and treatment pathways while staying vigilant where HCT uniquely elevates risk—skin and oral mucosa.
Screening should therefore be boring and relentless: full-skin and oral cavity examinations at routine follow-up, explicit inspection of genital skin in men with a history of genital cGVHD, standard age-based screening for prostate cancer per prevailing guidelines, and a low threshold to biopsy suspicious lesions. When malignancy emerges, treat per best oncologic practices; transplant history shapes context, not necessarily regimen choice.
A Practical Clinic Algorithm (That Fits in Real Life)
The best survivorship programs run on checklists. Build one that respects transplant biology and daily clinic realities. At every visit, ask about genital changes and sexual function; annually, examine genital skin. For symptomatic men, check fasting morning testosterone (repeat if low) and consider free testosterone when SHBG is likely perturbed. At one year post-allogeneic HCT (earlier if indicated), evaluate bone density and fracture risk and treat per standard osteoporosis guidelines. Before HCT, offer sperm banking to everyone; after HCT, assess fertility desires and arrange semen analysis and referral as needed. Throughout, perform complete skin and oral exams, with attention to men with cGVHD. None of this requires heroics; all of it prevents years of avoidable morbidity.
Treatment pathways then become modular. For genital cGVHD, use high-potency topical steroids or calcineurin inhibitors for inflammatory lesions; escalate to systemic therapy when genital disease is just the visible tip of active multisystem cGVHD; call urology when structure—not inflammation—drives symptoms. For hypogonadism, employ testosterone replacement thoughtfully, with hematocrit and prostate monitoring; do not let bone health ride shotgun—address it directly. For sexual dysfunction, stack interventions: correct hormones, use PDE-5 inhibitors for erections, and address the person in front of you (relationship counseling and sexual therapy when appropriate). For fertility, remember that early planning beats late heroics almost every time.
If this sounds like ordinary medicine, that is because it is. The novelty is not the treatments; it is our willingness to systematize attention to topics that are easy to sidestep. Survivorship care that treats male-specific issues as routine parts of the visit sends a message patients hear loud and clear: your quality of life matters as much as your counts.
Research Gaps and the Case for Team Sport
Evidence for male genital cGVHD management is still dominated by case reports and small cohorts; therapeutic trials are few, and organ scoring remains a work in progress. Hypogonadism studies struggle with case definitions and inconsistent testing, making prevalence estimates swing from single digits to north of 80%. Sexual health interventions need larger, controlled trials that compare practical multimodal approaches rather than inventing yet another single-agent solution to a multi-factor problem. Fertility data are heavily descriptive; prospective registries that capture both desire for paternity and attempts (assisted or not) would make counseling far better.
The interconnections deserve dedicated study. Does genital cGVHD independently depress fertility via testicular or epididymal inflammation? How do immunosuppressants interact with the hypothalamic–pituitary–gonadal axis in the long run? Where does testosterone replacement meaningfully move bone outcomes in HCT populations, beyond general-population extrapolations? These are not esoteric questions; they shape decisions daily.
Finally, the care model matters. Multidisciplinary clinics—transplant physicians partnering with urology, dermatology, endocrinology, and sexual health—build competence and lower the activation energy for patients to seek help. Standard operating procedures can lock the routine tasks (screening, exams, labs) into quality systems so they happen even on busy days. None of this will make headlines. It will, however, make better lives.
Two Small Lists to Make the Work Easier
- Red-flag prompts to ask at every follow-up: new genital burning, tightness, or plaques; painful intercourse; changes in erections or libido; hot flashes or fatigue out of proportion; any new oral lesions, non-healing skin spots, or color changes; desire for future children (yes, ask the question).
- A minimalist surveillance cadence: yearly focused genital exam; bone density at 1 year post-allogeneic HCT (earlier if high-dose steroids or no baseline), then per results; fasting morning testosterone when symptomatic (repeat to confirm); full skin and oral inspection each visit; pre-HCT sperm banking for all, post-HCT semen analysis for those who wish to conceive.
Conclusion: Routine, Relentless, Respectful
Male-specific late effects after HCT do not require a new subspecialty; they require a new reflex. Ask about genital symptoms and sexual health without waiting for permission. Examine the skin you cannot see from across the room. Measure testosterone properly and treat hypogonadism when it matters, while protecting bone regardless. Plan fertility preservation before the countdown begins, and do not abandon the conversation after transplant. Watch carefully for skin and oral cancers, and manage prostate and testicular health by the same rules you would use in any man, with a little extra vigilance where transplant biology nudges risk.
If there is irony here, it is gentle: in a field defined by cellular engineering and graft immunology, the biggest gains now come from well-timed questions, a focused exam, and steady follow-through. Survivorship is not an epilogue; it is the rest of the story. Let us write it with our patients, not for them.
FAQ
1) Should every male HCT candidate bank sperm—even if he has had chemotherapy already?
Yes. Offer sperm banking to all adult men before HCT whenever feasible. Prior chemotherapy reduces success rates but does not make preservation pointless; even limited viable sperm can enable assisted reproduction later. When ejaculate is azoospermic, consider micro-TESE for sperm retrieval and cryopreservation. Early planning outperforms late improvisation.
2) When and how should I check for hypogonadism after HCT?
Test when symptoms suggest it—low libido, ED, fatigue, muscle loss—using a fasting morning total testosterone, repeating if low. Assess free testosterone in borderline cases or when SHBG is perturbed (e.g., on glucocorticoids). Treat symptomatic hypogonadism after shared decision-making, monitor hematocrit and prostate parameters, and manage bone health in parallel. Expect that some men recover within a year; time since HCT contextualizes results.
3) Are male HCT survivors at uniquely higher risk for prostate or testicular cancer?
Current evidence does not show a significantly increased risk of prostate or testicular cancer compared with the general population. Do follow standard age-based screening and maintain vigilance. Where male risk is clearer is for skin and oral squamous cell carcinomas—hence the emphasis on full-skin and oral examinations at follow-up, especially in men with cGVHD or prior inflammatory genital disease.
