Abstract
Sickle cell disease (SCD) is one of the most common hereditary diseases in the world. It leads to hemolytic anemia and painful vaso-occlusive crises that can damage target organs at the cardiopulmonary, cerebrovascular, and renal levels. SCD has also significant consequences on reproductive functions and fertility. Moreover, the treatments designed to alleviate and reduce vaso-occlusive crises directly impact male reproductive functions. Nevertheless, literature assessing the impact of SCD and its treatments on male reproductive functions remains limited and lacks robust evidence. A systematic review of the literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendation was carried out on the reproductive functions of men with SCD and the reproductive options available to them. Most studies have found that men with SCD frequently exhibit impaired sperm parameters. In addition, hydroxyurea (HU), proposed to relieve and reduce vaso-occlusive crises, is also known to impact male reproductive functions, and the reversibility of these consequences on sperm parameters remains hypothetical. Hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment. However, conditioning treatments are highly gonadotoxic and can permanently alter spermatogenesis. Young men with SCD should therefore be informed about fertility at an early stage, and fertility preservation should be discussed in pubescent men, especially if treatment with HU or HSCT is to be initiated. In prepubertal boys about to undergo HSCT, immature testicular tissue freezing should be discussed, even though this technique is still experimental.
Keywords: fertility preservation, hydroxyurea, male reproductive functions, sickle cell disease, sperm parameters
INTRODUCTION
Sickle cell disease (SCD) is one of the most common hereditary diseases in the world.1 Initially present in malaria-endemic regions, it then spread to most countries during migrations and slavery.2,3 It mainly affects populations in Sub-Saharan Africa, India, the Mediterranean basin, and the Middle East. It is estimated that 300 000 children are born each year worldwide with severe SCD.4,5 Because of the lack of neonatal screening and appropriate care in low-resource countries, 50%–90% of children with SCD die within the first 5 years of life.6 On the other hand, countries with adapted care programs have been able to increase the life expectancy of these children, who are now reaching adulthood.7 As a result, the median age of death increased, reaching 43 years in the USA in 2017.8 However, the life expectancy of patients with SCD is still around 20 years shorter than that of the general population.9
SCD is an autosomal recessive inherited genetic disorder that affects the hemoglobin in red blood cells. SCD is caused by a single point mutation in the β-globin gene (HBB), where adenine is replaced by thymine in codon 6. This nucleotide substitution changes the codon from GAG to GTG, leading to the replacement of glutamic acid with valine at the sixth position of the β-globin chain.10 The resulting hemoglobin is abnormal and is called “sickle cell hemoglobin” or hemoglobin S (HbS). HbS has a reduced solubility and an increased polymerization, deforming the red blood cells into the characteristic sickle shape and altering their rheology in the vessels and their survival.9
SCD thus results in hemolytic anemia and painful vaso-occlusive crises, which can lead to damage in target organs, particularly affecting the heart, lungs, brain, and kidneys.10 Moreover, SCD also has consequences on reproductive functions and fertility. Thus, in men, hypoxic–ischemic crises and chronic inflammation can challenge testicular functions and impact sperm production. Consequently, men with SCD frequently exhibit significant abnormalities in sperm parameters.11,12
In addition, the treatments proposed to relieve and reduce vaso-occlusive crises may also impact male reproductive functions. Hydroxyurea (HU), approved by the USA Food and Drug Administration since 1998, has been involved in sperm parameters alterations.13,14 Moreover, hematopoietic stem cell transplantation (HSCT) with a compatible donor is increasingly proposed to patients with severe SCD, and myeloablative conditioning treatments for bone marrow transplants are known to severely and permanently impair male reproductive functions.15
Given the potential impact of SCD and its treatments on male fertility, along with the increased life expectancy of these patients, it is important to integrate fertility considerations into the overall management of these young men. Thus, complete information on this subject should be given to each man treated for SCD and fertility preservation (FP) proposed as soon as it is necessary and possible.
The objective of this review is to summarize what is currently known about the reproductive functions of men with SCD. We focused on men with SCD before the initiation of gonadotoxic treatments, and evaluated the impact of SCD treatments.
DOCUMENTARY RESEARCH AND SELECTION AND DATA SYNTHESIS
A search was carried out in PubMed, Embase, and Google Scholar databases between January 1974 and June 2024, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations.16 The review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) as CRD42023393434. The search strategy was based on the following combined search terms: (Sperm [title/abstract]) or (Sperm [mesh terms]) or (fertility [title/abstract]) or fertility ([mesh terms])) and ((sickle [title/abstract]) or (sickle [mesh terms])).
After removal of duplicates, the articles were first preselected by reading the title and abstracts by two independent readers (CL and CD). The preselected articles were then classified as “excluded”, “doubtful”, or “included”. The “doubtful” articles were discussed between CL and CD to determine whether they can be retained or should be excluded. Any disagreement or uncertainty was resolved by a third reviewer (IB). The articles preselected as “retained” were then read in full text by the two independent authors (CL and CD).
The articles were classified according to their theme: “sickle cell disease and semen parameters in adulthood”, “hydroxyurea treatment for sickle cell disease and semen parameters in adulthood”, “hydroxyurea treatment during childhood for sickle cell disease and semen parameters”, “effect of sickle cell disease and hydroxyurea treatment on spermatogonial pool”, “HSCT for sickle cell disease and sperm parameters”, and “transfusion for sickle cell disease and sperm parameters”.
In order to characterize the included studies, the following details were extracted: authors, journal of publication, year of publication, country, type of study, number of patients, number of controls, treatments received, sample size, and semen parameters (i.e., ejaculate volume, sperm concentration, sperm count, progressive motility, total motility, and typical sperm forms).
IDENTIFICATION OF ARTICLES OF INTEREST
The search strategy identified a total of 244 articles, and 188 articles remained after removing duplicates. Two additional articles were included following a manual search. Of these, 55 articles were selected based on their title, and 44 articles were further selected based on their abstract. Finally, 24 full-text articles were assessed for eligibility for quantitative analysis and included in the systematic review (Figure 1).
Figure 1.
Flowchart of study selection for systematic review. *Search limited to the title only.
SPERM PARAMETERS IN MEN WITH SCD
Eight studies evaluated sperm parameters in men with SCD (Table 1). Of them, four studies were purely observational.11,13,17,18 The semen parameters of men with SCD were not compared with those of controls, and the numbers of patients involved were limited (range: 4–50). Nevertheless, the authors all concluded that men with SCD were at increased risk of impaired semen parameters according to the reference values applicable at the time of the study. The other four studies were case–control studies.19,20,21,22 Most of them highlighted impaired sperm parameters in men with SCD compared to controls (P < 0.001).19,20,21 However, contrary to what has been observed in all other studies, Singh et al.22 observed a significant increase in sperm concentration in men with SCD from Chhattisgarh (India). It is important to note that there was a significant bias in this study, as men with azoospermia were excluded.
Table 1.
Semen parameters in men with sickle cell disease
| Study | Study design | Population | Status | Sample size | Abstinence time (day) | Semen parameters | Standard | Conclusion | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
| ||||||||||||||
| n | Age (year) | Volume (ml) | Concentration (×106 ml−1) | Total count (×106) | Progressive motility (%) | Total motility (%) | Typical form (%) | |||||||
| Singh et al.22 2022 | Case–control | 58 | 18–45a | HbSS | NA | 2–7 | 1.9±1.1b | NA | 57.6*±38.2b | 35.8±27.2b | 58.7±26.0b | 78.3±20.3b | WHO 201046 | Alteration of sperm parameters was not found in Chhattisgarh (India) adult males with sickle cell disease |
| 58 | 18–45a | HbAA | NA | 2.7±1.1b | NA | 39.8±28.1b | 52.6±25.6b | 62.1±26.5b | 79.8±10.6b | |||||
| Modebe and Ezeh20 1995 | Comparative transversale | 14 | 18–40a | HbSS | NA | ≥3 | 2.2±0.9b | 21.4*±17.5b | NA | NA | 42.3*±21.0b | 58.1*±22.5b | Eliasson47 | Significant decrease in sperm parameters in adult males with sickle cell disease 57.1% of patients have impaired sperm concentration |
| 20 | 18–40a | HbAA | NA | 2.9±0.9b | 69.1±30.4b | NA | NA | 73.6±22.8b | 86.1±6.4b | |||||
| Agbaraji et al.19 1988 | Case–control | 25 | NA | HbSS | NA | NA | Decreased | Decreased | NA | Decreased | NA | Decreased | NA | Significant alteration of sperm parameters in adult males with sickle cell disease Alteration of the sperm morphology type “stress pattern” |
| 25 | NA | HbAA | NA | NA | NA | NA | NA | NA | NA | NA | ||||
| Osegbe et al.21 1981 | Case–control | 23 | 20.6 (17–30)c | 20 HbSS, 3 HbSC | 46 | 4–5a | 1.9±1.9 (0.2–6)d | 17.9*±2.6 (0–98)d | 52.7*±12.1b | 18.1*±2.0b | NA | 24.8*±2.3b | Eliasson47 and Freud48 | Significant alteration of sperm parameters in adult males with sickle cell disease |
| 25 | NA | Fertile | 50 | 2.5±1.3b | 63.4±13.2b | 119.7±20.1b | 44.8±29.6b | NA | 77.7±18.9b | |||||
| Sahoo et al.18 2017 | Prospective | 50 | 26.02±6.9 (18–45)d | HbSS | NA | ≥3 | NA | 48.6±27.7b | NA | 59.0±26.2 | NA | 77.3±20.7b | WHO 201046 | 22% of sickle cell patients have oligo-azoospermia |
| Berthaut et al.13 2008 | Retrospective multicenter | 34 | 25.8 (16–48)c | HbSS, HbSC, HbSβthal | 76 | 2–7a | 3.1±1.7 (0.3–8)d | 38.6±43.1 (0.02–280)d | 114.2±124.1 (0.07–588)d | 28.7±18.4 (0–60)d | NA | 21.9±14.6 (0–53)d | WHO 199949 | 91% of patients have at least one altered sperm parameter before treatment Progressive mobility and sperm morphology are the most altered parameters (“stress pattern”) |
| Nahoum et al.17 1980 | Observational | 12 | 20–42a | HbSS | 12 | 4 | 2.1 (0.9–3.5)c | 58.2 (8–176)c | NA | 9.2 (0–20)c | 52.9 (5–65)c | 53.3 (30–75)c | NA | 100% of patients have a decrease in progressive mobility and 91.7% an alteration of sperm morphology type “stress pattern” |
| Friedman et al.11 1974 | Observational | 4 | 23–34a | HbSS | 4 | 7 | 2.5 (2–3)c | 19.3 (2–52)c | NA | NA | 30–50a | NA | NA | 75% of patients have oligozoospermia |
*P<0.05 (statistically significant difference). aRange. bMean±s.d. cMedian (range). dMean±s.d. (range). HbSS/HbSC/HbSβthal: hemoglobin electrophoresis profile of patients with sickle cell disease; HbAA: hemoglobin electrophoresis profile of healthy patients; NA: not available; s.d.: standard deviation
SPERM PARAMETERS IN MEN WITH SCD TREATED WITH HU
Data from the studies assessing sperm parameters of men with SCD treated with HU (during and after the stop of the treatment) are reported in Table 2 and Supplementary Table 2. It presents the individual results of eight men published in three studies.23,24,25 In all patients, a significant alteration in sperm parameters was observed during treatment. And, Table 2 also shows longitudinal studies evaluating the variation in sperm parameters with HU treatment and following treatment discontinuation.13,18,23,26 All four studies observed a significant alteration in sperm parameters during HU treatment with an increased risk of developing azoospermia. The number of participants with azoospermia or cryptozoospermia increased more than 10-fold, reaching almost 1 in 3 men and making natural conception almost impossible for them.23 Treatment reversibility was little assessed, but semen alteration seems partially reversible following treatment discontinuation.13,24 In one patient, azoospermia persisted for 4 years after stopping HU.13 However, a study showed that 73% of men regained normal sperm parameters 3 months following treatment discontinuation,18 but the data were not reported in the manuscript (Table 2).
Table 2.
Semen parameters in men with sickle cell disease treated with hydroxyurea
| Study | Study design | Population | HU | Sample size | Abstinence time (day) | Semen parameter | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
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|
|
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| n | Age (year) | Status | State | Dose | Volume (ml) | Concentration (×106 ml-1) | Total count (×106) | Vitality (%) | Progressive motility (%) | Total motility (%) | Typical form (%) | ||||
| Case study | |||||||||||||||
| Berthaut et al.13 2008 | Retrospective, multicenter, and individual follow-up | 1 | NA | SCD | Before HU | 0 | 3 | NA | Abke | 28.7 | 44.9 | 58.7 | 5.0 | NA | NA |
| Stopped 4 years ago (after 6 months of HU) | 0 | 1 | NA | 0.9 | 3.3 | 3.0 | 48.0 | 5.0 | NA | 2 | |||||
| Stopped 5 years ago (after 6 months of HU) | 0 | 1 | NA | 2.4 | 1.2 | 2.9 | 10.0 | 0.0 | NA | NA | |||||
| 1 | NA | SCD | Before HU | 0 | 2 | NA | 5 | 39.8 | 198.1 | 52.5 | 32.5 | NA | 33 | ||
| Stopped 1 year ago (after 5 years of HU) | 0 | 1 | NA | 1 | 0 | 0 | 0 | 0 | 0 | 0 | |||||
| Stopped 4 years ago (after 5 years of HU) | 0 | 1 | NA | 1.4 | 0 | 0 | 0 | 0 | 0 | 0 | |||||
| 1 | NA | SCD | Before HU | 0 | 3 | NA | 5.5 | 53.3 | 296.7 | 94.7 | 38.3 | NA | NA | ||
| Stopped 1 year ago (after 6 years of HU) | 0 | 3 | NA | 3.6 | 1.46 | 5.3 | 25.7 | 31.7 | NA | 16 | |||||
| Stopped 3 years ago (after 6 years of HU) | 0 | 2 | NA | 10.6 | 0.72 | 6.4 | 24.5 | 7.5 | NA | 24.5 | |||||
| 1 | NA | SCD | Before HU | 0 | 2 | NA | 4 | 31 | 124 | 91.5 | 32.5 | NA | 42 | ||
| Stopped 1 year ago (after 4 years of HU) | 0 | 2 | NA | 4.3 | 77 | 329.5 | 54.5 | 40 | NA | 45.5 | |||||
| Grigg et al.25 2007 | Retrospective, individual follow-up | 1 | 24–41 | SCD | Ongoing for 17 months | 1500 mg per day | NA | NA | NA | 26 | NA | NA | NA | 35 | 35 |
| Stopped 32 months ago | 0 | NA | NA | NA | 15 | NA | NA | NA | 21 | 6 | |||||
| 1 | 24–41 | Ongoing for 4 years | 1250 mg per day | NA | NA | NA | NA | NA | NA | NA | NA | NA | |||
| Stopped 12 months ago | 0 | NA | NA | NA | 15 | NA | NA | NA | 58 | 50 | |||||
| 1 | 24–41 | Ongoing for 8 months | 1000 mg er day | NA | NA | NA | 7 | NA | NA | NA | 44 | 12 | |||
| Ongoing for 23 months | 1000 mg per day | NA | NA | NA | 4 | NA | NA | NA | 47 | 15 | |||||
| Ongoing for 44 months | 1000 mg per day | NA | NA | NA | 4 | NA | NA | NA | 32 | 30 | |||||
| Garozzo et al.24 2000 | Case report | 1 | 27 | HbSS | Ongoing for over 1 month | 20 mg kg-1 per day | 1 | NA | NA | 88 | NA | NA | 70% | 75% | NA |
| Ongoing for 1 month | 20 mg kg-1 per day | 1 | NA | NA | 92 | NA | NA | NA | NA | NA | |||||
| Ongoing for 6 months | 20 mg kg-1 per day | 1 | NA | NA | 0 | NA | NA | NA | NA | NA | |||||
| Ongoing for 7 months | 20 mg kg-1 per day | 1 | NA | NA | 0 | NA | NA | NA | NA | NA | |||||
| Stopped 10 months ago | 0 | 1 | NA | NA | 35 | NA | NA | 40% | 40% | NA | |||||
| Longitudinal study | |||||||||||||||
| Koras et al.26 2022 | Prospective comparative | 50 | 18–45 | HbSS | Ongoing for 36 of 50 patients | NA | 50 | 3–5a | 3.0 (2.0–3.0)b | 20.0* (14.9–23.0)b | 45.0* (20.0–66.0)b | NA | NA | 31.0* (24.0–38.0)b | 3* (2–4)b |
| 88 | 18–45 | Fertiles | NA | 0 | 88 | 3–5a | 3.0 (2.0–3.5)b | 28.5 (21.3–50.0)b | 83.0 (50.0–142.0)b | NA | NA | 40.6 (29.0–54.6)b | 5 (4–6)b | ||
| Sahoo et al.18 2017 | Prospective | 50 | 26.02±6.9 (18–45)d | HbSS | Before HU | 0 | 50 | 3–5a | Normal | 54.3±16.2c | NA | NA | 71.1±11.0c | NA | 85.3±10.3c |
| Ongoing | 10 mg kg-1 per day | 50 | 3–5a | 39.3*±29.3c | NA | NA | 56.2±23.5c | NA | 75.3± 31.0c | ||||||
| Berthaut et al.23 2017 | Prospective comparative | 35 | 33.6±9.2 (20–51)d | HbSS | Before HU | 0 | 35 | NA | 2.3±1.7c | NA | 129.8±150 (6.5–210)d | NA | NA | NA | NA |
| Ongoing for 6 months | 15–30 mg kg-1 per day | NA | 2.5±2.0c | NA | 24.1*±54.1 (0.0001–17)d | NA | NA | NA | NA | ||||||
| Berthaut et al.13 2008 | Retrospective multicenter | 44 | 25.8 (16–48)d | 41 HbSS, 1 HbSC, 2 HbSβthal | Before HU | 0 | 76 (34 patients) | NA | 3.1±1.7 (0.3–8)d | 38.6±43.1 (0.02–280)d | 114.2±124.1 (0.07–588)d | 59.8±21.6 (0–95)d | 28.7±18.4 (0–60)d | NA | 21.9±14.6 (0–53)d |
| Ongoing for 2–10 years | 20–30 mg kg-1 per day | 6 (5 patients) | NA | 2.7±1.3 (1.5–4)d | 2.7±3.8 (cryptozoospermia–8.75)d | 7.0±10.2 (c*–21.9)d | 52.0±14.2 (40–68) | 30.0±5.8 (25–50)d | NA | 34.5±21.9 (19–65)d | |||||
| Stopped for 6 months to 5 years ago | 0 | 26 (8 patients) | NA | 3.0±2.9 (0.4–15)d | 18.5±26.9 (0–86)d | 61.1±107.4 (0–387)d | 44.4±20.1 (0–90)d | 29.5±20.1 (0–80)d | NA | 19.2±16.3 (0–49)d | |||||
*P<0.05 (statistically significant difference). aRange. bMedian (range). cMean±s.d. dMean±s.d. (range). HbSS/HbSC/HbSβthal: hemoglobin electrophoresis profile of patients with sickle cell disease; NA: not available; HU: hydroxyurea; s.d.: standard deviation
Supplementary Table 2.
Standard and conclusion in men with sickle cell disease treated with hydroxyurea
| Study | Standard | Conclusion |
|---|---|---|
| Case study | ||
| Berthaut et al.13 2008 | WHO 199949 | In three of the four patients, semen parameters were altered after hydroxyurea. A patient has persistent azoospermia after discontinuation of treatment |
| Grigg et al.25 2007 | WHO 199949 | Altered semen parameters partially reversible |
| Garozzo et al.24 2000 | WHO 199949 | Partially reversible alteration of semen parameters.Azoospermia was reversible after discontinuation of HU without return to initial state. |
| Longitudinal study | ||
| Koras et al.26 2022 | WHO 202150 | Significant decrease in count, total motility and typical forms in patients with sickle cell disease on HU. |
| Sahoo et al.18 2017 | WHO 201046 | During HU treatment, significant decrease in sperm concentration (30% oligoazoospermia) |
| Berthaut et al.23 2017 | WHO 201150 | During HU treatment, significant decrease in sperm count, and increase in azoospermia cases |
| Berthaut et al.13 2008 | WHO 199949 | All patients have altered semen parameters during HU treatment. After stopping HU, all patients retain altered sperm parameters |
HU: hydroxyurea
SPERM PARAMETERS IN MEN WITH SCD TREATED WITH HU BEFORE PUBERTY
Some young patients start HU treatment before puberty. HU was approved by the USA Food and Drug Administration in 2017 to treat patients aged over 2 years.27 Only two studies detail sperm parameters in men with SCD who received HU in childhood (Table 3 and Supplementary Table 3). Lukusa and Vermylan28 presented data from four men who had started HU in childhood and were still on treatment at the time of analysis. All men had a marked decrease in sperm concentration, and the men with azoospermia were those with the longest duration of exposure. Joseph et al.29 presented a retrospective study comparing sperm parameters in men who had started HU in childhood (stopped at the time of the study) with those of men who had never been treated. No significant difference was found between these two groups. No correlation was observed between sperm parameters and age of onset, dose, or duration of HU treatment. According to the authors, HU received during childhood does not therefore appear to have an irreversible cytotoxic effect on spermatogenesis.
Table 3.
Sperm parameters in men with sickle cell disease who received hydroxyurea during childhood
| Study | Study design | Population | Hydroxyurea treatment | Sample size | Abstinence time (day) | Semen parameters | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
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| n | Age (year) | Status | Age of onset (year) | Duration | Dose | Volume (ml) | Concentration (×106 ml-1) | Total count (×106) | Vitality (%) | Progressive motility (%) | Typical form (%) | ||||
| Joseph et al.29 2021 | Retrospective, comparative, and multicenter | 15 | 17 (16–23)a | HbSS | 6 (1–14)a | 4 (0.5–10)a years | 22.4±3.7b mg kg-1 per day | 26 | 6 (2–90)a | 2.7 (0.20–10.35)a | 25.3 (0–210)a | 77.5 (0.40–525)a | 52.5 (12–77)a | 32 (0-75)a | 6.0 (0–25.0)a |
| 23 | 20 (16–24)a | HbSS | NA | NA | NA | 46 | 5 (2–30)a | 2.0 (0.25–5.90)a | 8.0 (0–120)a | 12 (0–523.90)a | 58 (0–87)a | 35 (1–55)a | 9.5 (0–38)a | ||
| Lukusa et al.28 2008 | Observational | 4 | 24 | HbSS | 16c | Ongoing for 8 years | 20 mg kg-1 per day | 1c | 5c | 0.8c | 2.48c | 1.98c | 72c | 4c | 5c |
| 19 | 10c | Ongoing for 9 years | 1c | 5c | 2.7c | 0.6c | 1.63c | 70c | 50c | 0c | |||||
| 23 | 11c | Ongoing for 12 years | 1c | 5c | 1.8c | 0c | 0 | NA | NA | NA | |||||
| 23 | 8c | Ongoing for 15 years | 1c | 2c | 1.8c | 0c | 0 | NA | NA | NA | |||||
aMedian (range). bMean±s.d. cMean. HbSS: hemoglobin electrophoresis profile of patients with sickle cell disease; NA: not available; s.d.: standard deviation; HU: hydroxyurea
Supplementary Table 3.
Standard and conclusion in men with sickle cell disease who received hydroxyurea during childhood
| Study | Standard | Conclusion |
|---|---|---|
| Joseph et al.29 2021 | WHO 201046 | No significant difference in semen parameters between patients treated with HU during childhood and patients who had never received HU (NB: all patients had stopped HU at the time of analysis) |
| Lukusa et al.28 2008 | WHO 199949 | The two patients with azoospermia had the longest duration of treatment |
NB: nota bene; HU: hydroxyurea
IMPACT OF SCD AND HU ON THE SPERMATOGONIAL POOL
Stukenborg et al.30 were the first to assess the potential effects of HU on immature testicular tissue (Table 4). Using histological sections of prepubertal testicular tissue, they evaluated the impact of treatments for malignant and nonmalignant conditions on spermatogonial pool. A spermatogonia-to-tubule (S/T) ratio was established, reflecting the number of spermatogonia per seminiferous tubule cross-section. The study found a significant reduction in the S/T ratio in boys with SCD exposed to HU compared to control samples.30 Similarly, Gille et al.31 assessed the S/T ratio in 30 patients with SCD, including 13 who had not been exposed to HU and 17 who had received HU at a median dose of 22.0 mg kg−1 per day for a median duration of 36 months. Among HU-treated patients, six were undergoing treatment at the time of sampling, while 11 had discontinued treatment for a median of 5.2 months. Histological analysis revealed no significant differences in the S/T ratio between HU-exposed and nonexposed patients or between subgroups of patients currently on HU and those who had discontinued treatment. However, spermatogonial reserves in SCD patients were significantly lower than in reference values from boys without SCD, suggesting that spermatogonial depletion may be primarily attributable to SCD itself rather than HU toxicity.31 Benninghoven-Frey et al.32 further investigated the spermatogonial reserve in 29 boys with SCD. Their findings also indicated reduced spermatogonial counts compared to values from boys without SCD. No significant differences in spermatogonial numbers were observed between HU-exposed and nonexposed patients. However, an earlier age at HU initiation appeared to correlate with more pronounced spermatogonial depletion.32 Finally, a retrospective multicenter study involving 101 prepubertal boys under 14 years of age examined the impact of various conditions, including solid tumors, malignant hematological disorders, and nonmalignant hematological disorders such as SCD and thalassemia (n = 18), on spermatogonial reserve. Prepubertal patients with nonmalignant hematological disorders were significantly more likely to exhibit reduced spermatogonial counts compared to reference values from boys without SCD. Among SCD patients treated with HU at the time of biopsy, a reduction in spermatogonial counts was observed compared to patients with nonmalignant hematological disorders who had never received HU. Across all conditions, younger patients (aged 0–4 years and 4–7 years) were more likely to present reduced spermatogonial counts compared to reference values.33
Table 4.
Impact of sickle cell disease and hydroxyurea on the spermatogonial pool
| Study | Study design | Population | Treatment | Analysis | Main results | Conclusion | ||
|---|---|---|---|---|---|---|---|---|
|
| ||||||||
| n | Age (year) | Status | ||||||
| Stukenborg et al.30 2018 | Observational study | 6 | 7.9±3.6a | HbSS | HU | Testicular histology; S/T ratio | Significant reduction in S/T ratio in boys with SCD exposed to HU (0.3±0.6a) compared to controls (4.1±4.6a; P=0.008) | HU may reduce the spermatogonial pool, but further data are needed |
| 14 | 5.6±5.0a | HbAA | NA | |||||
| Gille et al.31 2021 | Observational study | 13 | 8.8 (4.2–15.0)b | HbSS | Nonexposed | Testicular histology; S/T ratio | S/T ratio significantly lower in SCD patients compared to reference values (P<0.0001) No significant difference in S/T ratio between HU-exposed and nonexposed patients | Spermatogonial depletion appears primarily due to SCD rather than HU toxicity |
| 17 | 8.0 (4.2–11.8)b | HbSS | HU (median dose: 22.0 mg kg−1 per day for 36 months) | |||||
| Benninghoven-Frey et al.32 2022 | Observational study | 3 | 7.1 (2.8–15.1)b | HbSS | Nonexposed | Spermatogonial count | Spermatogonial reserve reduced compared to reference values No significant difference between HU-exposed and nonexposed groups Earlier HU initiation correlated with more severe spermatogonial depletion | Early HU initiation may exacerbate spermatogonial depletion |
| 21 | HbSS | HU exposed | ||||||
| Masliukaite et al.33 2023 | Retrospective multicenter study | 18 | 0–14c | HbSS | HU exposed and nonexposed | Spermatogonial counts across conditions; analysis of HU impact on spermatogonia | Patients with SCD had reduced spermatogonial reserve (48.5% vs 31% in reference values) SCD patients under HU: reduced reserve compared to non-HU-exposed (58.3% vs 50%) Younger patients (0–7c years) more likely to show depletion | Combined impact of SCD and HU is difficult to disentangle; younger patients particularly vulnerable |
| 83 | 0–14c | Malignant disease | ||||||
aMean±standard deviation. bMedian (range). cRange. HbSS: hemoglobin electrophoresis profile of patients with sickle cell disease; HbAA: hemoglobin electrophoresis profile of healthy patients; HU: hydroxyurea; S/T ratio: spermatogonia-to-tubule ratio; SCD: sickle cell disease; NA: not available
SPERM PARAMETERS IN MEN WITH SCD WHO HAVE RECEIVED BLOOD TRANSFUSIONS
Several studies have suggested a beneficial short-term effect of blood transfusion treatment on sperm parameters in patients with SCD (Supplementary Table 1). Indeed, Friedman et al.11 observed that the patient with normal sperm parameters was the only one transfused regularly to relieve his painful attacks. Soliman et al.34 presented a prospective comparative study in which the sperm parameters of men with SCD were analyzed before transfusion and 7 days later. Although the delay was very short, a significant increase in sperm concentration, motility, and morphology was observed after transfusion. Finally, a positive correlation was observed between sperm count and the duration of transfusion therapy in men, regardless of HU treatment status.29
Supplementary Table 1.
Semen parameters in men with sickle cell disease who received blood transfusions
| Study | Study design | Population | Abstinence time (day) | HU in childhood | Blood transfusion | Semen parameters | Standard | Conclusion | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
|
|
||||||||||||
| n | Age (year) | Status | Concentration (×106 ml−1) | Progressive motility (%) | Typical form (%) | ||||||||
| Joseph et al.29 2021 | Retrospective, comparative, and multicenter | 15 | 17 (16–23)a | HbSS | 6 (2–90)a | Yes | Yes (100%) | NA | NA | NA | NA | WHO 201046 | Positive correlation between sperm count and duration of transfusions (Mann–Whitney U-test) |
| 23 | 20 (16–24)a | HbSS | 5 (2–30)a | No | Yes (52%) | NA | NA | NA | NA | ||||
| Soliman et al.34 2013 | Prospective | 18 | 20.7±2.88b | HbSS | 3–4c | NA | Yes | After 7 days | 146.2*±51.25b | 93.4*±38.3b | 53.8*±3.57b | WHO 201046 | Significant increase in sperm concentration. Motility and typical sperm forms 7 days after transfusion |
| Before | 87.4±24.6b | 40.8±11.1b | 31.9±5.27b | ||||||||||
| Friedman et al.11 1974 | Observational | 4 | 23–34c | HbSS | 7d | No | Yes | NA | 52d | NA | NA | NA | The only patient with normal sperm concentration received regular transfusions |
| No | NA | 2d | NA | NA | |||||||||
| No | NA | 14.2d | NA | NA | |||||||||
| No | NA | 8.8d | NA | NA | |||||||||
*P<0.05 (statistically significant difference). aMedian (range). bMean±standard deviation. cRange. dMean. HbSS: hemoglobin electrophoresis profile of patients with sickle cell disease; NA: not available; HU: hydroxyurea
SPERM PARAMETERS IN MEN WITH SCD WHO HAVE RECEIVED A HSCT
Myeloablative treatments prior to HSCT are known to permanently and severely alter spermatogenesis.35 Two studies have evaluated the impact of HSCT on sperm parameters in men with SCD (Table 5).36,37 After HSCT, sperm parameters are deeply altered in most patients. Lukusa et al.36 presented the sperm parameters of six men who had undergone HSCT for SCD. Three of them had persistent azoospermia many years following HSCT (15–19 years). The other three recovered spermatogenesis following discontinuation of treatment, with sperm parameters remaining impaired in two of them and normal spermatogenesis observed in the third.36 A younger age (under 10 years) at the time of HSCT may indicate a better prognosis for sperm parameters. However, the data are still very limited, and further observations will be necessary to confirm this hypothesis. Radiation conditioning, on the other hand, appears to be a risk factor for azoospermia. The impact of a reduced-intensity conditioning regimen (RIC) for HSCT was studied in three men with SCD.37 Two of the three had azoospermia and one had severe oligozoospermia. Although puberty was not affected by the treatment, the RIC protocol appeared to cause severe alterations in spermatogenesis. It should be noted that all three patients had received HU treatment prior to the RIC protocol.
Table 5.
Semen parameters in men with sickle cell disease who have received hematopoietic stem cell transplantation
| Study | Study design | Population | HSCT | Abstinence time (day) | Semen parameters (mean) | Standard | Conclusion | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
|
|
|
|||||||||||||
| n | Status | Age at time of treatment (year), mean | Conditioning | GvHD prevention | Time since HSCT (year), mean | Volume (ml) | Concentration (×106 ml−1) | Vitality (%) | Progressive motility (%) | Typical form (%) | |||||
| Zhao et al.37 2019 | Observational, case series | 3 | HbSS | 14 | Cam/Flu/Mel | NR | 4 | 1–4a | NS | 0.5 | NA | Altered | NA | WHO 201046 | Two of the three patients had azoospermia after HSCT |
| 15 | Cam/Flu/Mel | NR | 5 | 1–4a | 0 | NA | NA | NA | |||||||
| 14 | Cam/Flu/Mel | NR | 11 | 1–4a | 0 | NA | NA | NA | |||||||
| Lukusa et al.36 2009 | Observational, case series | 6 | HbSS | 1 | CY-BU | CsA | 21 | 3b | 3.1 | 6.7 | 51 | 44 | 4 | WHO 199949 | Sperm parameters were impaired in all patients. A younger age at the time of HSCT seems to favor better sperm parameters afterward Patients treated with radiotherapy appear to be at greater risk of azoospermia |
| 4 | CY-BU | CsA | 14 | 4b | 1.7 | 48.57 | 83 | 52 | 4 | ||||||
| 12 | CY-BU-TLI | CsA + MTX | 15 | 10b | 1 | 0 | NA | NA | NA | ||||||
| 13 | CY-BU-TLI | CsA + MTX | 16 | 7b | 3.2 | 0 | NA | NA | NA | ||||||
| 13 | CY-BU-TLI | CsA | 19 | 3b | 2 | 0 | NA | NA | NA | ||||||
| 26 | CY-BU | CsA | 8 | 3b | 3.3 | 16.53 | 87 | 64 | 11 | ||||||
aRange. bMean. HSCT: hematopoietic stem cell transplantation; Cam: alemtuzumab; Flu: fludarabine; Mel: melphalan; CY: cyclophosphamide; BU: busulfan; TLI: total lymph node irradiation; GvHD: graft-versus-host disease; CsA: cyclosporine; MTX: methotrexate; HbSS: hemoglobin electrophoresis profile of patients with sickle cell disease; NA: not available
FERTILITY AND PARENTHOOD
To date, only four studies have provided data on the fertility of men with SCD. Berthaut et al.13 reported that, among the 42 patients living with their partners, 17 (i.e., 40%) were responsible for at least one pregnancy. A total of 36 pregnancies were documented in this cohort, including 35 natural conceptions and one obtained following in vitro fertilization with microinjection, resulting in 29 healthy live births. Notably, one patient’s partner experienced three spontaneous miscarriages, and four patients opted for elective abortion. Among them, 12 had not started HU yet and 5 had received HU before and during conception.
In a similar study by Sahoo et al.,18 13 of the 14 married patients without HU and 6 of the 7 patients with HU reported being responsible for at least one pregnancy. In contrast, Osegbe et al.21 observed that none of the four married patients had children with their wives, although three of them reported having fathered children out of marriage. Among 36 unmarried patients, only one reported having a child. None of the patients had been treated by HU. Modebe and Ezeh20 also noted that only one of the three married participants reported fathering a child. He had never been treated by HU. However, the assessment of fertility of patients is challenging, as it is based on self-reported data from patients. Finally, very little data are available on the fertility of men treated with HU. Grigg25 reported that one of the three patients included fathered a child before starting treatment, while the partner of the third patient (Table 2) became pregnant during the 3rd year of his treatment, but opted for a termination of pregnancy. In the study by Sahoo et al.,18 among the 50 patients in the HU group, 7 were married and 6 reported at least one pregnancy at the time of inclusion.
DISCUSSION
Despite numerous methodological limitations, most studies agreed that men with SCD frequently have impaired semen parameters.11,13,17,18,19,20,21 As early as 1974, Friedman et al.11 hypothesized that local ischemia, secondary to vaso-occlusive crises, would be one of the factors responsible for the results observed. Moreover, defective lipid metabolism in SCD subject38 may also challenge spermatogenesis, but studies specifically evaluating this point are necessary to formally confirm this hypothesis. However, the mechanisms involved in impaired fertility are probably numerous and complex and may begin in childhood. Indeed, the authors have observed a link between SCD and reduced spermatogonial reserve in prepubertal children.31,32 The decrease in spermatogonial quantity in young patients with SCD could be explained by subclinical testicular vaso-occlusive episodes or asymptomatic infarctions, as well as a testicular perfusion deficit resulting from chronic anemia.39 In addition, boys with SCD experience delayed puberty and exhibit differences in genitalia and secondary sexual characteristics, including reduced facial and body hair, smaller testicular size, and shorter penis length.40 Hormonal abnormalities, such as low testosterone levels, are common, with inconsistent findings on luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels.41 Primary hypogonadism, resulting from testicular failure, is recognized as the main cause of this hormonal imbalance, though instances of secondary and compensated hypogonadism have also been reported.42 Due to vaso-occlusive crises and hormonal disorders, patients with SCD are at increased risk of complications such as priapism and erectile dysfunction, which can also adversely affect fertility.43
These observations may constitute an argument for discussing fertility considerations as soon as possible with young men suffering from SCD. In addition, most of the treatments proposed to limit vaso-occlusive crises are gonadotoxic. Indeed, studies have highlighted that HU treatment alters the reproductive functions of pubescent men with SCD,13,18,23,24,25,26 while the reversibility following treatment discontinuation has been poorly studied. Data from only five patients have been described before and after treatment with HU,13,24 one of whom had persistent azoospermia 4 years after stopping treatment.13 In this context, offering fertility preservation through sperm cryopreservation is crucial for patients who will undergo HU treatment. It is important to acknowledge that policies regarding fertility preservation in SCD vary significantly across countries, often influenced by financial disparities. In countries where sperm banking is covered by healthcare systems, it is easier to systematically propose sperm freezing as part of standard care. Conversely, in countries with limited or no financial support for such procedures, access remains a significant barrier, potentially leading to unequal opportunities for patients to preserve their fertility. This underscores the necessity for SCD to be universally recognized as a disease that can impair fertility, thereby making fertility preservation an integral component of medical care worldwide. In addition, given the lack of definitive evidence regarding the safety of HU on sperm quality and integrity, it is recommended to offer sperm cryopreservation before initiating treatment. This precaution helps avoid conception during treatment or the need to suggest a therapeutic window, which could compromise the patient’s health. By offering fertility preservation, patients can be reassured about the potential impact of HU on their sperm, which may, in turn, improve their adherence to treatment and alleviate concerns about their future fertility.
Only two studies have investigated the impact of initiating HU treatment in childhood on fertility. Despite methodological limitations, studies suggest that the toxic effect of HU on spermatogenesis should not be a major concern for boys with SCD requiring treatment before puberty.29,44 It has been suggested that the dose of HU used in young patients with SCD may be too low to alter spermatogonial reserve. However, the effect of HU introduced in very young boys has not been studied, the median age of introduction of treatment being 5 years, whereas the initiation of HU at a very young age would be correlated with a lower spermatogonial reserve.32 This consideration is particularly significant given that, since 2014, international guidelines have recommended initiating hydroxyurea therapy for all infants with SCD starting at 9 months of age.45 The spermatogonial reserve of children born after 2014 is thought to be more impaired than that of their elders who received the first dose of treatment later.32 Early childhood is a very important period for testicular development;33 indeed, minipuberty, which occurs shortly after birth, is a sensitive period for the testicles of young boys. The testicles of boys under the age of 3 years may therefore be more sensitive to HU treatment. Further studies are needed to fully understand what happens during this period. Nevertheless, the benefit–risk balance of the treatment and the reassuring data on reproductive functions should not call into question the use of HU in very young children. Furthermore, studies have shown a reduction in spermatogonial reserve in patients with SCD, even in the absence of treatment.31,32 Parents and young patients can therefore be made aware of this issue at an early stage, and a fertility consultation can be offered to the young man and his family. Treatment with HU often takes priority over fertility considerations, as HU reduces complications and improves the overall prognosis.
The development of new therapeutic approaches has made it possible to HSCT to patients with very severe SCD who are not relieved by other therapeutic alternatives. Despite the benefits of HU in reducing the frequency of vaso-occlusive crises and improving quality of life, this treatment does not eliminate the disease. HSCT is the only curative treatment currently available for patients. This treatment, most often used to treat malignant hemopathies, is highly gonadotoxic. Only two studies have assessed the impact of HSCT on sperm parameters in men with SCD. Despite very small numbers, it has been proposed that young age (<10 years) at the time of initiation of treatment could be a good prognostic factor for recovery of spermatogenesis, but more data are needed to confirm this hypothesis.36 Pediatric induction protocols for HSCT in the context of SCD use reduced doses of alkylating agents. The impact on spermatogonial reserve may therefore be less severe. Nevertheless, given the severity of the gonadotoxic impact of these treatments, it is important to discuss fertility preservation with the young patient and his parents.
Ultimately, the treatments offered to patients with SCD have led to a major increase in the life expectancy of these young men. The question of fertility must therefore be considered, especially as the disease itself, but also the treatments, can have an impact on reproductive functions. After this comprehensive literature review, we propose a flowchart that aligns well with French practices in fertility preservation. Indeed, in France, fertility preservation is guided by established medical protocols and legal frameworks. Additionally, the French public health insurance system covers medical fertility preservation procedures, ensuring accessibility for patients undergoing treatments that may affect fertility (Supplementary Figure 1 (71.4KB, tif) ). In young pubescent men, sperm cryopreservation should be offered prior to initiation of HU treatment and is essential prior to HSCT. If HU treatment has already been started, a therapeutic window of 3 months is recommended before sperm freezing. In prepubertal boys, testicular biopsy followed by cryopreservation of immature testicular tissue may be proposed prior to HSCT. As this procedure is still experimental, and the possibility of using cryopreserved testicular tissue remains uncertain, the benefit–risk balance is not currently in favor of this technique in young boys about to receive HU treatment.
CONCLUSION
Improved management of patients with SCD in resource-rich countries has significantly increased their life expectancy, allowing many of these individuals to reach adulthood. As a result, the issue of fertility becomes relevant from an early age, necessitating the introduction of fertility preservation strategies tailored to their treatments. Offering fertility counseling at the onset of treatment and at key stages throughout the patient’s life can help raise awareness among parents of young boys and adolescent men about the potential impact of SCD and its treatments on reproductive health. This early engagement allows them to make informed decisions and actively participate in fertility preservation efforts, which can sometimes be complex. Ultimately, the goal is to provide comprehensive support for these patients, helping them navigate their treatment when preserving their potential for future parenthood and fulfilling their family planning aspirations.
AUTHOR CONTRIBUTIONS
CL, IB, and CD reviewed the literature, collected data, and wrote the manuscript. NS, LOA, AL, DRD, GB, FL, AS, AGC, KK, and RL collaborated in writing, revising, and editing the manuscript. All authors read and approved the final manuscript.
COMPETING INTERESTS
All authors declare no competing interests.
Supplementary Information is linked to the online version of the paper on the Asian Journal of Andrology website.
Decision tree concerning fertility management of male patients with SCD. SCD: sickle cell disease; HSCT: hematopoietic stem cell transplantation
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Associated Data
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Supplementary Materials
Decision tree concerning fertility management of male patients with SCD. SCD: sickle cell disease; HSCT: hematopoietic stem cell transplantation