Sickle cell disease (SCD) represents the most common hereditary hematologic disorder in the United States, affecting an estimated 100,000 Americans, primarily among African-American populations, and millions of individuals worldwide1. Characterized by a single-point mutation in the β-globin gene leading to hemoglobin S polymerization under hypoxic conditions, SCD results in chronic hemolysis, vaso-occlusion, and multisystem organ damage. Patients with SCD experience recurrent acute complications, including painful vaso-occlusive episodes and acute chest syndrome2, as well as chronic complications involving the heart, kidneys, brain, and endocrine systems. These pathophysiological features lead to significantly elevated morbidity and mortality. Historically, SCD was considered a pediatric and young-adult disease due to its severe natural history, with limited survival into adulthood. However, the implementation of universal newborn screening, prophylactic penicillin, immunizations, hydroxyurea therapy, and comprehensive supportive care has substantially improved survival rates over the past three decades. Consequently, recent studies estimate the median survival for individuals with SCD has risen to approximately 60 years, with some patients surviving even longer. This encouraging progress, however, has revealed a growing burden of chronic complications, including endocrinopathies, as patients live well beyond childhood and adolescence3. One of the significant endocrine consequences of SCD is hypogonadism, which is generally defined by serum total testosterone concentrations below 300 ng/dL. Studies have demonstrated that up to 25% of adult men with SCD develop hypogonadism, a markedly higher prevalence than that seen in the general population, where symptomatic hypogonadism is estimated to affect only about 6–12% of middle-aged and older men as part of age-related testosterone decline4. The clinical impact of hypogonadism in the SCD male population is substantial and multifaceted. Symptoms may include impaired progression through puberty, reduced libido, erectile dysfunction, infertility, decreased muscle strength, increased fatiguability, mood disturbances, and reduced quality of life5. These consequences can exacerbate the already heavy physical and psychosocial burden borne by men living with SCD. The precise mechanisms leading to hypogonadism in SCD, however, remain incompletely elucidated. Several hypotheses have been proposed6, including chronic hypoxia affecting the hypothalamic–pituitary–gonadal (HPG) axis, iron overload due to repeated transfusions damaging gonadotropic cells, and direct testicular ischemic injury from vaso-occlusion7. Furthermore, systemic inflammation, oxidative stress, and nutritional deficiencies may also contribute to dysregulation of the HPG axis. Limited studies have differentiated between primary (testicular) versus secondary (hypothalamic or pituitary) hypogonadism in SCD8, but emerging data suggest that secondary hypogonadism is more prevalent, potentially due to chronic suppression of gonadotropin-releasing hormone or pituitary dysfunction9. These insights, while preliminary, underscore the importance of further research to characterize the pathophysiology of hypogonadism in SCD, which is vital for developing appropriate screening, prevention, and treatment strategies. As the life expectancy of patients with SCD continues to rise, attention to reproductive and sexual health will become increasingly relevant to their overall well-being and quality of life10. Therefore, addressing testosterone deficiency through appropriate endocrinologic evaluation and carefully considered hormone replacement therapy, while balancing risks in a population prone to vaso-occlusive crises, is crucial. Ultimately, a deeper understanding of hypogonadism’s prevalence, mechanisms, and impact in SCD could contribute substantially to improving the comprehensive care of this growing adult population.

AIM

Study of Hypogonadism in Patients with Sickle Cell Disease: Central or Peripheral?

This observational study was conducted at the Late Shrimati Indira Gandhi Memorial Government Medical College associated with Komaldev Hospital, Kanker, Chhattisgarh. Eligible participants included adult male patients with sickle cell disease (SCD) who were not on testosterone therapy and had no acute illness within seven days before enrollment.  A total of 45 patients consented to participate. Blood samples were collected from participants in the early morning and sent for hormonal assays. Total testosterone levels were measured using an ELISA method, while FSH and LH levels were assessed via a two-site sandwich immunoassay chemiluminescence method (Centaur XP, Siemens). The intra-assay and inter-assay coefficients of variation for all hormone measurements were maintained below 5%. Additional clinical and laboratory parameters, including body mass index (BMI), hemoglobin, total bilirubin, ferritin, and creatinine levels, were extracted. Participants were categorized as hypogonadal if their serum testosterone was less than 250 ng/dL and normogonadal if it was ≥250 ng/dL. Reference ranges for FSH and LH were 1.5–12.4 mIU/mL and 2–14 mIU/mL, respectively. Hypogonadal participants with elevated FSH and LH were classified as having primary (peripheral) hypogonadism, whereas those with inappropriately normal or low gonadotropins were classified as having secondary (central) hypogonadism.

Table 1: Age parameter of Study Population

 Among men with testosterone >250 ng/dL, most were aged 21–30 years (15/34), while hypogonadal men (≤250 ng/dL) were primarily in the 31–40 age group (7/11).

Table 2: Characteristics of Study Population

Most participants had BMI within the normal range (18.5–24.9) among normogonadal men (25/34), while overweight or obesity (BMI ≥ 25) was more frequent in hypogonadal men (7/11); all participants across both groups had hemoglobin levels below normal (<13 g/dL) and elevated total bilirubin (>1.2 mg/dL).

Table 3: Testosterone levels in SCD Men with Normogonadism and Hypogonadism

In this study, nearly all men with testosterone >250 ng/dL had levels within the normal range of 300–1000 ng/dL (31/34), whereas all hypogonadal men (11/11) had testosterone levels below 300 ng/dL, highlighting a clear separation between the two groups.

Table 4: FSH and LH Profiles in SCD Men with Normogonadism and Hypogonadism

In this study, most normogonadal men (33/34) had normal FSH levels (1.5–12.4 mIU/ml), while the majority of hypogonadal men (9/11) had low FSH (<1.5 mIU/ml); similarly, normal LH levels (2–14 mIU/ml) were seen in all normogonadal men (34/34), whereas low LH (<2 mIU/ml) was found in 8/11 hypogonadal men.

Table 5: Ferritin Profile in SCD Men with Normogonadism and Hypogonadism

In this study, most normogonadal men (23/34) and hypogonadal men (7/11) had ferritin levels within the normal range (30–400 ng/dL), while elevated ferritin (>400 ng/dL) was observed in 11 normogonadal and 4 hypogonadal participants.

Almost all participants in our study have a homozygous SCD-SS genotype, except 3 with SCD-SC and one with  SCD-S - + thalassemia.11 out of 45 patients (24%) had serum testosterone levels below 250 ng/dl and were classified as hypogonadal. Hypogonadal men were somewhat older and heavier than normogonadal men.

In this study, among participants with testosterone levels above 250 ng/dL (n=34), the largest group was aged 21–30 years (15 participants), followed by 9 in the 31–40 age range, 7 between 41–50, and 3 aged 20 or younger. In contrast, among those with testosterone levels ≤250 ng/dL (n=11), most were aged 31–40 years (7 participants), with 3 in the 21–30 group and 1 in the 41–50 group, and none aged 20 or below. This distribution suggests that hypogonadism was more common in older age groups within this sickle cell disease cohort. Overall, younger men tended to have higher testosterone levels, while lower levels were observed more frequently with advancing age.

In this study, most participants with testosterone levels >250 ng/dL (n=34) had a normal BMI (18.5–24.9) in 25 cases, while 9 were overweight or obese (BMI ≥25). In contrast, among men with testosterone ≤250 ng/dL (n=11), only 4 had normal BMI, while 7 were overweight or obese, suggesting a higher rate of elevated BMI among hypogonadal men. Hemoglobin levels were below the normal range (13–17 g/dL) in all participants, reflecting universal anemia in both groups. Similarly, total bilirubin was elevated (>1.2 mg/dL) in all 45 men, indicating common hemolysis consistent with sickle cell disease. Comparatively, the hypogonadal group showed a higher prevalence of overweight status, suggesting a possible link between increased BMI and lower testosterone. Overall, both groups showed similar trends in anemia and hyperbilirubinemia, but differed in BMI distribution.

In this study, nearly all hypogonadal men (11/11) had testosterone levels below 300 ng/dL, consistent with their classification. In contrast, 31 of 34 normogonadal men had testosterone levels between 300–1000 ng/dL, reflecting a physiologically normal range, while one had a supraphysiologic value above 1000 ng/dL. Only two normogonadal men fell below 300 ng/dL, suggesting borderline values despite overall normal classification. These findings highlight a clear separation in testosterone profiles between the groups, with hypogonadal men clustering entirely in the deficient range, and normogonadal men maintaining adequate or even high-normal levels. This underscores the clinical validity of using 250–300 ng/dL as a threshold for identifying hypogonadism.  In this study, most normogonadal men (33 out of 34) had FSH levels within the normal range of 1.5–12.4 mIU/ml, with only one below normal, while hypogonadal men showed a markedly different pattern, with 9 out of 11 having FSH below 1.5 mIU/ml, indicating gonadotropin deficiency. Similarly, LH levels in the normogonadal group were all within the normal range of 2–14 mIU/ml, whereas 8 of 11 hypogonadal men had LH levels below 2 mIU/ml, consistent with central (secondary) hypogonadism. Only 3 hypogonadal men showed LH within normal limits, suggesting inadequate compensatory response. Overall, the normogonadal group maintained normal pituitary function, while the hypogonadal group demonstrated predominantly low gonadotropin levels. This pattern supports the interpretation that secondary hypogonadism was the principal mechanism for low testosterone in these patients. These findings highlight the need for endocrine evaluation in hypogonadal SCD patients to confirm hypothalamic-pituitary axis dysfunction.  This pattern mirrors the results reported by Taddesse et al. (2012)11. In their cohort of 34 men with SCD, those with low testosterone also showed significantly lower LH (p=0.001) and FSH (p=0.01) compared to normogonadal men. Similarly, Dada and Nduka (1980)12 described decreased LH, FSH, and testosterone in men with SCD, which was interpreted as hypothalamic-pituitary dysfunction rather than primary gonadal failure

In this study, among men with testosterone >250 ng/dL (n=34), 23 had ferritin levels within the normal range (30–400 ng/dL), while 11 showed elevated ferritin levels above 400 ng/dL. In contrast, among hypogonadal men with testosterone ≤250 ng/dL (n=11), 7 had ferritin within the normal range and 4 had elevated ferritin. This distribution suggests that iron overload, as reflected by high ferritin, was present in both groups but proportionally higher among normogonadal men (32% vs. 36%). Despite the slightly greater proportion of elevated ferritin in the hypogonadal group, the difference was not statistically significant. Elevated ferritin may reflect iron overload due to chronic hemolysis in sickle cell disease rather than a direct association with testosterone levels. Overall, ferritin distribution did not differ markedly between normogonadal and hypogonadal men, highlighting that iron overload is a shared complication among sickle cell patients regardless of gonadal status. Similarly, a study by S. Karger13 did not show statistically significant differences in ferritin levels between hypogonadal and normogonadal men.

This study revealed that 24% of men with sickle cell disease (SCD) were hypogonadal, with hypogonadism more prevalent among older and heavier participants. Most hypogonadal men showed low FSH and LH levels, indicating central (secondary) hypogonadism, in line with previous studies by Taddesse et al. and Dada and Nduka. BMI was higher among hypogonadal men, suggesting excess weight as a potential contributing factor. Universal anemia and elevated bilirubin reflected chronic hemolysis typical of SCD across both groups. Ferritin levels, indicating iron overload, were elevated in a similar proportion in normogonadal and hypogonadal men, without significant difference. Overall, these findings highlight the need for routine endocrine evaluation in SCD patients to detect and manage central hypogonadism early, potentially improving quality of life.

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