Sickle cell disease (SCD) is the most common hereditary hematologic disorder in the United States, which affects an estimated 100,000 Americans, mostly African-Americans, and millions of people globally (1). Patients with SCD experience acute complications, such as painful vaso-occlusive episodes, and chronic multi-organ damage, which heighten their risks for morbidity and mortality (2). SCD was long considered to be a disease of children and young adults because of its devastating natural progression. Due mostly to universal newborn screening and early therapeutic intervention, life expectancy in patients with SCD has steadily improved over the last 30 years, and recent studies have estimated the median survival for patients with SCD at 60 years (3). Extended survival outcomes have, however, led to an increase in long-term complications of this disease.

SCD is associated with hypogonadism (total testosterone levels below 300 ng/dl), which develops in up to 25% of men with this disease (4). This rate contrasts with the 6-12% prevalence rate of symptomatic hypogonadism in otherwise healthy middle aged and older men, who manifest an age-related decline in testosterone production (5). The impact of testosterone deficiency in the SCD male population is evident, based on its symptomatic effects, e.g., impaired physical and sexual maturation, reduced libido, erectile dysfunction, decreased physical strength, fatiguability, mood changes, and infertility (6, 7). Attempts to address this problem are, however, hampered by limited understanding of the mechanism of hypogonadism in SCD.

This review focuses on the mechanism of testosterone deficiency in SCD, the impact of hypogonadism on health- and reproduction-related issues in SCD males, and novel strategies to drive endogenous testosterone biosynthesis. These strategies may translate into clinical therapeutic opportunities for preserving sexual function and fertility, and possibly other conditions, adversely affected by hypogonadism in SCD.

SCD is caused by a single point mutation in the β-globin gene of hemoglobin, leading to the expression of abnormal sickle hemoglobin (HbS). Traditionally, the pathophysiology of SCD was thought to result exclusively from the polymerization of HbS under hypoxic conditions, causing erythrocytes to become deformed, sludge, and occlude blood vessels, along with oxidative stress, inflammation, and hemolytic anemia (8). More recent studies show that SCD is also characterized by a chronic deficiency of the endogenous vasodilator nitric oxide (NO) and vascular dysfunction (8, 9). As a consequence, SCD leads to progressive multi-organ failure resulting in pulmonary hypertension, leg ulcers, renal failure, stroke, infarct, retinopathy, neurocognitive impairment, bone loss, and priapism (2, 9, 10).

Traditional approaches for managing testosterone deficiency in general have largely centered on exogenous administration of testosterone. Testosterone therapies and their relative usages are: transdermal testosterone gel therapy (70%), testosterone injections (17%), transdermal testosterone patches (10%), and other forms of testosterone therapy, such as an oral formulation (3%) (65, 66). However, limitations exist with these current therapies. Adverse side effects are commonly described in association with exogenous testosterone administration, including supraphysiologic levels of testosterone, local irritation with applications, gynecomastia, erythrocystosis, hepatotoxicity, and sleep apnea (67). Adverse prostate health risks of benign prostate enlargement and prostate cancer as well as cardiovascular risks (i.e., edema, heart attack, stroke) have also been contended to be potential risks of testosterone therapy (68). Impaired sperm production and infertility are also documented risks of exogenous testosterone therapies, by virtue of feedback inhibition of central gonadotropin release. Such therapies suppress LH, which in turn suppress Leydig cell-stimulated testosterone production, resulting in reduced intratesticular testosterone concentrations needed for spermatogenesis (67, 69). Because of the contraceptive effect exerted by exogenous testosterone preparations, many young men with hypogonadism desiring to retain reproductive function are precluded from pursuing exogenous testosterone therapies as a therapeutic option.

Alternatives to exogenous testosterone treatment have been explored, with the main objective to drive endogenous testosterone production and in turn preserve fertility. Current options include selective estrogen receptor modulators (SERMs), aromatase inhibitors, and human chorionic gonadotropin (hCG) (70). Both SERMs (e.g., clomiphene citrate and tamoxifen citrate), which serve as estrogen receptor antagonists, and aromatase inhibitors (e.g., letrozole, anastrozole, and testolactone), which block the conversion of testosterone to estradiol, result in decreased estrogen feedback to the hypothalamus thereby effecting a natural increase in gonadotropin release (70). Their efficacy in increasing testosterone production is limited in men with normal or elevated LH levels who manifest a testosterone production defect at the testicular level. hCG, operating as an LH analogue, serves to stimulate Leydig cell production of testosterone. Its efficacy is limited in men whose Leydig cells are not functionally responsive to LH because of decreased receptor function or capacity for testosterone production (65, 71).

These reports indicate that currently available testosterone therapeutic options aiming to enhance endogenous testosterone production fall short in addressing testosterone deficiency associated with testicular failure. This shortcoming is relevant generally and for hypogonadal males with SCD. Specifically in males with SCD, exogenous testosterone would further affect fertility by decreasing intratesticular testosterone production needed for spermatogenesis.

Targeting mechanism-specific endogenous sources of testosterone production in the SCD testis to produce eugonadal levels of the hormone directly addresses primary hypogonadism. As transfer of cholesterol from the outer to the inner mitochondrial membrane of Leydig cells in the testis is the principal site of regulation of steroid hormone biosynthesis, and is impaired in SCD, targets for stimulating testosterone production may involve transduceosome protein components. The transduceosome is an ensemble of mitochondrial and cytosolic proteins responsible for cholesterol translocation from intracellular stores to the inner mitochondrial membrane (72). Translocator protein (TSPO) is a high-affinity drug- and cholesterol-binding mitochondrial protein, and its protein expression is decreased in the testis of SCD mice (73, 74). The TSPO-dependent import of StAR into mitochondria and the association of TSPO with the outer/inner mitochondrial membrane contact sites drives intramitochondrial cholesterol transfer and subsequent steroid formation (73). Previous studies have shown that TSPO drug ligands activate steroid production by MA-10 mouse Leydig tumor cells and by mitochondria isolated from other steroidogenic cells (75–77). Furthermore, pharmacologic stimulation of TSPO stimulates testosterone production, both in vitro by Leydig cells isolated from aged rats and in vivo in aged rats, without reducing intratesticular testosterone concentrations or sperm number (78, 79). These studies oppose several previous reports which questioned the role and extent of involvement of TSPO in mitochondrial cholesterol import and steroidogenesis (80, 81).

A recent study in a SCD mouse model demonstrated that pharmacologic stimulation of TSPO corrects priapism. Treatment of SCD mice with TSPO-selective drug ligand N,N-dihexyl-2-(4-fluorophenyl) indole-3-acetamide (FGIN-1-27) produces eugonadal levels of testosterone. Normalized testosterone levels corrects priapism without decreasing intratesticular testosterone production (74). At the molecular level, TSPO ligand, by normalizing testosterone levels, restores PDE5 activity and decreases NOX-mediated increase in oxidative stress in the penis. Conceivably, this effect of testosterone pertains to recovered control of NO/cGMP responsiveness associated with restored PDE5 function. The mechanism underlying testosterone’s inhibitory effect on NOX expression and activity is not known, but may be indirect through the improvement of endothelial function. In human endothelial cells and mouse aorta, NO S-nitrosylates and inhibits p47phox subunit of NOX, inhibits protein expression of gp91phox and p47phox subunits of NOX, and inhibits superoxide production (82–84). These findings suggest that targeting endogenous testosterone production in the SCD testis by pharmacologic activation of protein components involved in cholesterol transport could be a novel, targetable pathway to correct primary hypogonadism and ameliorate testosterone deficiency-associated health conditions without affecting fertility.

While not examined, it is plausible that, in addition to TSPO, other cytosolic or outer mitochondrial membrane protein components involved in cholesterol transport from intracellular stores to the inner mitochondrial membrane (such as voltage dependent anion channel 1, negative protein adaptor 14-3-3ϵ, or AAA domain-containing protein 3A) (72), may be targeted in the SCD testis to increase endogenous testosterone production. Because pharmacologic activation of TSPO is independent of LH, it is conceivable that this approach may treat secondary hypogonadism, or mixed primary and secondary hypogonadism, as well. Other possible mechanism-based targets in the SCD testis include increased oxidative stress, or enzymatic sources of oxidative stress (such as NOX), which are enhanced in SCD-associated primary hypogonadism ( Figure 1 ).

Of note, L-glutamine, one of the 3 recently FDA-approved treatments for SCD (L-glutamine, crizanlizumab, and voxelotor), increases glutathione-dependent anti-oxidation in the testis and testosterone levels, at least in sleep-deprived rats (85), while alleviating primary hypogonadism and protecting erythrocytes against oxidative damage.

SCD affects millions of people throughout the world, mostly of African ancestry, and is recognized by the World Health Organization and United Nations as a global health issue. In the United States, health outcomes for people with SCD have improved in the past few decades. Despite medical advances, life expectancy for individuals with SCD in the United States remains 20 to 30 years lower than that of the average American. It has been recognized that research and treatment efforts for SCD lag behind that of other chronic genetic illnesses, such as hemophilia and cystic fibrosis, requiring legislative attention (86, 87). In correlation, less FDA-approved therapies are currently available for SCD. The Sickle Cell Disease Comprehensive Care Act, signed into law in December 2018, represents a commitment by the government to continue research towards increasing the understanding of prevalence, distribution, outcomes, and therapies associated with SCD.

Amidst health care disparities among ethnic populations in the United States, limited knowledge and action surround hypogonadism in SCD, in spite of its long-term and costly health problems. While many studies have evaluated the mechanism and health-related issues of hypogonadism in the general adolescent population, very few studies have focused on hypogonadism in the SCD population. For example, although an estimated 1 in 4 SCD patients exhibits low testosterone levels, no studies have assessed the testosterone-dependent health-related quality of life profiles of SCD patients.

Despite inequity in federal and foundation research funding, basic scientific advances and potential new directions to target testosterone deficiency in SCD are being made in recent years. The objective of finding and targeting mechanism-specific endogenous sources of testosterone production appears necessary for preserving sexual function and fertility in the SCD young adult population, particularly in light of the harms of exogenous testosterone therapies.

The authors confirm contribution to the manuscript as follows: BM and AB critically reviewed the literature. BM drafted the article. BM and AB reviewed and revised the manuscript. BM and AB contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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