Testosterone Deficiency in Sickle Cell Disease: Recognition and Remediation

Abstract

Hypogonadism is common in men with sickle cell disease (SCD) with prevalence rates as high as 25%. Testicular failure (primary hypogonadism) is established as the principal cause for this hormonal abnormality, although secondary hypogonadism and compensated hypogonadism have also been observed. The underlying mechanism for primary hypogonadism was elucidated in a mouse model of SCD, and involves increased NADPH oxidase-derived oxidative stress in the testis, which reduces protein expression of a steroidogenic acute regulatory protein and cholesterol transport to the mitochondria in Leydig cells. In all men including those with SCD, hypogonadism affects physical growth and development, cognition and mental health, sexual function, as well as fertility. However, it is not understood whether declines in physical, psychological, and social domains of health in SCD patients are related to low testosterone, or are consequences of other abnormalities of SCD. Priapism is one of only a few complications of SCD that has been studied in the context of hypogonadism. In this pathologic condition of prolonged penile erection in the absence of sexual excitement or stimulation, hypogonadism exacerbates already impaired endothelial nitric oxide synthase/cGMP/phosphodiesterase-5 molecular signaling in the penis. While exogenous testosterone alleviates priapism, it disadvantageously decreases intratesticular testosterone production. In contrast to treatment with exogenous testosterone, a novel approach is to target the mechanisms of testosterone deficiency in the SCD testis to drive endogenous testosterone production, which potentially decreases further oxidative stress and damage in the testis, and preserves sperm quality. Stimulation of translocator protein within the transduceosome of the testis of SCD mice reverses both hypogonadism and priapism, without affecting intratesticular testosterone production and consequently fertility. Ongoing research is needed to define and develop therapies that restore endogenous testosterone production in a physiologic, mechanism-specific fashion without affecting fertility in SCD men.

Endocrinopathies in Hemoglobinopathies: What Is the Role of Iron?

“…Furthermore, Martins et al proposed androgen resistance as a possible mechanism of hypogonadism in SCD (peripheral hypogonadism) [129]. Primary hypogonadism has been suggested as the major cause of abnormal testosterone levels, attributed to increased oxidative stress, leading to diminished transport of cholesterol to mitochondria of Leydig cells [130,131]. Recurrent testicular infractions could contribute to the development of primary gonadal failure in these men [132,133].…”

“…Eunuchoid habitus, small testicular size, absence of secondary sexual characteristics, poor libido, and infertility are manifestations of hypogonadism in SCD male individuals [9,123]. Reduced testosterone levels have been associated with priapism in SCD males [130]. Testosterone replacement therapy and clomiphene have been administrated to mitigate the symptoms of hypogonadism in SCD male subjects with variable outcomes [136,137].…”

Family planning needs of young adults with sickle cell disease

“…SCD is associated with delayed sexual development [1], and there are increasingly recognized sex‐specific SCD complications. People with testicles are at risk for hypogonadism, priapism, and infertility [2–4]. People with ovaries are at risk for menstruation‐associated sickle cell pain and dyspareunia, have thrombophilic risks exacerbated by hyperestrogenemic states that complicate pregnancy and contraceptive choices, and they may also have infertility risk factors [5–8].…”

Knowledge of fertility and perception of fertility treatment among adults with sickle cell disease (KNOW FERTILITY)

“…Chronic pain is a risk factor for dyspareunia ( 11 ) and SCD negatively impacts sexual function, which is poorer for those with SCD than in unaffected people, a finding associated with infertility in one study ( 12 ). For men with SCD, infertility risks are a consequence of hypogonadism, sperm abnormalities, recurrent priapism, and erectile dysfunction ( 3 , 13 ).…”

“…Sickle cell disease (SCD) is a common, inherited autosomal recessive hematologic disorder with myriad life limiting complications (1). Improved childhood survival is leading to a growing population of adults facing SCDspecific reproductive healthcare challenges which include the accumulation of disease-and treatment-associated infertility risk factors (2)(3)(4)(5)(6)(7). Women with SCD have late onset menarche, accelerated decline in ovarian reserve, and an increased risk of miscarriage (5,(8)(9)(10).…”