Research Article: Sickling Cells, Cyclic Nucleotides, and Protein Kinases: The Pathophysiology of Urogenital Disorders in Sickle Cell Anemia

Date Published: June 13, 2012

Publisher: Hindawi Publishing Corporation

Author(s): Mário Angelo Claudino, Kleber Yotsumoto Fertrin.


Sickle cell anemia is one of the best studied inherited diseases, and despite being caused by a single point mutation in the HBB gene, multiple pleiotropic effects of the abnormal hemoglobin S production range from vaso-occlusive crisis, stroke, and pulmonary hypertension to osteonecrosis and leg ulcers. Urogenital function is not spared, and although priapism is most frequently remembered, other related clinical manifestations have been described, such as nocturia, enuresis, increased frequence of lower urinary tract infections, urinary incontinence, hypogonadism, and testicular infarction. Studies on sickle cell vaso-occlusion and priapism using both in vitro and in vivo models have shed light on the pathogenesis of some of these events. The authors review what is known about the deleterious effects of sickling on the genitourinary tract and how the role of cyclic nucleotides signaling and protein kinases may help understand the pathophysiology underlying these manifestations and develop novel therapies in the setting of urogenital disorders in sickle cell disease.

Partial Text

Sickle cell anemia (SCA) has been first described over a century ago [1] and has become one of the best studied inherited human diseases. Despite being caused by a single point mutation in the HBB gene, multiple pleiotropic effects of the abnormal hemoglobin S production range from vaso-occlusive crisis, stroke, and pulmonary hypertension to osteonecrosis and leg ulcers [2–4].

Priapism is defined as a prolonged and persistent penile erection, unassociated with sexual interest or stimulation, and is one of the complications associated with sickle cell anemia (SCA) since early in 1934 [7]. Priapism reaches a frequency of up to 45% in male patients with SCA, and the rate of resulting erectile dysfunction (ED) exceeds 30% [8–10]. Although this complication has been previously reviewed in depth in this journal [11], the main concepts behind its pathophysiology will be summarized here for better understanding of the mechanisms discussed throughout the paper, but readers are encouraged to read the previous review.

Progress in the therapy of SCD, particularly the use of hydroxyurea, has considerably improved the prognosis of patients with SCD [100, 101], with their mean life expectancy reaching much over 40 years [102–104], rendering infertility an important issue. Nevertheless, long before hydroxyurea became a standard of care in SCD, seminal fluid parameters of SCD males had been reported to fall within the subfertile range due to decreased sperm concentration, total count, motility, and altered morphology [105–107], and a more recent study reported over 90% of patients had at least one abnormal sperm parameter [108].

The etiology of hypogonadism in SCD patients is multifactorial, as several mechanisms have been suggested to contribute to its occurrence, such as primary gonadal failure [117, 122, 123], associated with or caused by repeated testicular infarction [124], zinc deficiency [125, 126], and partial hypothalamic hypogonadism [127].

Segmental testicular infarction is an infrequent cause of acute scrotum and is rarely reported, with fewer than 40 cases published at the time of this paper. Its etiology is not always well defined, and it may be, at first, clinically mistaken for a testicular tumour [153, 154]. Common causes for testicular infarction are torsion of the spermatic cord, incarcerated hernia, infection, trauma, and vasculitis [131]. The usual presentation is a painful testicular mass unresponsive to antibiotics [155]. This testicular disorder has been associated with epididymitis, hypersensitivity angiitis, intimal fibroplasia of the spermatic cord arteries, polycythemia, anticoagulant use, benign testicular tumors and, in the interest of this review, sickle cell trait and sickle cell disease [124, 131, 155–158].

The urinary bladder has two important functions: urine storage and emptying. Urine storage occurs at low pressure, implying that the bladder relaxes during the filling phase. Disturbances of the storage function may result in lower urinary tract symptoms (LUTSs), such as urgency, increased frequency, and urge incontinence, the components of the hypoactive or overactive bladder syndromes [172, 173]. The passive phase of bladder filling allows an increase in volume at a low intravesical pressure. The bladder neck and urethra remain in a tonic state to prevent leakage, thus maintaining urinary continence. Bladder emptying is accompanied by a reversal of function in which detrusor smooth muscle (DSM) contraction predominates in the bladder body that is accompanied by a concomitant reduction in outlet resistance of the bladder neck and urethra [174–176]. The bladder filling and emptying are regulated by interactions of norepinephrine (sympathetic component released by hypogastric nerve stimulation), acetylcholine and ATP (parasympathetic components released by pelvic nerve stimulation) with activation of adrenergic, muscarinic, and purinergic receptors, respectively [175].

Urogenital disorders in SCD are the result of pleotropic effects of the production of the abnormal sickling hemoglobin S. While priapism still stands out as the most frequently encountered, current knowledge of the effects of cyclic nucleotide production and activation of protein kinases allows to suspect underdiagnosis of bladder dysfunction and hypogonadism secondary to testicular failure. Moreover, despite our growing understanding of these complications, adequate, efficacious, and well-tolerated treatments are still unavailable, and male patients continue to suffer from infertility and erectile dysfunction. Further work in, both clinical assessments and experimental studies in this field are promising and should help increase physicians’ awareness of the importance of more accurate diagnoses, design improved therapeutic strategies, and eventually, achieve better quality of life for SCD patients.




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