The histamine H4 receptor is detected in neonatal human Leydig cells, and in prepubertal Leydig cells tumors. Possible involvement in neonatal Leydig cells pool preservation

ALIBERTI, PAULA; MONDILLO, CAROLINA; ABIUSO, ADRIANA MARÍA BELÉN; PIGNATARO, OMAR PEDRO; RIVAROLA, MARCO AURELIO; BELGOROSKY, ALICIA; BERENSZTEIN, ESPERANZA

San Diego

Congreso; 97th Annual Meeting and Expo of the Endrocrine Society; 2015

Endocrine Society

Histamine (HA) is an endogenous biogenic amine synthesized from L-histidine exclusively through the catalytic activity of histidine decarboxylase (HDC). HDC is expressed by testicular mast cells and germ cells [1]. HA is now known to elicit a vast spectrum of physiological and pathological actions, including the pathogenesis of several tumors, through binding to four G protein-coupled receptors, designated as HRH1-4 [2]. Numerous studies have reported the ability of HA to modulate steroidogenesis through H1R and H2R in rodents Leydig cells, and their proliferation under pathological conditions [3]. In human testes of infertile patients, the expression of H1R, and H2R by germinal, interstitial, and peritubular cells was reported [4]. The H4 receptor (H4R), the newest member of the family, is considered a promising drug target for allergy, inflammation, autoimmune disorders, and cancer [5]. Very recently, we reported for the first time that H4R is functionally expressed in murine Leydig cells, and that its selective activation can significantly inhibit gonadotropin-stimulated stereoidogenesis via a reduction in cAMP levels [6]. However, there is no information available on HR4 expression in immature human testes. Aim of the study: 1) to evaluate the developmental immunoexpression of H4R in normal immature human testis from neonatal to late prepuberty, and 2) to compare the H4R immunoexpression pattern in normal immature testis vs Leydig cell tumors. Material and Methods: Human normal testes (n=10) were collected at the time of necropsy from subjects without endocrine or metabolic diseases. For the analysis of results, samples were divided according to age: neonatal (< 1 month old, n=3), infant (postnatal activation, 1 to 7 months old, n=4), and prepubertal (stage of development devoid of morphologically identified Leydig cells), (1 to 12 years old, n=3). Leydig cell tumors were collected from two patients at time of surgery: 3.92 and 6.0 years old. Specific anti-H4R antibody (sc-33967, Santa Cruz Biotechnology) was used for immunohistochemistry. Results: We detected positive H4R expression in cells exhibiting the characteristic histological appearance of Leydig cells (LC) in all normal newborns and in only the youngest of the four infants (age: 2 months). Positive H4R in some interstitial cells was also found. No H4R was detected in prepubertal testes. In contrast, LC tumors showed high H4R staining not only in tumor LC but also in inflammatory- or fibroblastic-like cells. Conclusions: Since HRH4 was only detected in LC of neonates and in one 2 months old infant, it could be proposed that H4R pathway activation might be involved in the preservation of neonatal LC pool, by inhibiting cell apoptosis. This mechanism might also be involved in LC tumor growth regulation. Finally, these findings should be considered in the design of selective HRH4 agonists for therapeutic purposes.