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12.2% 122000 135M Top 1% 154 4800 We are IntechOpen, the world’s leading publisher of Open Access books Built by scientists, for scientists 4,800 122,000 135M Open access books available International authors and editors Downloads Our authors are among the 154 TOP 1% 12.2% Countries delivered to most cited scientists Contributors from top 500 universities Selection of our books indexed in the Book Citation Index in Web of Science™ Core Collection (BKCI) Interested in publishing with us? Contact [email protected] Numbers displayed above are based on latest data collected. For more information visit www.intechopen.com Chapter 1 Morphological Bases of Human Leydig Cell Dysfunction Maria P. De Miguel,Maria P. De Miguel, Pilar Gonzalez-PeramatoPilar Gonzalez-Peramato andand Manuel NistalManuel Nistal Additional information is available at the end of the chapter http://dx.doi.org/10.5772/intechopen.79201 Abstract In this chapter, we describe the histophysiology of human Leydig cells, their cytologi- cal characteristics, their differentiation processes, and the physiopathological processes occurring at various times throughout life. We first focus on the normal development of fetal Leydig cells as well as the pathologies of fetal Leydig cells that can affect num- bers or hyperplasic processes (e.g., hypogonadotropic hypogonadism, cryptorchidism, congenital Leydig cell hyperplasia secondary to diabetes, and isoimmunization). Next, we explain the changes occurring at puberty with the onset and differentiation of adult Leydig cells and the pathophysiology of delayed puberty. We then describe the histophysiology of adult Leydig cells and the most frequent pathologies (e.g., hypogo- nadotropic hypogonadism, testicular dysgenesia, mild androgen insensitivity syndrome, 5-α-reductase defect, and Klinefelter syndrome). Finally, we discuss the morphological changes of these cells in the elderly. Keywords: fetal Leydig cells, adult Leydig cells, testosterone, puberty, elderly, dysgenesia, pathology 1. Introduction Leydig cells are the primary producers of testosterone. They perform important functions during fetal life, in the first months of life, and in adults, ranging from male sexual differentia- tion and testicular descent to the acquisition of a normal number of spermatogonial stem cells, the development of spermatogenesis and thus fertility, and the maintenance of typical male characteristics in adulthood. © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. distribution, and reproduction in any medium, provided the original work is properly cited. 2 Advances in Testosterone Action 2. Fetal stage 2.1. Origin and development of fetal Leydig cells During development, two different types of Leydig cells appear sequentially, fetal Leydig cells and adult Leydig cells, which display different functional characteristics, reflecting their morphology, steroid capacity, and regulatory mechanisms. Fetal Leydig cells are detected immediately after gonadal sex differentiation [1]. Adult Leydig cells begin to develop at the beginning of puberty and acquire their maximum numbers at the end of puberty. The origin of both Leydig cell types is debated: some suggest a parent-common progenitor pool in the fetal testis [2, 3] and others have suggested that Leydig cells in adults might originate in precursors to fetal Leydig cells 4[]. In addition, a three-phase model of the development of Leydig cells has been proposed: fetal, neonatal, and adult Leydig cells5]. [ 2.1.1. Development of fetal Leydig cells The mesonephros and the coelomic epithelium are considered the two most plausible origins of fetal Leydig cells. The progenitor cells expressing SF1 actively proliferate and ultimately lose this marker when cell differentiation begins in week 8 of human gestation. The first sign of differentiation is the histochemical detection of 3-beta hydroxysteroid dehydrogenase (3β- HSD) in the cytoplasm. About 83% of 3β-HSD-positive cells show a high intensity of andro - gen receptors (ARs) immunoreaction. Fetal Leydig cells express various steroidogenic enzymes required for androgen synthesis, such as acute regulatory protein, CYP11A1 (P450 side chain cleavage), CYP17A1 (P450C17), and 3β-HSD. The most important androgenic product of fetal Leydig cells is androstenedione. Fetal Sertoli cells make testosterone from androstenedione through the enzyme 17-β hydroxys- teroid dehydrogenase (HSD17β3) at this stage of fetal testis development. Differentiation of fetal Leydig cells has been a subject of debate in recent decades and appears to be an andro- gen-independent process [6]. Their proliferation and subsequent development do so under the stimulus of human chorionic gonadotropin (hCG) in the first half of the gestation period and with the help of luteinizing hormone (LH) secreted by the pituitary gland in the last half. Both hormones are glycoproteic in nature and act through the same receptor (LHCGR). 2.1.2. Evolution throughout fetal life Fetal Leydig cells are identified by positivity for the 3β-HSD enzyme. The maximum peak of Leydig cell numbers is reached at week 19 of gestation (Figure 1). Remarkably, this peak occurs in parallel with the disappearance of one of the two layers of peritubular cells of the seminiferous epithelium, the outermost layer of peritubular cells, between weeks 17 and 19 of gestation. These two occurrences also match the maximum production of testosterone between the 14th and 19th weeks of fetal life. After a few weeks of Leydig cell quiescence, from week 22 of gestation, a progressive decrease in the number of Leydig cells is observed. Most fetal Leydig cells disappear after birth; however, a subpopulation persists in the postna- tal testis that is estimated to represent 10% of all Leydig cells in adulthood [ 7–9]. Given that Morphological Bases of Human Leydig Cell Dysfunction 3 http://dx.doi.org/10.5772/intechopen.79201 Figure 1. Fetus at 19 weeks. Seminiferous tube showing two gonocytes in the center, with the remaining cells, the Sertoli cells. In the interstitium, Leydig cells with peripheral nuclei and broad eosinophilic cytoplasm are abundantly found. fetal Leydig cells do not express HSD17β3, they cannot directly synthesize testosterone; thus, their functional importance in adults is unknown. 2.2. Functions of fetal Leydig cells 2.2.1. Differentiation of the genitals Under the action of testosterone, the differentiation of the Wolff tubes takes place. This dif- ferentiation is ipsilateral and gives rise to the development of the epididymis, vas deferens, and seminal vesicle. When testosterone is converted into dihydrotestosterone by the enzyme 5-α-reductase, differentiation of the prostate and development of the external genitalia occur: male urethra, penis, and scrotum. 2.2.2. Testicular descent The two stages of testicular descent, transabdominal and inguinoscrotal, are controlled directly or indirectly by fetal Leydig cells. Transabdominal descent depends on an androgen- independent peptide, insulin-like growth factor 3 (INLS3), whereas inguinoscrotal descent is mediated by androgens through the masculinization they produce in the genitofemoral nerve neurons. Those neurons produce calcitonin gene-related peptide (CGRP), which is respon- sible for the development that the gubernaculum acquires, allowing testicle descent10]. [ 2.3. Pathology of fetal Leydig cells 2.3.1. Defective androgen synthesis Defects in the synthesis of androgens due to various autosomal hereditary syndromes result in absent or incomplete virilization. They include lipoid congenital adrenal hyperplasia (lipoid CAH), deficits in 3-βHSD/17,20-lyase, α-hydroxylase 17/17,20-lyase deficiency, deficit in 17,20 desmolase, and deficit in 17-β hydroxysteroid dehydrogenase. 4 Advances in Testosterone Action 2.3.1.1. Lipoid CAH It is the most severe form of congenital adrenal hyperplasia. It affects the synthesis of adrenal and gonadal steroid hormones. Genetically 46,XY patients are phenotypically women with severe salt-losing syndrome. There is no uniformity in the histological descriptions of the Leydig cells; in some cases, they are described as having large accumulations of lipids11], [ whereas in others, such lipid inclusions are absent [12]. 2.3.1.2. 3-βHSD/17,20-lyase deficit Patients with a mild deficiency have normal external genitalia; some consult for hypospadias or micropenis [13], and the testicles are smaller than normal. 2.3.1.3. 17-α Hydroxylase/17,20-lyase deficiency Patients have a significant degree of undermasculinization; they can even mature as girls and consult at puberty for amenorrhea. The testes show a delay in pubertal development and hyperplasia of Leydig cells. 2.3.1.4. 17,20 Desmolase deficit It presents with a high variability in external genital development, from a female pheno- type to males with micropenis that is hardly virilized, bifid scrotum, perineal hypospa- dias, and cryptorchidism, due to the insufficient production of testosterone during fetal life. 2.3.1.5. 17-β-Hydroxysteroid dehydrogenase deficit Patients show a female phenotype at birth, grow up as girls, and suffer significant virilization
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