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Ferraguti, G.;  Fanfarillo, F.;  Tarani, L.;  Blaconà, G.;  Tarani, F.;  Barbato, C.;  Minni, A.;  Ralli, M.;  Francati, S.;  Greco, A.; et al. NGF and the Male Reproductive System. Encyclopedia. Available online: (accessed on 05 December 2023).
Ferraguti G,  Fanfarillo F,  Tarani L,  Blaconà G,  Tarani F,  Barbato C, et al. NGF and the Male Reproductive System. Encyclopedia. Available at: Accessed December 05, 2023.
Ferraguti, Giampiero, Francesca Fanfarillo, Luigi Tarani, Giovanna Blaconà, Francesca Tarani, Christian Barbato, Antonio Minni, Massimo Ralli, Silvia Francati, Antonio Greco, et al. "NGF and the Male Reproductive System" Encyclopedia, (accessed December 05, 2023).
Ferraguti, G.,  Fanfarillo, F.,  Tarani, L.,  Blaconà, G.,  Tarani, F.,  Barbato, C.,  Minni, A.,  Ralli, M.,  Francati, S.,  Greco, A.,  Petrella, C., & Fiore, M.(2022, November 18). NGF and the Male Reproductive System. In Encyclopedia.
Ferraguti, Giampiero, et al. "NGF and the Male Reproductive System." Encyclopedia. Web. 18 November, 2022.
NGF and the Male Reproductive System

Infertility is a worldwide health issue defined by the World Health Organization (WHO) as the inability to establish a pregnancy after 12 months or more of regular and unprotected sexual intercourse. Male infertility etiology can be related to either congenital or acquired factors. The therapeutical approach to male infertility depends on the underlying causes and includes medical and surgical treatments. The potential role of nerve growth factor (NGF) in male reproductive physiology has been proposed. It has been hypothesized that neurotrophins might be involved in testis morphogenesis and regulation of several aspects of spermatogenesis. Moreover, it has been shown that NGF exerts its role on gonadotropin-releasing hormone (GnRH) neurons through the activation of the PKC/p–ERK1/2/p–CREB cascade, which leads to the activation of hypothalamic cells and the consequent activation of hypothalamus–pituitary–gonadal axis (HPG) with the secretion of GnRH.

male infertility oligozoospermia asthenozoospermia azoospermia sperm cryopreservation assisted reproduction nerve growth factor neurotrophins

1. Introduction

During the past years, there has been growing interest in the understanding of male infertility causes and treatments. Infertility has an important social impact because it can affect mental health, being related to depression, anxiety disorders, and other psychological diseases. According to the WHO, the quality of life and psychological health depend directly on sexual health. Many factors can be related to male infertility, such as hormonal disease, obesity, diabetes, ejaculatory disorders, urogenital infections, testicular trauma, chemo/radiotherapy, or surgical treatments.
Recent findings reported the implication of nerve growth factor (NGF) in male reproductive pathophysiology. A wide number of animal and human studies demonstrated the involvement of NGF in spermatogenesis, testis morphogenesis, and the hypothalamus–pituitary–gonadal (HPG) axis and its improving effect on sperm traits. Therefore, NGF might be exploited in male infertility treatment, suggesting potential new strategies for male infertility therapy.

1.1. Male Infertility

1.1.1. Epidemiology

Infertility is a worldwide health issue defined by the World Health Organization (WHO) as the inability to establish a pregnancy after 12 months or more of regular and unprotected sexual intercourse [1][2]. Infertility affects approximately 15% of reproductive-aged couples and 186 million individuals globally [3]. Data suggest that in about 50% of infertility cases, “male factor” infertility has an important role and is solely responsible in 20–30% of cases [4]. Infertility is related to psychological distress, leading to depression and anxiety disorders, and has an important social impact [5][6].

1.1.2. Etiology

The etiology of male infertility can be related to a variety of factors, which can be distinguished into congenital or acquired [2]. Both congenital and acquired causes of male infertility can be classified into three categories: pretesticular, post-testicular, and testicular causes [7]. Among the pretesticular causes of male infertility, hypogonadotropic hypogonadism (HH) is one of the main causes [8]. Patients affected by HH have a deficit of LH and FSH secretion, which can be due either to a pituitary or hypothalamic dysfunction [9][10].
The hyposecretion of LH and FSH compromises normal spermatogenesis and production of testosterone, being responsible for infertility [11][12]. Other pretesticular causes of male infertility are coital disorders, such as ejaculatory disorders (e.g., anejaculation, retrograde ejaculation) [13][14] and erectile dysfunction [15]. It should be noted that some authors included coital disorders among the post-testicular causes of male infertility [16]. Post-testicular causes of male infertility also include primarily all the obstructions of the seminal tract [17][18]. Infections of the urogenital tract are also among the post-testicular causes of male infertility; in fact, microorganisms and leucocytes in the semen might damage sperm motility [19][20]. Moreover, activated leucocytes might produce reactive oxygen radicals (ROS), inducing sperm cell dysfunction [21].
Furthermore, inflammatory diseases of the accessory glands (e.g., prostatitis) and autoimmune reaction against the spermatozoa are included in the post-testicular causes of male infertility [22]. Post-testicular diseases might also be congenital, as in the case of CAVD (congenital absence of the vas deferens) [23]. Lastly, male infertility can be due to primitive testicular dysfunction, which causes impaired sperm production [24].
Testicular causes of male infertility include orchitis, testicular trauma, torsion, cryptorchidism (congenital or acquired) [25][26][27], systemic diseases, iatrogenic forms, and genetic abnormalities. Varicocele can be considered a cofactor of defective sperm production because it is associated with testicular atrophy and Leydig cell dysfunction [28]. In about 50% of cases, the etiology of male infertility still remains unknown (idiopathic infertility) [29]. Idiopathic infertility is probably, in most cases, related to genetic causes, considering that more than one thousand genes are involved in spermatogenesis [30].

1.1.3. Treatments

The therapeutical approach to male infertility depends on the underlying causes and includes medical and surgical treatments [31]. Medical treatment of male infertility mainly involves hormonal treatment [32], which is based on the use of gonadotropin-releasing hormone (GnRH), gonadotropins, testosterone, dopamine agonists, aromatase inhibitors (AI), and selective estrogen receptor modulators (SERMs) [33].
Men affected by hypogonadotropic hypogonadism related to a reduced secretion of GnRH from the hypothalamus can be treated with GnRH therapy [34]. The pulsatile administration of GnRH stimulates the anterior pituitary to release gonadotropins [35], with the re-establishment of the hypothalamus–pituitary–gonadal (HPG) axis leading to high levels of testosterone and stimulation of Sertoli cells by the FSH [36]. In about 85% of patients treated with pulsatile GnRH, spermatogenesis is induced [37][38][39].
The administration of gonadotropins can be useful in men with hypogonadotropic hypogonadism related to pituitary dysfunction. It has been shown that gonadotropin therapy induces spermatogenesis in about 80% of patients [40][41]. Dopamine agonists are used for the treatment of male infertility associated with prolactin-secreting pituitary adenoma [42]. SERMs are indicated for the treatment of idiopathic infertility [43]. Their action is based on the inhibition of central estrogen feedback upregulating the production of pituitary gonadotropins [44]. Surgical therapy for male infertility is indicated mainly in men with obstructive azoospermia (OA) [45][46].
When treatment has failed or no specific treatment is available for the condition underlying male infertility, assisted reproductive technologies (ARTs) are indicated [47]. Among them, the most used and successful are intrauterine insemination (IUI), in vitro fertilization (IVF), and intracytoplasmic sperm injection (ICSI) [48][49].
IUI is a technique that involves the introduction of spermatozoa through the cervix using a catheter [50]. This technique is indicated in case of mild male infertility or unexplained infertility [51]. However, IUI needs a good semen quality and thus it is not fully indicated for “idiopathic oligozoospermia and asthenozoospermia or in men affected by retrograde ejaculation and anejaculation [51][52].
IVF facilitates fertilization by bringing the spermatozoa close to the oocyte [52] occurring outside the female body. IVF techniques usually include (i) a transvaginal ovum retrieval whereby a small needle is inserted through the back of the vagina and guided via ultrasound into the ovarian follicles to collect the fluid that contains the eggs and (ii) an embryo transfer whereby one or several embryos are placed into the uterus of the female with the intent to establish a pregnancy.
ICSI is the treatment of choice in case of IVF failure [53] and it consists of the injection of a single spermatozoon directly into the oocyte’s cytoplasm [54]. It can be used with ejaculated sperm, epididymal sperm, or testicular sperm. Retrieved epididymal or testicular spermatozoa are often cryopreserved to avoid repeated aspirations or biopsy in case of ART failure [55].

2. NGF

2.1. Neurotrophins

Neurotrophins are a family of growth factors mainly involved in the regulation of neuronal survival, function, and plasticity within the central and peripheral nervous systems. Neurotrophins include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4) [56]. These factors exert their effects by binding two major receptor types: the p75 neurotrophin receptor (p75NTR) and the tropomyosin-related tyrosine kinase (Trk) receptors. P75NTR is a low-affinity receptor to which all neurotrophins can bind; neurotrophins, in the absence of Trk receptors, can bind to p75NTR, which acts as a death receptor.
Trk receptors are a family of three receptors including TrkA, which functions mainly as a receptor for NGF, TrkB (as a receptor for BDNF and NT-4), and TrkC (as a receptor for NT-3) [57]. Neurotrophins binding to Trk receptors activate different intracellular signaling cascades, including Ras/mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase/protein kinase B-mammalian target of rapamycin (PI3K/Akt-mTOR), and phosphoinositide-specific phospholipase C-γ (PLC-γ) pathways [58][59][60]. The activation of the Ras/MAPK and PI3K/Akt pathways is involved in promoting neuronal differentiation and survival [61][62]. PLC-γ pathways trigger the intracellular release of calcium ions from the endoplasmic reticulum, leading to the activation of calcium-dependent proteins and the expression of transcription factors and ion channels [63][64][65].
Among the neurotrophin family, nerve growth factor (NGF) was the first to be discovered. It was identified in the early 1950s by Rita Levi-Montalcini in mouse sarcoma cultures [66]. NGF shows neuroprotective and neurotrophic effects in the central nervous system and regulates the survival and maturation of developing neurons within the peripheral nervous system [67][68]. Moreover, NGF is involved in the neural response to damage in nociceptive sensory neurons, Schwann cells, and α motor neurons [69][70][71][72]. Neurotrophins are mainly known for their neurotrophic role, but they also exert a variety of effects outside the nervous system [73][74]. Changes in NGF in the serum and plasma were shown during the beginning and progression of many pathologies, including neurological, psychiatric and immune diseases [75][76], and physiopathological conditions, such as cardiometabolic disruptions [77][78], oxidant circumstances [79][80], stressful events [81][82], alcohol addiction [83][84][85], and aging [86][87][88].
Indeed, the expression of neurotrophin receptors in several non-neuronal tissues and the involvement of neurotrophins in essential non-neuronal functions, such as the maintenance of immune cells, has been demonstrated. In particular, NGF induces the differentiation of B lymphocytes [89] and is involved in the maintenance of neutrophils, peritoneal mast cells, and B lymphocytes [90][91][92].

2.2. NGF Expression in the Reproductive System

It is known that NGF plays a pivotal role in regulating neuronal cell growth and survival; increasing evidence shows that NGF also exerts a variety of effects on non-neuronal cells. In recent studies, the expression of NGF and its receptors (TrkA and p75NTR) outside the nervous system has been demonstrated, in particular in the male reproductive system [93][94][95][96], leading to the hypothesis that NGF could have a role in the reproductive system [97][98]. Moreover, pieces of evidence show that the testis and brain share a common embryonic origin [99][100], explaining the expression of neural receptors in sperm cells [101].
Ayer-LeLievre et al., in 1988, demonstrated that in testis and epididymis of rats and mice, NGF and TrkA were expressed [102]. Successively, a large body of studies confirmed these results. The presence of NGF was first detected in the prostate of guinea pigs [103], rabbits, and bulls [104]. In a study conducted on golden hamsters, it was found that NGF expression is greater in the caudal portion of the epididymis than in the other regions [105]. Many studies conducted on a variety of species, such as camelids, llamas, rabbits, and alpacas, demonstrated the presence of NGF and its receptors in seminal plasma [106][107][108][109][110]. In 2010, Li et al. reported the presence of NGF, TrkA, and p75NTR in the spermatozoa’s tail and head. Moreover, they showed that oligo/asthenozoospermic men had lower levels of NGF in their semen compared to fertile men [111]. All these findings suggest the potential role of NGF in male reproductive physiology [112][113].

3. NGF Specific Functions in the Male Reproductive System

3.1. NGF’s Role in Testis Morphogenesis

It has been demonstrated that neurotrophins are involved in the morphogenetic process regulating local cell–cell interactions in many tissues, such as kidney, tooth, dermatome, and ovary [114][115][116][117]. Moreover, neurotrophins play a role in germ cell survival and differentiation [118]. Therefore, it has been hypothesized that neurotrophins might be implicated in testis morphogenesis. The expression of neurotrophins in postnatal testis has been shown [102][119][120].
The expression of p75NTR in the mesenchymal tissue that surrounds the testis cord has been observed [121][122]. Levine et al. studied the effects of neurotrophins on seminiferous cord formation using the Trk-specific inhibitor K252a and the inhibitory TrkC-IgG antagonist [123]. They demonstrated that the inhibition of the neurotrophin pathway resulted in an inhibition of testis cord formation, suggesting that neurotrophins play a crucial role in testis morphogenesis [124].
Cupp et al. studied the role of TrkA and TrkC in the process of testis development, finding that TrkA is involved in the early stages of testis morphogenesis, whereas TrkC is involved in the later stages, both being implicated in the regulation of the germ cells number [125].

3.2. NGF Role in Spermatogenesis

Spermatogenesis involves a complex system of processes that lead to the production of mature spermatozoa in the seminiferous tubules (ST) [126][127]. The spermatogenic process requires three crucial steps: the mitotic division of spermatogonia [128]; meiosis I, with the generation of spermatocytes, and meiosis II, with the generation of spermatids [129]; and spermiogenesis, culminating in the production of mature spermatozoa [130]. Spermatogenesis is regulated by both endocrine and paracrine mechanisms [131][132].
The hormonal control is mediated by follicle-stimulating hormone (FSH) and testosterone [133]. The paracrine mechanism of regulation of spermatogenesis is mediated by Sertoli cells and germ cells [134], which are involved in the production of a variety of regulatory factors [135][136]. The proteins secreted by germ cells exert their effect on Sertoli cells, stimulating them to produce many molecules involved in the process of spermatogenesis, such as ABP [137], transferrin [138][139], IL-1a [140], SGP-2/1 [141], inhibin [142], and ceruloplasmin [143]. Moreover, germ cells inhibit the production of 17b-estradiol [144].
The process of spermatogenesis requires a synergic and/or redundant action of regulatory molecules in order to occur correctly [145][146]. Among these molecules involved in spermatogenesis regulation, there is growing attention on neurotrophins. The presence of different neurotrophins in mammalian testis has been demonstrated [147], but among them, the NGF is the only one that showed a potential role in spermatogenesis.
Many studies indicated the impact of NGF on several aspects of spermatogenesis. The presence of NGF protein [148] and mRNA [102] in germ cells has been shown, and its mitogen activity has been demonstrated [118]. NGF shows different effects, such as guaranteeing the physiological integrity of seminiferous epithelial cells [149], stimulating DNA synthesis within the seminiferous tubules [150], and inducing the secretion of ABP from Sertoli cells [120]. These effects are exerted through the binding between NGF and its receptors, p75NT and Trk [119][151], which are expressed on Sertoli cells.
The presence of NGF receptors on Sertoli cells in animals’ testis suggested the role of NGF in spermatogenesis regulation. Subsequently, the presence of NGF mRNA and p75NTR mRNA and protein in human testis was demonstrated [152][153].

3.3. The Impact of NGF on the Hypothalamus-Pituitary-Gonadal (HPG) Axis

Spermatogenesis is regulated by the hypothalamus–pituitary–gonadal (HPG) axis [154]. The hypothalamus produces gonadotropin-releasing hormone (GnRH) and releases it in a pulsatile manner [155]. The pulsatile secretion of neuropeptide is essential for stimulating the gonadotropic cells of the anterior pituitary to synthesize and secrete LH and FSH [156].
The stimulus of LH and FSH on testis cells activates two crucial endocrine signals: LH stimulates the production of testosterone from Leydig cells [157], and FSH induces the production of ABP (androgen-binding protein) and inhibin from Sertoli cells [158]. FSH and LH have a pivotal role in regulating spermatogenesis, mainly because they mediate the production of Sertoli factors, respectively, in a direct or indirect (through a testosterone–androgen receptor) way [159]. The HPG axis is finely regulated by a negative feedback mechanism [160].
Testosterone, in high levels, inhibits the hypothalamic secretion of GnRH and the pituitary secretion of LH [161]. Inhibin acts on the anterior pituitary, inhibiting the production of FSH [162]. The NGF is involved in the regulation of the hypothalamus–pituitary axis [163][164]. Luo et al. in 2018 demonstrated that NGF can activate GnRH neurons in the hypothalamus and, thus, regulate the hypothalamic secretion of GnRH [165]. Moreover, they found that by using TrkA inhibitors, the effects of NGF on the HPG axis were extinguished. This finding led to the hypothesis that the impact of NGF on the hypothalamic secretion of GnRH was mediated by the TrkA receptor (see Figure 1).
Figure 1. NGF regulates the hypothalamus–pituitary–gonadal (HPG) axis stimulating the hypothalamic production of GnRH. The binding of the NGF to the TrkA receptor activates many intracellular pathways, including the PI3Kinase pathway, which leads to the activation of Akt kinase, the Ras pathway, which leads to MAP kinase activation, and the PLC pathway, which leads to the activation of PKC. These intracellular pathways are involved in regulating the expression of neuronal survival and differentiation genes and the transcription of GnRH gene and neuropeptide production.
The binding of NGF to TrkA activates many intracellular signaling cascades, such as MAPK, PI3K, and PLC-γ-PKC pathways [166]. GnRH transcription and neuropeptide production in GT1-7 cells are regulated by PKC, PKA, and MAPK pathways [167][168]. TrkA activation leads to the activation of ERK1/2 and ERK5. These kinases phosphorylate and activate CREB, Elk-1, and MEF2, which are transcription factors involved in regulating the expression of neuronal survival and differentiation genes [61][169]. The NGF exerts its role on GnRH neurons through the activation of the PKC/p-ERK1/2/p-CREB cascade, which leads to the activation of hypothalamic cells and the consequent activation of the HPG axis with the secretion of GnRH [170][171].

3.4. NGF Effects on Sperm Traits

Various studies demonstrated that nerve growth factor (NGF) exerts a variety of effects on mature sperm traits [172]. the expression of NGF receptors in sperm cells has been demonstrated: p75NTR is mainly in the midpiece and tail, whereas TrKA is expressed in the head and acrosome [173]. In 2010, two different studies reported the presence of NGF and the expression of TrkA receptor in animal sperm. One group studied hamster sperm, demonstrating that the NGF stimulates acrosome reaction and increases sperm motility (see Figure 2).
Figure 2. NGF exerts its effects on sperm cells through its binding to its two receptors: TrkA and p75NTR. The activation of the TrkA receptor is involved in stimulating cells’ survival and modulating the acrosomal reaction through the activation of the kinases’ pathway. The binding of the NGF to p75NTR receptor, instead, is involved in modulating sperm cells’ apoptosis by triggering the mitochondrial activity and the production of ROS. Moreover, the activation of p75NTR is involved in modulating sperm motility through the activation of the sperm’s respiratory chain.
This stimulating effect of NGF on sperm motility was found to be time- and dose-dependent. The other group studied bovine sperm, demonstrating the presence of NGF and TrkA receptors in ejaculated sperm. They showed that exogenous NGF had positive effects on sperm viability and apoptosis, although the NGF did not affect acrosome reaction [174]. Two years later, a study on human sperm was published; it reported that NGF has an improving effect on human sperm motility traits, such as straight-line velocity, curvilinear velocity, average path velocity, linearity, and beat-cross frequency [175]. After incubating the sperm in vitro with NGF, the sperm motility increased in a dose-dependent manner [176]. Bezerra et al. studied the proteome of seminal plasma in rabbits and suggested that NGF expression might increase sperm motility [177].


  1. Zegers-Hochschild, F.; Adamson, G.D.; Dyer, S.; Racowsky, C.; de Mouzon, J.; Sokol, R.; Rienzi, L.; Sunde, A.; Schmidt, L.; Cooke, I.D.; et al. The International Glossary on Infertility and Fertility Care, 2017. Fertil. Steril. 2017, 108, 393–406.
  2. Fainberg, J.; Kashanian, J.A. Recent advances in understanding and managing male infertility. F1000Research 2019, 8, 670.
  3. Vander Borght, M.; Wyns, C. Fertility and infertility: Definition and epidemiology. Clin. Biochem. 2018, 62, 2–10.
  4. Thoma, M.E.; McLain, A.; Louis, J.F.; King, R.B.; Trumble, A.C.; Sundaram, R.; Louis, G.B. Prevalence of infertility in the United States as estimated by the current duration approach and a traditional constructed approach. Fertil. Steril. 2013, 99, 1324–1331.e1.
  5. Bak, C.W.; Seok, H.H.; Song, S.H.; Kim, E.S.; Her, Y.S.; Yoon, T.K. Hormonal imbalances and psychological scars left behind in infertile men. J. Androl. 2012, 33, 181–189.
  6. Wu, A.K.; Elliott, P.; Katz, P.P.; Smith, J.F. Time costs of fertility care: The hidden hardship of building a family. Fertil. Steril. 2013, 99, 2025–2030.
  7. Dimitriadis, F.; Adonakis, G.; Kaponis, A.; Mamoulakis, C.; Takenaka, A.; Sofikitis, N. Pre-Testicular, Testicular, and Post-Testicular Causes of Male Infertility. In Endocrinology of the Testis and Male Reproduction; Simoni, M., Huhtaniemi, I., Eds.; Springer International Publishing: Cham, Switzerland, 2017; pp. 1–47.
  8. Lenzi, A.; Balercia, G.; Bellastella, A.; Colao, A.; Fabbri, A.; Foresta, C.; Galdiero, M.; Gandini, L.; Krausz, C.; Lombardi, G.; et al. Epidemiology; diagnosis, and treatment of male hypogonadotropic hypogonadism. J. Endocrinol. Investig. 2009, 32, 934–938.
  9. Huhtaniemi, I.; Alevizaki, M. Mutations along the hypothalamic-pituitary-gonadal axis affecting male reproduction. Reprod. Biomed. Online 2007, 15, 622–632.
  10. Bianco, S.D.C.; Kaiser, U.B. The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism. Nat. Rev. Endocrinol. 2009, 5, 569–576.
  11. Whitcomb, R.W.; Crowley, W.F. Male hypogonadotropic hypogonadism. Endocrinol. Metab. Clin. N. Am. 1993, 22, 125–143.
  12. Fraietta, R.; Zylberstejn, D.S.; Esteves, S.C. Hypogonadotropic hypogonadism revisited. Clinics 2013, 68 (Suppl. S1), 81–88.
  13. Aust, T.R.; Lewis-Jones, D.I. Retrograde ejaculation and male infertility. Hosp. Med. 2004, 65, 361–364.
  14. Kondoh, N. Ejaculatory dysfunction as a cause of infertility. Reprod. Med. Biol. 2012, 11, 59–64.
  15. Lotti, F.; Maggi, M. Sexual dysfunction and male infertility. Nat. Rev. Urol. 2018, 15, 287–307.
  16. Wiser, H.J.; Sandlow, J.; Köhler, T.S. Causes of male infertility. In Male Infertility; Parekattil, S., Agarwal, A., Eds.; Springer: New York, NY, USA, 2012; pp. 3–14.
  17. Wong, T.W.; Straus, F.H.; Jones, T.M.; Warner, N.E. Pathological aspects of the infertile testis. Urol. Clin. N. Am. 1978, 5, 503–530.
  18. Cocuzza, M.; Alvarenga, C.; Pagani, R. The epidemiology and etiology of azoospermia. Clinics 2013, 68, 15–26.
  19. Merino, G.; Carranza-Lira, S.; Murrieta, S.; Rodriguez, L.; Cuevas, E.; Moran, C. Bacterial infection and semen characteristics in infertile men. Syst. Biol. Reprod. Med. 1995, 35, 43–47.
  20. Diemer, T.; Huwe, P.; Ludwig, M.; Hauck, E.W.; Weidner, W. Urogenital infection and sperm motility. Andrologia 2003, 35, 283–287.
  21. Krausz, C.; Mills, C.; Rogers, S.; Tan, S.L.; Aitken, R.J. Stimulation of oxidant generation by human sperm suspensions using phorbol esters and formyl peptides: Relationships with motility and fertilization in vitro. Fertil. Steril. 1994, 62, 599–605.
  22. Restrepo, B.; Cardona Maya, W. Antisperm antibodies and fertility asociation. Actas Urol. Esp. 2013, 37, 571–578.
  23. Bieth, E.; Hamdi, S.M.; Mieusset, R. Genetics of the congenital absence of the vas deferens. Hum. Genet. 2021, 140, 59–76.
  24. Sharma, A.; Minhas, S.; Dhillo, W.S.; Jayasena, C.N. Male infertility due to testicular disorders. J. Clin. Endocrinol. Metab. 2021, 106, E442–E459.
  25. Villumsen, A.L.; Zachau-Christiansen, B. Spontaneous alterations in position of the testes. Arch. Dis. Child. 1966, 41, 198–200.
  26. Wohlfahrt-Veje, C.; Boisen, K.A.; Boas, M.; Damgaard, I.N.; Kai, C.M.; Schmidt, I.M.; Chellakooty, M.; Suomi, A.-M.; Toppari, J.; Skakkebaek, N.E.; et al. Acquired cryptorchidism is frequent in infancy and childhood. Int. J. Androl. 2009, 32, 423–428.
  27. Main, K.M.; Skakkebæk, N.E.; Virtanen, H.E.; Toppari, J. Genital anomalies in boys and the environment. Best Pract. Res. Clin. Endocrinol. Metab. 2010, 24, 279–289.
  28. Kantartzi, P.D.; Goulis, C.D.; Goulis, G.D.; Papadimas, I. Male infertility and varicocele: Myths and reality. Hippokratia 2007, 11, 99–104.
  29. Ferlin, A.; Arredi, B.; Foresta, C. Genetic causes of male infertility. Reprod. Toxicol. 2006, 22, 133–141.
  30. Linn, E.; Ghanem, L.; Bhakta, H.; Greer, C.; Avella, M. Genes Regulating Spermatogenesis and Sperm Function Associated With Rare Disorders. Front. Cell Dev. Biol. 2021, 9, 634536.
  31. Leaver, R.B. Male infertility: An overview of causes and treatment options. Br. J. Nurs. 2016, 25, S35–S40.
  32. Kamischke, A.; Nieschlag, E. Analysis of medical treatment of male infertility. Hum. Reprod. 1999, 14, 1–23.
  33. Dabaja, A.A.; Schlegel, P.N. Medical treatment of male infertility. Transl. Androl. Urol. 2014, 3, 9–16.
  34. Nachtigall, L.B.; Boepple, P.A.; Pralong, F.P.; Crowley, W.F. Adult-Onset Idiopathic Hypogonadotropic Hypogonadism—A Treatable Form of Male Infertility. N. Engl. J. Med. 1997, 336, 410–415.
  35. Conn, P.M.; Hansen, J.R. Gonadotropin-releasing hormone and its analogs. Iowa Med. 1986, 76, 372–377.
  36. Zitzmann, M.; Nieschlag, E. Hormone substitution in male hypogonadism. Mol. Cell. Endocrinol. 2000, 161, 73–88.
  37. Blumenfeld, Z.; Frisch, L.; Conn, P.M. Gonadotropin-releasing hormone (GnRH) antibodies formation in hypogonadotropic azoospermic men treated with pulsatile GnRH-Diagnosis and possible alternative treatment. Fertil. Steril. 1988, 50, 622–629.
  38. Wei, C.; Long, G.; Zhang, Y.; Wang, T.; Wang, S.; Liu, J.; Ma, D.; Liu, X. Spermatogenesis of male patients with congenital hypogonadotropic hypogonadism receiving pulsatile gonadotropin-releasing hormone therapy versus gonadotropin therapy: A systematic review and meta-analysis. World J. Mens Health 2020, 38, 654–665.
  39. Liu, L.; Banks, S.M.; Barnes, K.M.; Sherins, R.J. Two-year comparison of testicular responses to pulsatile gonadotropin-releasing hormone and exogenous gonadotropins from the inception of therapy in men with isolated hypogonadotropic hypogonadism. J. Clin. Endocrinol. Metab. 1988, 67, 1140–1145.
  40. Madhukar, D.; Rajender, S. Hormonal treatment of male infertility: Promise and pitfalls. J. Androl. 2009, 30, 95–112.
  41. Burgués, S.; Calderón, M.D. Subcutaneous self-administration of highly purified follicle stimulating hormone and human chorionic gonadotrophin for the treatment of male hypogonadotrophic hypogonadism. Hum. Reprod. 1997, 12, 980–986.
  42. Dabbous, Z.; Atkin, S.L. Hyperprolactinaemia in male infertility: Clinical case scenarios. Arab J. Urol. 2018, 16, 44–52.
  43. Cannarella, R.; Condorelli, R.A.; Mongioì, L.M.; Barbagallo, F.; Calogero, A.E.; La Vignera, S. Effects of the selective estrogen receptor modulators for the treatment of male infertility: A systematic review and meta-analysis. Expert Opin. Pharmacother. 2019, 20, 1517–1525.
  44. Goldstein, S.R.; Siddhanti, S.; Ciaccia, A.V.; Plouffe, L. A pharmacological review of selective oestrogen receptor modulators. Hum. Reprod. Update 2000, 6, 212–224.
  45. Velasquez, M.; Tanrikut, C. Surgical management of male infertility: An update. Transl. Androl. Urol. 2014, 3, 64–76.
  46. Schiff, J.D.; Ramírez, M.L.; Bar-Chama, N. Medical and Surgical Management Male Infertility. Endocrinol. Metab. Clin. N. Am. 2007, 36, 313–331.
  47. Tournaye, H. Male factor infertility and ART. Asian J. Androl. 2012, 14, 103–108.
  48. Duran, H.E.; Morshedi, M.; Kruger, T.; Oehninger, S. Intrauterine insemination: A systematic review on determinants of success. Hum. Reprod. Update 2002, 8, 373–384.
  49. Huang, J.Y.J.; Rosenwaks, Z. Assisted reproductive techniques. Methods Mol. Biol. 2014, 1154, 171–231.
  50. Aboulghar, M.; Baird, D.T.; Collins, J.; Evers, J.L.H.; Fauser, B.C.J.M.; Lambalk, C.B.; Somigliana, E.; Sunde, A.; Tarlatzis, B.; Crosignani, P.G.; et al. Intrauterine insemination. Hum. Reprod. Update 2009, 15, 265–277.
  51. Keck, C.; Gerber-Schafer, C.; Wilhelm, C.; Vogelgesang, D.; Breckwoldt, M. Intrauterine insemination for treatment of male infertility. Int. J. Androl. Suppl. 1997, 20, 55–64.
  52. Hasler, J.F.; Barfield, J.P. Vitro Fertilization. In Bovine Reproduction; StatPearls Publishing LLC.: Treasure Island, FL, USA, 2021; pp. 1124–1141.
  53. Palermo, G.D.; Neri, Q.V.; Hariprashad, J.J.; Davis, O.K.; Veeck, L.L.; Rosenwaks, Z. ICSI and its outcome. Semin. Reprod. Med. 2000, 18, 161–169.
  54. O’Neill, C.L.; Chow, S.; Rosenwaks, Z.; Palermo, G.D. Development of ICSI. Reproduction 2018, 156, F51–F58.
  55. Justice, T.; Christensen, G. Sperm Cryopreservation Methods. Methods Mol. Biol. 2013, 927, 209–215.
  56. Skaper, S.D. Neurotrophic Factors: An Overview. Methods Mol. Biol. 2018, 1727, 1–17.
  57. Bothwell, M. Keeping track of neurotrophin receptors. Cell 1991, 65, 915–918.
  58. Chao, M.V. Neurotrophins and their receptors: A convergence point for many signalling pathways. Nat. Rev. Neurosci. 2003, 4, 299–309.
  59. Casaccia-Bonnefil, P.; Carter, B.D.; Dobrowsky, R.T.; Chao, M.V. Death of oligodendrocytes mediated by the interaction of nerve growth factor with its receptor p75. Nature 1996, 383, 716–719.
  60. Friedman, W.J.; Greene, L.A. Neurotrophin signaling via Trks and p75. Exp. Cell Res. 1999, 253, 131–142.
  61. Pearson, G.; Robinson, F.; Beers Gibson, T.; Xu, B.E.; Karandikar, M.; Berman, K.; Cobb, M.H. Mitogen-Activated Protein (MAP) Kinase Pathways: Regulation and Physiological Functions. Endocr. Rev. 2001, 22, 153–183.
  62. Yuan, X.-B.; Jin, M.; Xu, X.; Song, Y.-Q.; Wu, C.-P.; Poo, M.-M.; Duan, S. Signalling and crosstalk of Rho GTPases in mediating axon guidance. Nat. Cell Biol. 2003, 5, 38–45.
  63. Rose, C.R.; Blum, R.; Pichler, B.; Lepier, A.; Kafitz, K.W.; Konnerth, A. Truncated TrkB-T1 mediates neurotrophin-evoked calcium signalling in glia cells. Nature 2003, 426, 74–78.
  64. Toledo-Aral, J.J.; Brehm, P.; Halegoua, S.; Mandel, G. A single pulse of nerve growth factor triggers long-term neuronal excitability through sodium channel gene induction. Neuron 1995, 14, 607–611.
  65. Minichiello, L.; Calella, A.M.; Medina, D.L.; Bonhoeffer, T.; Klein, R.; Korte, M. Mechanism of TrkB-mediated hippocampal long-term potentiation. Neuron 2002, 36, 121–137.
  66. Nahum, L.H. the Nerve Growth Factor (Ngf). Conn. Med. 1964, 28, 508–512.
  67. Fiore, M.; Amendola, T.; Triaca, V.; Tirassa, P.; Alleva, E.; Aloe, L. Agonistic encounters in aged male mouse potentiate the expression of endogenous brain NGF and BDNF: Possible implication for brain progenitor cells’ activation. Eur. J. Neurosci. 2003, 17, 1455–1464.
  68. Ciafrè, S.; Ferraguti, G.; Tirassa, P.; Iannitelli, A.; Ralli, M.; Greco, A.; Chaldakov, G.N.; Rosso, P.; Fico, E.; Messina, M.P.; et al. Nerve growth factor in the psychiatric brain. Riv. Psichiatr. 2020, 55, 4–15.
  69. Wood, S.J.; Pritchard, J.; Sofroniew, M.V. Re-expression of Nerve Growth Factor Receptor after Axonal Injury Recapitulates a Developmental Event in Motor Neurons: Differential Regulation when Regeneration is Allowed or Prevented. Eur. J. Neurosci. 1990, 2, 650–657.
  70. Verge, V.M.K.; Richardson, P.M.; Benoit, R.; Riopelle, R.J. Histochemical characterization of sensory neurons with high-affinity receptors for nerve growth factor. J. Neurocytol. 1989, 18, 583–591.
  71. Ruit, K.G.; Osborne, P.A.; Schmidt, R.E.; Johnson, E.M.; Snider, W.D. Nerve growth factor regulates sympathetic ganglion cell morphology and survival in the adult mouse. J. Neurosci. 1990, 10, 2412–2419.
  72. Heumann, R.; Lindholm, D.; Bandtlow, C.; Meyer, M.; Radeke, M.J.; Misko, T.P.; Shooter, E.; Thoenen, H. Differential regulation of mRNA encoding nerve growth factor and its receptor in rat sciatic nerve during development, degeneration, and regeneration: Role of macrophages. Proc. Natl. Acad. Sci. USA 1987, 84, 8735–8739.
  73. Chaldakov, G.N.; Stankulov, I.S.; Fiore, M.; Ghenev, P.I.; Aloe, L. Nerve growth factor levels and mast cell distribution in human coronary atherosclerosis. Atherosclerosis 2001, 159, 57–66.
  74. Aloe, L.; Alleva, E.; Fiore, M. Stress and nerve growth factor: Findings in animal models and humans. Pharmacol. Biochem. Behav. 2002, 73, 159–166.
  75. Schulte-Herbruggen, O.; Braun, A.; Rochlitzer, S.; Jockers-Scherubl, M.C.; Hellweg, R. Neurotrophic factors—A tool for therapeutic strategies in neurological, neuropsychiatric and neuroimmunological diseases? Curr. Med. Chem. 2007, 14, 2318–2329.
  76. Bruscolini, A.; Sacchetti, M.; La Cava, M.; Nebbioso, M.; Iannitelli, A.; Quartini, A.; Lambiase, A.; Ralli, M.; de Virgilio, A.; Greco, A. Quality of life and neuropsychiatric disorders in patients with Graves’ Orbitopathy: Current concepts. Autoimmun. Rev. 2018, 17, 639–643.
  77. Chaldakov, G.N.; Fiore, M.; Tonchev, A.B.; Aloe, L. Neuroadipology: A novel component of neuroendocrinology. Cell Biol. Int. 2010, 34, 1051–1053.
  78. Tore, F.; Tonchev, A.; Fiore, M.; Tuncel, N.; Atanassova, P.; Aloe, L.; Chaldakov, G. From Adipose Tissue Protein Secretion to Adipopharmacology of Disease. Immunol. Endocr. Metab. Agents Med. Chem. 2007, 7, 149–155.
  79. Carito, V.; Ceccanti, M.; Tarani, L.; Ferraguti, G.; Chaldakov, G.N.; Fiore, M. Neurotrophins’ Modulation by Olive Polyphenols. Curr. Med. Chem. 2016, 23, 3189–3197.
  80. Petrella, C.; Di Certo, M.G.; Gabanella, F.; Barbato, C.; Ceci, F.M.; Greco, A.; Ralli, M.; Polimeni, A.; Angeloni, A.; Severini, C.; et al. Mediterranean Diet, Brain and Muscle: Olive Polyphenols and Resveratrol Protection in Neurodegenerative and Neuromuscular Disorders. Curr. Med. Chem. 2021, 28, 7595–7613.
  81. Ceci, F.M.; Ferraguti, G.; Petrella, C.; Greco, A.; Tirassa, P.; Iannitelli, A.; Ralli, M.; Vitali, M.; Ceccanti, M.; Chaldakov, G.N.; et al. Nerve Growth Factor, Stress and Diseases. Curr. Med. Chem. 2020, 28, 2943–2959.
  82. Rosso, P.; Iannitelli, A.; Pacitti, F.; Quartini, A.; Fico, E.; Fiore, M.; Greco, A.; Ralli, M.; Tirassa, P. Vagus nerve stimulation and Neurotrophins: A biological psychiatric perspective. Neurosci. Biobehav. Rev. 2020, 113, 338–353.
  83. Carito, V.; Ceccanti, M.; Ferraguti, G.; Coccurello, R.; Ciafrè, S.; Tirassa, P.; Fiore, M. NGF and BDNF Alterations by Prenatal Alcohol Exposure. Curr. Neuropharmacol. 2019, 17, 308–317.
  84. Ciafrè, S.; Ferraguti, G.; Greco, A.; Polimeni, A.; Ralli, M.; Ceci, F.M.; Ceccanti, M.; Fiore, M. Alcohol as an early life stressor: Epigenetics, metabolic, neuroendocrine and neurobehavioral implications. Neurosci. Biobehav. Rev. 2020, 118, 654–668.
  85. Ceci, F.M.; Ferraguti, G.; Petrella, C.; Greco, A.; Ralli, M.; Iannitelli, A.; Carito, V.; Tirassa, P.; Chaldakov, G.N.; Messina, M.P.; et al. Nerve Growth Factor in Alcohol Use Disorders. Curr. Neuropharmacol. 2020, 19, 45–60.
  86. Fiore, M.; Triaca, V.; Amendola, T.; Tirassa, P.; Aloe, L. Brain NGF and EGF administration improves passive avoidance response and stimulates brain precursor cells in aged male mice. Physiol. Behav. 2002, 77, 437–443.
  87. Chaldakov, G.; Fiore, M.; Tonchev, A.; Dimitrov, D.; Pancheva, R.; Rancic, G.; Aloe, L. Homo obesus: A Metabotrophin-Deficient Species. Pharmacol. Nutr. Insight Curr. Pharm. Des. 2007, 13, 2176–2179.
  88. Miranda, M.; Morici, J.F.; Zanoni, M.B.; Bekinschtein, P. Brain-Derived Neurotrophic Factor: A Key Molecule for Memory in the Healthy and the Pathological Brain. Front. Cell. Neurosci. 2019, 13, 363.
  89. Otten, U.; Ehrhard, P.; Peck, R. Nerve growth factor induces growth and differentiation of human B lymphocytes. Proc. Natl. Acad. Sci. USA 1989, 86, 10059–10063.
  90. Torcia, M.; Bracci-Laudiero, L.; Lucibello, M.; Nencioni, L.; Labardi, D.; Rubartelli, A.; Cozzolino, F.; Aloe, L.; Garaci, E. Nerve growth factor is an autocrine survival factor for memory B lymphocytes. Cell 1996, 85, 345–356.
  91. Kannan, Y.; Usami, K.; Okada, M.; Shimizu, S.; Matsuda, H. Nerve growth factor suppresses apoptosis of murine neutrophils. Biochem. Biophys. Res. Commun. 1992, 186, 1050–1056.
  92. Horigome, K.; Bullock, E.D.; Johnson, E.M. Effects of nerve growth factor on rat peritoneal mast cells. Survival promotion and immediate-early gene induction. J. Biol. Chem. 1994, 269, 2695–2702.
  93. Shaoxia, P.U.; Changwei, Q.U.; Zhi, L.I.; Yansen, L.I.; Chunmei, L.I. Expression of nerve growth factor (NGF) and its receptors TrkA and p75 in the reproductive organs of laying hens. Rev. Bras. Cienc. Avic. 2016, 18, 187–192.
  94. Perrard, M.-H.; Vigier, M.; Damestoy, A.; Chapat, C.; Silandre, D.; Rudkin, B.B.; Durand, P. Β-Nerve Growth Factor Participates in an Auto/Paracrine Pathway of Regulation of the Meiotic Differentiation of Rat Spermatocytes. J. Cell. Physiol. 2007, 210, 51–62.
  95. Artico, M.; Bronzetti, E.; Saso, L.; Felici, L.M.; D’Ambrosio, A.; Forte, F.; Grande, C.; Ortolani, F. Immunohistochemical profile of some neurotransmitters and neurotrophins in the seminiferous tubules of rats treated by lonidamine. Eur. J. Histochem. 2007, 51, 19–24.
  96. Adams, G.P.; Ratto, M.H. Ovulation-inducing factor in seminal plasma: A review. Anim. Reprod. Sci. 2013, 136, 148–156.
  97. Hou, Y.; Jia, L.; Zhang, Y.; Ji, W.; Li, H. Activation of the NGF/TrkA signaling pathway attenuates diabetic erectile dysfunction. Oncotarget 2017, 8, 105692–105702.
  98. Spinnler, K.; Fröhlich, T.; Arnold, G.J.; Kunz, L.; Mayerhofer, A. Human tryptase cleaves pro-nerve growth factor (Pro-NGF): Hints of local, mast cell-dependent regulation of NGF/PRO-NGF action. J. Biol. Chem. 2011, 286, 31707–31713.
  99. Guo, J.; Zhu, P.; Wu, C.; Yu, L.; Zhao, S.; Gu, X. In silico analysis indicates a similar gene expression pattern between human brain and testis. Cytogenet. Genome Res. 2003, 103, 58–62.
  100. Graves, J.A.M. Review: Sex Chromosome Evolution and the Expression of Sex-Specific Genes in the Placenta. Placenta 2010, 31, S27–S32.
  101. Ramírez-Reveco, A.; Villarroel-Espíndola, F.; Rodríguez-Gil, J.E.; Concha, I.I. Neuronal signaling repertoire in the mammalian sperm functionality. Biol. Reprod. 2017, 96, 505–524.
  102. Ayer-LeLievre, C.; Olson, L.; Ebendal, T.; Hallbook, F.; Persson, H. Nerve growth factor mRNA and protein in the testis and epididymis of mouse and rat. Proc. Natl. Acad. Sci. USA 1988, 85, 2628–2632.
  103. Harper, G.P.; Barde, Y.A.; Burnstock, G.; Carstairs, J.R.; Dennison, M.E.; Suda, K.; Vernon, C.A. Guinea pig prostate is a rich source of nerve growth factor. Nature 1979, 279, 160–162.
  104. Harper, G.P.; Thoenen, H. The Distribution of Nerve Growth Factor in the Male Sex Organs of Mammals. J. Neurochem. 1980, 34, 893–903.
  105. Jin, W.Z.; Tanaka, A.; Watanabe, G.; Matsuda, H.; Taya, K. Effect of NGF on the motility and acrosome reaction of golden hamster spermatozoa in vitro. J. Reprod. Dev. 2010, 56, 437–443.
  106. Jin, W.; Arai, K.Y.; Shimizu, K.; Kojima, C.; Itoh, M.; Watanabe, G.; Taya, K. Cellular localization of NGF and its receptors trkA and p75LNGFR in male reproductive organs of the Japanese monkey, Macaca fuscata fuscata. Endocrine 2006, 29, 155–160.
  107. Levanti, M.B.; Germanà, A.; de Carlos, F.; Ciriaco, E.; Vega, J.A.; Germanà, G. Effects of increased nerve growth factor plasma levels on the expression of TrkA and p75NTR in rat testicles. J. Anat. 2006, 208, 373–379.
  108. Kumar, S.; Sharma, V.K.; Singh, S.; Hariprasad, G.R.; Mal, G.; Srinivasan, A.; Yadav, S. Proteomic identification of camel seminal plasma: Purification of β-nerve growth factor. Anim. Reprod. Sci. 2013, 136, 289–295.
  109. Druart, X.; Rickard, J.; Mactier, S.; Kohnke, P.; Kershaw-Young, C.; Bathgate, R.; Gibb, Z.; Crossett, B.; Tsikis, G.; Labas, V.; et al. Proteomic characterization and cross species comparison of mammalian seminal plasma. J. Proteomics 2013, 91, 13–22.
  110. Harper, G.P.; Glanville, R.W.; Thoenen, H. The purification of nerve growth factor from bovine seminal plasma. Biochemical characterization and partial amino acid sequence. J. Biol. Chem. 1982, 257, 8541–8548.
  111. Li, C.; Zheng, L.; Wang, C.; Zhou, X. Absence of nerve growth factor and comparison of tyrosine kinase receptor A levels in mature spermatozoa from oligoasthenozoospermic, asthenozoospermic and fertile men. Clin. Chim. Acta 2010, 411, 1482–1486.
  112. Adams, G.P.; Ratto, M.H.; Silva, M.E.; Carrasco, R.A. Ovulation-inducing factor (OIF/NGF) in seminal plasma: A review and update. Reprod. Domest. Anim. 2016, 51, 4–17.
  113. Seidl, K.; Buchberger, A.; Erck, C. Expression of nerve growth factor and neurotrophin receptors in testicular cells suggest novel roles for neurotrophins outside the nervous system. Reprod. Fertil. Dev. 1996, 8, 1075–1087.
  114. Brill, G.; Kahane, N.; Carmeli, C.; Von Schack, D.; Barde, Y.A.; Kalcheim, C. Epithelial-mesenchymal conversion of dermatome progenitors requires neural tube-derived signals: Characterization of the role of Neurotrophin-3. Development 1995, 121, 2583–2594.
  115. Dissen, G.A.; Newman Hirshfield, A.; Malamed, S.; Ojeda, S.R. Expression of neurotrophins and their receptors in the mammalian ovary is developmentally regulated: Changes at the time of folliculogenesis. Endocrinology 1995, 136, 4681–4692.
  116. Mitsiadis, T.A.; Luukko, K. Neurotrophins in odontogenesis. Int. J. Dev. Biol. 1995, 39, 195–202.
  117. Ojeda, S.R.; Dissen, G.A.; Junier, M.P. Neurotrophic factors and female sexual development. Front. Neuroendocrinol. 1992, 13, 120–162.
  118. Onoda, M.; Pflug, B.; Djakiew, D. Germ cell mitogenic activity is associated with nerve growth factor-like protein(s). J. Cell. Physiol. 1991, 149, 536–543.
  119. Persson, H.; Lievre, C.A.-L.; Söder, O.; Villar, M.J.; Metsis, M.; Olson, L.; Ritzen, M.; Hökfelt, T. Expression of β-nerve growth factor receptor mRNA in Sertoli cells downregulated by testosterone. Science 1990, 247, 704–707.
  120. Lonnerberg, P.; Soder, O.; Parvinen, M.; Ritzen, E.M.; Persson, H. β-Nerve growth factor influences the expression of androgen-binding protein messenger ribonucleic acid in the rat testis. Biol. Reprod. 1992, 47, 381–388.
  121. Wheeler, E.F.; Bothwell, M. Spatiotemporal patterns of expression of NGF and the low-affinity NGF receptor in rat embryos suggest functional roles in tissue morphogenesis and myogenesis. J. Neurosci. 1992, 12, 930–945.
  122. Russo, M.A.; Odorisio, T.; Fradeani, A.; Rienzi, L.; De Felici, M.; Cattaneo, A.; Siracusa, G. Low-affinity nerve growth factor receptor is expressed during testicular morphogenesis and in germ cells at specific stages of spermatogenesis. Mol. Reprod. Dev. 1994, 37, 157–166.
  123. Levine, E.; Cupp, A.S.; Skinner, M.K. Role of neurotropins in rat embryonic testis morphogenesis (Cord formation). Biol. Reprod. 2000, 62, 132–142.
  124. Cupp, A.S.; Kim, G.H.; Skinner, M.K. Expression and action of neurotropin-3 and nerve growth factor in embryonic and early postnatal rat testis development. Biol. Reprod. 2000, 63, 1617–1628.
  125. Cupp, A.S.; Tessarollo, L.; Skinner, M.K. Testis developmental phenotypes in neurotropin receptor trkA and trkC null mutations: Role in formation of seminiferous cords and germ cell survival. Biol. Reprod. 2002, 66, 1838–1845.
  126. Neto, F.T.L.; Bach, P.V.; Najari, B.B.; Li, P.S.; Goldstein, M. Spermatogenesis in humans and its affecting factors. Semin. Cell Dev. Biol. 2016, 59, 10–26.
  127. Nishimura, H.; L’Hernault, S.W. Spermatogenesis. Curr Biol. 2017, 27, R988–R994.
  128. De Kretser, D.M.; Loveland, K.L.; Meinhardt, A.; Simorangkir, D.; Wreford, N. Spermatogenesis. Hum. Reprod. 1998, 13, 1–8.
  129. Larose, H.; Kent, T.; Ma, Q.; Shami, A.N.; Harerimana, N.; Li, J.Z.; Hammoud, S.S.; Handel, M.A. Regulation of meiotic progression by Sertoli-cell androgen signaling. Mol. Biol. Cell 2020, 31, 2841–2862.
  130. Hess, R.A.; De Franca, L.R. Spermatogenesis and cycle of the seminiferous epithelium. Adv. Exp. Med. Biol. 2008, 636, 1–15.
  131. Holdcraft, R.W.; Braun, R.E. Hormonal regulation of spermatogenesis. Int. J. Androl. 2004, 27, 335–342.
  132. Rossi, P.; Dolci, S. Paracrine mechanisms involved in the control of early stages of mammalian spermatogenesis. Front. Endocrinol. 2013, 4, 181.
  133. Sofikitis, N.; Giotitsas, N.; Tsounapi, P.; Baltogiannis, D.; Giannakis, D.; Pardalidis, N. Hormonal regulation of spermatogenesis and spermiogenesis. J. Steroid Biochem. Mol. Biol. 2008, 109, 323–330.
  134. Griswold, M.D. 50 years of spermatogenesis: Sertoli cells and their interactions with germ cells. Biol. Reprod. 2018, 99, 87–100.
  135. Schlatt, S.; Meinhardt, A.; Nieschlag, E. Paracrine regulation of cellular interactions in the testis: Factors in search of a function. Eur. J. Endocrinol. 1997, 137, 107–117.
  136. Iliadou, P.K.; Tsametis, C.; Kaprara, A.; Papadimas, I.; Goulis, D.G. The sertoli cell: Novel clinical potentiality. Hormones 2015, 14, 504–514.
  137. Galdieri, M.; Monaco, L.; Stefanini, M. Secretion of Androgen Binding Protein by Sertoli Cells Is Influenced by Contact with Germ Cells. J. Androl. 1984, 5, 409–415.
  138. Le Magueresse, B.; Jégou, B. In vitro effects of germ cells on the secretory activity of sertoli cells recovered from rats of different ages. Endocrinology 1988, 122, 1672–1680.
  139. Onoda, M.; Djakiew, D. A 29,000 Mr protein derived from round spermatids regulates Sertoli cell secretion. Mol. Cell. Endocrinol. 1993, 93, 53–61.
  140. Haugen, T.B.; Landmark, B.F.; Josefsen, G.M.; Hansson, V.; Högset, A. The mature form of interleukin-1α is constitutively expressed in immature male germ cells from rat. Mol. Cell. Endocrinol. 1994, 105, R19–R23.
  141. Onoda, M.; Djakiew, D. Pachytene spermatocyte protein(s) stimulate sertoli cells grown in bicameral chambers: Dose-dependent secretion of ceruloplasmin, sulfated glycoprotein-1, sulfated glycoprotein-2, and transferrin. Vitr. Cell. Dev. Biol.-Anim. 1991, 27, 215–222.
  142. Pineau, C.; Sharpe, R.M.; Saunders, P.T.K.; Gérard, N.; Jégou, B. Regulation of Sertoli cell inhibin production and of inhibin α-subunit mRNA levels by specific germ cell types. Mol. Cell. Endocrinol. 1990, 72, 13–22.
  143. Onoda, M.; Djakiew, D. Modulation of Sertoli cell secretory function by rat round spermatid protein(s). Mol. Cell. Endocrinol. 1990, 73, 35–44.
  144. Le Magueresse, B.; Jegou, B. Possible involvement of germ cells in the regulation of oestradiol-17,β and ABP secretion by immature rat sertoli cells (in vitro studies). Biochem. Biophys. Res. Commun. 1986, 141, 861–869.
  145. Vigier, M.; Weiss, M.; Perrard, M.H.; Godet, M.; Durand, P. The effects of FSH and of testosterone on the completion of meiosis and the very early steps of spermiogenesis of the rat: An in vitro study. J. Mol. Endocrinol. 2004, 33, 729–742.
  146. Hakovirta, H.; Kaipia, A.; Söder, O.; Parvinen, M. Effects of activin-A, inhibin-A, and transforming growth factor-β1 on stage-specific deoxyribonucleic acid synthesis during rat seminiferous epithelial cycle. Endocrinology 1993, 133, 1664–1668.
  147. Olson, L.; Ayer-LeLievre, C.; Ebendal, T.; Seiger, Å. Nerve growth factor-like immunoreactivities in rodent salivary glands and testis. Cell Tissue Res. 1987, 248, 275–286.
  148. MacGrogan, D.; Desprès, G.; Romand, R.; Dicou, E. Expression of the β-nerve growth factor gene in male sex organs of the mouse, rat, and guinea pig. J. Neurosci. Res. 1991, 28, 567–573.
  149. Seidl, K.; Holstein, A.F. Organ culture of human seminiferous tubules: A useful tool to study the role of nerve growth factor in the testis. Cell Tissue Res. 1990, 261, 539–547.
  150. Parvinen, M.; Pelto-Huikko, M.; Soder, O.; Schultz, R.; Kaipia, A.; Mali, P.; Toppari, J.; Hakovirta, H.; Lönnerberg, P.; Ritzén, E.M. Expression of β-nerve growth factor and its receptor in rat seminiferous epithelium: Specific function at the onset of meiosis. J. Cell Biol. 1992, 117, 629–641.
  151. Djakiew, D.; Pflug, B.; Dionne, C.; Onoda, M. Postnatal expression of nerve growth factor receptors in the rat testis. Biol. Reprod. 1994, 51, 214–221.
  152. MacGrogan, D.; Saint-André, J.-P.; Dicou, E. Expression of Nerve Growth Factor and Nerve Growth Factor Receptor Genes in Human Tissues and in Prostatic Adenocarcinoma Cell Lines. J. Neurochem. 1992, 59, 1381–1391.
  153. Robinson, L.L.L.; Townsend, J.; Anderson, R.A. The human fetal testis is a site of expression of neurotrophins and their receptors: Regulation of the germ cell and peritubular cell population. J. Clin. Endocrinol. Metab. 2003, 88, 3943–3951.
  154. Plant, T.M. The hypothalamo-pituitary-gonadal axis. J. Endocrinol. 2015, 226, T41–T54.
  155. Jin, J.M.; Yang, W.X. Molecular regulation of hypothalamus-pituitary-gonads axis in males. Gene 2014, 551, 15–25.
  156. Stamatiades, G.A.; Kaiser, U.B. Gonadotropin regulation by pulsatile GnRH: Signaling and gene expression. Mol. Cell. Endocrinol. 2018, 463, 131–141.
  157. Zirkin, B.R.; Papadopoulos, V. Leydig cells: Formation, function, and regulation. Biol. Reprod. 2018, 99, 101–111.
  158. Oduwole, O.O.; Peltoketo, H.; Huhtaniemi, I.T. Role of follicle-stimulating hormone in spermatogenesis. Front. Endocrinol. 2018, 9, 763.
  159. Ramaswamy, S.; Weinbauer, G.F. Endocrine control of spermatogenesis: Role of FSH and LH/testosterone. Spermatogenesis 2014, 4, e996025.
  160. Tilbrook, A.J.; Clarke, I.J. Negative feedback regulation of the secretion and actions of gonadotropin-releasing hormone in males. Biol. Reprod. 2001, 64, 735–742.
  161. Corradi, P.F.; Corradi, R.B.; Greene, L.W. Physiology of the Hypothalamic Pituitary Gonadal Axis in the Male. Urol. Clin. N. Am. 2016, 43, 151–162.
  162. Luisi, S.; Florio, P.; Reis, F.M.; Petraglia, F. Inhibins in female and male reproductive physiology: Role in gametogenesis, conception, implantation and early pregnancy. Hum. Reprod. Update 2005, 11, 123–135.
  163. Scaccianoce, S.; Cigliana, G.; Nicolai, R.; Muscolo, L.A.; Porcu, A.; Navarra, D.; Perez-Polo, R.; Angelucci, L. Hypothalamic involvement in the activation of the pituitary-adrenocortical axis by nerve growth factor. Neuroendocrinology 1993, 58, 202–209.
  164. Kumar, A.; Kumar, P.; Pareek, V.; Faiq, M.A.; Narayan, R.K.; Raza, K.; Prasoon, P.; Sharma, V.K. Neurotrophin mediated HPA axis dysregulation in stress induced genesis of psychiatric disorders: Orchestration by epigenetic modifications. J. Chem. Neuroanat. 2019, 102, 101688.
  165. Luo, J.; Yang, Y.; Zhang, T.; Su, Z.; Yu, D.; Lin, Q.; Chen, H.; Zhang, Q.; Xiang, Q.; Xue, W.; et al. Nasal delivery of nerve growth factor rescue hypogonadism by up-regulating GnRH and testosterone in aging male mice. EBioMedicine 2018, 35, 295–306.
  166. Marlin, M.C.; Li, G. Biogenesis and Function of the NGF/TrkA Signaling Endosome. Int. Rev. Cell Mol. Biol. 2015, 314, 239–257.
  167. Higa-Nakamine, S.; Maeda, N.; Toku, S.; Yamamoto, H. Involvement of protein kinase D1 in signal transduction from the protein kinase C pathway to the tyrosine kinase pathway in response to gonadotropin-releasing hormone. J. Biol. Chem. 2015, 290, 25974–25985.
  168. Sasson, R.; Dearth, R.K.; White, R.S.; Chappell, P.E.; Mellon, P.L. Orexin A induces GnRH gene expression and secretion from GT1-7 hypothalamic GnRH neurons. Neuroendocrinology 2007, 84, 353–363.
  169. Riccio, A.; Ahn, S.; Davenport, C.M.; Blendy, J.A.; Ginty, D.D. Mediation by a CREB family transcription factor of NGF-dependent survival of sympathetic neurons. Science 1999, 286, 2358–2361.
  170. Liu, Y.Z.; Chrivia, J.C.; Latchman, D.S. Nerve growth factor up-regulates the transcriptional activity of CBP through activation of the p42/p44(MAPK) cascade. J. Biol. Chem. 1998, 273, 32400–32407.
  171. Wortzel, I.; Seger, R. The ERK cascade: Distinct functions within various subcellular organelles. Genes Cancer 2011, 2, 195–209.
  172. Sanchez-Rodriguez, A.; Abad, P.; Arias-Alvarez, M.; Rebollar, P.G.; Bautista, J.M.; Lorenzo, P.L.; García-García, R.M. Recombinant rabbit beta nerve growth factor production and its biological effects on sperm and ovulation in rabbits. PLoS ONE 2019, 14, e0219780.
  173. Li, C.; Zhou, X. The potential roles of neurotrophins in male reproduction. Reproduction 2013, 145, R89–R95.
  174. Li, C.; Sun, Y.; Yi, K.; Ma, Y.; Zhang, W.; Zhou, X. Detection of nerve growth factor (NGF) and its specific receptor (TrkA) in ejaculated bovine sperm, and the effects of NGF on sperm function. Theriogenology 2010, 74, 1615–1622.
  175. Shi, C.-G.; Lin, K.; Xu, X.-B.; Zhang, S.-C.; Wang, N.; Fan, M. Evidence for the involvement of NGF in human sperm motility. J. Biomed. Sci. Eng. 2012, 5, 534–541.
  176. Lin, K.; Ding, X.-F.; Shi, C.-G.; Zeng, D.; QuZong, S.; Liu, S.-H.; Wu, Y.; LuoBu, G.; Fan, M.; Zhao, Y.-Q. Nerve growth factor promotes human sperm motility in vitro by increasing the movement distance and the number of A grade spermatozoa. Andrologia 2015, 47, 1041–1046.
  177. Bezerra, M.; Arruda-Alencar, J.; Martins, J.; Viana, A.; Neto, A.V.; Rêgo, J.; de Oliveira, R.V.; Lobo, M.; Moreira, A.; Moreira, R.; et al. Major seminal plasma proteome of rabbits and associations with sperm quality. Theriogenology 2019, 128, 156–166.
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