A classification of genes involved in normal and delayed male puberty : Asian Journal of Andrology

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A classification of genes involved in normal and delayed male puberty

Akram, Maleeha1,; Rizvi, Syed Shakeel Raza1; Qayyum, Mazhar1; Handelsman, David J2

Author Information

1Department of Zoology, Wildlife and Fisheries, Pir Mehr Ali Shah Arid Agriculture University Rawalpindi, Shamsabad, Murree Road, Rawalpindi 46300, Pakistan

2Andrology Laboratory, The ANZAC Research Institute, Hospital Road, Concord, NSW 2139, Australia

Correspondence: Dr. M Akram ([email protected])

This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 4.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Asian Journal of Andrology 25(2):p 230-239, Mar–Apr 2023. | DOI: 10.4103/aja202210

Abstract

INTRODUCTION

Puberty is a pivotal biological process that completes sexual maturation to achieve full reproductive capability.1 Occurring in early adolescence, it comprises appearance of changes in growth, behavior, and psychology of the individual becoming a reproductively competent adult.2 Puberty is a major transformational period of life with its timing strongly influenced by genetic makeup of the individual, with strong influence from various internal and external factors including environmental factors on the genetic background.2 A number of genes are turned on or off to develop a complicate series of physiological events fundamental for pubertal onset.3 Day et al.4 revealed the importance of biological genetic mechanisms on the timing and tempo of pubertal development. A recent study has shown that the genetic factors contribute about 50%–80% in determining the time for initiation of puberty.5 Some additional environmental factors are also fundamental in regulating the time of puberty, e.g., metabolic status of individuals such as malnutrition or obesity,6,7 the presence of harmful chemicals in the environment known as endocrine disruptors (EDs),8 and physical conditions of individuals, e.g., hard-exercise or chronic disease (including malabsorption). These conditions may also delay the onset of puberty and subsequently impair reproductive function.9 Due to this strong interplay between timing of puberty and number of internal and external factors, extensive research has been conducted towards elucidating mechanisms involved in pubertal onset, modulatory factors that regulate the process of puberty, and how pubertal onset is affected in health and disease.2

Although the ultimate trigger to initiate the cascade of molecular events that culminate in puberty is not yet known, the process of pubertal onset involves interaction of numerous complex signaling pathways of hypothalamo-pituitary-testicular (HPT) axis.10 These include (i) the development of the hypothalamus during embryonic development, (ii) the formation of neuronal connections between gonadotropin releasing hormone (GnRH) neurons and suprahypothalamic neurons during the process of synaptogenesis, (iii) maintenance of neuron homeostasis, (iv) the presence of molecules that regulate the synthesis and secretion of GnRH, (v) the presence of appropriate receptors/proteins on GnRH neurons for its production and release, (vi) the activation of proper signaling molecules by the receptors, (vii) the ability of GnRH neurons to coordinate and regulate GnRH synthesis and release, (viii) the ability of the pituitary gland to produce and release gonadotropins (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]), (ix) proper development of testes, (x) appropriate synthesis and release of steroid hormones from testes, and (xi) suitable action of steroid hormones in the downstream effector tissues. This review provides a list of 598 genes (excluding the duplicated genes), gathered from literature to identify important genes involved in the development of the HPT axis. Furthermore, 75 genes were identified among them in which genetic mutations have been reported to delay or disrupt male puberty.

HYPOTHALAMIC DEVELOPMENT

During embryonic development after gastrulation phase, nervous system, including the hypothalamus, begins to form under the influence of various morphogens. At the initial stages, these morphogens are secreted from nonneural cells such as mesodermal domain, anterior prechordal plate, axial notochord, and other extra lateral tissues. Later on, these morphogens are produced from neural cells, which are close to the hypothalamic area. As the development progresses, sharp boundaries within the nervous system are formed, which are controlled by transcription factors that identify the final fate of neural cells and form different hypothalamic nuclei.11,12

The embryonic development of the hypothalamus starts from prechordal germ layer and involves four subsequent processes: (i) formation of regional territories and subdivisions of regional territories of the hypothalamus for the residence of GnRH neurons, (ii) differentiation of GnRH neurons, (iii) migration of neurons, and (iv) establishment of nuclei of the hypothalamus. It was suggested that an enormous number of transcripts are involved at different levels of the development of the hypothalamus.13

Formation of regional territories and subdivisions of regional territories of the hypothalamus

The two most important signaling pathways fundamental for nervous system development are sonic hedgehog (Shh) and wingless family (Wnt) pathways. Shh and Wnt act as mitogens to control the production of neural tissues and maintain the transcription and translation rates of downstream genes. Shh and Wnt pathways are also required for the establishment of hypothalamic regional territories during embryogenesis.13

The mechanism by which the ventricular zone (VZ) of the neuroepithelium is initiated to form the hypothalamus is complex. Experiments on zebrafish, chicken and mouse embryos have shown that the axial mesoderm plays a fundamental role in the development of hypothalamic regional territories through Shh signaling.14,15 It was observed that morphogens cause the movement of neural plate and axial mesoderm, which sequentially expose the hypothalamic floor plate.16 Afterward, Shh17 and Wnt18 signaling pathways interact with other signaling cascades such as fibroblast growth factors (FGFs), bone morphogenetic protein 7 (BMP7), and Nodal signaling to instruct the progenitor cells to form four hypothalamic regions: preoptic, anterior, tuberal, and mammillary.15 The previous work has also shown that during the formation of regional territories and subdivisions of regional territories of the hypothalamus, a number of transcription factors play their roles.13 The list of 53 genes that have an established role in the development of hypothalamic regional territories and subdivisions of regional territories10,13,15,19–23 is shown in Supplementary Table 1, and mutations in 8 genes have previously been identified to cause delayed puberty24–26 (Table 1).

T1
Table 1:
List of 75 genes in which mutations have been confirmed to cause delayed puberty

GnRH neuron differentiation

GnRH neurons are a small population of more than 2000 neurons in humans.27 They are randomly distributed in preoptic area (POA) and arcuate nucleus (ARC) of the hypothalamus and form an “inverted Y-shape”.28 In humans and other primates, most of the GnRH neuron cell bodies are present more dorsally in the ARC but the exact number is not known.29 The morphology of GnRH neurons is also unique in that they have two “dendrons” extending from opposite sides of their cell bodies. Dendrons are processes that function both as dendrites and axons. Since GnRH neurons receive synaptic input and produce action potentials, they are also known as dendrons.1,30

In 1989, two separate research teams identified that GnRH neurons, which were presented in the hypothalamus in an adult, did not originate in this area of the brain.31,32 It was revealed that some GnRH neurons (approximately 30%) originate from neural crest cells33 and the remaining population (approximately 70%) originate from nasal/olfactory placode.15,32,34 Thus, the differentiation of GnRH neurons takes place at two levels – neural crest cells and nasal placode. A number of previous studies have demonstrated that certain growth factors are involved in neuronal differentiation.35,36Supplementary Table 2 represents the list of 71 genes that have a role in GnRH neuronal differentiation10,23,35,36 and mutations in 10 genes have been reported to be involved in delayed puberty25,26,37,38 (Table 1).

GnRH neuron migration

After their differentiation, GnRH neurons from neural crest cells move to nasal placode, join the other population and then all neurons move to the hypothalamus along with vomeronasal axons.32,39,40 The migration process of GnRH neurons is represented in four processes. (i) After their origination in the olfactory placode, GnRH neurons migrate accompanied by vomeronasal axons toward the forebrain through the nasal mesenchyme.32,41 During this process, additional factors such as anosmin, ephrins, nasal embryonic LHRH factor (NELF), fibroblast growth factor 8/fibroblast growth factor receptor 1 (FGF8/FGFR1), and prokineticin and its receptor (PROK2/PROKR2)41 are required for keeping the GnRH and vomeronasal axons together during the movement. (ii) When both GnRH and vomeronasal axons reach the cribriform plate, vomeronasal axons divide and produce one branch that leads the GnRH neurons towards the forebrain. At this point, guidance molecules such as netrin 1/deleted in colorectal cancer (DCC), semaphorins/plexins and reelin41 guide the movement of GnRH neurons. (iii) During their movement from cribriform plate to the hypothalamus, GnRH neurons extend their branches toward median eminence (ME) under the influence of molecules such as hepatocyte growth factor (HGF), AXL/TYRO3 and stromal cell derived factor/CXC chemokine receptor (SDF1/CXCR4).41 (iv) In the last step, the GnRH neurons separate from their guides, distribute randomly in the hypothalamus and stop their movement.41,42

Along the migration from nose to the brain, a number of molecules guide the GnRH neurons in correct direction and also control the speed of migrating neurons. Gamma amino butyric acid (GABA) is known to decrease the speed of migrating neurons by causing depolarization but it helps the neurons to move in straight direction.43 Similarly, another molecule SDF increases the speed of neurons by triggering hyperpolarization of G-protein coupled inwardly rectifying potassium (GIRK) channels. Alternative guiding cues such as Semaphorins44 and HGFs45 also regulate movement of GnRH neurons. Table 2 shows the list of 117 genes that have a role in the migration of GnRH neurons,4,10,23,24,40,46–48 and mutations in 34 genes have been identified to cause delayed puberty24–26,37,38,49,50 (Table 1).

T2
Table 2:
List of 117 genes involved in the migration of GnRH neurons

Development of hypothalamic nuclei

Although the hypothalamus is small, it consists of discrete nuclei that are scattered throughout the space it occupies and they secrete a number of neurotransmitters and peptide hormones.51 The development of hypothalamic nuclei begins by origination and migration of specific neurons.13 The previous work revealed that transcription factors such as NK2 homeobox 1 (NKX2.1), empty spiracles homeobox 2 (EMX2), distal-less homeobox 2 (DLX2), retinal homeobox protein 3 (RX3), and growth factors such as FGFs are important for hypothalamic nuclei development.13,21,52,53 These transcription factors are directly or indirectly regulated by Shh and Wnt signaling pathways.53Supplementary Table 3 represents the list of 25 genes that have a role in hypothalamic nuclei formation10,13,23 and mutations in 3 genes have been reported to be involved in delayed puberty24 (Table 1).

SYNAPTOGENESIS

Even though GnRH neurons reach the hypothalamus during embryonic development, they need to make contacts with other neurons, such as glutamatergic, GABAergic, kisspeptin-neurokinin B-dynorphin (KNDy) neurons. This process of making connections among neurons is known as synaptogenesis. GnRH neurons also make connections with nonneural cells called glia, which secrete different chemicals known as gliotransmitters, which control the activity of GnRH neurons.54 Studies have shown that each GnRH neuron is connected to about 5 000 000 other neurons, as second order connections.42,55 These suprahypothalamic neurons control the synthesis and secretion of GnRH to regulate the synthesis of gonadotropins from the pituitary.42

The process of synaptogenesis is regulated by internal environment of GnRH neurons as well as many external factors.54 Certain growth factors such as Wnt, transforming growth factors (TGFs), tumor necrosis factors (TNFs),56 and ligand/receptor partners (such as semaphorins/plexins-neuropilins, Slit/Robo, Eph/ephrins, and netrins/Unc5-Dcc57,58), act as regulators of axon guidance for synaptogenesis. Supplementary Table 4 represents the list of 74 genes that have a role in synaptogenesis,10,23,24,56–58 and mutations in 28 genes have previously been identified to cause delayed puberty24–26,37,38,49,50 (Table 1).

NEURON HOMEOSTASIS

Within the nervous system, most neurons are born during embryonic development and operate without replacement throughout the lifetime of the individual.59 Proteins are continuously made and degraded in neurons, and correct protein degenerative pathways are necessary for maintaining the homeostasis and efficient operations of neurons.60,61 In neurons, two mechanisms exist for maintaining the homeostasis. The first is autophagy, where lysosomes engulf and destroy the superfluous components of the neuron. The other is ubiquitination, where enzymes mark and degrade the misfolded or older proteins.62 Failure in these mechanisms results in axonal degeneration or neuronal death.63Supplementary Table 5 represents the list of 25 genes that have a role to play in maintaining neuronal homeostasis in the HPT axis,4,23,25,26,49,64 and mutations in 8 genes have been reported to be involved in delayed puberty25,26,65,66 (Table 1).

MOLECULES THAT REGULATE GNRH NEURON ACTIVITY

The onset of puberty is dependent on increase in the GnRH neuronal activity, which, in turn, increases the expression of GnRH1 gene, and secretes GnRH into hypophyseal portal blood in pulses.67 The exact mechanism triggering the onset of pulsatile GnRH secretion is still not well characterized.68 However, it has been proposed that the GnRH neuronal activity is controlled by upstream neuronal networks through neurotransmitters and neuromodulators.69 These upstream signals provide the information about body’s status to GnRH neurons and determine whether puberty should be initiated or not. This complex network allows GnRH neurons, scattered in the hypothalamus, to synchronize and release GnRH in pulses.70

A variety of neurotransmitters as well as neuromodulators plays roles in regulating the GnRH neuronal activity. Some are stimulatory such as kisspeptin, glutamate, leptin, neurokinin B, and insulin while others such as GABA, neuropeptide Y (NPY), opioids, ghrelin, cholecystokinin, and dopamine are inhibitory to GnRH neurons.69 The involvement of multiple innervations from suprahypothalamic areas may provide flexibility and precise coordination in the regulation of the GnRH neuronal activity manifested in the episodic release of GnRH.71Table 3 shows the list of 51 genes that have been identified to modulate GnRH neuronal activity4,10,23,37,38,49,64,72 and mutations in 9 genes have been identified to cause delayed puberty4,25,26,72 (Table 1).

T3
Table 3:
List of 51 genes that code for molecules involved in regulating the GnRH neuron activity

RECEPTORS/PROTEINS ON GNRH NEURONS

GnRH neurons are responsive to a wide array of neurotransmitters and neuromodulators, which is reflected in the large number of receptors identified on adult GnRH neurons28,73 as well as GnRH neurons in nasal explants.28,74,75Supplementary Table 6 represents the list of 63 genes coding for receptors/proteins present on GnRH neurons that control the synthesis and secretion of GnRH,4,10,23,26,37,49,64 and mutations in 3 genes have been reported to be involved in delayed puberty26,76 (Table 1).

SIGNALING MOLECULES

When the neurotransmitters or neuromodulators bind to their receptors on GnRH neurons, the activated receptors stimulate multiple signaling pathways. The signaling molecules act as on/off switches to transfer information from outer membrane to DNA inside the nucleus, where the information is further processed through DNA transcription and translation.77 Most of the receptors are G protein coupled receptors (GPCR), while some are receptor tyrosine kinases (RTKs).

GPCRs are heterotrimeric proteins, i.e., composed of α, β, and γ subunits and are able to bind different G proteins isoforms: Gs, Gi, Gq/11, and G12/13.78,79 When a ligand binds to GPCR, a conformational change occurs leading to the formation of guanosine triphosphate (GTP) from guanosine diphosphate (GDP). Gs isoform stimulates adenylate cyclase (AC), which stimulates cyclic adenosine monophosphate (cAMP) production, which, in turn, activates two processes; desensitizing GPCR together with activating cAMP response element (CREB),80 and mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase (ERK) pathway.81 In addition, Gq/11 isoform activates phospholipase C (PLC) pathways, which convert phosphatidyl inositol 4,5-bisphosphate (PIP2) to inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 and DAG sequentially increase the concentrations of intracellular Ca2+ ions, and regulate the nuclear factor kappa light chain enhancer of activated B cells (NF-κB).82 This, in turn, activates numerous protein kinase and signaling pathways, like protein kinase C (PKC)/MAPK/ERK.78,79 Furthermore, Gi isoform inhibits the AC. G12/13 isoform activates glycogen synthase kinase 3 (GSK3) in neurons,79,83 which is involved in tau phosphorylation.84 GSK3, in turn, is inhibited by protein kinase B (Akt) and PKC.81 Moreover, by using β and γ subunits, GPCRs can activate phosphatidyl inositol 3-kinase (PI3K)/Akt cascades.79,81

In addition, when a ligand binds to RTKs, the receptor becomes phosphorylated and activates growth factor receptor bound protein 2 (GRB2) and Son of Sevenless (SOS), which further triggers Ras (small, monomeric GTP-binding proteins) and Ras activates serine/threonine kinase rapidly accelerated fibrosarcoma (Raf). Raf phosphorylates MAP/ERK kinase 1, 2 (Mek1/2), which sequentially phosphorylates and stimulates Erk1/2. Raf also activates MAP3 kinases that activate mitogen-activated protein kinase kinase 4, 7 (MKK4/7), mitogen-activated protein kinase kinase kinase 3, 6 (MKKK3/6 or MAP3Ks) and MEK5, which sequentially activates Jun N-terminal kinase 1, 2 (JNK1/2), p38, and ERK5. Furthermore, phosphorylation of RTKs also activates PI3K, which consecutively activates Akt and mammalian target of rapamycin (mTOR) within the mammalian target of rapamycin complex 1 (mTORC1) complex, which also regulates Akt. Moreover, PLC can also be activated by RTKs, leading to Ca2+ mobilization and activation of PKC.36,85,86

Earlier research on embryonic mouse nasal explants has shown that all signaling pathways activated by GPCRs and RTKs are found in GnRH neural cells and the GnRH neuronal activity is controlled by downstream effectors of these receptors.28 It was identified that the TAM receptor family, which includes Tyro3, Axl and Mer, involved in GnRH neuron migration, activates several intracellular signaling pathways, including PI3K-Akt, ERK1/2, and/or p38 MAPK.87,88 Gas6/Axl stimulates the remodeling of cytoskeleton and causes the migration of GnRH neuronal cells through p38 PI3K and Rho family GTPase Rac signaling pathway. Axl phosphorylates the p85 subunit of PI3K and contributes to Rac activation, which is required for Gas6/Axl-induced neuron migration.88,89 Furthermore, semaphorin/neuropilin/plexin pathways that play different roles in the GnRH neuron biology by regulating migration and survival during embryonic development as well as secretion in adulthood use RTK signaling through FARP2, Rac1, Rnd1, PAK, LIMK1, and Cofilin pathways.90,91 Furthermore, kisspeptin/GPR54 system activates PLC pathway using Gq-dependent signaling pathway28,92 and causes depolarization of GnRH neurons to regulate its secretion.93 Similarly, NPY inhibits the GnRH neuronal activity by utilizing Gi protein-coupled receptors, which inhibits AC and this represses signaling through the cAMP/PKA pathway.28,94 In addition, gliotransmitters secreted by glial cells control the synthesis and release of GnRH by using RTKs such as fibroblast growth factor receptor (FGFR), epidermal growth factor receptors (EGFRs), hepatocyte growth factor receptors (HGFRs), insulin and insulin-like growth factor receptors (IR and IGFR), vascular endothelial growth factor receptors (VEGFRs), and platelet-derived growth factor receptors (PDGFRs).36,95Supplementary Table 7 shows the list of 21 genes that have been identified to code for signaling molecules for GnRH production and secretion,10,23,35 and no mutations in signaling molecules have been identified to cause delayed puberty.

SYNTHESIS AND SECRETION OF GNRH

The hypothalamic POA and ARC house the soma of most of the GnRH neurons69,96 but they extend their branches (>1 mm long) to ME, where they secrete GnRH into the hypophyseal portal blood system.97 Even though GnRH neurons are physically scattered in the hypothalamus, functionally they are highly coordinated.69

At the time of pubertal onset, the expression of GnRH gene increases due to augmented influence from stimulatory neurotransmitters, which increase the synthesis of GnRH. The GNRH1 gene codes GnRH protein and consists of 3 exons and 3 introns. After translation, prepro-GnRH peptide is produced, which consists of 92 amino acids.67 Prepro-GnRH is comprised of N-terminal signal peptide, GnRH, cleavage signal and C-terminal GnRH associated peptide (GAP). Prepro-GnRH is converted into pro-GnRH peptide by removing the N-terminal signal peptide. Pro-GnRH is further cleaved by endopeptidases into GnRH peptide and GAP. Afterward, carboxypeptidase enzymes remove basic amino acids from C-terminus and glutaminyl cyclase enzymes convert the N-terminal glutamine to produce final bioactive GnRH peptide.67,98

The process of GnRH production is controlled at various steps such as transcription rate, posttranscriptional modifications, stability of mRNA, translation rate, and posttranslational modifications including conversion of inactive prepro-GnRH to biologically active GnRH decapeptide.67 Earlier studies have shown that transcription factors such as homeodomain protein orthodenticle homeobox 2 (OTX2)99 and the POU homeodomain protein transcription factor OCT1100 are fundamental for GnRH gene transcription. Since then, numerous transcription factors have been identified to play a role in GnRH synthesis.67 Furthermore, a number of enzymes such as prohormone convertases (PCs), carboxypeptidases, glutaminyl cyclase, peptidylglycine α-amidating monooxygenase, and prolyl hydroxylase are also essential for full processing of GnRH molecule.101Table 4 represents the list of 104 genes that have a role to play in GnRH synthesis,4,10,23–25,49,67 and mutations in 7 genes have been reported to be involved in delayed puberty24,26,49,102 (Table 1).

T4
Table 4:
List of 104 genes involved in the synthesis of GnRH

SYNTHESIS AND SECRETION OF GONADOTROPINS

At the time of pubertal onset, the pulsatility of GnRH increases as required for the augmentation of gonadotropins secretion and consequent final maturation of mature gonads.54 The pulsatility of GnRH is due to coordinated interaction between multiple GnRH neurons, which are controlled by stimulatory and inhibitory signals. The stimulatory signals increase the activity of voltage sensitive ion channels, causing an influx of Ca2+ ions. Broad changes in Ca2+ ions allow the GnRH vesicles to move toward the plasma membrane of GnRH neurons and by the process of exocytosis, secrete GnRH in the hypophyseal portal capillary bloodstream at the ME.70,103 In an adult male, GnRH neurons produce one pulse of GnRH every 2 h, which is required for continuous spermatogenesis leading to preparation of mature sperm capable of fertilizing oocytes when delivered to the site of fertilization in the female reproductive tract.69

GnRH is secreted into the pituitary portal bloodstream to arrive at the pituitary gonadotrope cells, which are specialized for producing gonadotropins (LH and FSH). At the pituitary gonadotropes, GnRH binds with gonadotropin releasing hormone receptor (GnRHR) on the gonadotrope cell surface membrane. GnRHR is a GPCR that consists of seven transmembrane domains.69 The activation of GnRHR is dependent on the episodic secretion of the hypothalamic GnRH.68 When GnRH binds with GnRHR, Gq/11 isoform activates and stimulates the PLC signaling pathway. As a result, IP3 and DAG are produced. IP3 activates its receptor IP3R, causing an influx of Ca2+ ions to release gonadotropins from their vesicles into systemic circulation. On the other hand, DAG along with Ca2+, stimulates PKC, which activates Raf/MEK/ERK cascade. In addition, Ca2+ stimulates calmodulin (CaM) that triggers CaM-dependent protein kinases (CaMK) and the phosphatase calcineurin (Cn), which, in turn, activate Ca2+-dependent transcription factor nuclear factor of activated T-cells (NFAT). NFAT- and ERK-activated transcription factors work in synergy to regulate the synthesis of gonadotropins.104

GnRH is secreted in pulses to drive pulses of gonadotropin release and is essential for normal reproduction. Its effects are dependent on pulse frequency. In humans and other primates, GnRH pulses have a duration of a few minutes and intervals of 30 min to several hours.104 When the levels of GnRH increase, GnRHR activates Gq/11 signaling pathway to increase the concentrations of Ca2+, which allows the fusion of vesicles with the plasma membrane thus, at high concentrations, GnRH causes the release of gonadotropins.104,105 Ca2+ also activates CaM pathway to activate the Ca2+-dependent transcription factor NFAT. In addition, GnRH stimulates MAPK pathway for the activation of the Raf/MEK/ERK cascade. NFAT- and ERK-activated transcription factors then act in combination to control gene expression of gonadotropins genes. Thus, chronically GnRH regulates the gonadotropin content of the vesicles.104 The stimulatory effects of GnRH on LH and FSH secretion are different. The secretion of FSH is more irregular than LH in humans, which is essentially related to the pulsatility and different stimulatory effects of GnRH. LH is synthesized when the frequency of GnRH pulses is high, while FSH is produced at lower frequency of GnRH pulses.106 Furthermore, there is a negative feedback effect of inhibin B on FSH secretion. Other factors are also involved, such as differences in LH and FSH storage (more scarce for the FSH), the existence of different gonadotrophic subpopulations, or diverse response times to GnRH.107,108Table 5 shows the list of 35 genes that have a role to play in gonadotropins synthesis and secretion,10,23,24,37,49,64,109 and mutations in 16 genes have previously been identified to cause delayed puberty24–26,102,110 (Table 1).

T5
Table 5:
List of 35, 16, and 12 genes involved in the synthesis and secretion of gonadotropins, development of testes and steroidogenesis, respectively

DEVELOPMENT OF TESTES

The testicular development begins with the formation of the genital ridge. The primordial germ cells (PGCs) begin to colonize the gonads by approximately 5th week of gestation. By the 6th week, the PGCs invade the genital ridges.111,112 In genetically male embryos, testis determination occurs due to the presence of sex-determining region of the Y chromosome (SRY) gene, which stimulates the production of sex-determining proteins.112,113

The SRY gene encodes for a transcription factor that activates the testis-specific enhancer (TESCO) of a related autosomal gene known as SRY-box transcription factor 9 (SOX9). The SOX9 gene plays an important role in the differentiation of the Sertoli cells from supporting cell precursors. In addition to SRY, other factors such as steroidogenic factor 1 (encoded by the gene nuclear receptor subfamily 5 group A member 1 [NR5A1]), are also important for the differentiation of the Sertoli cells.112,114

SRY increases the concentrations of SOX9 and once the levels of SRY and SOX9 are high enough inside the cells/tissue, the transcription of SOX9 protein is maintained at higher levels in the Sertoli cells. As soon as the SOX9 positive cells reach sufficient levels in the gonads, morphological changes occur and the process of testes formation begins.112,115 This process involves the differentiation of interstitial cell lineages (Leydig cells and peritubular myoid cells), the mitotic arrest of germ cells, epithelialization of the Sertoli cells, and the formation of the testicular cords.112,116

The descent of testes from inside the abdomen to the scrotum is a continuous process that is divided into two main phases: the transabdominal phase and the inguinoscrotal phase. During the first transabdominal phase, the testes are attached with the inner entrance of the future inguinal canal, while in the second inguinoscrotal phase, the testes move through the inguinal canal and reach their final position, the scrotum. Studies on humans have shown that the transabdominal phase occurs between the gestational weeks 10 and 15 while the inguinoscrotal phase occurs between the 25th and 35th gestational weeks.117,118Table 5 shows the list of 16 genes involved in the development of testes,112,118 and mutations in 5 genes have previously been reported to cause delayed puberty24,119–121 (Table 1).

STEROIDOGENESIS

LH and FSH are secreted in the systemic circulation, which takes them to testes, where receptors for both hormones are present on the target cell surface membranes. LH receptors (LHR or LHCGR) are present on the Leydig cells while the testicular Sertoli cells house FSH receptors (FSHR).122 When LH binds with LHR, there is a conformational change in LHR, which activates Gs isoform and stimulates AC, PLC/IP3123,124 and ERK1/2/AKT signaling pathways.125 All these pathways work together to control the process of steroidogenesis in males.124,126

In the Leydig cells, steroidogenesis takes place to produce testosterone (T). Testes are responsible for production of >95% of the circulating T. On the other hand, adrenal glands are also involved in the production of minor quantity of T.127,128 Like other steroid hormones, T is synthesized from cholesterol. When LH binds with LHR, signaling cascade starts, which activates steroidogenic acute regulatory protein (StAR) to transfer cholesterol molecules into mitochondria. In the mitochondria, cholesterol is converted to pregnenolone through cytochrome P450 family 11 subfamily A member 1 (CYP11A1 or P450scc) and its redox partners, ferredoxin (FDX1) and ferredoxin reductase (FDXR). Pregnenolone is further converted to 17α-hydroxypregnenolone (17OHPreg) and dehydroepiandrosterone (DHEA) by using delta 5 pathway and CYP17A1 (P450c17) enzyme. DHEA is then converted to either androstenedione by using 3β-hydroxysteroid dehydrogenase type II (HSD3B2/3βHSDII) or to androstenediol through 17β-hydroxysteroid dehydrogenase 3 (HSD17B3/17βHSD3/AKR1C3).128,129 Most of the T is converted to dihydrotestosterone (DHT) by steroid 5α-reductase, alpha polypeptide 1 (SRD5A1).128,130Table 5 shows the list of 12 genes that are involved in the process of steroidogenesis,128,131,132 and mutations in only 1 gene have been reported to be involved in delayed puberty132 (Table 1).

STEROID HORMONE ACTION

The action of androgens, notably T, occurs through androgen receptors (ARs; NR3C4), which are a family of nuclear, ligand-activated transcription factor receptors.133,134 In the absence of androgens, ARs are bound to heat shock proteins (HSPs) and co-repressors and are located in the cytoplasm in a latent state, devoid of any biological activity. When androgens bind with ARs, conformational changes occur, ARs become separated from HSPs and co-repressors and are transported to the nucleus by co-regulators.135 Inside the nucleus, ARs bind to specific androgen response elements leading to stimulation of various transcription factors to control the expression of downstream genes (canonical signaling). In addition, ARs can also activate Ca2+, IP3 and DAG signaling pathways for its nonclassical effects.128,136 Moreover, when androgens are present in small amounts, nongenomic signaling of ARs occurs through MAPK/Akt pathways. This nongenomic signaling regulates the propagation and survival of cells.137Supplementary Table 8 represents the list of 115 genes that have a role to play in the action of steroid hormones138–140 and mutations in 5 genes have been identified to cause delayed puberty26,66,76,119,141 (Table 1).

MOLECULAR BASIS OF DELAYED PUBERTY

Male puberty requires an intact operational HPT axis and any interruption in this axis may result in temporary or permanent dysfunction of reproductive axis manifested as delayed or failed puberty.142 A mature, functional HPT axis of a reproductively competent adult requires properly regulated and coordinated development of the hypothalamus, pituitary, and testes during embryogenesis (Figure 1). After embryonic development, GnRH neurons need to coordinate and regulate GnRH synthesis and release, which is required to stimulate the pituitary glands for the production and release of gonadotropins. In turn, gonadotropins must be capable of stimulating the testes for steroidogenesis (to produce androgens) and spermatogenesis (to produce mature sperm capable of fertilization). The steroids produced must also be able to perform their function correctly in the downstream effector tissues. Any abnormality in the development of the entire system either during embryonic development, childhood, adolescence or adulthood may disrupt or nullify puberty, leading to long-term male infertility and/or hypogonadism.143

F1
Figure 1:
A complex regulation of HPT axis. HPT: hypothalamo-pituitary-testicular; NKB: neurokinin B; GALP: galanine-like peptide; GABA: gamma amino butyric acid; DA: dopamine; NPY: neuropeptide Y; ENK: enkephalins; T: testosterone; DHT: dihydrotestosterone; GnRH: gonadotropin releasing hormone; LH: luteinizing hormone; FSH: follicle stimulating hormone.

Male puberty is said to be delayed if it does not commence with increase in testis growth as the first external sign by the age of 14 years leading to persistence of immature small testes, which lack mature testis functions evident with impaired spermatogenesis in small testes of typically <4 ml of volume, reduced or absent sperm production (azoospermia or oligo-zoospermia) and deficient virilization due to impaired T secretion.48,144

Failure of the hypothalamus to develop properly, failure of GnRH neurons to differentiate, inability of GnRH neurons to reach the proper place in the hypothalamus and form appropriate connections, failure of GnRH neurons to coordinate with each other in producing GnRH, inability of GnRH to activate the pituitary gland, failure to stimulate steroidogenesis through gonadotropins or failure to activate ARs by steroids means that puberty is not initiated. The origin of most or all of these conditions is primarily genetic.67

Although extensive research has been carried out on regulation of the male puberty, only 75 out of 598 genes have been identified to be mutated leading to delayed puberty. Table 1 represents the list of genes along with the references in which mutations have been confirmed to cause delayed puberty. The genetic basis of delay in puberty remains unknown among 50% of the cases,24,145 presumably those in the group of 598 genes not included among the 75 so far known genes associated with disruption of the male puberty or possibly still others. These unidentified cases will be increasingly revealed by using advanced genomics methods like next-generation sequencing (NGS) technologies, where massively parallel sequencing approaches produce millions of short-read sequences in a much shorter time, at a much cheaper cost and with higher throughput compared to Sanger sequencing.146 Two methods, whole genome sequencing (WGS; the method to determine the order of all the nucleotides in an individual’s DNA) and whole exome sequencing (WES; the method of sequencing all the exons) are increasingly used in healthcare and research to identify genetic variations. These approaches are known as NGS.147 By using NGS, it is expected that more accurate and much less costly outcomes can be obtained to make them routine diagnostic tests making the transition from expensive research tests.24 It was observed that same mutation in different patients showed different phenotypes, even in monozygotic twins.148 This proposed the concept of digenicity or oligogenicity, where mutations in two or more genes enhance the effect of each other and produce variable phenotypes, as well as compound heterozygosity, where two different mutated alleles are present at a particular gene locus.46,47 It was also suggested that heterozygous mutations in different genes along the HPT axis synergize the effect of each other in producing the phenotype, but the contribution of each gene may be different in each patient and also, if these variants are present alone in heterozygous state then they may not contribute to the disease.48 In view of these observations, it was suggested that mutations in any of the genes involved in the development and functioning of the HPT axis may cause delayed puberty, Kallmann syndrome, or idiopathic hypogonadotropic hypogonadism.48

Limitations

There are a number of genes, which are involved in multiple processes along normal functioning HPT axis. Explaining the exact mechanism for each gene is beyond the scope of this article. For example, PIN1 is a peptidyl-prolyl cis-trans isomerase that catalyses the isomerization of phosphorylated Ser/Thr-Pro peptide bonds. It was observed in PIN1 knock-out mice that their reproductive development and function were markedly abnormal causing hypogonadotropic hypogonadism.110,149 The main role of PIN1 is in the transcription of gonadotropin-subunit genes. It promotes the ubiquitination of SF1 by using a phosphorylation-regulated pathway, which, in turn, allows the SF1 to interact with paired like homeodomain 1 (Pitx1) and increase the transcriptional activity of SF1.150 SF1 is involved in the regulation of transcription of several enzymes having a role in steroid/androgen biosynthesis. In the pituitary gonadotropes, GnRH-induced signaling cascades maintain the higher levels of activated PIN1 through transcriptional and posttranslational regulation. This indicates that PIN1 is involved in the GnRH signaling pathway and gonadotropin gene expression.151 PIN1 modulates the activity of various transcription factors for initiating the transcription of the gonadotropin β-subunit. PIN1 was also identified at the promoters of both gonadotropin β-subunit genes and it was predicted that this recruitment was due to its interaction with SF1, Pitx1, and/or early growth response 1 (Egr-1).110,152,153 In addition to its role in the synthesis of gonadotropins, PIN1 is also involved in the differentiation of neural progenitor cells by interacting with β-catenin and providing a postphosphorylation signaling mechanism for the regulation of developmental stage-specific functioning of β-catenin signaling in neuronal differentiation.154

CONCLUSIONS

This review provides a classification of mechanisms controlled by a large number of genes, whose normal function leads to the proper development and function of the HPT axis and progression of normal male puberty. The disruption of the HPT axis due to mutations in some of the genes identified so far delays or disrupts male puberty. The present study is an interim synopsis of the genes involved in normal and disrupted male puberty and future studies are likely to still add more genes to already identified ones.

AUTHOR CONTRIBUTIONS

MA and SSRR conceived and designed the work. MA performed data collection. SSRR, MQ and DJH supervised the work and helped in the critical revision of this article. All authors read and approved the final manuscript.

COMPETING INTERESTS

All authors declare no competing financial interests.

Supplementary Information is linked to the online version of the paper on the Asian Journal of Andrology website.

Supplementary Table 1

List of 53 genes involved in the establishment of the hypothalamic regional territories and subdivisions of regional territories

Supplementary Table 2

List of 71 genes involved in the GnRH neuron differentiation

Supplementary Table 3

List of 25 genes involved in the hypothalamic nuclei development

Supplementary Table 4

List of 74 genes involved in the process of synaptogenesis

Supplementary Table 5

List of 25 genes involved in maintaining the neuronal homeostasis

Supplementary Table 6

List of 63 genes coding for receptors/proteins present on GnRH neurons that control the synthesis and secretion of GnRH

Supplementary Table 7

List of 21 genes coding for signalling molecules that control the GnRH synthesis and release

Supplementary Table 8

List of 115 genes involved in the action of steroid hormones

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The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (https://links.lww.com/AJOA/A999).

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ACKNOWLEDGMENTS

The authors are very grateful to the ANZAC Research Institute, NSW, Australia, for accommodating and helping the researcher (Maleeha Akram) during her stay in Australia.

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Keywords:

delayed puberty; gonadotropin releasing hormone; hypogonadism; male puberty; puberty; testosterone

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