Androgens play a major role during male pubertal development

[madman]

The role of androgen signaling in male sexual development at puberty



Abstract

Puberty is characterized by major changes in the anatomy and function of reproductive organs. Androgen activity is low before puberty, but during pubertal development, the testes resume the production of androgens. Major physiological changes occur in the testicular cell compartments in response to the increase in intratesticular testosterone concentrations and androgen receptor expression. Androgen activity also impacts the internal and external genitalia. In target cells, androgens signal through a classical and a nonclassical pathway. This review addresses the most recent advances in the knowledge of the role of androgen signaling in postnatal male sexual development, with a special emphasis on human puberty.




Introduction

Puberty is a unique stage during postnatal development, of variable duration according to species, characterized by substantial anatomical and physiological changes leading to the mature state, typical of adulthood, of most organs. Throughout history, most of the attention has been directed to the physiology and pathology of the organs in their adult stage [1]. The accelerated progress of technological tools during the last decades has nurtured the advancements in developmental biology, encompassing both prenatal and postnatal stages, until the achievement of the mature state. Androgen action is key for the virilization of the fetus but after birth, particularly in humans and other long-lived mammals, the prepubertal stage is characterized by a lack of evident activity in gonadal steroid secretion. During pubertal development, the testes resume the production of androgens, whose actions become patent in the development of male secondary sexual characteristics.

The onset and progression of puberty are controlled by the hypothalamic-pituitary-gonadal axis. The hypothalamus synthesizes gonadotropin-releasing hormone (GnRH) and releases it in a pulsatile manner to the portal system that drives it to the anterior pituitary where they reach the gonadotrophs expressing the GnRH receptor [2]. Gonadotrophs secrete both luteinizing hormone (LH), responsible for androgen synthesis in Leydig cells, and follicle-stimulating hormone (FSH), acting on the seminiferous tubule [3]. The hypothalamic-pituitary-gonadal axis is active during fetal development and for three to six months after birth in the human male. Thereafter, an active inhibition of GnRH secretion ensues throughout childhood, probably due to the effect of neurotransmitters such as catecholamines, GABA, and glutamate, and to the most recently described makorin ring-finger protein 3 (MKRN3) [2]. A progressive increase in pulsatile GnRH secretion is responsible for the onset and progression of puberty. The mechanisms leading to the reinstatement of pulsatile GnRH secretion involve a complex interaction between genetic and environmental factors. Specific microRNAs (miRNAs) have recently been shown to lift the inhibitory actions of prepubertal blockers [4,5], thus leading to the activation of kisspeptin and tachykinin systems that control GnRH neuron activity [2].

The testes are not only a source but also a target of androgen action, and major physiological changes occur in the various cell populations of the male gonads in response to variations in intratesticular testosterone concentrations. Testosterone is the most abundant circulating androgen produced by the testes. Dihydrotestosterone (DHT) is a more potent androgen [6], produced essentially in peripheral tissues by the classical pathway involving 5α-reduction from testosterone, and also by a “backdoor” pathway in the absence of testosterone as a precursor [7]. In target cells, androgens act essentially through two different mechanisms, one classical and one nonclassical, both involving the same receptor [8]. There is a differential impact of androgen action on the various target organs according to the stage of development. This review will address the most recent advances in the knowledge of the role of androgens and their signaling mechanisms in the different postnatal stages of male sexual development, with a special focus on human puberty.




*Androgen action in target cells
- Testosterone and DHT
- Androgen signaling
- Classical pathway of androgen signaling
- Non-classical pathways of androgen signaling
- AR-independent pathways of androgen action




*Androgens during postnatal development of the male reproductive tract

*Androgen effects within the testis
- Testicular changes during the prepubertal period
- Role of androgen signaling in the prepubertal testis
- Physiological changes and the role of androgen signaling in the pubertal testis




*Androgen effects on the internal reproductive tract
- Epididymis
- Vas deferens
- Seminal vesicle
- Prostate



*The external genitalia
- Changes during childhood and pubertal development
- Role of androgen signaling in the pubertal changes of external genitalia




Conclusions

Androgens play a major role during male pubertal development. The testis is the major source of testosterone, which acts in a paracrine way mainly through Sertoli and peritubular myoid cells to induce and maintain adult spermatogenesis. Rapid responses are mediated by nongenomic pathways whereas the best characterized long-term actions involving upregulation and downregulation of androgen-dependent genes are mediated by genomic pathways. In the internal and external genitalia, testosterone needs to be the more potent androgen DHT to be efficacious. While the effects of androgens and of their withdrawal have been extensively characterized at the level of the internal and external genitalia, remarkably little information exists on the molecular mechanisms involved.

 

[madman]

Figure 1. Sex steroid synthesis in the male: the classical pathway is shown in green, and the “backdoor” pathway of DHT synthesis is shown in blue.

 

[madman]

Figure 2. Pathways of androgen signaling. Androgens, such as testosterone (T) or dihydrotestosterone (DHT) represented as blue circles, cross the cell membrane and bind to the androgen receptor (AR) in target cells, displacing chaperones as the heat shock proteins (HSP), In the “classical” or “genomic” pathway, the ligand-bound AR translocates to the nucleus and forms homodimers that interact with androgen response elements (ARE) in target gene promoters or with other transcription factors (TF), finally regulating gene expression. In the “non-classical” or “non-genomic” pathway, the ligand-bound AR migrates to the inner side of the cell membrane and interact with the Steroid receptor coactivator (Src) and activates the epidermal growth factor receptor (EGFR) signaling cascade involving e.g. the mitogen-activated protein kinase (MEK), the extracellular signal-regulated kinase (ERK), and the cAMP response element-binding protein (CREB). Modified from: Edelsztein NY, Rey RA. Importance of the androgen receptor signaling in gene transactivation and transrepression for pubertal maturation of the testis. Cells. 2019;8:1-17, with permission from the authors © 2019, licensee MDPI, Basel, Switzerland (open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license)

 

[madman]

Figure 3. Schematics of changes in serum hormone levels, the anatomy of the external genitalia, histology of the testis, illustrative components of the blood-testis barrier (BTB, reproduced with permission from ref. [8]), and testicular volume (in ml, as compared to Prader’s orchidometer) throughout postnatal life in humans. AMH: anti-Müllerian hormone, T: testosterone, AR: androgen receptor, G1-G5: genital stages according to Marshall and Tanner [41], SC: Sertoli cells, Sg: Spermtaogonia, Sc: Spermatocytes, Sd: Spermatids. Prader’s orchidometer: numbers represent testicular volume in ml.

 

[madman]

Figure 4. The molecular mechanism explaining the androgen-induced downregulation of antiMüllerian hormone (AMH) expression in pubertal Sertoli cells. (A) Before puberty, in the absence of androgen action, AMH is highly expressed in response to transcription factors SF1, GATA4 and WT1. (B) During puberty and adulthood, the ligand-bound androgen receptor (AR) inhibits AMH transcription through either a direct interaction with SF1 sites on the AMH promoter (blockage by competition, which impedes SF1 binding to its specific response elements) or a protein-protein interaction with SF1 (blockage by interaction, resulting in the inactivation of SF1 transcriptional activity). In both cases, the AR prevents SF1 from upregulating AMH expression. Reproduced from: Edelsztein NY, Rey RA. Importance of the androgen receptor signaling in gene transactivation and transrepression for pubertal maturation of the testis. Cells. 2019;8:1-17, with permission from the authors © 2019, licensee MDPI, Basel, Switzerland (open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license).