Testosterone and the Androgen Receptor

[madman]

Testosterone and the Androgen Receptor (2023)
Thomas Gerald, MD, Ganesh Raj, MD, PhD


INTRODUCTION

The steroid hormone testosterone is among the most widely studied in the endocrine system. Testosterone is the major sex hormone in men and critically influences male development and maintenance of physiologic functions of multiple organ systems across all ages, including in sexual differentiation, development of male secondary sexual organs, sperm production, libido, muscle size and strength, and bone growth and strength. The male phenotype strongly depends on the expression of testosterone and its byproducts. Adolescent boys with too little testosterone may not experience normal masculinization. In contrast, athletes who use anabolic steroids, testosterone, or related hormones to increase muscle mass and athletic performance have abnormally high testosterone levels.

Testosterone levels are carefully regulated by an elegant multitier feedback system with positive and negative feedback mechanisms that tightly regulate hormonal levels and expected physiologic changes. Testosterone is the ligand for the androgen receptor (AR), which produces its effects through the regulation of both gene transcription and translation of proteins as well as through second messenger systems for both prolonged and rapid effects.




*HISTORICAL EFFECTS OF TESTOSTERONE


*ANDROGEN STEROIDOGENESIS FROM CHOLESTEROL


*TESTOSTERONE REGULATION, PRODUCTION, AND TRANSPORT


*TESTOSTERONE VARIATION AND FUNCTION


*ANDROGEN DEPRIVATION THERAPY


*THE ANDROGEN RECEPTOR


*METABOLISM OF TESTOSTERONE (AROMATASE, 5a-REDUCTASE)




SUMMARY

Testosterone and its steroid metabolite hormones play an exceedingly important role in the development of male sexual characteristics and function and in the homeostasis of numerous organ systems throughout the life cycle. Although the endocrine products of the testis created curiosity and excitement among early physiologists and physicians as a wondrous curative agent for everything from loss of strength, cognition, and vitality to bowel and bladder habits, little was known regarding its production, mechanism of action and metabolism at that time. Present-day investigators have established the HPG axis as a tightly controlled feedback mechanism designed to strictly control homeostasis and have made great strides in the characterization of the AR and its implications in normal physiologic as well as pathologic processes.

 

[madman]

Fig. 1. Androgen steroidogenesis. Cholesterol is the precursor for androgen synthesis and is transported into the cell by lipoprotein receptors. It is transported to the mitochondrial membrane by steroidogenic acute regulatory protein. CYP17, 3b-HSDII, and 17a-HSD3 are involved with subsequent synthesis steps for testosterone. Testosterone may then enter the circulation and act primarily on target tissues or be converted to DHT or estradiol peripherally by 5AR and aromatase, respectively.

 

[madman]

Fig. 2. Hypothalamic-pituitary-gonadal axis. Hypothalamic GnRH release into the hypophyseal portal system is driven by central neurotransmitter release in a pulsatile manner. The anterior pituitary is stimulated to produce LH and follicle-stimulating hormone. LH primarily acts on the Leydig cells in the testis to produce testosterone. Testosterone may then act on the Sertoli cells via androgen-binding protein within the seminiferous tubule to facilitate sperm production and maturation or enter the circulation bound to SHBG to affect distant target tissues. Peripherally, testosterone may be converted to DHT by 5⍺-reductase or estradiol by aromatase, which exerts their own effects on target tissues. Testosterone and estradiol function as negative hypothalamic and pituitary feedback inhibitors. (Adapted from Matsumoto AM, Anawalt BD. Testicular Disorders. In: Melmed S, ed. Williams Textbook of Endocrinology. 14th ed. Philadelphia: Elsevier; 2020:668-755; with permission.)

 

[madman]

Fig. 3. Testosterone peaks in fetal, infant, and adolescent life. There are 3 peaks of serum testosterone in the lifetime of a man. The first is during fetal development and driven by maternal hCG and later by pituitary LH. The second occurs at 3 to 6 months of life and is responsible for penile growth, testicular descent, and Sertoli cell proliferation and development. Adolescence marks the third peak and gives rise to secondary sexual characteristics and homeostatic mechanisms. (From Griffin JE, Wilson JD. The testis. In: Bondy PK, Rosenberg LE, eds. Metabolic Control and Disease, 8th ed. Philadelphia, PA: WB Saunders; 1980:1535–1578.)

 

[madman]

Table 1 Testosterone replacement therapies with Food and Drug Administration approval

 

[madman]

Fig. 4. AR. The AR is composed of a ligand-binding domain (LBD) at the C-terminus, which is separated from the DBD and N-terminal transcription domain by the Hinge region.

 

[madman]

Fig. 5. Classical and nonclassical AR signal transduction. Androgens may affect changes in a target cell via the AR via classical and nonclassical mechanisms. In the classical mechanism, the AR ultimately regulates gene transcription and protein expression, producing an effect over hours to days. The nonclassical mechanism uses a second messenger signal transduction mechanism and produces an effect over seconds to minutes. (Rana Kesha, Davey Rachel A, Zajac Jeffrey D, Human androgen deficiency: insights gained from androgen receptor knockout mouse models, 2014, 16 (2), 169–177.)

 

[madman]

Table 2 Agents targeting the androgen receptor

 

[madman]

KEY POINTS

*Testosterone is a critical steroid hormone involved in the development of male sexual characteristics and function as well as the regulation of many homeostatic mechanisms throughout life

*The production and metabolism of testosterone are tightly regulated by the hypothalamic-pituitary (HPG) axis in order to maintain strict homeostasis among the involved physiologic processes

*Additional steroid hormones involved in testosterone steroidogenesis and metabolism, including dihydrotestosterone and estradiol, occupy an important position in exerting effects on target tissues and in regulating the HPG axis

*When activated by androgens, the androgen receptor is involved in genomic and nongenomic signal transduction to exert the intended effect on the target tissue

 

[madman]

CLINICAL CARE POINTS

*Testosterone is a critical hormone in the development and maintenance of male characteristics and health

*Testosterone levels predictably follow a normal lifetime and circadian pattern that should be considered during the evaluation and management of hypogonadism

*There are many options and delivery modalities for testosterone replacement therapy, each with their own profile and strengths, and weaknesses

*Androgen deprivation therapy is a mainstay in the management of advanced prostate cancer. Clinicians treating patients in this setting should be familiar with the indications and side effects of each agent, particularly as the number of options and their applications expands