Testosterone is a hormone that is produced primarily in the testicles. It is responsible for the development of male characteristics, such as a deep voice, facial hair, and muscle mass. Testosterone also plays a role in sperm production and sex drive. In addition to its effects on the body, testosterone also has an impact on the brain.
Studies have shown that testosterone affects areas of the brain that are associated with memory and learning. Testosterone levels fluctuate throughout the day, with levels typically being highest in the morning. Production of testosterone declines with age, which can lead to reduced muscle mass, increased body fat, change in body composition and reduced sex drive. Testosterone replacement therapy can help to reduce these effects by increasing testosterone levels. The structure, metabolism, physiologic effects and mechanism of action of testosterone will be reviewed.
Origin of Testosterone
Charles-Édouard Brown-Séquard, an eminent clinician known to medical trainees – “Brown-Séquard Syndrome” carried out a rather bizarre experiment in the 1800s. He prepared a rather nauseating concoction composed of “blood from the testicular vein…semen and testicular juice extract from a dog or guinea pig”.
He injected himself with this concoction in a scene that might seem illogical to modern clinicians. Being an eminent clinician of the day, he was allowed to present his findings at the academy of science in Paris, France. Brown-Séquard, then aged 72 years, reported experiencing an improvement in his physical strength and powers of concentration. Brown-Séquard’s extract became an overnight sensation worldwide with claims of being the new “Elixir of life.”
It, however, goes without saying that this was most likely a placebo effect. Indeed later evidence showed that to obtain an appreciable amount of testosterone from the testes, about one-quarter ton of a bull’s testes would be required. Organotherapy, the process of injecting the extracts of various glands, became a medical fad after Brown-Séquard’s experiment.
Structure of Testosterone
The chemical structure of testosterone (C19H28O2) was first determined in 1935 by Adolf Butenandt and Gunter Hanisch[1]. Testosterone is a steroid hormone from the androgen group. It is primarily secreted in the testicles of males and the ovaries of females, although small amounts are also secreted by the adrenal glands. The chemical structure of testosterone is C19H28O2. It has 19 carbon atoms, 28 hydrogen atoms, and 2 oxygen atoms. The molecular weight of testosterone is 288.4 g/mol.
Normal serum testosterone levels vary depending on a person’s age and stage of development, but generally fall within a range of 300 to 1,000 ng/dL.
Regulation of testosterone production
Testosterone regulation is dependent on an intimate relationship between the hypothalamus, anterior pituitary gonadotrophs and the testes. Firstly, hypothalamic neurons produce gonadotropin releasing hormone (GnRH), which is transported by the hypothalamic-hypophyseal venous portal system in order to reach anterior pituitary gonadotrophs. The pulsatile release of gonadotropin releasing hormone is critical in regulating the secretion of gonadotropins (both LH and FSH)
Leydig cells of the testes under direct stimulation by LH produces testosterone. The release of testosterone also occurs in a complex pulsatile and diurnal fashion, with peak serum concentrations in the early morning around 8 am and the lowest levels around 8 pm.
In this somewhat closed endocrine feedback loop, testosterone self-regulates its plasma concentration via negative feedback inhibition of both GnRH neurons (hypothalamus) and gonadotropins (LH and FSH). Sertoli cells of the testes under direct stimulation by FSH produce sperm. Intra-testicular is a critical “co-factor” in ensuring spermiogenesis occurs unhindered.
Testosterone metabolism
About 7mg of testosterone is produced by a male each day. Approximately 90 percent of it undergoes hepatic metabolism, resulting in two major inactive metabolites – these are etiocholanolone and androsterone. Also, 10% of endogenous testosterone is converted to dihydrotestosterone, which further enhances its effects on the androgen receptor. It is also worth noting that dihydrotestosterone can also undergo further processing at the level of the liver, to produce androstanediol, androsterone, and androstenedione. Finally, the remaining 0.1% of testosterone gets transformed into estradiol by the enzyme aromatase (which is present in adipose tissue).
Transportation of Testosterone
Circulating testosterone exists in plasma, either bound to proteins or in a free form. 54% of testosterone is bound to albumin, approximately 44% is bound to sex hormone-binding globulin (SHBG) and 1-2% is present in an active free form (also known as free testosterone) responsible for the physiologic effects of testosterone [2].
Sex hormone binding globulin (SHBG), a glycoprotein, has an affinity for the following sex steroids (testosterone, dihydrotestosterone, and estradiol) [3].
Causes of a high sex hormone binding globulin
· Hyperthyroidism
· Estrogens
· Cirrhosis
· Aging
· HIV infection
Causes of a low sex hormone binding globulin
· Hypothyroidism
· Progestins, androgens, and glucocorticoids
· Nephrosis
· Acromegaly and Diabetes mellitus.
· Obesity
Based on reference [4]
Pathways of testosterone action in target tissues
Testosterone exerts various physiologic effects as outlined below
- 5 alpha-reductase enzyme converts testosterone into dihydrotestosterone
- Aromatase enzyme converts testosterone into estradiol
- Serum testosterone binds to the androgen receptor.
The mechanism and physiologic effects of testosterone
| Physiologic effect | Mechanism(s) |
| Increase in bone mineral density | 1. Testosterone induces bone formation by binding to its corresponding androgen receptors present on osteoblasts 2. Testosterone mediates insulin-like growth factor 1 mediated proliferation of osteoblasts. 3. The aromatase enzyme converts testosterone to estrogen. Estrogen subsequently inhibits RANKL-mediated bone resorption5. |
| Hair growth and sebum production | 1. The proliferation of androgen-dependent hair occurs due to the activation of androgen receptors present on dermal papilla cells by androgens. 2. Also, androgen receptors present on sebaceous glands are stimulated by testosterone. Increased sebum production by sebaceous gland increases the risk of acne6. |
| Muscle growth | How testosterone directly induces muscle protein synthesis and hypertrophy remains unclear at this time7. |
| Reproductive roles | 1. Testosterone is responsible for critical pubertal changes in males. These include testicular descent, spermiogenesis, enlargement of the phallus and growth of the testes. 2. Testosterone promotes libido8. |
| Erythropoiesis (promotes an increase in hemoglobin and hematocrit) | 1. Testosterone induces the synthesis of erythropoietin (by the kidney) 2. Testosterone also suppresses hepcidin (a potent inhibitor of intestinal iron absorption) 3. Iron mobilization (critical in hemoglobin synthesis)9 |
Mechanism of action of testosterone
Testosterone exhibits its physiologic effects in target tissues by binding and stimulating the androgen receptor. Various downstream processes occur after testosterone to androgen receptor interaction. Two critical post-receptor processes include either a classical (gene expression) or a nonclassical (kinase activation) pathway[10].
Schematic representation of intracellular steroid hormone signaling
The classical and nonclassical pathways testosterone signaling.
The classical signaling pathway : Testosterone first diffuses through the cell membrane of its target cell and subsequently interacts with its corresponding cytosolic receptor [11]. Afterwards, this induces a conformational change in the androgen receptor. This allows the androgen receptor to dissociate from its heat shock proteins (these are HSP 70 and HSP 90). The androgen receptor then crosses the nuclear membrane and then binds to unique androgen response elements (AREs) present in DNA. Subsequently, specific ligand activated transcription factors promotes the transcription and translation of various genes10.
The nonclassical pathway: This pathway occurs in the cytosol of target cells. An interaction of testosterone with its cytosolic androgen receptor leads to the activation of the mitogen-activated protein kinase (MAPK) cascade. Activation of MAPK promotes the sequential phosphorylation of various proteins, including RAF, MEK, and ERK, responsible for various physiological effects of testosterone [11].
References
1. Butenandt A, Hanisch G. Über die Umwandlung des Dehydro-androsterons in Δ4-Androsten-ol-(17)-0n-(3) (Testosteron); ein Weg zur Darstellung des Testosterons aus Cholesterin (Vorläuf. Mitteil.). Berichte Dtsch Chem Ges B Ser. 1935;68(9):1859-1862. doi:10.1002/cber.19350680937
2. Czub MP, Venkataramany BS, Majorek KA, et al. Testosterone meets albumin – the molecular mechanism of sex hormone transport by serum albumins. Chem Sci. 2019;10(6):1607. doi:10.1039/c8sc04397c
3. Hautanen A. Synthesis and regulation of sex hormone-binding globulin in obesity. Int J Obes Relat Metab Disord J Int Assoc Study Obes. 2000;24 Suppl 2:S64-70. doi:10.1038/sj.ijo.0801281
4. Bhasin S, Brito JP, Cunningham GR, et al. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society* Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(5):1715-1744. doi:10.1210/jc.2018-00229
5. Shigehara K, Izumi K, Kadono Y, Mizokami A. Testosterone and Bone Health in Men: A Narrative Review. J Clin Med. 2021;10(3):530. doi:10.3390/jcm10030530
6. Zouboulis CC, Degitz K. Androgen action on human skin – from basic research to clinical significance. Exp Dermatol. 2004;13(s4):5-10. doi:10.1111/j.1600-0625.2004.00255.x
7. Sheffield-Moore M. Androgens and the control of skeletal muscle protein synthesis. Ann Med. 2000;32(3):181-186. doi:10.3109/07853890008998825
8. Kalfa N, Gaspari L, Ollivier M, et al. Molecular genetics of hypospadias and cryptorchidism recent developments. Clin Genet. 2019;95(1):122-131. doi:10.1111/cge.13432
9. Bachman E, Travison TG, Basaria S, et al. Testosterone Induces Erythrocytosis via Increased Erythropoietin and Suppressed Hepcidin: Evidence for a New Erythropoietin/Hemoglobin Set Point. J Gerontol A Biol Sci Med Sci. 2014;69(6):725. doi:10.1093/gerona/glt154
10. Walker WH. Testosterone signaling and the regulation of spermatogenesis. Spermatogenesis. 2011;1(2):116. doi:10.4161/spmg.1.2.16956
11. Shihan M, Bulldan A, Scheiner-Bobis G. Non-classical testosterone signaling is mediated by a G-protein-coupled receptor interacting with Gnα11. Biochim Biophys Acta BBA – Mol Cell Res. 2014;1843(6):1172-1181. doi:10.1016/j.bbamcr.2014.03.002
Kindly Let Us Know If This Was helpful? Thank You!
