Physiology, Testosterone (2024)

Introduction

Testosterone is the primary male hormone responsible for regulating sex differentiation, producing male sex characteristics, spermatogenesis, and fertility. Testosterone’s effects are first seen in the fetus. During the first 6 weeks of development, the reproductive tissues of males and females are identical. At around week 7 in utero, theSRY (sex-related gene on the Y chromosome)initiates the development of the testicl*s.Sertoli cells from the testis cords (fetal testicl*s) eventually develop into seminiferous tubules. Sertoli cells produce a Mullerian-inhibiting substance (MIS), which leads to the regression of the Fallopian tubes, uterus, and upper segment of the vagin* (Mullerian structures normally present in females). FetalLeydigcells and endothelial cells migrate into the gonad and produce testosterone, which supports the differentiation of the Wolffian duct (mesonephric duct) structures that go on tobecome the male urogenital tract. Testosterone also gets converted to dihydrotestosterone (DHT) in the periphery (discussed below) and induces the formation of the prostate and male external genitalia.Testosterone is also responsible for testicular descent through the inguinal canal, which occurs in the last 2 months of fetal development. When an embryo lacks a Y chromosome and thus the SRY gene, ovaries develop. Fetal ovaries do not produce adequate amounts of testosterone, thus the Wolffian ducts do not develop. There is also an absence of MIS in these individuals, leading to the development of the Mullerian ducts and female reproductive structures.[1]

Function

Testosterone is responsible for the development of primary sexual development, which includes testicular descent, spermatogenesis, enlargement of the penis and testes, and increasing libido.The testes usually begin the descent into the scrotum around 7months of gestation, when the testes begin secreting reasonable quantities of testosterone. If a male child is born with undescended but normal testes that do not descend by 4 to 6 months of age, administration of testosterone can help the testes descend through the inguinal canals.[2]

Testosterone is also involved in regulating secondary male characteristics, which are those responsible for masculinity. These secondary sex characteristics include male hair patterns, vocal changes, and voice deepening, anabolic effects, which include growth spurts in puberty (testosterone increases tissue growth at the epiphyseal plate early on and eventual closure of plate later in puberty) and skeletal muscle growth (testosterone stimulates protein synthesis). Testosterone also stimulates erythropoiesis, which results in a higher hematocrit in males versus females. Testosterone levels tend todrop with increasing age; because of this, men tend toexperience a decrease in testicular size, a drop in libido, lower bone density, muscle mass decline, increased fat production, and decreased erythropoiesis, which leads to possibleanemia.

Mechanism

In puberty, the hypothalamic-pituitary-gonadal axisplaysa major role in regulating testosterone levels and gonadal function. The hypothalamus secretes GnRH, which travels down thehypothalamohypophysealportal system to the anterior pituitary, which secretes luteinizing hormone (LH) and follicle-stimulatinghormone (FSH). LH and FSH are two gonadotropic hormones that travel through the blood and act on receptors in the gonads. LH, in particular, acts on the Leydig cells to increase testosterone production. Testosterone limits its own secretion via negative feedback. High levels of testosterone in the blood feedback to the hypothalamus to suppress the secretion of GnRH and also feedback to the anterior pituitary, making it less responsive to GnRH stimuli.[3]

Throughout the reproductive life of males, the hypothalamus releases GnRH in pulses every 1 to 3 hours. Despite this pulsatile release, however, average plasma levels of FSH and LH remain fairly constant from the start of puberty, where levels spike, to the third decade of life, where levels peak and slowly begin todecline. Prior to puberty, testosterone levels are low, reflecting the low secretion of GnRH and gonadotropins. Changes in neuronal input to the hypothalamus and brain activity during puberty cause a dramatic rise in GnRH secretion.

Leydig cells in the testes function to turn cholesterol into testosterone. LH regulates the initial step in this process. Two important intermediates in this process are dehydroepiandrosterone (DHEA) and androstenedione. Androstenedione is converted to testosterone by the enzyme 17-beta-hydroxysteroiddehydrogenase. The majority of testosterone is bound to plasma proteins such as sex-hormone-binding-globulin and albumin. This majority supply of protein-bound testosterone acts as a surplus of testosterone hormone for the body. The small amounts of free testosterone in the blood act at the level of the tissues, primarily the seminal vesicles, bone, muscle, and prostate gland. At the cellular level, testosterone gets converted to dihydrotestosterone by the enzyme 5-alpha-reductase. Testosterone and dihydrotestosterone can bind to cell receptors and regulate protein expression. Both men and women also produce weak acting androgens in the zona reticularis of the adrenal glands. These weak-acting androgens are known as dehydroepiandrosterone and androstenedione. They bind to testosterone receptors with weaker affinity but can also be converted to testosterone in the peripheral tissues if produced at high amounts.[4]

Related Testing

Features of testosterone deficiency can be very apparent, which is why the first steps in diagnosing male hypogonadism involve adequate history taking and physical exam. The features indicative of male hypogonadism can be divided into pre and post-pubertal. Pre-pubertal features include small testes (less than 20 mL in volume), small phallus, decreased secondary sex characteristics (e.g., facialor axillary hair), gynecomastia, difficulty gaining muscle mass, eunuchoid proportions, low sperm count, and low energy/libido. Post-pubertal features include those previously mentioned (except phallus size and eunuchoid proportions) as well as osteoporosis and hot flashes with severe hypogonadism.

If a clinician expects hypogonadism based on history and physical, a total serum testosterone between 8 AM and 10 AM should be drawn. Normal levels may indicate eugonadal low testosterone. If levels are low, a repeat level should be obtained along with FSH and LH levels. Low testosterone in the setting of normal FSH/LH indicates secondary hypogonadism. The next steps would be to get prolactin, T4, 8 AM cortisol, iron, and ferritin levels as well as brain MRI. Low testosterone in the setting of elevated FSH/LH indicated primary hypogonadism. In the case of primary hypogonadism, a karyotype should be established.

Hyperandrogenism also has various clinical presentations, depending on puberty status and gender. Prepubertal boys with hyperandrogenism may present with virilization. Virilization includes penile enlargement, excess hair growth in androgen-dependent areas, and voice deepening. In prepubertal girls, hyperandrogenism may lead to cl*toromegaly, acne, and hirsutism. In adult males, the effects of excess testosterone depend on whether the source is from the adrenals or exogenous. Adrenal androgen elevations have few observable effects in males and do not cause an increase in muscle mass or hair growth. In adult females, increased adrenal androgens can lead to acne, hirsutism, menstrual irregularities, infertility, male-pattern baldness, or virilization.

Testosterone can be used to treat and manage various medical conditions. Medical conditions in which testosterone can be used include metastatic breast cancer, delayed puberty, hypogonadotropic hypogonadism (congenital or acquired), and primary hypogonadism.Toxic effects of testosterone and synthetic androgens includeover-masculinization, hirsutism, decreased menses,acne, and cl*toral enlargement.Rarely, synthetic androgens can cause hepatic adenoma, cholestatic jaundice, and prostatic hypertrophy. Synthetic androgens and testosterone are contraindicated in pregnancy.

Androgen antagonists come in different types. GnRH analogs, if given continuously, can act as medical castration drugs and are used in treating prostate cancer. Androgen receptor inhibitors, like flutamide and spironolactone, can be used for patients with hirsutism. Steroid synthesis inhibitors, like ketoconazole, can be used in Cushing disease. 5-alpha reductase inhibitors, like finasteride, can be used to treat benign prostatic hyperplasia.[5]

Clinical Significance

Pathology related to testosterone involves either over-production, under-production, receptor insensitivity, or impaired metabolism of testosterone. The following are a few of the more common and highly tested testosterone pathologies.

Over-production of androgens can occur in the following conditions: polycystic ovarian syndrome (PCOS), adrenal virilization/adrenaltumors, ovarian or testiculartumors, Cushing syndrome, and as a result of exogenous steroid use.To better understand some of these pathologies it is important to note the differences between testosterone anddehydroepiandrosterone (DHEA). DHEA is a relatively weak androgen produced by the adrenals and ovaries/testes. DHEA serves as a precursor for other hormones including testosterone and estrogen. The sulfated form of DHEA, DHEAS, is specific for the adrenal glands.In polycystic ovary syndrome (PCOS), abnormal gonadotropin-releasing hormone (GnRH) secretion leads to an increase in LH secretion. LH stimulates androgen production by ovarian theca cells which leads to hirsutism, male escutcheon, acne and androgenic alopecia in women affected with PCOS.[6]In adrenal and ovariantumors, there is usually rapidly progressing androgenic symptoms (hirsutism, virilization). If testosterone is elevated and DHEAS is normal, this is most likely from an ovariantumor. If DHEAS is elevated and testosterone is relatively normal, this is most likely an adrenaltumor.

Decreased production of testosterone can occur withaging, certain medications, chemotherapy, hypothalamus-pituitary axis disorders, primary hypogonadism, cryptorchidism and orchitis, and with genetic disorders such as Klinefelter and Kallmann syndrome. Klinefelter syndrome is the most common congenital abnormality that results in primary hypogonadism. In Klinefelter, there is dysgenesis of seminiferous tubules andloss of Sertoli cellswhich leads toa decrease in inhibinlevels and a resultantincrease in FSH. FSH upregulates aromatase leading to increased conversion of androgens to estrogens. In Klinefelter, there is also Leydig cell dysfunctionwhich leads todecreased testosteronelevels and an increase in LH due to loss of negative feedback. In Kallmann syndrome, failed migration ofGnRH-producing neuronsleads to lack of GnRH. No GnRH results ina decrease in LH, FSH, testosterone, and sperm count. Specific to Kallmann syndrome, in comparison to other causes of hypogonadotropic hypogonadism, is defects in the sensation of smell (hyposmia or anosmia).[7],[8],[9]

5-alpha reductase is an enzyme that converts testosterone to dihydrotestosterone. Male patients with 5-alpha reductase deficiencypresent with normal female or male genitalia or ambiguous genitalia at birth due to lack of dihydrotestosterone. These patients have a male internal urogenital tract (anti-Mullerian hormone is still present).At puberty, adolescents with this enzyme deficiency, who may have been raised as girls due to lack of secondary male characteristics, begintodevelop male secondary sex characteristics and have primary amenorrhea. These patients will have normal testosterone and LH, low DHT, and an increased testosterone-to-DHT ratio.In contrast to 5-alpha reductase deficiency, androgen insensitivity is a condition in whichpatients lack functional androgen receptors resulting in under-virilization. These patients, like those with5-alpha reductase deficiency, have a 46 XY karyotype. In contrast, however, these patients have normal female external genitalia and usually undescended testes. In adolescence, they experience primary amenorrhea and breast development but have nopubicor axillary hair and lack the deepening voice changes that occur with puberty. They will have a blind vagin*l pouch and abnormal internal reproductive organs (fallopian tubes, uterus, andthe upperportion of the vagin*) due to the production of the Mullerian inhibiting factor. These patients will have high levels of testosterone and LH.[10]

Review Questions

References

1.: Basaria S. Reproductive aging in men. Endocrinol Metab Clin North Am. 2013 Jun;42(2):255-70. [PubMed: 23702400]
2.: Kalfa N, Gaspari L, Ollivier M, Philibert P, Bergougnoux A, Paris F, Sultan C. Molecular genetics of hypospadias and cryptorchidism recent developments. Clin Genet. 2019 Jan;95(1):122-131. [PubMed: 30084162]
3.: Plant TM, Marshall GR. The functional significance of FSH in spermatogenesis and the control of its secretion in male primates. Endocr Rev. 2001 Dec;22(6):764-86. [PubMed: 11739331]
4.: Clark BJ, Prough RA, Klinge CM. Mechanisms of Action of Dehydroepiandrosterone. Vitam Horm. 2018;108:29-73. [PubMed: 30029731]
5.: Baillargeon J, Kuo YF, Westra JR, Urban RJ, Goodwin JS. Testosterone Prescribing in the United States, 2002-2016. JAMA. 2018 Jul 10;320(2):200-202. [PMC free article: PMC6396809] [PubMed: 29998328]
6.: Walters KA, Bertoldo MJ, Handelsman DJ. Evidence from animal models on the pathogenesis of PCOS. Best Pract Res Clin Endocrinol Metab. 2018 Jun;32(3):271-281. [PubMed: 29779581]
7.: Spaziani M, Mileno B, Rossi F, Granato S, Tahani N, Anzuini A, Lenzi A, Radicioni AF. Endocrine and metabolic evaluation of classic Klinefelter syndrome and high-grade aneuploidies of sexual chromosomes with male phenotype: are they different clinical conditions? Eur J Endocrinol. 2018 Apr;178(4):343-352. [PubMed: 29371337]
8.: Bozzola M, Bozzola E, Montalbano C, Stamati FA, Ferrara P, Villani A. Delayed puberty versus hypogonadism: a challenge for the pediatrician. Ann Pediatr Endocrinol Metab. 2018 Jun;23(2):57-61. [PMC free article: PMC6057016] [PubMed: 29969875]
9.: Hauser LJ, Jensen EL, Mirsky DM, Chan KH. Pediatric anosmia: A case series. Int J Pediatr Otorhinolaryngol. 2018 Jul;110:135-139. [PubMed: 29859575]
10.: Zhang JR, Zhang PY, Sun LG. [Mild androgen insensitivity syndrome: a case report]. Zhonghua Nei Ke Za Zhi. 2018 Aug 01;57(8):600-602. [PubMed: 30060335]
11.: Burdea L, Mendez MD. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Jul 31, 2023. 21-Hydroxylase Deficiency. [PMC free article: PMC493164] [PubMed: 29630216]

: Disclosure: George Nassar declares no relevant financial relationships with ineligible companies.
: Disclosure: Stephen Leslie declares no relevant financial relationships with ineligible companies.