Testicular Androgens

The term androgen is derived from the Greek word andr— meaning ‘man '. Androgens are the natural or synthetic ste­roid hormones that regulate the development and functions of testes, expression of male secondary sexual characteristics, masculinization, libido, and spermatogenesis.

19.3.1 The Site of Androgen Production

In the male, the testis is the principal site of androgen pro­duction and constitutes about 95% of the total androgen secreted in the body. Ovaries are also able to produce a minimal amount of androgens. The Leydig cell of the inter­stitial space of the seminiferous tubule of testes is the major site of testosterone production. The predominant extragonadal source of androgens is the zona reticularis of adrenal cortex. But, the extragonadal androgens are less potent and contribute only 5% of total androgen production in mammals. The androgen production starts during foetal life and supports the differentiation of male sex organs. The peak androgen production under the influence of LH around puberty supports spermatogenesis.

19.3.2 Chemistry of Androgens

Androgens belong to the group of steroid hormones containing 19 carbon atoms; hence, they are called C-19 steroids. Testosterone (C₁₉H₂₈O₂) has 17β-hydroxy and

3- oxo groups and unsaturation at C-4-C-5 (Fig. 19.21). Dihy­drotestosterone (DHT, 5α-DHT) (C₁₉H₃₀O₂) is a metabolite of testosterone formed by the action of the enzyme 5- α-reductase. Androstenedione (C₁₉H₂₆O₂) is the direct pre­cursor of testosterone. The structure of testosterone is similar in all mammals, reptiles, birds, and fish.

19.3.3 BiosynthesisofAndrogens (Steroidogenesis in Testis)

The synthesis of androgens and other associated intermediates (progesterone, oestrogens, cortisol) has occurred in the testes through a series of enzymatic reactions called steroidogenesis (Fig.

19.3.3.1 Biosynthesis of Oestrogen in Testes

The testosterone may be converted to oestradiol (C-18 ste­roid) by the enzyme aromatase (Fig. 19.22). The aromatase can convert the androstenedione into estrone (another C-18 steroid). The oestradiol can be transformed into estrone by 17β-HSD. The enzyme aromatase is highly expressed in the Sertoli cells, adipose tissue, bone, and the brain.

19.3.3.2 BiosynthesisofProgesteroneand Cortisol in Testes

The enzyme 3β-HSD converts pregnenolone into progester­one (C-21 steroid). The progesterone can be further metabolized into corticosterone (C-21) with the help of CYP21 and CYP11 (Fig.

19.3.4 TransportofAndrogens

The majority of the androgens are bound with the plasma proteins, and only a small fraction is available in free form to act on seminal vesicles, bone, muscle, and prostate gland. Globulin has a higher affinity for testosterone compared to albumin. The predominant plasma proteins responsible for androgen transport are sex hormone-binding globulin (SHBG) (also known as Testosterone Estradiol Binding Globulin, TeBG or steroid-binding protein, SBP) and andro­gen binding protein (ABP). SHBG is a β-globulin mainly produced from hepatocytes and contains single androgen

Fig. 19.21 Steroid hormones androgens and their precursor (cholesterol). [a: Depicted the chemical structures of the precursor of testosterone, the C-19 and b: depicted the chemical structures of two major forms of androgen, the DHEA (dehydroepiandrosterone) and AED (androstene)]

binding site per molecule. ABP is mainly produced from Sertoli cells in the testes. Albumin can also bind with androgens but dissociates quickly due to less affinity. Dehy­droepiandrosterone and androstenedione remain primarily in an albumin-bound form in the human serum in contrast to testosterone and dihydrotestosterone bound principally with SHBG. The other proteins capable of binding with androgens are prostate binding protein (PBP), uteroglobin, and a1 acid glycoprotein. The SHBG also binds with oestrogens, and other steroid hormones, like progesterone and cortisol.

The distribution of androgens in free and bound forms in normal human serum is presented in Table 19.6. The testos­terone dissociates from its carrier proteins in the capillaries, and the endothelial glycocalyx causes structural modifications of the androgen binding sites and reduces its affinity towards androgens.

Table 19.6 Distribution of androgens in free and bound form in normal serum of human

(Ref: Dunn et al. 1981; Mendel 1989)

Fig. 19.22 Steroidogenesis of the testes. [Reactions under dotted lines occurred in foetal Leydig cells (FLC), whereas the entire reactions took place place in adult Leydig cells (ALC). Major enzymes involved in the process are cytochrome P450 oxidase (s) (P450scc, CYP11A1, CYP11, CYP17, CYP21), hydroxysteroid dehydrogenase (HSD, 3β-HSD, 17β-HSD), aromatase and 5α-reductase]

19.3.5 Plasma Levels of Androgens

The concentration of androgens in the plasma is dynamic and influenced by species (Table 19.7), general and testicular health, circadian rhythms, age, and environment. The diurnal variation of testosterone concentration with morning peak has also been found. In older age, the baseline level is decreased due to the reduction of ALC. Increased androgens synthesis is seen in seminiferous tubules hypertrophy due to increased gonadal temperature.

19.3.6 Mechanism of Action of Androgens

Androgens enter the target cells either through direct diffu­sion or receptor-mediated endocytosis. The receptor- mediated endocytosis is facilitated by LDL receptor, steroid carrier, or steroid channels. In LDL receptor-mediated endo- cytosis, the lipoprotein bound androgens bind with LDL receptors at the plasma membrane and are taken up. The LDL is degraded in the lysosomes, and androgens enter different metabolic pathways. The hormone and its carrier proteins internalize endocytosis of androgens into the target tissues through steroid carrier or steroid channels, and the carrier is degraded intracellularly. Recently a low-density lipoprotein named megalin has been involved in the receptor-mediated endocytosis of androgen-SHBG complexes across the plasma membrane. Androgens act through intracellular nuclear receptors. The receptor has sev­eral domains, namely a ligand-binding domain (binds with hormone), a constitutionally activating function domain (leads to the activation of the receptors), a nuclear localiza­tion signal domain (helps in translocation of the hormone- receptor complex into the nucleus), and a highly conserved

Table 19.7 Normal circulatory level of androgens in adult male animals

DHEA dehydroepiandrosterone; AE androstenedione

DNA-binding domain (binds with genomic DNA and induce transcription).

19.3.7 Biological Roles of Androgens

Androgen receptors are present in various tissues, such as testes, epididymis, seminal vesicles, prostate, muscles, kid­ney, heart, spleen, salivary glands, pituitary, and hypothala­mus, exerting a variety of functions (Fig.

19.3.7.1 Role in Reproduction

Spermatogenesis Testosterone is the predominant androgen that regulates spermatogenesis. After secreted from Leydig cells, testosterone diffuses into the seminiferous tubule and acts as a paracrine factor to promote spermatogenesis. Tes­tosterone regulates four critical spermatogenesis processes, viz. maintenance of blood testes barriers, meiosis, spermatid adhesion with Sertoli cells, and sperm release.

Testicular Descent Transinguinal migration of testes is mediated by the androgens. Androgens, particularly

Fig. 19.23 Major site of production, functions, and metabolism of testosterone. [1, 2, and 3 are the major functional ways and 4 is the metabolism and elimination route]

Table 19.8 Function of testosterone

testosterone, cause the reduction of the gubernaculum by altering its viscoelastic properties and helps in testicular descent.

Growth of Male Genitalia Both testosterone and DHT favour the growth of male genitalia. The masculiniza­tion of the Wolffian duct is under the influence of testoster­one, and DHT controls the differentiation of external genitalia. The growth of the penis is directly correlated with testosterone concentration after puberty.

Growth of Accessory Sex Glands The main androgen that acts over epididymis, vas deferens, and seminal vesicles is DHT, produced from testosterone by 5α-reductase. DHT acts over the epididymis, seminal and prostate to control these glands’ growth, development, maturation, and secre­tion. The growth of the prostate gland is also mediated via oestrogen produced after the aromatization of testosterone.

Development of Secondary Sexual Characteristics Testosterone plays a vital role in sexual maturity. The androgens promote masculinization through their anabolic effects on smooth and striated muscles. Tes­tosterone causes glycogen synthesis in the striated muscles and hypertrophy of the fibres. Androgens stimulate bone mineralization, linear growth, prevent osteoporosis and increase bone density. The DHT acts on the skin to increase its thickness and texture, the quantity of melanin, sweat glands, and sebaceous glands. It also promotes sebum pro­duction. In humans, the development of pubic hairs and beards is under androgens’ influence. The change in the voice around puberty in humans is mediated by testosterone, and it causes the growth of the larynx and the vocal cords.

19.3.7.2 Role in Brain Development

Androgens play a significant role in the sex-specific brain development of males during intrauterine life. Testosterone and DHT promote the cognition skill of males during adoles­cence by stimulating the cortico-limbic system.

19.3.7.3 Role in Sexual Behaviour

Androgens regulate a variety of sexual dimorphic behavioural patterns. Androgens are responsible for the expression of aggressive behaviour in male animals, and the copulatory patterns of the males are under androgenic con­trol. The specialized sexual behaviours (musth in elephants, male dominance in mice) are also regulated by androgens.

19.3.7.4 Role in the Haematopoietic System

Androgens stimulate erythropoiesis by increasing erythropoi­etin production. The action of androgens on haematopoietic stem cells promotes haemoglobin synthesis. The androgens are associated with blood coagulation and fibrinolytic mech­anism, and androgen deficiency leads to decreased fibrinolysis.

19.3.7.5 Blood Pressure Regulation

Testosterone causes vasoconstriction by upregulating throm­boxane A2, angiotensin II, endothelin-1, and norepinephrine. Testosterone also helps in vascular remodelling and affects atherosclerosis, and it promotes sodium and water retention in the body.

19.3.7.6 Role of Androgens in Birds

In birds, testosterone promotes the development of comb, wattle, and plumage. It regulates bird’s vocalization (call and song) around mating season. Testosterone increases the bioavailability of carotenoids in birds. The carotenoids are responsible for the red, yellow, and orange colours of the skin and feathers. Commercially the rooster is castrated (caponization) to eliminate the effect of testosterone. The caponised birds accumulate fat and can produce tenderer, juicier and flavoured meat.

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Measurement of glucuronidated or sulphated products of testosterone in urine and faeces (faecal testosterone, fT) using high-performance liquid chromatography (HPLC), radioimmunoassay (RIA), and enzyme-immunoassay (EIA) is considered as one of the best non-invasive processes for assessment of male sex steroid in the verte­brate mammals. The rate of metabolism is significantly variable with species, gut passage time, and circadian rhythm (more in the dark phase). Conservation Physiol­ogy extensively uses this procedure to study and monitor the reproduction, welfare, and ecological balance of wild lives and laboratory animals.

19.3.7 Metabolism and Fate of Testosterone

The half-life of testosterone is only 10-100 min. Both testos­terone and DHT are metabolized mainly in the liver. Most testosterone is metabolized either by glucuronidated or sulphated conjugating with glucuronide by glucuronosyltransferases and joining with sulphate by sulfotransferases. The 17-ketosteroids androsterone and etiocholanolone are the two other forms of metabolism of testosterone with the involvement of 5α- and 5β-reductases, 3α-hydroxysteroid dehydrogenase, and 17β-HSD enzymes. The 17-ketosteroids androsterone and etiocholanolone are further than glucuronidated or sulphated. The testosterone conjugated glucuronidated or sulphated products are finally released from the liver in the bile and excreted through urine or gut. Only a small fraction is excreted unchanged form of testosterone in the urine. Hence, glucuronidated or sulphated products of testosterone in urine and faeces are used to measure testosterone concentration in wild lives.

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