Testosterone
Sex Hormones

Author: Susanna Briccarello
Date: 09/12/2008

Description

Testosterone is a steroid hormone from the androgen group. It is the principal male sex hormone, but small amounts are produced also in females.

  • women produce less than 300 μg of testosterone in 24 hours, and about on-fourth of this is probably formed in the ovary directly. The physiologic significance of these small amount of androgens is not established, but they may be partly responsible for normal hair growth at puberty and may have other important metabolic effects.(1)
  • in male more than 95% is secreted by testis wich produces approximately 6-7 mg per day. (2)
    Testosterone in the male is sythesized in the testes by the Leydig cells and less than 5 per cent is produced by the adrenal.(1)

The production of steroid is not limitated to endocrine gland but very small amount, mainly pregnane derivative, can also be produced in brain cells (3)
Although the contribution of cells in the nervous system to circulating hormones is very small, local production of steroids can be physiologically very important (4)

TESTOSTERONE SYNTHESIS AND SECRETION

The biosynthetic pathway is similar in both endocrine glands and it is summarized schematically in figure 1. Testosterone is synthesized by an enzymatic sequence of steps from cholesterol
The cholesterol is predominantly formed by de novo synthesis from acetyl coenzyme A although preformed cholesterol either from intracellular cholesterol ester stores or extracellular supply from circulating low-density lipoproteins also contributes.

  1. The first reaction, the conversion of cholesterol to pregnegnolone, occurs within mitochondria and is catalyzed by the cytochrome P450 side-chain cleavage enzyme, P450scc.P450scc catalyzes two sequential hydroxylation of cholesterol side chain at C22 and C20, producing 22R-hydroxycholesterol and 20,22-dihydroxycholesterol intermediates. Subsequent cleavage of the bond between C20 and C22 by P450scc produces pregnenolone and releases isocaproaldehyde.
  2. Pregnegnolone diffuse out of mitochondria and can be converted to testosterone by two alternative routes referred to as the Δ4 pathway, bases on whether the steroid intermediates are 3-keto, Δ4 steroids (Δ4) or 3 hydroxy, Δ5 steroids (Δ5).
    • In the Δ4 pathway, which predominates in rodents, pregnenolone is metabolized to progesterone by 3β-hydroxysteroid dehydrogenase/ Δ5- Δ4 isomerase (3βHSD)
    • Progesterone is than hydroxylated at C17 to form 17α-hydroxyprogesterone, followed by cleavage of the bond between C17 and C20 to produce androstenedione. Both reactions are catalyzed by cytochrome CyP17
    • Finally the C17 keto group of androstenedione is reduced to a hydroxyl group to produce testosterone.This reaction is catalyzed by 17β-hydroxysteroid dehydrogenase (17βHSD).
    • In the Δ5 pathway, the initial reactions are catalyzed by P450c17; C17 hydroxylation of pregnenolone to form 17 α-hydroxypregnenolone, and cleavage of the bond between C17 and C20 of 17 α-hydroxypregnenolone to produce DHEA, a 3-hydroxy Δ5-steroid.
    • Oxidation of the 3β-hydroxy group and isomerization of the double bond between C5 and C6 of DHEA by 3βHSD forms androstendione that is subsequently bioconverted to testosterone by 17βHSD.
      (5)

Figure 1. Biosynthetic pathway for testosterone synthesis in human. Steroid structures and names are shown. The open arrows indicate the major route of steroidogenesis in human Leydig cells. The enzymes are shown with corresponding reactions (arrows). The box indicates the reactions catalyzed by 3βHSD and schematically separates the Δ5 from the Δ4 pathway

The mechanism of transport of testosterone and other steroids from site of production to blood and lymph is not completely understood.(Williams Textbook of endocrinology – 9th edition – Wilson, Foster, Kronenberg, Larsen – Saunders.) ??????????

REGULATION OF TESTOSTERONE SYNTHESIS

LH

The rate-limiting reaction in testosterone synthesis under most circumstances is the conversion of cholesterol to pregnenolon. LH regulates the rate of this reaction and thus controls the overall rate of testosterone synthesis.
Luteinizing hormone (LH) activates testosterone synthesis in Leyding cells through a G protein associated seven transmembrane repector with an uncommonly long extra-cellular domain.
As shown in Figure 2, LH binding initiates a signaling cascade by activating Gs, a small GTPase protein, that stimulates adenylate cyclase activity to increase levels of intracellular cAMP and activate cAMP-dependent protein kinase A (PKA). cAMP-dependent PKA activates two temporally distinct responses that stimulate testosterone synthesis. The acute response, which occurs within minutes of hormonal stimulation, is defined as the stimulated increase in cholesterol transport into the mitochondria. The chronic response, which requires several hours, involves transcriptional activation of genes encoding the steroidogenic enzymes of the testosterone biosynthetic pathway.
** Acute regulation
Cholesterol for steroidogenesis is acquired by receptor-mediated endocytosis of circulating low-density lipoprotein (LDL) or cholesterol ester uptake from circulating high-density lipoprotein (HDL) or is synthesized de novo from acetyl-CoA. In humans LDL appears to be the preferred cholesterol source for adrenal and gonadal steroidogenesis under physiological conditions. (5)
The transport of cholesterol into the mitochondria is now estabilished to be regulated by the steroidogenic acute regulatory (StAR) protein. StAR is nuclear-encoded mitochondrial protein. Stimulation of StAR synthesis in Leydig cells by LH acutely increases steroid production. StAR appears to function at the mitochondrial outer membrane, but the mechanism of action for cholesterol transport is not yet known. (7)
** Long Term Regulation
The mechanism by which LH stimulates testosterone synthesis also involves increased expression of the steroidogenic enzymes P450scc, P450c17, 3βHSD and 17βHSD. These enzymes are increased by transcriptional and posttranscriptional mechanisms, but the best characterized response to LH so far is the cAMP-dependent transcriptional activation of P450scc and P450c17. Perhaps the most striking observation from this research is the apparent lack of coordination for regulation of these two genes; both are responsive to cAMP, but distinct promoter elements and transcription factor are required for gene activation.
We include references for recent review article that provide more comprehensive information on specific aspects of adrenal function and regulation: Transcriptional regulation of adrenocortical steroidogenic gene expression - Sewer MB, Dammer EB, Jagarlapudi S.- Drug Metab Rev. 2007;39(2-3):371-88. (8)
# Other factors that influence testosterone synthesis
** Early studies with purified follicle-stimulating hormone (FSH) preparations suggested that FSH anhanced Leydig cell responsiveness to LH.
** Many studies have proposed that prolactin (PRL) affects testosterone production, but the function of PRL in male remains controversial. PRL receptors are found on Leydig cells, and PRL may increase LH-stimulated testosterone production by increasing LH binding.
** Growth hormone (GH) has been proposed to stimulate testosterone biosynthesis directly, or via testicular insulin-like growth factor-1 (IGF-1) and IGF-1 receptors on Leydig cells.
** There is a direct stimulatory effect of T3 on the production of testosterone and estradiol by Leydig cells, in part, by increasing Star expression.
** PACAP or vasoactive intestinal polypeptide (VIP), which, like LH, activate cAMP-dependent PKA and may stimulate fetal Leydig cells. On the other hand, anti-Mullerian hormone may function as a negative modulator of Leydig cells and acts through high-affinity receptors on Leydig cell membranes to negatively regulate LH action by inhibiting gonadotropin-induced cAMP generation and thereby decrease androgen production.
** CRH also increases IL-1 in Sertoli cells, and IL1 inhibits Leydig cell steroidogenesis in vitro. In this way, testicular CRH may play a role in the decline in testosterone production with stress and inflammation.
** Arginine vasopressine (AVP) is present in the testis, receptors for AVP are present in Leydig cells, and AVP inhibits testosterone synthesis in vitro, but the significance of these finding is unknown.
** The Leydig cell not only produces testosterone and estradiol but also is a target for the actions of these steroid hormones. Both androgen receptors and estrogen receptors are found in Leydig cells and may mediate autocrine genomic effects of these hormones. For example, testosterone suppresses P450c17 activity as well as the cAMP-activated transcription of P450c17, and estradiol decreases testosterone production by decreasing the LH receptor concentration and reducing the mRNA for P450c17. (5)

Figure 2. Schematic representation of the mechanisms by which LH regulates testosterone byosynthesis. LH activates the cAMP-PKA signaling pathway that, in turn, promotes (+) cholesterol mobilization and StAR synthesis and thereby cholesterol transport to acutely increase sterois secretion. Chronic stimulation is indicated (+) as transcriptional regulation of the steroidogenic cytochrome P450 enzymes P450Scc and P457c17 and the dehydrogenase enzymes 3βHSD and 17βHSD. Gs, stimulatory guanine-nucleotide triphosphate-binding protein; AC, adenylate cyclase; SER, smooth endoplasmic reticulum.

ethanol

FEBS Lett. 1984 Jul 9;172(2):177-82.
Inhibition of testosterone biosynthesis by ethanol: relation to the pregnenolone-to-testosterone pathway. 1984

Eriksson CJ, Widenius TV, Leinonen P, Härkönen M, Ylikahri RH.

The concentrations of metabolites in the pregnenolone in equilibrium testosterone pathway were determined in freeze-stopped testes in control rats and during ethanol intoxication (2 h after injection of 1.5 g ethanol/kg body wt). Ethanol lowered the mean testicular concentrations of testosterone (by 63-74%), androstenedione (49-81%), 17-hydroxyprogesterone (60-76%), progesterone (29-67%) and pregnenolone (12-25%). 4-Methylpyrazole had no effect on the ethanol-induced changes. The present results reveal no inhibition at the 17-hydroxyprogesterone----androstenedione----testosterone steps, but do not exclude inhibition before the step yielding pregnenolone and at the pregnenolone----progesterone----17-hydroxyprogesterone steps.

Mechanism of Action

The effects of testosterone occur by way of two main mechanisms:

  • directly
    • by activation of the androgen receptor (as T or DHT)
    • by non genomic effects
  • by conversion to estradiol

REFERENCE:

Comments
2008-12-10T14:11:21 - Gianpiero Pescarmona

Testosterone postmenopausale alto e rischi metabolici
Nelle donne in postmenopausa, livelli elevati di testosterone aumentano il rischio di resistenza all'insulina, sindrome metabolica e patologie coronariche. Sono i risultati di un trial pubblicato su Journal of Clinical Endocrinology and Metabolism. L'indagine ha riguardato 344 donne di età media pari a 74,4 anni in cui è emerso che l'incremento del testosterone totale (p = 0,003) e libero (p = 0,02) determina un aumento graduale della resistenza all'insulina e, conseguentemente, una graduale diminuzione della sensibilità all'insulina (p< 0,001 e p = 0,002, rispettivamente). Livelli elevati di testosterone totale e libero sono, inoltre, risultati associati a obesità addominale, elevato glucosio a digiuno e alle due componenti della sindrome metabolica maggiormente legate alla resistenza all'insulina. Le donne con il maggiore contenuto di testosterone totale hanno mostrato un rischio di sindrome metabolica e patologie cardiovascolari molto più elevato rispetto a quelle con livelli inferiori (or= 3,15 e 2,95, rispettivamente). Le concentrazioni di testosterone libero non sono, invece, correlate né a sindrome metabolica né malattie cardiovascolari. "Trattandosi di uno studio osservazionale, non possiamo ancora stabilire se il testosterone può considerarsi un marker o mediatore di patologie cardiovascolari in donne anziane" ha commentato Anne R. Cappola, principale autore dello studio. (L.A.)

J Clin Endocrinol Metab. 2009 Dec;94(12):4776-84. Epub 2009 Oct 21.

il link ai lavori va fatto direttamente dove sono citati
Enhancement of long-term testosterone secretion stereidogenic enzyme expression in human Leydig cells by co-culture with human Sertoli cell-enriched populations. 1998

"Obesity and Polycystic Ovary Syndrome: Adiposity and Steroid Metabolism":

Sex steroids pathways

5 alpha reductase Androsterone
5 beta reductase Etiocolanolone

ET/AN

  • high = low 5 alpha reductase (hypoandrogenism) and aromatase activity
  • low = high 5 alpha reductase (hyperandrogenism) and (probably) low aromatase activity

What Is DHT? What is its Role in Hair Loss?

DHT -Google Textbooks

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