Which testicular cells produce testosterone

The testes lie outside of the body and are maintained at a temperature about two degrees Centigrade lower than the body's core temperature. This is because sperm production and quality is optimal at this lower temperature. The testes have two functions — to produce sperm and to produce hormones, particularly testosterone.

Sperm are produced in the seminiferous tubules of the testes. There are about of these tubes in each testis, each is the length of an arm and the width of a few hairs; the whole collection of tubules is longer than a football pitch!

Once the sperm are produced in the seminiferous tubules they pass into the epididymis, a long coiled tube in which sperm mature as they are conveyed along it. They are then ready to be released at ejaculation via the vas deferens. The main hormone secreted by the testes is testosterone, an androgenic hormone. Testosterone is secreted by cells that lie between the seminiferous tubules, known as the Leydig cells. Testosterone is important in the first stages of developing the male reproductive organs in a foetus.

It also causes the development of male characteristics such as growth of facial hair, deepening of the voice and the growth spurt that takes place during puberty. From puberty onwards, testosterone provides the main stimulus for sperm production.

Many things can wrong with the testes; they can be grouped into physical injury and diseases or conditions that affect the function of the testes:. Other factors that can affect the function of the testes are radiation and chemotherapy used in the treatment of cancer , certain drugs, and disorders of the pituitary gland that stop signals from the hormone endocrine system that trigger production of testosterone from the testes.

About Contact Events News. Search Search. You and Your Hormones. Detailed studies [ 49 , 62 , 63 ] demonstrated that STAR acts at the mitochondria to trigger cholesterol movement across the membranes. The rapid induction of STAR formation by LH and its targeting and processing at the outer mitochondrial membrane increase testosterone formation [ 49 , 64 ].

The importance of STAR was made evident by the observation that mutations of the STAR gene resulted in a severe deficiency in mineralocorticoids and, consistent with this, that there were severe defects in adrenal steroids seen in STAR knockout mice, mimicking features of lipoid congenital adrenal hyperplasia in patients [ 65 ]. Gonadal hormones in the knockout mice did not differ significantly from levels in wild-type littermates, suggesting that although adrenal steroid production was dramatically reduced in the STAR knockout mice, the mice retained their capacity for androgen biosynthesis [ 66 ].

However, Star -deficient mice were reported to exhibit female external genitalia, suggesting possible effects of STAR knockout on androgen production by the fetal testis [ 67 ]. Once targeted to the outer mitochondrial membrane, cholesterol must be translocated to the inner mitochondrial membrane, and there converted to pregnenolone by CYP11A1. Numerous studies have suggested that cholesterol translocation is mediated by the formation of a mitochondrial scaffold, the transduceosome, created by protein—protein interactions of cytosolic and outer mitochondrial membrane proteins [ 64 ].

This complex contains proteins that mediate the import of cholesterol from cytosolic sources into mitochondria, including the hormone-induced STAR, translocator protein TSPO , and voltage dependent anion channel 1 VDAC1.

Aghazadeh et al. The proteins were found to be hormonally induced and to function at the initiation of steroidogenesis by delaying maximal steroidogenesis in MA mouse tumor Leydig cells. TSPO 18 kDa is an outer mitochondrial membrane protein that is abundant in steroid synthesizing cells and has high affinity for cholesterol [ 74 ]. Data from a number of independent laboratories, published over the course of many years, have indicated an important role of TSPO in steroidogenesis.

In particular, knockdown of Tspo expression using antisense oligonucleotides reduced the ability of cultured cells to form steroids. Additionally, several TSPO-specific ligands were shown to stimulate cholesterol import into mitochondria and thus steroid formation by MA and primary Leydig cells in vitro, and to result in elevated testosterone production when administered in vivo [ 78—82 ].

Consistent with this, blocking the CRAC domain of TSPO was shown to block hormone-induced steroid formation in cells both in vitro and in vivo [ 83—87 ]. These studies strongly support the contention that TSPO plays an important role in cholesterol import into mitochondria and thus in steroidogenesis [ 88—90 ]. It should be noted, however, that the specific mechanism by which it does so was not determined.

Additionally, it is technically challenging to be certain as to whether the effects seen on steroidogenesis in such studies were affected by TSPO knockdown alone or reduced cell viability [ 80 ]. Protein—protein interactions driving cholesterol import into mitochondria.

Cholesterol import into mitochondria is the result of series of protein—protein interactions. The presence of CYP11A1, adrenodoxin reductase and adenodoxin as well as the extremely high levels of expression of the cholesterol binding protein TSPO are characteristics of steroidogenic cell mitochondria. Although studies conducted over the course of many years and by many labs concluded that TSPO plays a significant role in steroid biosynthesis, this conclusion recently has been called into question [ 91—94 ].

This was in contrast to previous reports showing significant reduction of steroid production in the same cell line after TSPO knockdown using antisense oligodeoxynucleotides [ 95 ] or antisense knockdown [ 80 ]. As yet, the explanation for the difference in results is uncertain.

It should be pointed out, however, that whereas TSPO drug ligands at nanomolar and low micromolar concentrations have specificity for TSPO, at high micromolar concentrations they do not [ 88 ]. Additionally, whereas mice with Leydig cell-targeted Tspo conditional knockout were reported to show lack of effect on androgen production [ 92 ], the Papadopoulos lab generated steroidogenic cell-targeted Tspo knockout mice that showed a lack of ability to produce steroid corticosterone in response to adrenocorticotropic hormone ACTH [ 97 ].

Notably, increased accumulation of lipid droplets was seen in Leydig cells of the knockouts, suggesting an effect on lipid homeostasis in the testis.

In agreement with these findings, Barron and colleagues generated TSPO KO mice that showed reduced total steroidogenic output and age-dependent androgen deficiency [ 98 ]. Recently, using zinc finger nuclease technology to perform Tspo -targeted genome editing, a null mutant rat line was generated lacking TSPO expression as was a line expressing a truncated TSPO protein which lacks the fifth transmembrane domain, containing the cholesterol recognition amino acid consensus motif [ 99 ]. The Tspo mutations in both rat models resulted in accumulation of esterified cholesterol in all steroidogenic cells examined, and with loss of corticosteroid formation in response to ACTH.

Basal testosterone production was also reduced in the Tspo homozygous mutant rats [ 99 ]. It should be noted that even if the studies reporting no effect of Tspo knockout on gonadal steroid formation were found to be correct, such studies would not disprove the conclusion of many investigations that TSPO plays a critical role in steroidogenesis.

Rather, it might be the case that the role of TSPO is not indispensable. For example, potential compensatory mechanisms may become involved in steroid formation when TSPO is knocked out in cells or in animals, and particularly so in the latter case when the knockouts are in vivo. It also should be noted that the role of TSPO in different steroid-producing organs might differ. For example, the effect of knocking out STAR in the adrenal and testis has been reported to differ significantly, with an earlier and far more dramatic phenotype seen in the adrenal than the testis [ 66 , ].

Effects seen in MA cells also seem likely to differ from both the adrenal and testis. Such differences might result from differences in the amounts of the transduceosome components and cell-specific protein—protein interactions.

Steroid hormone synthesis must be a precisely regulated process because insufficient or excess production is detrimental. In addition to the well-established regulation of steroid formation by PKA, several regulators signaling molecules, kinases, transcription factors of Leydig cell differentiation and function were identified in the last two decades.

Moreover, a cell-autonomous AMPK-dependent mechanism actively represses steroidogenesis, thus preventing excessive production of steroid hormones [ ]. Several nuclear receptors have also been shown to have either direct or indirect roles in Leydig cell function e. NR5A1 [ ]. In addition to phosphorylation and protein kinases, protein phosphatases were also shown to be critical in the regulation of steroid hormone production by Leydig cells [ ].

Reduced serum levels of testosterone hypogonadism can occur in both young and aging men. In some men, reduced serum testosterone results from reduced serum LH hypogonadotropic hypogonadism [ ]. In most, however, serum LH either does not change or increases, indicative of primary testicular deficiency primary hypogonadism [ — ].

Although changes in GnRH gene expression and LH pulse amplitude often occur with aging, LH administration typically results in lesser stimulation of testosterone in aged than young men [ ], indicating reduced LH responsiveness of old Leydig cells. Whether in aging or young men, reduced serum testosterone is associated with a number of metabolic and quality-of-life changes, including decreased lean body mass, bone mineral density, muscle mass, libido and sexual function, increased adiposity, osteoporosis and cardiovascular disorders, and altered mood [ , ].

In hypogonadal men in whom there are deficiencies in central stimulation hypogonadotropic hypogonadism, Kallman's syndrome , serum testosterone can be elevated directly by administering LH or hCG, or indirectly with clomiphene or aromatase inhibitors.

However, hypogonadism in most patients is not the result of central deficiencies, but rather results from the decreased responsiveness of the Leydig cells to LH. In such men, attempts to increase Leydig cell testosterone production and thus serum testosterone levels by LH administration typically are not effective.

Administering exogenous testosterone, known as testosterone replacement therapy, reverses many of the symptoms of low testosterone. The primary objective of TRT is to raise serum testosterone levels into the eugonadal range.

The testosterone preparations in use are injections; scrotal and nonscrotal transdermal patches; and oral, buccal, and gel preparations [ — ]. With injections, serum testosterone levels initially are supraphysiologic and then reduced, requiring testosterone levels to be monitored and sometimes adjusted between injections. Testosterone administered by gels and other transdermal methods are easier to use and produce more constant testosterone concentrations.

However, recent studies suggest that there may be increased risk of cardiovascular disease in older men after TRT [ — ], resulting in the FDA cautioning September that men who take exogenous testosterone may face increased risk of stroke and heart attack. There are also reports suggesting that exogenous testosterone treatment might increase the risk of prostate cancer [ ]. Although there is agreement that testosterone replacement in young hypogonadal men is relatively safe and has beneficial effects, exogenous testosterone typically will suppress LH, resulting in reduced Leydig cell testosterone production and therefore in the suppression of spermatogenesis.

The recovery of spermatogenesis after cessation of treatment often requires 6—15 months or more [ ]. Thus, exogenous testosterone administration is inappropriate for men who wish to father children [ — ]. Although there are methods by which to increase serum testosterone without TRT, including hCG or aromatase inhibitors for men with secondary hypogonadism, these approaches typically are ineffective in men with primary hypogonadism [ ].

In rodents as in humans, serum testosterone levels decline progressively with aging [ , ]. In both, these decreases result from reduced testosterone production by aging Leydig cells, not from a reduction in cell numbers.

As in men, aging in Brown Norway rats is characterized by reduced serum testosterone and unchanged or increased LH levels, and by the reduced ability of the Leydig cells to produce testosterone in response to LH [ , ]. Although steroidogenic enzyme levels are reduced in aged cells, high levels of testosterone are produced if enough cholesterol is available to the inner mitochondrial membrane steroidogenic enzyme CYP11A1 [ ]. Knowledge of the steps and mechanisms in testosterone formation has made it possible to consider the use of pharmacological means to increase serum and intratesticular testosterone by stimulating the Leydig cells themselves.

Activation of TSPO by specific drug ligands was found to result in increased testosterone production by aged Leydig cells in vitro, and treating old rats with TSPO drug ligands resulted in elevated serum testosterone levels [ 82 ]. Whether or not such increase would be specific to Leydig cells remains uncertain. Thus, ligand activated TSPO might reestablish normal TSPO activity and be responsible for the recovery of testosterone formation perhaps in a testis-specific manner.

Similarly, TSPO drug ligands have been shown to induce neurosteroid formation in the human brain, but only in cases of neurological and psychiatric disease symptoms conditions where TSPO levels were found to be reduced [ , ]. If the negative regulation of the proteins could be removed, there would be increased testosterone production by the Leydig cells and therefore increased testosterone levels in the serum and intratesticular fluid.

Furthermore, peptides containing VDAC1 S, when administered directly to the testes of adult male Sprague-Dawley rats, induced increased intratesticular and plasma testosterone levels in a manner independent of LH in vivo [ 73 ]. Such an approach, or targeting TSPO with specific drug ligands, hold promise for providing new means by which to increase serum testosterone levels without administering LH-suppressive testosterone. In addition to providing potential benefit to aging men, the design of new therapies that increase intratesticular bioactive androgen levels without affecting the hypothalamic—pituitary axis could be of importance for subfertile and infertile young men, including most men diagnosed with idiopathic infertility and present with reduced circulating testosterone levels, and men with orchitis and following trauma injury to genitalia, spinal cord injury , torsion, surgery, chemotherapy, irradiation, and in response to some medications acquired hypogonadism.

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