Restoration Effects of Exogenous Luteinizing Hormone on the Testicular Steroidogenesis and Leydig Cell Ultrastructure*

Wing, Tung-Yang; Ewing, Larry L.; Zegeye, Zegeye; Zirkin, Barry R.

doi:10.1210/endo-117-5-1779

Cited by 32 publications

(18 citation statements)

References 23 publications

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“…As also reported previously (15,23), the response of 3␤-HSD activity to exogenously administered testosterone was less than that of the other steroidogenic enzyme activities. Two months after the implants were removed from the 11-or 21-month-old rats, the activities of each of the previously suppressed enzymes were at the high levels of 13-month-old control rats, significantly higher than those of the 23-month-old controls.…”

Section: Resultssupporting

confidence: 85%

Long-term suppression of Leydig cell steroidogenesis prevents Leydig cell aging

Chen

Zirkin

1999

Proc. Natl. Acad. Sci. U.S.A.

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Male aging is accompanied by reduced testosterone production by the Leydig cells, the testosterone-producing cells of the testis. The mechanism by which this occurs is unknown. Based on the observations that reactive oxygen is capable of damaging components of the steroidogenic pathway and that reactive oxygen is produced during steroidogenesis itself, we hypothesized that long-term suppression of steroidogenesis might inhibit or prevent age-related deficits in Leydig cell testosterone production. To test this, we administered contraceptive doses of testosterone to groups of young (3 months old) and middle-aged (13 months old) Brown Norway rats via Silastic implants to suppress endogenous Leydig cell testosterone production. After 8 months, the implants were removed, which rapidly (days) restores the ability of the previously suppressed Leydig cells to produce testosterone. Two months after removing the implants, when the rats of the two groups were 13 and 23 months of age, respectively, the Leydig cells in both cases were found to produce testosterone at the high levels of young Leydig cells, whereas significantly lower levels were produced by the 23-month-old controls. Thus, by placing the Leydig cells in a state of steroidogenic ''hibernation,'' the reductions in Leydig cell testosterone production that invariably accompany aging did not occur. If hormonal contraception in the human functions the same way, the adverse consequences of reduced testosterone in later life (osteoporosis, reduced muscle mass, reduced libido, mood swings, etc.) might be delayed or prevented.

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Section: Resultssupporting

confidence: 85%

Long-term suppression of Leydig cell steroidogenesis prevents Leydig cell aging

Chen

Zirkin

1999

Proc. Natl. Acad. Sci. U.S.A.

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“…The PLCs proliferate and also exhibit certain aspects of differentiated function (60). LH receptors first appear as the PLCs differentiate (61), and the development of the steroidogenic capacity of PLCs requires stimulation by LH (62).…”

Section: Discussionmentioning

confidence: 99%

“…GATA-1 transactivates the inhibin/activin ␣ gene in Sertoli and Leydig tumor cell lines (56,61), and this is achieved through the interaction with two GATA motifs in the promoter region (56). The mutation of either or both of the GATA motifs markedly reduced the basal promoter activity of the ␣-subunit gene in testicular cells, but this did not influence the stimulatory effects of cAMP on the transcription of the ␣-subunit gene (56).…”

Section: Discussionmentioning

confidence: 99%

ARR19 (Androgen Receptor Corepressor of 19 kDa), an Antisteroidogenic Factor, Is Regulated by GATA-1 in Testicular Leydig Cells

Qamar

Park

Gong

et al. 2009

Journal of Biological Chemistry

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ARR19 (androgen receptor corepressor of 19 kDa), which encodes for a leucine-rich protein, is expressed abundantly in the testis. Further analyses revealed that ARR19 was expressed in Leydig cells, and its expression was differentially regulated during Leydig cell development. Adenovirus-mediated overexpression of ARR19 in Leydig cells inhibited testicular steroidogenesis, down-regulating the expression of steroidogenic enzymes, which suggests that ARR19 is an antisteroidogenic factor. Interestingly, cAMP/luteinizing hormone attenuated ARR19 expression in a fashion similar to that of GATA-1, which was previously reported to be down-regulated by cAMP. Sequence analysis of the Arr19 promoter revealed the presence of two putative GATA-1 binding motifs. Further analyses with 5 deletion and point mutants of putative GATA-1 binding motifs showed that these GATA-1 binding sites were critical for high promoter activity. CREB-binding protein coactivated GATA-1 and markedly increased the activity of the Arr19 promoter. Both GATA-1 and CREB-binding proteins occupied the GATA-1 motifs within the Arr19 promoter, which was repressed by cAMP treatment. Altogether, these findings demonstrate that ARR19 is the target gene of GATA-1 and suggest that ARR19 gene expression in testicular Leydig cells is regulated by luteinizing hormone/cAMP signaling via the control of GATA-1 expression, resulting in the control of testicular steroidogenesis.

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“…An important function of Leydig cells is the production of testosterone, a critical hormone for male reproductive function, upon the stimulation of LH (33,39). LH binding onto its receptor, which is located on the plasma membrane of Leydig cells, signals testosterone production through activation of the cAMP pathway (13,19).…”

Section: Nhe8mentioning

confidence: 99%

Disruption of NHE8 expression impairs Leydig cell function in the testes

Chen

et al. 2015

American Journal of Physiology-Cell Physiology

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Multiple sodium/hydrogen exchanger (NHE) isoforms are expressed in the testes, and they play various roles in cell volume regulation, intracellular pH regulation, and fluid absorption. NHE8, the most recently characterized NHE family member, is detected in the Leydig cells in humans and mice in great abundance by immunohistochemistry in the current study. Male mice lacking NHE8 expression were infertile. Despite having intact male reproductive organs, male NHE8 Ϫ/Ϫ mice have smaller testes and lacked spermatozoon in the seminiferous tubules and the epididymis. At the age of 39 wk, few spermogonia were seen in the testis in NHE8 Ϫ/Ϫ mice. Although male NHE8 Ϫ/Ϫ mice have normal serum levels of luteinizing hormone and follicle-stimulating hormone, serum testosterone level was significantly reduced. These mice have decreased expression of luteinizing hormone receptor in the testes. In NHE8 small-interfering RNA-transfected mouse Leydig cells (MLTC-1), silencing of NHE8 decreased the expression of luteinizing hormone receptor by ϳ70%. Moreover, loss of NHE8 function in Leydig cells resulted in disorganized luteinizing hormone receptor membrane distribution. Therefore, male infertility in NHE8 Ϫ/Ϫ mice is at least partially due to the disruption of luteinizing hormone receptor distribution and consequent low testosterone production, which leads to Sertoli cell dysfunction. Our work identified a novel role of NHE8 in male fertility through its effect on modifying luteinizing hormone receptor function.

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Restoration Effects of Exogenous Luteinizing Hormone on the Testicular Steroidogenesis and Leydig Cell Ultrastructure*

Cited by 32 publications

References 23 publications

Long-term suppression of Leydig cell steroidogenesis prevents Leydig cell aging

Long-term suppression of Leydig cell steroidogenesis prevents Leydig cell aging

ARR19 (Androgen Receptor Corepressor of 19 kDa), an Antisteroidogenic Factor, Is Regulated by GATA-1 in Testicular Leydig Cells

Disruption of NHE8 expression impairs Leydig cell function in the testes

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