Constitutive regulation of the Insl3 gene in rat Leydig cells

Sadeghian, Helen; Anand‐Ivell, Ravinder; Balvers, Marga; Relan, Vandana; Ivell, Richard

doi:10.1016/j.mce.2005.03.017

Cited by 76 publications

(102 citation statements)

References 35 publications

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“…In fact, with the establishment of a functional hypothalamic-pituitarygonadal (HPG) axis during puberty, boar Leydig cells appear to be most responsive to LH at puberty as characterized by a dramatic increase in cell number, cell volume, LH receptor number, and intracellular organelles of the Leydig cells (Peyrat et al 1981, Lunstra et al 1986, Franca et al 2000, and also as indicated by our findings that the testosterone levels increased progressively toward puberty with an irregular fluctuation at subsequent ages, whereas E 2 levels increased in a stepwise fashion with advancing age, consistent with previous reports (FlorCruz & Lapwood 1978, Allrich et al 1982, Schwarzenberger et al 1993, Estienne et al 2000. In addition, in other species, INSL3 has been reported to be constitutively expressed and secreted by the Leydig cells under the long-term effects of LH/hCG and is not acutely regulated by LH/hCG and other hormones influencing Leydig cell differentiation, such as insulin-like growth factor1 (IGH1) (Foresta et al 2004, Bay et al 2005, Sadeghian et al 2005. In line with the lack of an acute stimulatory effect of LH, we did not find any correlation between LH and INSL3 in boars, although there are conflicting findings showing a positive correlation between them in normal men (Foresta et al 2004, Ferlin et al 2006.…”

Section: Discussionsupporting

confidence: 89%

Dynamics of insulin-like factor 3 and its receptor expression in boar testes

Minagawa¹,

Sagata²,

Pitia³

et al. 2014

Journal of Endocrinology

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Relaxin-like factor (RLF), now mainly known as insulin-like factor 3 (INSL3), is essential for testis descent during fetal development; however, its function in the adult testis is still being elucidated. As a major step toward understanding the as-yet-unknown function of INSL3 in boars, this study aimed to develop a time-resolved fluoroimmunoassay for boar INSL3, characterize the dynamics of INSL3 expression during development, and demonstrate the expression of the INSL3 hormone-receptor system in the testis. All samples were collected from Duroc boars. The sensitivity of the assay system established was 8.2 pg/well (164 pg/ml), and no cross-reactivity with other hormones, such as porcine relaxin, was observed. Circulating INSL3 was shown to increase progressively during development. INSL3 secreted from the Leydig cells was released not only into the blood circulation but also into the interstitial and seminiferous compartments in sufficient concentrations. A testicular fractionation study revealed that its receptor RXFP2 transcripts were expressed mainly in testicular germ cells. In addition, INSL3 bound to the germ cell membranes in a hormone-specific and saturable manner. These results reveal that INSL3 secreted into the interstitial compartment from the Leydig cells is transported into the seminiferous compartments, where its receptor RXFP2 is expressed mainly in the germ cells to which INSL3 binds, suggesting that INSL3 functions as a paracrine factor on seminiferous germ cells.

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Section: Discussionsupporting

confidence: 89%

Dynamics of insulin-like factor 3 and its receptor expression in boar testes

Minagawa¹,

Sagata²,

Pitia³

et al. 2014

Journal of Endocrinology

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“…Indeed, the present findings firstly suggest the existence of subtle alterations at gonadal level also in diabetic patients with normal testosterone values, regardless of the presence of symptoms of androgen deficiency. The global impairment of Leydig cell function in T2DM is confirmed by the finding of reduced circulating levels of INSL3, a novel peptide hormone mainly derived from Leydig cells (15,16,25,26), which have been indicated as an absolute measure of either quality or number of the Leydig cells, independently from gonadotropin stimulation (16,17,(27)(28)(29)(30). The higher LH levels in diabetic patients than in controls, though in the normal range, might suggest that when few or poor-quality Leydig cells are present, more LH is required to achieve normal circulating testosterone levels.…”

Section: Discussionmentioning

confidence: 90%

Peripheral insulin-like factor 3 concentrations are reduced in men with type 2 diabetes mellitus: effect of glycemic control and visceral adiposity on Leydig cell function

Ermetici

Donadio

Iorio

et al. 2009

European Journal of Endocrinology

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Background and aim: Hypogonadism frequently occurs in men with type 2 diabetes mellitus (T2DM), while the role of glycemic control and visceral obesity is still unclear. This study aimed to assess the Leydig cell function, including the new sensitive marker insulin-like factor 3 (INSL3), in T2DM patients without overt hypogonadism and the influence of either glycemic control or visceral adiposity. Subjects and methods: Thirty T2DM patients (age 57.1G6.2 years, body mass index (BMI) 28.0G4.3) without overt hypogonadism and 30 age-and BMI-matched controls were studied. Anthropometric, glycometabolic parameters and testosterone, SHBG, LH, INSL3 levels, bioavailable and free testosterone (BT and cFT) were evaluated. The human chorionic gonadotrophin (hCG) test was also performed. Results: Patients had lower total testosterone (452.6G130.0 vs 512.6G117.3 ng/dl, PZ0.06), BT (189.7G36.4 vs 237.1G94.1 ng/dl, PZ0.002), cFT (8.1G1.6 vs 10.1G4.0 ng/dl, PZ0.002), and higher LH levels (3.5G1.6 vs 2.6G1.2 mU/ml, PZ0.01) versus controls. Serum INSL3 concentrations were also lower in patients (1.1G0.3 vs 1.5G0.7 ng/ml, PZ0.01). These hormonal parameters, including INSL3, did not differ between T2DM patients with poor or good glycemic control (HbA1cO9 or !7% respectively). In patients, waist circumferences (97.9G12.4 cm) negatively correlated with INSL3 (PZ0.03) and basal, as well as hCG-stimulated testosterone levels (PZ0.04 and 0.004 respectively). Basal or stimulated hormonal levels and INSL3 concentrations were not different between patients with (40%) or without erectile dysfunction. Conclusions: An early impairment of the overall Leydig cell function is present in men with T2DM, mainly related to visceral adiposity rather than to glycemic control.

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“…However, if one takes into account that Insl3 is considered to be specifically secreted by mature Leydig cells in the adult testis and constitutively expressed without any feedback regulation (Ref. 40; R. Ivell, personal communication), the reduced body weight of the hypothyroid rats might overestimate the plasma Insl3 value. Assuming that the blood volume relates to a fixed portion of the body weight, one can hypothesize thus that the Insl3 concentration as a proportion of blood volume is artificially elevated in the case of the hypothyroid animals.…”

Section: Resultsmentioning

confidence: 99%

Prenatal induced chronic dietary hypothyroidism delays but does not block adult-type Leydig cell development

Rijntjes

Swarts²,

Anand‐Ivell³

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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Rijntjes E, Swarts HJ, Anand-Ivell R, Teerds KJ. Prenatal induced chronic dietary hypothyroidism delays but does not block adult-type Leydig cell development. Am J Physiol Endocrinol Metab 296: E305-E314, 2009. First published November 25, 2008 doi:10.1152/ajpendo.90750.2008.-Transient hypothyroidism induced by propyl-2-thiouracyl blocks postpartum Leydig cell development. In the present study, the effects of chronic hypothyroidism on the formation of this adult-type Leydig cell population were investigated, using a more physiological approach. Before mating, dams were put on a diet consisting of an iodide-poor feed supplemented with a low dose of perchlorate and, with their offspring, were kept on this diet until death. In the pups at day 12 postpartum, plasma thyroid-stimulating hormone levels were increased by 20-fold, whereas thyroxine and free tri-iodothyronine levels were severely depressed, confirming a hypothyroid condition. Adult-type progenitor Leydig cell formation and proliferation were reduced by 40 -60% on days 16 and 28 postpartum. This was followed by increased Leydig cell proliferation at later ages, suggesting a possible slower developmental onset of the adult-type Leydig cell population under hypothyroid conditions. Testosterone levels were increased 2-to 10-fold in the hypothyroid animals between days 21 and 42 postpartum compared with the age-matched controls. Combined with the decreased presence of 5␣-reductase, this implicates a lower production capacity of 5␣-reduced androgens. In 84-day-old rats, after correction for body weight-to-testis weight ratio, plasma insulin-like factor-3 levels were 35% lower in the hypothyroid animals, suggestive of a reduced Leydig cell population. This is confirmed by a 37% reduction in the Sertoli cell-to-Leydig cell ratio in hypothyroid rats. In conclusion, we show that dietary-induced hypothyroidism delays but, unlike propyl-2-thiouracyl, does not block the development of the adult-type Leydig cell population.

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Constitutive regulation of the Insl3 gene in rat Leydig cells

Cited by 76 publications

References 35 publications

Dynamics of insulin-like factor 3 and its receptor expression in boar testes

Dynamics of insulin-like factor 3 and its receptor expression in boar testes

Peripheral insulin-like factor 3 concentrations are reduced in men with type 2 diabetes mellitus: effect of glycemic control and visceral adiposity on Leydig cell function

Prenatal induced chronic dietary hypothyroidism delays but does not block adult-type Leydig cell development

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