Induction of Endogenous Insulin-Like Growth Factor-I Secretion Alters the Hypothalamic-Pituitary-Testicular Function in Growth Hormone-Deficient Adult Dwarf Mice1

Chandrashekar, Varadaraj; Bartke, Andrzej

doi:10.1095/biolreprod48.3.544

Cited by 100 publications

(51 citation statements)

References 36 publications

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“…Although IGF-I increases LH secretion in peri-pubertal, intact rats (Hiney et al 1996), studies have not examined specifically how IGF-I may modify gonadal steroid negative feedback at first ovulation in this species. However, GH deficiency enhances testosterone negative feedback inhibition of LH secretion in adult mice, an effect reversed by the administration of GH and the resulting increase in IGF-I (Chandrashekar & Bartke 1993). Taken together, these data suggest that the post-menarchial increase in GH-dependent IGF-I concentrations sets the tempo for the later stages of puberty, determining the occurrence of first ovulation in monkeys.…”

Section: Discussionmentioning

confidence: 80%

Premature elevation in serum insulin-like growth factor-I advances first ovulation in rhesus monkeys

Wilson

1998

Journal of Endocrinology

109

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Previous data suggest that developmental increases in peripheral concentrations of insulin-like growth factor-I (IGF-I) may be one of several neuroendocrine signals that regulate the timing of puberty. In order to test this hypothesis further, normal juvenile female rhesus monkeys (Con; n=6) were compared with age-matched animals (Igf; n=4) which received a constant subcutaneous infusion of recombinant human IGF-I (110 µg/kg/day) from 18 through 36 months of age. Menstrual bleeding was monitored and ovulation was inferred from a sustained rise in serum progesterone. In order to assess the sensitivity of luteinizing hormone-releasing hormone (LHRH) neurons to excitation, the response of serum LH to the acute administration of the glutamate receptor agonist N-methyl-, -aspartic acid (NMDA) was assessed prior to menarche, 2 months following menarche, and during the follicular phase of a female's third ovulation or 50 days after a female's first ovulation. In addition, the pituitary response of LH secretion to an LHRH agonist was assessed during the follicular phase of a female's fourth ovulation or 75 days following her first ovulation.IGF-I treatment effectively elevated serum concentrations by more than 86% of the values observed in Con animals. Although the treatment also enhanced the developmental increase in IGF binding protein-3 (IGFBP-3), IGF-I was increased proportionately more, resulting in a significantly higher molar ratio of IGF-I:IGFBP-3 in treated females throughout the course of the study. Treatment with IGF-I did not affect age at menarche but did significantly advance the age of first ovulation.Consequently, the interval between menarche and first ovulation was significantly shorter in Igf compared with Con females. Although the total number of ovulations exhibited by Igf (3·8 0·3) and Con females (3·0 0·5) in the 12 months following menarche was similar, significantly more of these were characterized by normal luteal phase progesterone secretion in Igf (100% 0) compared with Con females (64% 17). An analysis of cycles with a normal luteal phase revealed that serum estradiol during the luteal phase was significantly higher in Igf compared with Con females. Finally, IGF-treated females responded to NMDA treatment with a significantly greater increase in serum LH following menarche but not prior to menarche. In contrast, the response of serum LH to an LHRH agonist did not differ between Igf and Con females.These data suggest that the premature elevation in IGF-I levels, and consequently the ratio of IGF-I:IGFBP-3, accelerates the tempo of the final stages of puberty in rhesus monkeys. This action of IGF-I is probably the result of an increase in LHRH neuronal activity and is not due to a change in pituitary sensitivity to LHRH stimulation. In addition, ovarian sensitivity to LH stimulation during the luteal phase is also increased by IGF-I. Taken together, these data suggest that developmental increases in peripheral IGF-I secretion participate in the neuroendocrine regulation of puberty in...

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Section: Discussionmentioning

confidence: 80%

Premature elevation in serum insulin-like growth factor-I advances first ovulation in rhesus monkeys

Wilson

1998

Journal of Endocrinology

109

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“…In Laron-syndrome patients treated with high concentrations of exogenous IGF-I, levels of sex-steroid hormones have been shown to increase and some female patients developed hyperadrogenism with oligo/amenorrhoea and acne (59,60). There is also in vitro evidence that IGF-I enhances the LH-dependent ovarian (33,61,62) and adrenal (63,64) androgen production and that IGF-I might affect gonadotropin production at the pituitary level (65,66).…”

Section: Effect Of Bmi On Hormone Levelsmentioning

confidence: 99%

Body mass index, circulating levels of sex-steroid hormones, IGF-I and IGF-binding protein-3: a cross-sectional study in healthy women

Lukanova

Lundin

Zeleniuch‐Jacquotte

et al. 2004

European Journal of Endocrinology

284

211

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Objective: Excess weight has been associated with increased risk of cancer at several organ sites. In part, this effect may be modulated through alterations in the metabolism of sex steroids and IGF-I related peptides. The objectives of the study were to examine the association of body mass index (BMI) with circulating androgens (testosterone, androstenedione and dehydroepiandrosterone sulfate (DHEAS)), estrogens (estrone and estradiol), sex hormone-binding globulin (SHBG), IGF-I and IGFbinding protein (IGFBP)-3, and the relationship between sex steroids, IGF-I and IGFBP-3. Design and methods: A cross-sectional analysis was performed using hormonal and questionnaire data of 620 healthy women (177 pre-and 443 post-menopausal). The laboratory measurements of the hormones of interest were available from two previous case-control studies on endogenous hormones and cancer risk. Results: In the pre-menopausal group, BMI was not related to androgens and IGF-I. In the post-menopausal group, estrogens, testosterone and androstenedione increased with increasing BMI. The association with IGF-I was non-linear, with the highest mean concentrations observed in women with BMI between 24 and 25. In both pre-and post-menopausal subjects, IGFBP-3 did not vary across BMI categories and SHBG decreased with increasing BMI. As for the correlations between peptide and steroid hormones, in the post-menopausal group, IGF-I was positively related to androgens, inversely correlated with SHBG, and not correlated with estrogens. In the pre-menopausal group, similar but weaker correlations between IGF-I and androgens were observed. Conclusions: These observations offer evidence that obesity may influence the levels of endogenous sex-steroid and IGF-related hormones in the circulation, especially after menopause. Circulating IGF-I, androgens and SHBG appear to be related to each other in post-menopausal women.

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“…8,11 Little (Ghrhr lit ) mice with isolated GH deficiency exhibit a smaller but statistically significant increase in longevity. 11 Available evidence suggests that the remarkable increase in longevity of Ames dwarf mice is due to multiple mechanisms, including reduced IGF1 and mammalian Target Of Rapamycin (mTOR) signaling, 27,28 delayed onset and reduced incidence of fatal neoplastic disease, 29 increased sensitivity to insulin combined with reduced insulin levels, 22,23 hypothyroidism and reduced body core temperature, 19 increased activity of antioxidant enzymes and reduced oxidative damage (30,31; reviewed in 17) and resistance to various forms of oxidative, toxic and metabolic stress. 32,33 growTh hormone recepTor knockouT (ghrko) mice…”

Section: Ames Dwarf Micementioning

confidence: 99%

How diet interacts with longevity genes

Bartke¹,

Bonkowski²,

Masternak³

2008

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In laboratory mice, suppression of growth hormone (GH) signaling by spontaneous mutations or targeted disruption of GH-or IGF1-related genes can lead to an impressive increase of longevity. Hypopituitary Ames dwarf (Prop1 df ) and GH receptor knockout (GHRKO) mice live 35-70% longer than their normal littermates. Many phenotypic characteristics of these longlived mutants resemble findings in genetically normal animals subjected to calorie restriction (CR). Microarray and RT-PCR studies of gene expression suggest that effects of the "longevity assurance genes" (Prop1 df or Ghr-/-) and CR are overlapping but not identical. Subjecting Ames dwarf mice to 30% CR starting at 2 months of age leads to a further significant extension of their average and maximal lifespans. In contrast, identical CR regimen has either no or very little effect (depending on gender) on longevity of GHRKO mice. We suspect that this difference in response is related to the fact that CR improves insulin sensitivity in Ames dwarfs but does not further increase the extreme insulin sensitivity of GHRKO mice. To search for effects of CR associated with extension of longevity, we are studying expression of insulin and IGF1-related genes in the liver, skeletal muscle and heart of normal and GHRKO mice. Results obtained to date suggest that reduced Akt phosphorylation and PPAR β/δ expression in the liver, reduced JNK1 phosphorylation and increased PGC1α expression in the muscle, and increased expression of IGF1 and insulin receptor in the heart are either related to mechanisms of CR action on longevity or represent potential biomarkers of delayed aging.

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Induction of Endogenous Insulin-Like Growth Factor-I Secretion Alters the Hypothalamic-Pituitary-Testicular Function in Growth Hormone-Deficient Adult Dwarf Mice1

Cited by 100 publications

References 36 publications

Premature elevation in serum insulin-like growth factor-I advances first ovulation in rhesus monkeys

Premature elevation in serum insulin-like growth factor-I advances first ovulation in rhesus monkeys

Body mass index, circulating levels of sex-steroid hormones, IGF-I and IGF-binding protein-3: a cross-sectional study in healthy women

How diet interacts with longevity genes

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