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Gurule SC, Sustaita-Monroe JF, King LN, Landers RS, Garza V, West SM, Bynum SE, Perry L, Padmanabhan V, Cardoso RC. Reproductive neuroendocrine defects programmed by prenatal testosterone treatment between gestational days 60-90 are amplified by postnatal obesity in sheep. Front Physiol 2024; 15:1436954. [PMID: 39156826 PMCID: PMC11327049 DOI: 10.3389/fphys.2024.1436954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 07/01/2024] [Indexed: 08/20/2024] Open
Abstract
Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility in women of reproductive age, and obesity can increase the severity and development of the PCOS phenotype. Prenatal testosterone (T) treatment between gestational days 30-90 advanced puberty and disrupted the reproductive and metabolic phenotype in female sheep, recapitulating attributes of women with PCOS, with postnatal obesity amplifying its severity. On the other hand, prenatal T treatment from gestational days 60-90 led to a much milder phenotype. We hypothesized that reproductive neuroendocrine defects programmed by prenatal T treatment between gestational days 60-90 are amplified by postnatal obesity in sheep. Suffolk ewes received T propionate (T; 100 mg) or corn oil (C; vehicle) twice weekly from gestational days 60-90. At 5 months of age, T lambs were assigned to either a maintenance (100% of NRC requirements) or overfed (130% NRC) diet and C lambs were fed the maintenance diet. We compared the timing of puberty (n = 15/group) determined by twice weekly measurement of progesterone concentrations, estradiol positive feedback responsiveness (n = 8/group) determined by assessing LH secretion in response to exogenous estradiol, periovulatory LH dynamics during the second breeding season (n = 8/group) following synchronization with two injections of PGF2α, and progesterone negative feedback (n = 8/group) determined by characterizing LH pulses during the mid-luteal phase between C, T-maintenance and T-overfed groups. Our findings indicate that postnatal obesity: 1) exacerbated reproductive defects and further deteriorated reproductive cyclicity during the second breeding season (adulthood); 2) did not amplify the impairment in estradiol positive feedback in delaying the timing and amplitude of the LH surge, although it reduced the total amount of LH secreted during the preovulatory LH surge; 3) amplified the reduced responsiveness to progesterone negative feedback manifested as an increase in LH pulse amplitude and peak. These observations, in addition to supporting our previous findings that prenatal T treatment results in reproductive neuroendocrine dysfunction and periovulatory disruptions, provide evidence that these neuroendocrine defects programmed between gestational days 60-90 are amplified by postnatal obesity in female sheep.
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Affiliation(s)
- S. C. Gurule
- Department of Animal Science, Texas A&M University, College Station, TX, United States
| | - J. F. Sustaita-Monroe
- Department of Animal Science, Texas A&M University, College Station, TX, United States
| | - L. N. King
- Department of Animal Science, Texas A&M University, College Station, TX, United States
| | - R. S. Landers
- Department of Animal Science, Texas A&M University, College Station, TX, United States
| | - V. Garza
- Department of Animal Science, Texas A&M University, College Station, TX, United States
| | - S. M. West
- Department of Animal Science, Texas A&M University, College Station, TX, United States
| | - S. E. Bynum
- Department of Animal Science, Texas A&M University, College Station, TX, United States
| | - L. Perry
- Department of Animal Science, Texas A&M University, College Station, TX, United States
| | - V. Padmanabhan
- Department of Pediatrics, University of Michigan, Ann Arbor, MI, United States
| | - R. C. Cardoso
- Department of Animal Science, Texas A&M University, College Station, TX, United States
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Szymanska K, Rytelewska E, Zaobidna E, Kiezun M, Gudelska M, Kopij G, Dobrzyn K, Mlyczynska E, Kurowska P, Kaminska B, Nynca A, Smolinska N, Rak A, Kaminski T. The Effect of Visfatin on the Functioning of the Porcine Pituitary Gland: An In Vitro Study. Cells 2023; 12:2835. [PMID: 38132154 PMCID: PMC10742260 DOI: 10.3390/cells12242835] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 12/11/2023] [Accepted: 12/12/2023] [Indexed: 12/23/2023] Open
Abstract
Visfatin (VIS), also known as nicotinamide phosphoribosyltransferase (NAMPT), is the rate-limiting enzyme in the biosynthesis of nicotinamide adenine dinucleotide (NAD+). Recently, VIS has been also recognized as an adipokine. Our previous study revealed that VIS is produced in the anterior and posterior lobes of the porcine pituitary. Moreover, the expression and secretion of VIS are dependent on the phase of the estrous cycle and/or the stage of early pregnancy. Based on this, we hypothesized that VIS may regulate porcine pituitary function. This study was conducted on anterior pituitary (AP) glands harvested from pigs during specific phases of the estrous cycle. We have shown the modulatory effect of VIS in vitro on LH and FSH secretion by porcine AP cells (determined by ELISA). VIS was also found to stimulate cell proliferation (determined by Alamar Blue) without affecting apoptosis in these cells (determined using flow cytometry technique). Moreover, it was indicated that VIS may act in porcine AP cells through the INSR, AKT/PI3K, MAPK/ERK1/2, and AMPK signaling pathways (determined by ELISA or Western Blot). This observation was further supported by the finding that simultaneous treatment of cells with VIS and inhibitors of these pathways abolished the observed VIS impact on LH and FSH secretion (determined by ELISA). In addition, our research indicated that VIS affected the mentioned processes in a manner that was dependent on the dose of VIS and/or the phase of the estrous cycle. Thus, these findings suggest that VIS may regulate the functioning of the porcine pituitary gland during the estrous cycle.
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Affiliation(s)
- Karolina Szymanska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland; (K.S.); (E.R.); (M.K.); (G.K.); (B.K.); (A.N.); (N.S.)
| | - Edyta Rytelewska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland; (K.S.); (E.R.); (M.K.); (G.K.); (B.K.); (A.N.); (N.S.)
| | - Ewa Zaobidna
- Department of Biochemistry, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland;
| | - Marta Kiezun
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland; (K.S.); (E.R.); (M.K.); (G.K.); (B.K.); (A.N.); (N.S.)
| | - Marlena Gudelska
- Department of Human Histology and Embryology, School of Medicine, Collegium Medicum, University of Warmia and Mazury in Olsztyn, 10-082 Olsztyn, Poland;
| | - Grzegorz Kopij
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland; (K.S.); (E.R.); (M.K.); (G.K.); (B.K.); (A.N.); (N.S.)
| | - Kamil Dobrzyn
- Department of Zoology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland;
| | - Ewa Mlyczynska
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, 30-387 Krakow, Poland; (E.M.); (P.K.); (A.R.)
- Doctoral School of Exact and Natural Sciences, Jagiellonian University in Krakow, 30-348 Krakow, Poland
| | - Patrycja Kurowska
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, 30-387 Krakow, Poland; (E.M.); (P.K.); (A.R.)
| | - Barbara Kaminska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland; (K.S.); (E.R.); (M.K.); (G.K.); (B.K.); (A.N.); (N.S.)
| | - Anna Nynca
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland; (K.S.); (E.R.); (M.K.); (G.K.); (B.K.); (A.N.); (N.S.)
| | - Nina Smolinska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland; (K.S.); (E.R.); (M.K.); (G.K.); (B.K.); (A.N.); (N.S.)
| | - Agnieszka Rak
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, 30-387 Krakow, Poland; (E.M.); (P.K.); (A.R.)
| | - Tadeusz Kaminski
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland; (K.S.); (E.R.); (M.K.); (G.K.); (B.K.); (A.N.); (N.S.)
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Szymanska K, Zaobidna E, Rytelewska E, Mlyczynska E, Kurowska P, Dobrzyn K, Kiezun M, Kaminska B, Smolinska N, Rak A, Kaminski T. Visfatin in the porcine pituitary gland: expression and regulation of secretion during the oestrous cycle and early pregnancy. Sci Rep 2023; 13:18253. [PMID: 37880346 PMCID: PMC10600231 DOI: 10.1038/s41598-023-45255-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 10/17/2023] [Indexed: 10/27/2023] Open
Abstract
Visfatin is a multifunctional protein which, besides the control of energy homeostasis, seems to be also involved in the regulation of female fertility through the influence on the endocrine hypothalamus-pituitary-gonadal axis, including the pituitary. The aim of this study was to investigate the expression of visfatin mRNA and protein in the anterior (AP) and posterior pituitary lobes of the pig during the oestrous cycle and early pregnancy. In AP, we also examined colocalisation of visfatin with pituitary tropic hormones. Moreover, we aimed to evaluate the in vitro effects of GnRH, FSH, LH, and insulin on visfatin protein concentration and secretion in AP cells during the cycle. The study showed that visfatin is present in all types of porcine pituitary endocrine cells and its expression is reliant on stage of the cycle or pregnancy. GnRH, FSH, LH and insulin stimulated visfatin secretion by AP cells on days 17 to 19 of the cycle, while on days 2 to 3 visfatin release was enhanced only by LH. Summarising, visfatin is locally produced in the pituitary in a way dependent on hormonal milieu typical for reproductive status of pigs. Further research is required to clarify the role of visfatin in the pituitary gland.
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Affiliation(s)
- Karolina Szymanska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719, Olsztyn, Poland
| | - Ewa Zaobidna
- Department of Biochemistry, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719, Olsztyn, Poland
| | - Edyta Rytelewska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719, Olsztyn, Poland
| | - Ewa Mlyczynska
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, Gronostajowa 9, 30-387, Krakow, Poland
- Doctoral School of Exact and Natural Sciences, Jagiellonian University in Krakow, Lojasiewicza 11, 30-348, Krakow, Poland
| | - Patrycja Kurowska
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, Gronostajowa 9, 30-387, Krakow, Poland
| | - Kamil Dobrzyn
- Department of Zoology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 5, 10-719, Olsztyn, Poland
| | - Marta Kiezun
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719, Olsztyn, Poland
| | - Barbara Kaminska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719, Olsztyn, Poland
| | - Nina Smolinska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719, Olsztyn, Poland
| | - Agnieszka Rak
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, Gronostajowa 9, 30-387, Krakow, Poland
| | - Tadeusz Kaminski
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719, Olsztyn, Poland.
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Tenuta M, Carlomagno F, Cangiano B, Kanakis G, Pozza C, Sbardella E, Isidori AM, Krausz C, Gianfrilli D. Somatotropic-Testicular Axis: A crosstalk between GH/IGF-I and gonadal hormones during development, transition, and adult age. Andrology 2020; 9:168-184. [PMID: 33021069 DOI: 10.1111/andr.12918] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 07/31/2020] [Accepted: 09/28/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND The hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-somatotropic (HPS) axes are strongly interconnected. Interactions between these axes are complex and poorly understood. These interactions are characterized by redundancies in reciprocal influences at each level of regulation and the combination of endocrine and paracrine effects that change during development. OBJECTIVES To comprehensively review the crosstalk between the HPG and HPS axes and related pathological and clinical aspects during various life stages of male subjects. MATERIALS AND METHODS A thorough search of publications available in PubMed was performed using proper keywords. RESULTS Molecular studies confirmed the expressions of growth hormone (GH) and insulin-like growth factor-I (IGF-I) receptors on the HPG axis and reproductive organs, indicating a possible interaction between HPS and HPG axes at various levels. Insulin growth factors participate in sexual differentiation during fetal development, indicating that normal HPS axis activity is required for proper testicular development. IGF-I contributes to correct testicular position during minipuberty, determines linear growth during childhood, and promotes puberty onset and pace through gonadotropin-releasing hormone activation. IGF-I levels are high during transition age, even when linear growth is almost complete, suggesting its role in reproductive tract maturation. Patients with GH deficiency (GHD) and insensitivity (GHI) exhibit delayed puberty and impaired genital development; replacement therapy in such patients induces proper pubertal development. In adults, few studies have suggested that lower IGF-I levels are associated with impaired sperm parameters. DISCUSSION AND CONCLUSION The role of GH-IGF-I in testicular development remains largely unexplored. However, it is important to evaluate gonadic development in children with GHD. Additionally, HPS axis function should be evaluated in children with urogenital malformation or gonadal development alterations. Correct diagnosis and prompt therapeutic intervention are needed for healthy puberty, attainment of complete gonadal development during transition age, and fertility potential in adulthood.
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Affiliation(s)
- Marta Tenuta
- Department of Experimental Medicine, Sapienza University, Rome, Italy
| | | | - Biagio Cangiano
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - George Kanakis
- Athens Naval and Veterans Affairs Hospital, Athens, Greece
| | - Carlotta Pozza
- Department of Experimental Medicine, Sapienza University, Rome, Italy
| | - Emilia Sbardella
- Department of Experimental Medicine, Sapienza University, Rome, Italy
| | - Andrea M Isidori
- Department of Experimental Medicine, Sapienza University, Rome, Italy
| | - Csilla Krausz
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
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Yang R, Winters SJ, Moore JP. Signaling pathways and promoter regions that mediate pituitary adenylate cyclase activating polypeptide (PACAP) self-regulation in gonadotrophs. Mol Cell Endocrinol 2020; 512:110851. [PMID: 32439415 PMCID: PMC7339524 DOI: 10.1016/j.mce.2020.110851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 04/27/2020] [Accepted: 04/27/2020] [Indexed: 11/16/2022]
Abstract
Pituitary adenylate cyclase-activating polypeptide (PACAP) is thought to play a role in the development and regulation of gonadotrophs. PACAP levels are very high in the rodent fetal pituitary, and decline substantially and rapidly at birth, followed by a significant rise in FSHβ and GnRH-R expression. Because there is evidence that PACAP stimulates its own transcription, we propose that this self-regulation is interrupted around the time of birth. To begin to examine the mechanisms for PACAP self-regulation, we used two well-established gonadotroph cell lines, αT3-1 cells and the more mature LβT2 cells which were transfected with a PACAP promoter-reporter construct As in vivo, the basal PACAP transcription level is significantly lower in the more mature LβT2 cells in which basal cAMP signaling is also much reduced. The PACAP promoter was stimulated by PACAP in both cell lines. Treatment with inhibitors of second messenger pathways implicated PKA, PKC and MAPK in PACAP transcription. Three regions of the PACAP promoter were found to confer inhibition or stimulation of PACAP transcription. By inhibiting cAMP response element binding (CREB) activity and mutating a proximal CREB binding site, we found that CREB is essential for promoter activation. Finally, overexpression of PACAP receptor HOP1 isoform, to increase the level in LβT2 cells to that of αT3-1 cells and simulate the E19 pituitary, increased PACAP- stimulated sensitivity and significantly altered downstream gene transcription. These results provide novel insight into the feed-forward regulation of PACAP expression that may help initiate gonadotroph function at birth.
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Affiliation(s)
- Rongquiang Yang
- Department of Anatomical Sciences and Neurobiology, Louisville, KY, 40202, USA
| | - Stephen J Winters
- Division of Endocrinology & Metabolism, Department of Medicine, University of Louisville School of Medicine, Louisville, KY, 40202, USA
| | - Joseph P Moore
- Department of Anatomical Sciences and Neurobiology, Louisville, KY, 40202, USA; Division of Endocrinology & Metabolism, Department of Medicine, University of Louisville School of Medicine, Louisville, KY, 40202, USA.
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Yadon N, Owen A, Cakora P, Bustamante A, Hall-South A, Smith N, Felder MR, Vrana PB, Shorter KR. A high methyl donor diet affects physiology and behavior in Peromyscus polionotus. Physiol Behav 2019; 209:112615. [PMID: 31299371 DOI: 10.1016/j.physbeh.2019.112615] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 06/02/2019] [Accepted: 07/09/2019] [Indexed: 12/21/2022]
Abstract
Folic acid and other dietary methyl donors are widely supplemented due to their ability to prevent neural tube defects. Dietary methyl donors are also added to other consumables such as energy drinks due to energy-promoting attributes and other perceived benefits. However, there is mounting evidence that indicates developmental exposure to high levels of dietary methyl donors may have deleterious effects. We assessed whether behavior was affected in the social North American rodent species Peromyscus polionotus exposed to a diet enriched with folic acid, Vitamin B12, choline, and betaine/trimethylglycine(TMG). P. polionotus (PO) animals are very social and exhibit little repetitive behavior, particularly compared to their sister species, P. maniculatus. We assayed the effects of dietary methyl-donor supplementation on anxiety-like repetitive and social behaviors by testing young adult animals for novel cage behavior and in social interaction tests. Animals of both sexes exposed to the diet had increased repetitive behaviors and reduced social interactions. Males exposed to the diet became more aggressive compared to their control counterparts. Since methyl-diet animals were larger than control animals, DEXA scans and hormone analyses were performed. Animals exposed to the diet had increased body fat percentages and experienced hormonal changes typically associated with excess fat storage and anxiety-like behavior changes. Therefore, these data suggest the wide use of these dietary supplements makes further investigation imperative.
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Affiliation(s)
- Nicole Yadon
- Division of Natural Sciences and Engineering, University of South Carolina Upstate, Spartanburg, SC 29303, United States of America
| | - Amy Owen
- Dept. Biological Sciences, University of South Carolina, Columbia, SC 29208, United States of America
| | - Patricia Cakora
- Dept. Biological Sciences, University of South Carolina, Columbia, SC 29208, United States of America
| | - Angela Bustamante
- Division of Natural Sciences and Engineering, University of South Carolina Upstate, Spartanburg, SC 29303, United States of America
| | - April Hall-South
- Dept. Biological Sciences, University of South Carolina, Columbia, SC 29208, United States of America
| | - Nuri Smith
- Division of Natural Sciences and Engineering, University of South Carolina Upstate, Spartanburg, SC 29303, United States of America
| | - Michael R Felder
- Dept. Biological Sciences, University of South Carolina, Columbia, SC 29208, United States of America; Peromyscus Genetic Stock Center; University of South Carolina, Columbia, SC 29208, United States of America
| | - Paul B Vrana
- Dept. Biological Sciences, University of South Carolina, Columbia, SC 29208, United States of America; Peromyscus Genetic Stock Center; University of South Carolina, Columbia, SC 29208, United States of America
| | - Kimberly R Shorter
- Division of Natural Sciences and Engineering, University of South Carolina Upstate, Spartanburg, SC 29303, United States of America.
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Lopéz-Cedillo ZB, Rosales-Torres AM, Mendoza GD, Heuze Y, Ávila-Espítia AE, Guzmán A. Short-term methionine supplementation during the early post-partum period in primiparous rabbits improves prolificacy associated with an increase in serum concentrations of IGF-I. J Anim Physiol Anim Nutr (Berl) 2016; 101:e394-e403. [PMID: 27747966 DOI: 10.1111/jpn.12619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Accepted: 09/12/2016] [Indexed: 01/10/2023]
Abstract
The aim of this study was to evaluate the effects of methionine supplementation on energy metabolism and reproductive performance during the early post-partum period in primiparous does. Forty nulliparous New Zealand White does were used. Females were randomized in two groups at calving: the control group (n = 20) was fed with the basal diet, and the methionine group (n = 20) was fed the basal diet plus 1 g/animal/day of methionine from the day of calving to 4 days post-partum. Results showed that methionine supplementation increased (p = 0.032) the concentration of insulin-like growth factor-1 with respect to control group 4 days post-partum. It similarly increased the prolificacy (p = 0.03), the number of kits born alive per litter (p = 0.06) and the body gain weight of the litter during supplementation (p = 0.035). These results were observed despite the does in the methionine group having a deeper negative energy balance than the does in the control group. Finally, methionine supplementation did not affect receptivity (p = 0.23), fertility (p = 0.49), the number of kits born dead per litter (p = 0.86) insulin and metabolites as glucose, non-esterified fatty acids and triglycerides. In conclusion, our results show that methionine supplementation during the first 4 days of the post-partum period in rabbits increases total litter size and the corporal weight of kits and is associated with an increase in blood concentration of IGF-1.
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Affiliation(s)
- Z B Lopéz-Cedillo
- Universidad Autónoma Metropolitana-Xochimilco, Ciudad de México, México
| | | | - G D Mendoza
- Universidad Autónoma Metropolitana-Xochimilco, Ciudad de México, México
| | - Y Heuze
- Universidad Autónoma Metropolitana-Xochimilco, Ciudad de México, México
| | - A E Ávila-Espítia
- Universidad Autónoma Metropolitana-Xochimilco, Ciudad de México, México
| | - A Guzmán
- Universidad Autónoma Metropolitana-Xochimilco, Ciudad de México, México
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Kiezun M, Smolinska N, Maleszka A, Dobrzyn K, Szeszko K, Kaminski T. Adiponectin expression in the porcine pituitary during the estrous cycle and its effect on LH and FSH secretion. Am J Physiol Endocrinol Metab 2014; 307:E1038-46. [PMID: 25315693 DOI: 10.1152/ajpendo.00299.2014] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Female reproductive success is closely associated with nutritional status and energy balance. In this context, adiponectin appears to be a key hormone connecting reproductive system function and metabolism regulation. It is hypothesized that adiponectin expression in the pituitary depends on the phase of the estrous cycle. The effect of adiponectin on luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion is also postulated. Changes in the adiponectin gene and protein expression in the porcine anterior (AP) and posterior (NP) pituitaries as well as the effect of in vitro administration of adiponectin on basal and gonadotropin-releasing hormone (GnRH)- and/or insulin-stimulated LH and FSH secretion were investigated on days 2-3, 10-12, 14-16, and 17-19 of the estrous cycle. Adiponectin gene was more pronounced on days 2-3 in AP but on days 10-12 in NP. Protein concentration in AP was the highest on days 10-12 and in NP on days 10-12 and 17-19 of the cycle. In vitro, adiponectin did not affect basal LH secretion but increased FSH release by AP cells. Adiponectin administration affected GnRH- and/or insulin-induced LH and FSH output in a manner dependent on the phase of the estrous cycle. In this study we indicated for the first time adiponectin expression in the porcine AP and NP that was dependent on the phase of the estrous cycle. In vitro studies indicated that adiponectin may affect gonadotropin secretion. The above suggests that the studied adipokine may influence female reproductive functions via its effect on LH and FSH secretion by gonadotrophs, but the cellular mechanism of its action remains unknown.
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Affiliation(s)
- Marta Kiezun
- Department of Animal Physiology, University of Warmia and Mazury in Olsztyn, Olsztyn-Kortowo, Poland
| | - Nina Smolinska
- Department of Animal Physiology, University of Warmia and Mazury in Olsztyn, Olsztyn-Kortowo, Poland
| | - Anna Maleszka
- Department of Animal Physiology, University of Warmia and Mazury in Olsztyn, Olsztyn-Kortowo, Poland
| | - Kamil Dobrzyn
- Department of Animal Physiology, University of Warmia and Mazury in Olsztyn, Olsztyn-Kortowo, Poland
| | - Karol Szeszko
- Department of Animal Physiology, University of Warmia and Mazury in Olsztyn, Olsztyn-Kortowo, Poland
| | - Tadeusz Kaminski
- Department of Animal Physiology, University of Warmia and Mazury in Olsztyn, Olsztyn-Kortowo, Poland
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Park CH, Skarra DV, Rivera AJ, Arriola DJ, Thackray VG. Constitutively active FOXO1 diminishes activin induction of Fshb transcription in immortalized gonadotropes. PLoS One 2014; 9:e113839. [PMID: 25423188 PMCID: PMC4244159 DOI: 10.1371/journal.pone.0113839] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Accepted: 10/31/2014] [Indexed: 11/29/2022] Open
Abstract
In the present study, we investigate whether the FOXO1 transcription factor modulates activin signaling in pituitary gonadotropes. Our studies show that overexpression of constitutively active FOXO1 decreases activin induction of murine Fshb gene expression in immortalized LβT2 cells. We demonstrate that FOXO1 suppression of activin induction maps to the −304/−95 region of the Fshb promoter containing multiple activin response elements and that the suppression requires the FOXO1 DNA-binding domain (DBD). FOXO1 binds weakly to the −125/−91 region of the Fshb promoter in a gel-shift assay. Since this region of the promoter contains a composite SMAD/FOXL2 binding element necessary for activin induction of Fshb transcription, it is possible that FOXO1 DNA binding interferes with SMAD and/or FOXL2 function. In addition, our studies demonstrate that FOXO1 directly interacts with SMAD3/4 but not SMAD2 in a FOXO1 DBD-dependent manner. Moreover, we show that SMAD3/4 induction of Fshb-luc and activin induction of a multimerized SMAD-binding element-luc are suppressed by FOXO1 in a DBD-dependent manner. These results suggest that FOXO1 binding to the proximal Fshb promoter as well as FOXO1 interaction with SMAD3/4 proteins may result in decreased activin induction of Fshb in gonadotropes.
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Affiliation(s)
- Chung Hyun Park
- Department of Reproductive Medicine and the Center for Reproductive Science and Medicine, University of California San Diego, La Jolla, CA, United States of America
| | - Danalea V. Skarra
- Department of Reproductive Medicine and the Center for Reproductive Science and Medicine, University of California San Diego, La Jolla, CA, United States of America
| | - Alissa J. Rivera
- Department of Reproductive Medicine and the Center for Reproductive Science and Medicine, University of California San Diego, La Jolla, CA, United States of America
| | - David J. Arriola
- Department of Reproductive Medicine and the Center for Reproductive Science and Medicine, University of California San Diego, La Jolla, CA, United States of America
| | - Varykina G. Thackray
- Department of Reproductive Medicine and the Center for Reproductive Science and Medicine, University of California San Diego, La Jolla, CA, United States of America
- * E-mail:
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10
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Wolfe A, Divall S, Wu S. The regulation of reproductive neuroendocrine function by insulin and insulin-like growth factor-1 (IGF-1). Front Neuroendocrinol 2014; 35:558-72. [PMID: 24929098 PMCID: PMC4175134 DOI: 10.1016/j.yfrne.2014.05.007] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2013] [Revised: 04/01/2014] [Accepted: 05/27/2014] [Indexed: 12/27/2022]
Abstract
The mammalian reproductive hormone axis regulates gonadal steroid hormone levels and gonadal function essential for reproduction. The neuroendocrine control of the axis integrates signals from a wide array of inputs. The regulatory pathways important for mediating these inputs have been the subject of numerous studies. One class of proteins that have been shown to mediate metabolic and growth signals to the CNS includes Insulin and IGF-1. These proteins are structurally related and can exert endocrine and growth factor like action via related receptor tyrosine kinases. The role that insulin and IGF-1 play in controlling the hypothalamus and pituitary and their role in regulating puberty and nutritional control of reproduction has been studied extensively. This review summarizes the in vitro and in vivo models that have been used to study these neuroendocrine structures and the influence of these growth factors on neuroendocrine control of reproduction.
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Affiliation(s)
- Andrew Wolfe
- Johns Hopkins University School of Medicine, Department of Pediatrics, Division of Endocrinology, Baltimore, MD 21287, United States.
| | - Sara Divall
- Johns Hopkins University School of Medicine, Department of Pediatrics, Division of Endocrinology, Baltimore, MD 21287, United States
| | - Sheng Wu
- Johns Hopkins University School of Medicine, Department of Pediatrics, Division of Endocrinology, Baltimore, MD 21287, United States
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11
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Andrade J, Quinn J, Becker RZ, Shupnik MA. AMP-activated protein kinase is a key intermediary in GnRH-stimulated LHβ gene transcription. Mol Endocrinol 2013; 27:828-39. [PMID: 23518923 DOI: 10.1210/me.2012-1323] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
GnRH regulation of pituitary gonadotropin gene transcription is critical for fertility, and metabolic dysregulation is associated with reproductive disorders and altered hypothalamic-pituitary responses. Here, we examined signaling pathways in gonadotropes through which GnRH modulates gonadotropin levels, and potential common signaling pathways with insulin. Using LβT2 cells, we show that GnRH rapidly (5 minutes) triggers activating phosphorylation of AMP-activated protein kinase (AMPK) up to 5-fold; this stimulation is enhanced by insulin through increased total AMPKα levels and activity. GnRH also stimulated c-Jun N-terminal kinase (JNK) and ERK activation, whereas insulin alone stimulated Akt. Inhibition of AMPK activity by compound C, or diminishing AMPK levels by small interfering RNA against AMPKα, prevented GnRH-stimulated transcription of the endogenous LHβ gene and transfected LHβ promoter. Egr-1 (early growth response-1), a transcription factor required for LHβ expression, is synthesized in response to GnRH, and compound C prevents this induction. However, overexpression of Egr-1 in the presence of compound C did not restore GnRH stimulation of LHβ, suggesting that AMPK stimulation of transcription also occurs through additional mechanisms or signaling pathways. One such pathway may be JNK activation, because GnRH stimulation of JNK activity and LHβ transcription occurs more slowly than stimulation of AMPK activity, and AMPK inhibition by compound C or small interfering RNA also prevented GnRH-stimulated JNK phosphorylation. Finally, in primary mouse pituitary cells, GnRH also stimulates AMPK, and AMPK inhibition suppresses GnRH-stimulated LHβ transcription. These studies indicate a novel role for AMPK in GnRH-stimulated transcription in pituitary gonadotropes and a potential common mechanism for GnRH and metabolic modulation of fertility.
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Affiliation(s)
- Josefa Andrade
- Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia, Charlottesville, VA 22903, USA
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12
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Arriola DJ, Mayo SL, Skarra DV, Benson CA, Thackray VG. FOXO1 transcription factor inhibits luteinizing hormone β gene expression in pituitary gonadotrope cells. J Biol Chem 2012; 287:33424-35. [PMID: 22865884 DOI: 10.1074/jbc.m112.362103] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Synthesis of luteinizing hormone (LH) is tightly controlled by a complex network of hormonal signaling pathways that can be modulated by metabolic cues, such as insulin. One group of candidate genes that may be regulated by insulin signaling in pituitary gonadotrope cells is the FOXO subfamily of forkhead transcription factors. In this study we investigated whether FOXO1 is expressed in gonadotropes and if it can modulate LH β-subunit (Lhb) gene expression. We demonstrated that FOXO1 is expressed in murine gonadotrope cells and that insulin signaling increased FOXO1 phosphorylation and cytoplasmic localization in a PI3K-dependent manner. We also showed that FOXO1 repressed basal transcription and gonadotropin-releasing hormone (GnRH) induction of both the murine and human LHB genes in LβT2 cells, suggesting that FOXO1 regulation of LHB transcription may be conserved between rodents and humans. Although we did not detect FOXO1 binding to the proximal Lhb promoter, the FOXO1 DNA binding domain was necessary for the suppression, suggesting that FOXO1 exerts its effect through protein-protein interactions with transcription factors/cofactors required for Lhb gene expression. FOXO1 repression mapped to the proximal Lhb promoter containing steroidogenic factor 1 (SF1), pituitary homeobox 1 (PTX1), and early growth response protein 1 (EGR1) binding elements. Additionally, FOXO1 blocked induction of the Lhb promoter with overexpressed SF1, PTX1, and EGR1, indicating that FOXO1 repression occurs via these transcription factors but not through regulation of their promoters. In summary, we demonstrate that FOXO1 phosphorylation and cellular localization is regulated by insulin signaling in gonadotropes and that FOXO1 inhibits Lhb transcription. Our study also suggests that FOXO1 may play an important role in controlling LH levels in response to metabolic cues.
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Affiliation(s)
- David J Arriola
- Department of Reproductive Medicine and the Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, California 92093, USA
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13
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Roelfsema F, Kok P, Veldhuis JD, Pijl H. Altered multihormone synchrony in obese patients with polycystic ovary syndrome. Metabolism 2011; 60:1227-33. [PMID: 21272901 DOI: 10.1016/j.metabol.2010.12.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2010] [Revised: 12/03/2010] [Accepted: 12/20/2010] [Indexed: 11/20/2022]
Abstract
Luteinizing hormone (LH) concentrations and pulsatility are increased in obese women with polycystic ovary syndrome (PCOS). In addition, patients have hyperandrogenemia and insulin resistance. The mechanisms involved in aberrant hormone regulation in PCOS are still unclear. We investigated 15 obese PCOS women with a body mass index between 30 and 54 kg/m(2) and 9 healthy obese controls (body mass index, 31-60 kg/m(2)) with regular menstrual cycles. Subjects underwent 24-hour blood sampling at 10-minute intervals for later measurements of LH, leptin, testosterone, and insulin concentrations. Data were analyzed with a new deconvolution program, approximate entropy (and bivariate approximate entropy), and a cross-correlation network. Patients had increased LH pulse frequency and more than 2-fold greater daily LH secretion, with diminished pattern regularity. Testosterone secretion was increased 2-fold, but pattern regularity was similar to that in controls. In the network construct, insulin was correlated positively with LH, whereas leptin and testosterone were correlated negatively with LH. Bivariate synchrony of LH with insulin was decreased. Short-term caloric restriction paradoxically increased LH secretion by 1.5-fold and pattern irregularity, and reduced interpulse variability. Testosterone secretion and fasting concentrations of estradiol and sex hormone-binding globulin levels remained unchanged. Correlations between LH and insulin, leptin, and calculated free testosterone decreased. This study demonstrates marked alterations in the control of LH secretion in PCOS in the fed and calorie-restricted states. The ensemble results point to abnormal feedback control of not only the GnRH-gonadotrope complex, but also LH's relationships with leptin, insulin, and testosterone.
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Affiliation(s)
- Ferdinand Roelfsema
- Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Albinusdreef 2, 2333ZA, Leiden, the Netherlands.
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Derar DR, Taya K, Watanabe G, Miyake YI. Characterization of Immunoreactive IGF-I Pattern During the Peri-ovulatory Period of the Oestrous Cycle of Thoroughbred Mares and Its Relation to Other Hormones. Reprod Domest Anim 2011; 47:151-6. [DOI: 10.1111/j.1439-0531.2011.01819.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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15
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Clapper J, Taylor A. Components of the porcine anterior pituitary insulin-like growth factor system throughout the estrous cycle. Domest Anim Endocrinol 2011; 40:67-76. [PMID: 21055896 DOI: 10.1016/j.domaniend.2010.09.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2010] [Revised: 08/31/2010] [Accepted: 09/15/2010] [Indexed: 01/14/2023]
Abstract
Components of the circulating and anterior pituitary insulin-like growth factor (IGF) system vary in response to steroids in pigs. However, whether serum and anterior pituitary concentrations of the IGF system vary throughout the estrous cycle has not been determined. To further examine this relationship, estrus was synchronized in 40 gilts of similar age and weight (180 d; 120 kg) by feeding 15 mg altrenogest for 15 d to synchronize estrus. Gilts were checked twice daily for expression of estrus beginning 3 d after the end of altrenogest treatment and continuing for 7 d. The first day each gilt exhibited estrus was designated as day 1 of the estrous cycle. Blood samples were obtained by jugular venipuncture on days 1, 4, 7, 10, 13, 16, 19, and 22 of the estrous cycle. On days 7, 13, 19, and 22 of the estrous cycle 10 pigs were killed and anterior pituitary glands (AP) were collected. Serum concentrations of IGF-I and AP concentrations of IGF-I were determined by radioimmunoassay. Relative amounts of AP IGF binding protein (IGFBP) were determined by western ligand blot analysis. Relative expression of AP IGF-I, IGF-I receptor (IGF-I-R), gonadotropin-releasing hormone receptor (GnRHR), and luteinizing hormone (LH)-β subunit were determined by real-time reverse transcription polymerase chain reaction. Serum concentrations of IGF-I fluctuated throughout the estrous cycle. Mean serum concentrations of IGF-I decreased (P < 0.02) from day 1 through day 10, increased (P < 0.02) on days 13 through 16, and then decreased (P < 0.02) from days 19 through 22. Mean AP concentrations of IGF-I were greater (P < 0.03) on day 19 than on all other days, whereas no difference was detected (P > 0.05) in mean AP concentrations of IGF-I on days 7, 13, and 22. Mean relative amounts of AP IGFBP-2 and -5 were each greater (P < 0.02) in gilts on day 19 than on all other days, whereas no difference was detected (P > 0.05) in mean relative amounts of AP IGFBP-2 and -5 among pigs on days 7, 13, and 22 of the estrous cycle. Relative expression AP IGF-I was greater (P < 0.05) on days 13, 19, and 22 than on day 7 of the estrous cycle. Similarly, the relative expression of AP IGF-IR was increased (P < 0.05) in gilts on days 13, 19, and 22 compared with day 7. The relative expression of GnRHR was greater (P < 0.05) on days 13 and 22 of the estrous cycle than on day 7. The relative expression of LHβ subunit was greater (P < 0.05) on day 19 of the estrous cycle than on days 7, 13, and 22. Anterior pituitary release of LH throughout the porcine estrous cycle may be modulated by changes in the intrapituitary IGF system.
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MESH Headings
- Animals
- Base Sequence
- Estradiol/analysis
- Estradiol/blood
- Estrus/blood
- Female
- Gene Expression
- Insulin-Like Growth Factor Binding Proteins/analysis
- Insulin-Like Growth Factor Binding Proteins/blood
- Insulin-Like Growth Factor Binding Proteins/metabolism
- Insulin-Like Growth Factor I/analysis
- Insulin-Like Growth Factor I/metabolism
- Luteinizing Hormone, beta Subunit/analysis
- Luteinizing Hormone, beta Subunit/blood
- Pituitary Gland, Anterior/chemistry
- Pituitary Gland, Anterior/metabolism
- Progesterone/analysis
- Progesterone/blood
- RNA, Messenger/chemistry
- Receptor, IGF Type 1/analysis
- Receptor, IGF Type 1/blood
- Receptor, IGF Type 1/metabolism
- Receptors, LHRH/analysis
- Receptors, LHRH/blood
- Swine/physiology
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Affiliation(s)
- J Clapper
- Department of Animal and Range Sciences, South Dakota State University, 1039 N Campus Dr., Brookings, SD 57007, USA.
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16
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Brothers KJ, Wu S, DiVall SA, Messmer MR, Kahn CR, Miller RS, Radovick S, Wondisford FE, Wolfe A. Rescue of obesity-induced infertility in female mice due to a pituitary-specific knockout of the insulin receptor. Cell Metab 2010; 12:295-305. [PMID: 20816095 PMCID: PMC2935812 DOI: 10.1016/j.cmet.2010.06.010] [Citation(s) in RCA: 121] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2009] [Revised: 03/17/2010] [Accepted: 06/01/2010] [Indexed: 12/21/2022]
Abstract
Obesity is associated with insulin resistance in metabolic tissues such as adipose, liver, and muscle, but it is unclear whether nonclassical target tissues, such as those of the reproductive axis, are also insulin resistant. To determine if the reproductive axis maintains insulin sensitivity in obesity in vivo, murine models of diet-induced obesity (DIO) with and without intact insulin signaling in pituitary gonadotrophs were created. Diet-induced obese wild-type female mice (WT DIO) were infertile and experienced a robust increase in luteinizing hormone (LH) after gonadotropin-releasing hormone (GnRH) or insulin stimulation. By contrast, both lean and obese mice with a pituitary-specific knockout of the insulin receptor (PitIRKO) exhibited reproductive competency, indicating that insulin signaling in the pituitary is required for the reproductive impairment seen in DIO and that the gonadotroph maintains insulin sensitivity in a setting of peripheral insulin resistance.
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Affiliation(s)
- Kathryn J. Brothers
- Divisions of Pediatric Endocrinology and Metabolism and Department of Physiology, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD, 21287 USA
| | - Sheng Wu
- Divisions of Pediatric Endocrinology and Metabolism and Department of Physiology, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD, 21287 USA
| | - Sara A. DiVall
- Divisions of Pediatric Endocrinology and Metabolism and Department of Physiology, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD, 21287 USA
| | - Marcus R. Messmer
- Divisions of Pediatric Endocrinology and Metabolism and Department of Physiology, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD, 21287 USA
| | - C. Ronald Kahn
- Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston MA, 02215 USA
| | - Ryan S. Miller
- Divisions of Pediatric Endocrinology and Metabolism and Department of Physiology, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD, 21287 USA
| | - Sally Radovick
- Divisions of Pediatric Endocrinology and Metabolism and Department of Physiology, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD, 21287 USA
| | - Fredric E. Wondisford
- Divisions of Pediatric Endocrinology and Metabolism and Department of Physiology, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD, 21287 USA
| | - Andrew Wolfe
- Divisions of Pediatric Endocrinology and Metabolism and Department of Physiology, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD, 21287 USA
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Luckenbach JA, Dickey JT, Swanson P. Regulation of pituitary GnRH receptor and gonadotropin subunits by IGF1 and GnRH in prepubertal male coho salmon. Gen Comp Endocrinol 2010; 167:387-96. [PMID: 19800342 DOI: 10.1016/j.ygcen.2009.09.010] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2009] [Revised: 09/05/2009] [Accepted: 09/25/2009] [Indexed: 02/08/2023]
Abstract
Insulin-like growth factor 1 (IGF1) is a key somatotropic hormone that may convey growth status to the reproductive endocrine system. This study examined effects of IGF1 alone or in combination with gonadotropin-releasing hormone (GnRH) on pituitary transcripts for GnRH receptor (GnRHR) variants, follicle-stimulating hormone (FSH), luteinizing hormone (LH), growth hormone (GH), and IGF, as well as secretion of FSH in vitro. Three experiments were conducted with dispersed pituitary cells of prepubertal male coho salmon (Oncorhynchus kisutch) to determine the time course of the response to IGF1, IGF1 concentration response, and GnRH concentration response. IGF1 consistently elevated pituitary transcripts for gnrhr1 and the four gonadotropin subunits (fshb, lhb, cga1, and cga2) by day 10 of culture, while suppressing gh and igf2. Short-term treatment with GnRH (24h) induced minor increases in transcripts for fshb, cga1, and cga2, but suppressed lhb and strongly inhibited gnrhr1 expression. IGF1 significantly increased GnRH-stimulated FSH protein release by the pituitary cells, although not as robustly as previously observed in more reproductively advanced salmon. Our results demonstrate that IGF1 increases steady-state mRNA levels of gnrhr1 and four gonadotropin subunits, and may act alone or with GnRH to increase pituitary FSH release in male coho salmon, over 1year before puberty. These findings suggest that IGF1 may prime pituitary gonadotrope cells of prepubertal salmon to respond to GnRH by stimulating synthesis of GnRHR and FSH during puberty onset.
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Affiliation(s)
- J Adam Luckenbach
- School of Aquatic and Fishery Sciences, University of Washington, Seattle, WA 98195, USA.
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18
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Olivares A, Méndez JP, Zambrano E, Cárdenas M, Tovar A, Perera-Marín G, Ulloa-Aguirre A. Reproductive axis function and gonadotropin microheterogeneity in a male rat model of diet-induced obesity. Gen Comp Endocrinol 2010; 166:356-64. [PMID: 20005231 DOI: 10.1016/j.ygcen.2009.12.007] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2009] [Revised: 11/30/2009] [Accepted: 12/03/2009] [Indexed: 01/23/2023]
Abstract
Obesity causes complex metabolic and endocrine changes that may lead to adverse outcomes, including hypogonadism. We herein studied the reproductive axis function in male rats under a high-fat diet and analyzed the impact of changes in glycosylation of pituitary LH on the bioactivity of this gonadotropin. Rats were fed with a diet enriched in saturated fat (20% of total calories) and euthanized on days 90 or 180 of diet. Long-term (180 days), high-fat feeding rats exhibited a metabolic profile compatible with insulin resistance and metabolic syndrome; they concomitantly showed decreased intrapituitary and serum LH concentrations, low serum testosterone levels, and elevated serum 17beta-estradiol concentrations. A fall in biological to immunological ratio of intrapituitary LH was detected in 180 days control diet-treated rats but not in high-fat-fed animals, as assessed by a homologous in vitro bioassay. Chromatofocusing of pituitary extracts yielded multiple LH charge isoforms; a trend towards decreased abundance of more basic isoforms (pH 9.99-9.0) was apparent in rats fed with the control diet for 180 days but not in those that were fed the diet enriched in saturated fat. It is concluded that long-term high-fat feeding alters the function of the pituitary-testicular axis, resulting in hypogonadotropic hypogonadism. The alterations in LH function found in these animals might be subserved by changes in hypothalamic GnRH output and/or sustained gonadotrope exposure to an altered sex steroid hormone milieu, representing a distinctly different regulatory mechanism whereby the pituitary attempts to counterbalance the effects of long-term obesity on reproductive function.
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Affiliation(s)
- Aleida Olivares
- Research Unit in Reproductive Medicine, Hospital de Ginecobstetricia Luis Castelazo Ayala, IMSS, México D.F., Mexico.
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19
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Navratil AM, Song H, Hernandez JB, Cherrington BD, Santos SJ, Low JM, Do MHT, Lawson MA. Insulin augments gonadotropin-releasing hormone induction of translation in LbetaT2 cells. Mol Cell Endocrinol 2009; 311:47-54. [PMID: 19632296 PMCID: PMC2739255 DOI: 10.1016/j.mce.2009.07.014] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2009] [Revised: 06/23/2009] [Accepted: 07/06/2009] [Indexed: 10/20/2022]
Abstract
The integrated signaling of insulin and gonadotropin-releasing hormone in the pituitary gonadotropes may have a profound bearing on reproductive function, although the cross-receptor signaling mechanisms are unclear. We demonstrate that the insulin receptor is constitutively localized to non-caveolar lipid raft microdomains in the pituitary gonadotrope cell line LbetaT2. The localization to rafts is consistent with similar localization of the GnRH receptor. Insulin receptor phosphorylation occurs in raft domains and activates the downstream signaling targets Insulin Receptor Substrate1 and Akt/Protein Kinase B. Although insulin alone does not strongly activate the extracellular signal-regulated kinase second messenger cascade, co-stimulation potentiates the phosphorylation of the extracellular signal-regulated kinase by gonadotropin-releasing hormone. The co-stimulatory effect of insulin and gonadotropin-releasing hormone is also evident in increased activation of cap-dependent translation. In contrast, co-stimulation attenuates Akt/Protein Kinase B activation. Our results show that both gonadotropin-releasing hormone and insulin are capable of mutually altering their respective regulatory signaling cascades. We suggest that this provides a mechanism to integrate neuropeptide and energy homeostatic signals to modulate reproductive function.
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Affiliation(s)
- Amy M. Navratil
- Department of Reproductive Medicine, University of California, San Diego, La Jolla, CA 92093
| | - Hyunjin Song
- Department of Reproductive Medicine, University of California, San Diego, La Jolla, CA 92093
| | - Jeniffer B. Hernandez
- Department of Reproductive Medicine, University of California, San Diego, La Jolla, CA 92093
| | - Brian D. Cherrington
- Department of Reproductive Medicine, University of California, San Diego, La Jolla, CA 92093
| | - Sharon J. Santos
- Department of Reproductive Medicine, University of California, San Diego, La Jolla, CA 92093
| | - Janine M. Low
- Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093
| | - Minh-Ha T. Do
- Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093
| | - Mark A. Lawson
- Department of Reproductive Medicine, University of California, San Diego, La Jolla, CA 92093
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20
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Eyvazzadeh AD, Pennington KP, Pop-Busui R, Sowers M, Zubieta JK, Smith YR. The role of the endogenous opioid system in polycystic ovary syndrome. Fertil Steril 2009; 92:1-12. [PMID: 19560572 DOI: 10.1016/j.fertnstert.2009.05.012] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2008] [Revised: 04/29/2009] [Accepted: 05/07/2009] [Indexed: 11/18/2022]
Abstract
OBJECTIVE To review the complex role of the opioid system in reproduction and carbohydrate metabolism, abnormalities in the opioid system in women with polycystic ovary syndrome (PCOS), and the role of opioid antagonists in the management of PCOS-related infertility. DESIGN Pertinent articles were identified through a computer PubMed search. References of selected articles were hand searched for additional citations. CONCLUSION(S) Endogenous opioids are generally considered inhibitory central neurotransmitters. Peripherally, opioids are involved in the regulation of pancreatic islet function, hepatic insulin clearance, and glucose metabolism, potentially contributing to the pathogenesis of hyperinsulinemia and insulin resistance in PCOS. The presence of sex steroids is required for normal function of the opioid system in both GnRH secretion and carbohydrate metabolism. In women with PCOS, growing evidence suggests dysregulation of the opioid system both centrally and peripherally, with complex interactions. The opioid system effects on carbohydrate metabolism appear to be modulated by obesity. Finally, naltrexone has been demonstrated to successfully augment traditional ovulation induction regimens, but has limited support as a single ovulation induction agent for PCOS.
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Affiliation(s)
- Aimee D Eyvazzadeh
- Department of Obstetrics and Gynecology, School of Medicine and School of Public Health, University of Michigan, 1500 East Medical Center Drive, Women's Hospital, Ann Arbor, MI 48109-0276, USA
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21
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Suppression and recovery of gonadotropin and steroid secretion by a gonadotropin-releasing hormone receptor antagonist in healthy women with normal ovulation versus women with polycystic ovary syndrome in the early follicular phase. Fertil Steril 2009; 91:1857-63. [DOI: 10.1016/j.fertnstert.2008.02.120] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2007] [Revised: 02/11/2008] [Accepted: 02/12/2008] [Indexed: 11/24/2022]
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Olivares A, Méndez JP, Cárdenas M, Oviedo N, Palomino MA, Santos I, Perera-Marín G, Gutiérrez-Sagal R, Ulloa-Aguirre A. Pituitary-testicular axis function, biological to immunological ratio and charge isoform distribution of pituitary LH in male rats with experimental diabetes. Gen Comp Endocrinol 2009; 161:304-12. [PMID: 19523385 DOI: 10.1016/j.ygcen.2008.12.021] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2008] [Revised: 12/02/2008] [Accepted: 12/03/2008] [Indexed: 01/23/2023]
Abstract
Men with insulinopenic diabetes mellitus frequently present hypogonadism and exhibit circulating luteinizing hormone (LH) molecules with increased biological activity. To further study this latter issue, we analyzed the pattern of isoform distribution and the impact of changes in terminal glycosylation of pituitary LH on the bioactivity of this gonadotropin in experimental diabetes. Adult male rats were treated with streptozotocin or vehicle and euthanized on days 30, 60, or 90 posttreatment. All diabetic groups exhibited a significant decrease in serum insulin and testosterone levels as well as in sperm count; serum gonadotropins and 17beta-estradiol decreased only after 90 days of insulinopenia. Both the immunoreactive concentrations and the biological to immunological ratio of intrapituitary LH significantly increased in all experimental groups, as assessed by an in vitro homologous bioassay in HEK-293 cells expressing a recombinant LH receptor. Chromatofocusing of pituitary extracts revealed the presence of multiple LH charge isoforms; the pH distribution profile of LH in diabetic and control rats was indistinguishable on days 30 and 60 posttreatment. By contrast, the abundance of more basic isoforms (pH 9.99-9.0) decreased and that of isoforms with pH values 8.99-8.0 increased in rats with long-standing diabetes compared to controls. It is concluded that experimental diabetes alters the function of the pituitary-testicular axis, resulting in reduced sex steroids levels and hypogonadotropism. Long-standing insulinopenia leads to a paradoxical accumulation of intrapituitary LH molecules enriched in bioactivity with altered terminal glycosylation, which are apparently subserved by distinct mechanisms involving altered hypothalamic and/or gonadal inputs on the gonadotrope.
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Affiliation(s)
- Aleida Olivares
- Research Unit in Developmental Biology, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, 06720 México D.F., Mexico.
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Bordini B, Littlejohn E, Rosenfield RL. Blunted sleep-related luteinizing hormone rise in healthy premenarcheal pubertal girls with elevated body mass index. J Clin Endocrinol Metab 2009; 94:1168-75. [PMID: 19190110 PMCID: PMC2682481 DOI: 10.1210/jc.2008-1655] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
OBJECTIVE Our objective was to determine whether excessive adiposity is associated with alteration of the normal hormonal changes of early pubertal girls. DESIGN AND PARTICIPANTS Healthy 6.4- to 9.5-yr-old, prepubertal (PRE, n = 20) and 9.4- to 13.0-yr-old pubertal premenarcheal volunteers (PUB, n = 20) were divided into excessive-weight (EW) or normal-weight (NW) groups according to the 85th percentile body mass index. INTERVENTIONS AND SETTING: Overnight blood sampling; GnRH agonist (GnRHag), low-dose ACTH, oral glucose tolerance tests, and pelvic ultrasonograms were performed in our Clinical Research Center. RESULTS EW girls were similar in age and baseline and ACTH- and GnRHag-stimulated androgen levels to stage-matched NW girls. However, the sleep-related LH rise was blunted in EW-PUB girls compared with NW-PUB girls. The sleep-related rise of mean LH in EW-PUB [0.68 +/- 0.35 (sem) U/liter] was insignificant, less than that of NW-PUB (2.1 +/- 0.45, P < 0.05) and not significantly different from that of PRE girls (0.08+/-0.03). EW-PUB had slower LH pulse frequency and a lower rise in LH pulse amplitude during sleep than NW-PUB girls (both P < 0.05). Overnight FSH patterns paralleled LH patterns, whereas estradiol levels were similar in stage-matched NW and EW groups, differing between stages as expected. Early morning and peak LH, FSH, and estradiol responses to GnRHag were similar in EW-PUB and NW-PUB and significantly greater than those of PRE girls. CONCLUSIONS Healthy EW-PUB girls have significantly blunted sleep-related LH production. These data suggest that excess adiposity, in the absence of sex steroid excess, may subtly suppress hypothalamic-pituitary-gonadal function in premenarcheal pubertal girls.
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Affiliation(s)
- Brian Bordini
- Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, The University of Chicago Pritzker School of Medicine, Chicago, Illinois 60637, USA.
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24
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Abstract
PURPOSE OF REVIEW As the prevalence of pediatric obesity escalates, polycystic ovary syndrome is an increasingly common morbidity for adolescent females. This review describes recent insights into the pathophysiology and treatment of polycystic ovary syndrome, with special attention given to the relationship between polycystic ovary syndrome and obesity. RECENT FINDINGS Recent research has elucidated three key concepts in our understanding of polycystic ovary syndrome. First, patients may enter the hyperandrogenism-hyperinsulinism cycle of polycystic ovary syndrome via several pathways, including genetic polymorphisms that affect androgen synthesis, fetal programming that alters lipid and glucose metabolism, and obesity accompanied by insulin resistance. Second, obesity plays a significant role in the pathophysiology of polycystic ovary syndrome by increasing free androgen concentrations through multiple mechanisms. Finally, just as the etiology of polycystic ovary syndrome is multifactorial, successful treatment will probably require a combination of lifestyle modification and therapeutic interventions. SUMMARY Obesity contributes to the pathophysiology of polycystic ovary syndrome and increases the likelihood of associated metabolic and cardiovascular morbidities.
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Affiliation(s)
- Takara Stanley
- MassGeneral Hospital for Children and Harvard Medical School, Boston, Massachusetts 02114, USA.
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25
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Furukuma S, Onuma T, Swanson P, Luo Q, Koide N, Okada H, Urano A, Ando H. Stimulatory Effects of Insulin-Like Growth Factor 1 on Expression of Gonadotropin Subunit Genes and Release of Follicle-Stimulating Hormone and Luteinizing Hormone in Masu Salmon Pituitary Cells Early in Gametogenesis. Zoolog Sci 2008; 25:88-98. [DOI: 10.2108/zsj.25.88] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2007] [Accepted: 09/01/2007] [Indexed: 11/17/2022]
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26
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Eertmans F, Dhooge W, De Wever O, Bracke M, Comhaire F, Kaufman JM. Estrogen receptor alpha (ERalpha) and insulin-like growth factor I receptor (IGF-IR) cross-talk in the gonadotropic alphaT3-1 cell line. J Cell Physiol 2007; 212:583-90. [PMID: 17458895 DOI: 10.1002/jcp.21053] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
In reproductive tissues such as the breast and the uterus, cell proliferation and differentiation is strongly regulated by complex interactions between estrogen receptor alpha (ERalpha) and growth factor receptors. In the present study, we investigated the potential occurrence of such cross-talk in the murine, gonadotropic alphaT3-1 cell line, which expresses ERalpha and the IGF-I receptor (IGF-IR). Under estrogen-free conditions, basal cell proliferation and ER-mediated gene transcription was strongly inhibited by the selective estrogen receptor modulator (SERM) 4-hydroxy-tamoxifen (4-OH-Tam) and by the pure anti-estrogen ICI 182,780 (ICI). These effects can be reversed by either 17-beta-estradiol (E(2)) or insulin-like growth factor I (IGF-I), both exerting modest mitogenic effects in the alphaT3-1 cell line. Furthermore, IGF-I enhanced both basal and E(2)-induced ER-driven gene transcription. This may be explained, at least in part, by enhanced phosphorylation of ERalpha at serine 118, a prerequisite for the transactivation capacity of the receptor. Finally, the IGF-I-induced response on cell growth and ER-mediated transactivation can be inhibited with either ICI or 4-OH-Tam. In conclusion, our data indicate IGF-IR and ER interactions in the alphaT3-1 cell line, an in vitro model for the pituitary gonadotrophs, hereby suggesting a role of IGF-I in the regulation of gonadotropin synthesis and secretion.
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Affiliation(s)
- Frank Eertmans
- Department of Endocrinology, 6K12IE, Ghent University Hospital, De Pintelaan 185, Ghent, Belgium.
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27
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Eppler E, Jevdjovic T, Maake C, Reinecke M. Insulin-like growth factor I (IGF-I) and its receptor (IGF-1R) in the rat anterior pituitary. Eur J Neurosci 2007; 25:191-200. [PMID: 17241280 DOI: 10.1111/j.1460-9568.2006.05248.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Few and controversial results exist on the cellular sites of insulin-like growth factor (IGF)-I synthesis and the type 1 IGF receptor (IGF-1R) in mammalian anterior pituitary. Thus, the present study analysed IGF-I and the IGF-1R in rat pituitary. Reverse transcription-polymerase chain reaction revealed IGF-I and IGF-1R mRNA expression in pituitary. The sequences of both were identical to the corresponding sequences in other rat organs. In situ hybridization localized IGF-I mRNA in endocrine cells. The majority of the growth hormone (GH) cells and numerous adrenocorticotropic hormone (ACTH) cells exhibited IGF-1R-immunoreactivity at the cell membrane. At lower densities, IGF-1 receptors were also present at the other hormone-producing cell types, indicating a physiological impact of IGF-I for all endocrine cells. IGF-I-immunoreactivity was located constantly in almost all ACTH-immunoreactive cells. At the ultrastructural level, IGF-I-immunoreactivity was confined to secretory granules in co-existence with ACTH-immunoreactivity, indicating a concomitant release of both hormones. Occasionally, IGF-I-immunoreactivity was detected in an interindividually varying number of GH cells. In some individuals, weak IGF-I-immunoreactions were also detected also in follicle-stimulating hormone and luteinizing hormone cells. Thus, IGF-I seems to be produced as a constituent in ACTH cells, possibly indicating its particular importance in stress response. Generally, IGF-I from the endocrine cells may regulate synthesis and/or release of hormones in an autocrine/paracrine manner as well as prevent apoptosis and stimulate proliferation. Production of IGF-I in GH cells may depend on the physiological status, most likely the serum IGF-I level. IGF-I released from GH cells may suppress GH synthesis and/or release by an autocrine feedback mechanism in addition to the endocrine route.
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Affiliation(s)
- Elisabeth Eppler
- Division of Neuroendocrinology, Institute of Anatomy, University of Zürich, Winterthurerstr. 190, CH-8057 Zürich, Switzerland
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28
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Eppler E, Shved N, Moret O, Reinecke M. IGF-I is distinctly located in the bony fish pituitary as revealed for Oreochromis niloticus, the Nile tilapia, using real-time RT-PCR, in situ hybridisation and immunohistochemistry. Gen Comp Endocrinol 2007; 150:87-95. [PMID: 16963049 DOI: 10.1016/j.ygcen.2006.07.013] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2006] [Revised: 07/14/2006] [Accepted: 07/23/2006] [Indexed: 01/01/2023]
Abstract
In bony fish, IGF-I released from the liver under the control of pituitary GH is the main endocrine regulator of growth, maintenance and development, and the amount of circulating IGF-I regulates synthesis and release of GH. In mammals and amphibia, evidence indicates that anterior pituitary endocrine cells also contain IGF-I. However, only preliminary and conflicting data exist on IGF-I gene expression in bony fish pituitary. Thus, we investigated the presence of IGF-I in the tilapia (Oreochromis niloticus) pituitary by quantitative real-time RT-PCR, in situ hybridisation and immunohistochemistry. The absolute amount of IGF-I mRNA in the whole pituitary (7.4+/-3.3 x 10(-3)pg/microg total RNA) was 1000-times lower than in liver (7.5+/-3.1 pg/microg total RNA). IGF-I peptide occurred in both neuro- and adenohypophysis but IGF-I gene expression was mainly restricted to the adenohypophysis. In the neurohypophysis, only few cells, probably pituicytes, contained IGF-I mRNA whereas IGF-I peptide was found also in numerous axons in the pars nervosa. In the adenohypophysis, both IGF-I mRNA and peptide were present in the majority of ACTH cells in all individuals investigated. In alpha-MSH cells, only IGF-I mRNA but no IGF-I peptide was detected likely suggesting an immediate release of IGF-I after synthesis. IGF-I mRNA and peptide were further observed in GH cells but their presence showed pronounced inter-individual differences likely due to the physiological, e.g., nutritional, status of the individual. IGF-I released from the GH cells may serve as auto/paracrine mediator of a negative feedback mechanism in addition to liver-derived endocrine IGF-I. Generally, the constitutive synthesis of IGF-I in ACTH cells and the varying content in GH and alpha-MSH cells suggest particular roles for IGF-I. Local IGF-I may regulate synthesis and release of pituitary hormones in an autocrine and/or paracrine manner as well as prevent apoptosis and stimulate proliferation of endocrine cells.
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Affiliation(s)
- Elisabeth Eppler
- Division of Neuroendocrinology, Institute of Anatomy, University of Zürich, Winterthurerstr. 190, CH-8057 Zürich, Switzerland.
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29
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Littlejohn EE, Weiss RE, Deplewski D, Edidin DV, Rosenfield R. Intractable early childhood obesity as the initial sign of insulin resistant hyperinsulinism and precursor of polycystic ovary syndrome. J Pediatr Endocrinol Metab 2007; 20:41-51. [PMID: 17315528 DOI: 10.1515/jpem.2007.20.1.41] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
OBJECTIVE We report that intractable early childhood obesity may be associated with severe insulin resistance syndromes (pseudo-Cushing's syndrome and pseudo-acromegaly) and precede polycystic ovary syndrome (PCOS). STUDY DESIGN/RESULTS Patient 1 had prepubertal obesity followed by early puberty and was diagnosed with pseudo-Cushing's syndrome and insulin resistance at 10.3 years. Oligomenorrhea, androgen excess, and type 2 diabetes mellitus (DM2) emerged at 13.5 years. Patient 2 developed intractable prepubertal obesity followed by atypical true sexual precocity and pseudo-Cushing's syndrome in early childhood. By 11.3 years, oligomenorrhea, androgen excess, and DM2 had appeared. Patient 3 had prepubertal overgrowth in weight and height and was diagnosed with pseudo-acromegaly, menstrual irregularity, androgen excess, and impaired glucose tolerance at 14.3 years of age. Patient 4 had prepubertal overgrowth that evolved into pseudo-acromegaly, insulin resistance, secondary amenorrhea, and androgen excess at 15.6 years. CONCLUSIONS Intractable prepubertal obesity was recognized to culminate in early childhood pseudo-Cushing's syndrome or pseudo-acromegaly, which are manifestations of insulin-resistant hyperinsulinism, and to herald adolescent PCOS.
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Affiliation(s)
- Elizabeth E Littlejohn
- University of Chicago, Pritzker School of Medicine, Department of Pediatrics, Section of Pediatric Endocrinology, 5841 S. Maryland Avenue, IL 60637, USA.
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30
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Weiss JM, Xia YX, Polack S, Diedrich K, Ortmann O. Short-term effects of IGF-I and estradiol on LH secretion from female rat gonadotrophs. Growth Horm IGF Res 2006; 16:357-364. [PMID: 17070717 DOI: 10.1016/j.ghir.2006.09.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2006] [Revised: 09/12/2006] [Accepted: 09/15/2006] [Indexed: 11/26/2022]
Abstract
OBJECTIVE Growth factors and ovarian steroids modulate LH-secretion from pituitary gonadotrophs. Our previous studies demonstrated that long-term IGF-I treatment enhanced LH-secretion from female rat pituitary cells and estradiol facilitated this effect. The effects of estradiol on LH secretion are time-dependent. Short-term treatment inhibited, long-term treatment enhanced GnRH-induced LH-secretion in serum-containing medium. Here we tested the short-term actions of IGF-I and its interaction with estradiol and whether IGF-I is a prerequisite for the negative effect of short-term estradiol treatment in female rat pituitary cells. DESIGN Pituitary cells were incubated with a series of increasing concentrations of estradiol (1 pM, 10 pM, 50 pM, 100 pM, 500 pM, 1 nM, 10 nM and 100 nM) for 4 h, IGF-I (10 pM, 100 pM, 1 nM and 10 nM) for 4 h and 14 h and their combinations for 4h in serum-free medium, and then stimulated with 1 nM GnRH during the last 3h of incubation. To clarify the role of IGF-I, cells were incubated simultaneously with estradiol, IGF-I and antibody against IGF-I. LH was measured by radioimmunoassay. RESULTS Short-term IGF-I treatment did not modify basal or GnRH-induced LH-secretion. Short-term treatment with estradiol did not affect basal or GnRH-induced LH-secretion in serum-free medium. The addition of 100 pM IGF-I to serum-free medium established the negative effect of estradiol short-term treatment on GnRH-induced LH-secretion. The addition of IGF-I antibody fully abolished the negative effect of estradiol. CONCLUSIONS In conclusion, effects of IGF-I on LH-secretion in female rat pituitary cells require long-term treatment. The negative effect of estradiol short-term treatment on GnRH-induced LH-secretion is dependent on serum-containing medium or the addition of 100 pM IGF-I to serum-free medium.
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Affiliation(s)
- J-M Weiss
- Department of Obstetrics and Gynaecology, Medical University of Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany.
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31
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Ando H, Luo Q, Koide N, Okada H, Urano A. Effects of insulin-like growth factor I on GnRH-induced gonadotropin subunit gene expressions in masu salmon pituitary cells at different stages of sexual maturation. Gen Comp Endocrinol 2006; 149:21-9. [PMID: 16765954 DOI: 10.1016/j.ygcen.2006.04.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2005] [Revised: 04/17/2006] [Accepted: 04/30/2006] [Indexed: 10/24/2022]
Abstract
Effects of insulin-like growth factor I (IGF-I) and salmon gonadotropin-releasing hormone (sGnRH) on expression of gonadotropin (GTH) subunit genes were examined using primary pituitary cell cultures of masu salmon (Oncorhynchus masou). Fishes were assessed at three reproductive stages, i.e., in April (early maturation), in June (maturing), and in September (spawning). Amounts of GTH subunit mRNAs in pituitary cells were determined using real-time PCR after incubation with IGF-I and/or sGnRH. IGF-I alone had almost no effects on three GTH subunit mRNAs in both sexes, except for decrease in follicle-stimulating hormone (FSH) beta mRNA in males in June. sGnRH alone was effective in stimulation of FSHbeta and luteinizing hormone (LH) beta gene expression in males in April. Thereafter it had no significant effects on GTH subunit mRNAs, although in September it tended to increase FSHbeta and LHbeta mRNAs in females. Co-administered IGF-I counteracted the sGnRH-induced expression of FSHbeta and LHbeta genes in males in April, but not in females in September. These results suggest that IGF-I is involved in direct regulation of GTH subunit genes during sexual maturation. In particular, IGF-I differently modulates sGnRH-induced GTH subunit gene expression, depending on reproductive stages.
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Affiliation(s)
- Hironori Ando
- Division of Biological Sciences, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan.
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32
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Buggs C, Weinberg F, Kim E, Wolfe A, Radovick S, Wondisford F. Insulin augments GnRH-stimulated LHbeta gene expression by Egr-1. Mol Cell Endocrinol 2006; 249:99-106. [PMID: 16530935 PMCID: PMC3464308 DOI: 10.1016/j.mce.2006.02.001] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2005] [Revised: 02/01/2006] [Accepted: 02/01/2006] [Indexed: 11/29/2022]
Abstract
Previous studies have shown that insulin augments GnRH-stimulated LH synthesis and release from primary gonadotrophs. In this study, regulation of LHbeta gene expression by GnRH and insulin was examined in LbetaT2 cells. Endogenous LHbeta mRNA is stimulated 2.4-fold by insulin alone, 2.6-fold by GnRH alone, and 4.7-fold by insulin together with GnRH. This effect of insulin, like GnRH, mapped to sequences -140 to +1 in the mouse LHbeta gene. Insulin together with GnRH stimulates activity of an LHbeta-reporter gene 7.1-fold; whereas, GnRH alone or insulin alone stimulates the reporter activity 2.8- and 3.1-fold, respectively. Blocking the binding of Egr-1 to sequences -51 to -42 in the LHbeta gene inhibits effects of insulin and GnRH. Insulin together with GnRH increases Egr-1 mRNA levels and total Egr-1 binding to LHbeta DNA. These findings indicate that insulin may impact regulation of the reproductive axis at the level of the pituitary.
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Affiliation(s)
- Colleen Buggs
- Department of Pediatrics, Section of Pediatric Endocrinology, University of Chicago Children's Hospital, Chicago, IL 60637, USA.
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33
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Veldhuis JD, Roemmich JN, Richmond EJ, Bowers CY. Somatotropic and gonadotropic axes linkages in infancy, childhood, and the puberty-adult transition. Endocr Rev 2006; 27:101-40. [PMID: 16434512 DOI: 10.1210/er.2005-0006] [Citation(s) in RCA: 169] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Integrative neuroendocrine control of the gonadotropic and somatotropic axes in childhood, puberty, and young adulthood proceeds via multiple convergent and divergent pathways in the human and experimental animal. Emerging ensemble concepts are required to embody independent, parallel, and interacting mechanisms that subserve physiological adaptations and pathological disruption of reproduction and growth. Significant advances in systems biology will be needed to address these challenges.
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Affiliation(s)
- Johannes D Veldhuis
- Endocrine Research Unit, Department of Internal Medicine, Mayo Medical School, Mayo School of Graduate Medical Education, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905, USA.
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DERAR RI, HARAMAKI S, HOQUE SM, HASHIZUME T, OSAWA T, TAYA K, WATANABE G, MIYAKE YI. Immunoreactive Insulin-Like Growth Factor in Plasma during Pre- and Post-Partum Periods of Thoroughbred Mares from which the Newborn were Removed: its Pattern, Physiological Function and Relation to Other Hormones. J Equine Sci 2006. [DOI: 10.1294/jes.17.75] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
Affiliation(s)
- Refaat I. DERAR
- Department of Theriogenology, Faculty of Veterinary Medicine, Assiut University
- Laboratory of Theriogenology, Faculty of Agriculture, Iwate University
| | | | - Shafiqul M.D. HOQUE
- Laboratory of Theriogenology, Faculty of Agriculture, Iwate University
- Clinical Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University
- Department of Medicine and Surgery, Sylhet Govt. Veterinary College
| | - Tsutomu HASHIZUME
- Laboratory of Animal Breeding and Reproduction, Faculty of Agriculture, Iwate University
| | - Takeshi OSAWA
- Laboratory of Theriogenology, Faculty of Agriculture, Iwate University
- Clinical Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University
| | - Kazuyoshi TAYA
- Clinical Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University
- Laboratory of Veterinary Physiology, Tokyo University of Agriculture and Technology
| | - Gen WATANABE
- Clinical Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University
- Laboratory of Veterinary Physiology, Tokyo University of Agriculture and Technology
| | - Yoh-Ichi MIYAKE
- Laboratory of Theriogenology, Faculty of Agriculture, Iwate University
- Clinical Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University
- Laboratory of Theriogenology, Obihiro University of Agriculture and Veterinary Medicine
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35
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Yang D, Caraty A, Dupont J. Molecular mechanisms involved in LH release by the ovine pituitary cells. Domest Anim Endocrinol 2005; 29:488-507. [PMID: 16153499 DOI: 10.1016/j.domaniend.2005.02.015] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2004] [Revised: 02/14/2005] [Accepted: 02/22/2005] [Indexed: 11/15/2022]
Abstract
The luteinizing hormone-releasing hormone (LHRH) is a hypothalamic decapeptide and main positive regulator of luteinizing hormone (LH) secretion from pituitary cells. Insulin-like growth factor-I (IGF-1) also stimulates LH release and enhances the effect of LHRH. However, the molecular mechanisms involved in the interactions between LHRH and IGF-1 are unclear. Here, we first determined the effect of various types of LHRH [I (mammalian), II (chicken), III (lamprey), hyp9 and salmon] on both LH secretion and activation of MAPK (ERK1/2 and p38) in ovine pituitary cells. After 3h of treatment, LH secretion was significantly higher for LHRH-I than for the other LHRH tested. Interestingly, LHRH-III had no effect at any concentration used on the LH release by ovine pituitary cells. The phosphorylation of both MAPK ERK1/2 and p38 was also significantly higher after treatment with LHRH-I than LHRH-II, salmon LHRH or hyp9. These MAPKs were not activated or only very weakly activated by LHRH-III. We then used pharmacological inhibitors to show that MAPK ERK1/2 and PKCdelta participate in the LH release by ovine pituitary cells in response to LHRH-I. We identified the main substrates and signaling pathways [PI3K/Akt and MAPK (ERK1/2, p38 and JNK1/2] of IGF-1R and investigated the effect of IGF-1 on the stimulation of ovine pituitary cell LH secretion by the various LHRH. IGF-1 increases LH secretion in response to LHRH-I, LHRH-II, hyp9 and salmon LHRH but not the secretion after treatment with LHRH-III. Using specific inhibitors, we found that the MAPK ERK1/2 but not the PI3K/Akt signaling pathway is involved in the LH secretion in response to IGF-1. This is the first description of a common molecular mechanism, involving the MAPK ERK1/2, by which LHRH-R and IGF-1-R induce LH secretion in ovine pituitary cells.
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Affiliation(s)
- Dominique Yang
- Unité de Physiologie de la Reproduction et des Comportements, Institut National de la Recherche Agronomique, Nouzilly, France
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Kiyma Z, Alexander BM, Van Kirk EA, Murdoch WJ, Hallford DM, Moss GE. Effects of feed restriction on reproductive and metabolic hormones in ewes. J Anim Sci 2005; 82:2548-57. [PMID: 15446470 DOI: 10.2527/2004.8292548x] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
The goal of this study was to determine the effects of short-term feed withdrawal on reproductive and metabolic hormones during the luteal phase of the estrous cycle in mature ewes. Mature ewes observed in estrus were assigned randomly to control and fasted groups (n = 10 per group Trials 1 and 2). For Trials 1 and 2, control ewes had ad libitum access to feed, whereas fasted ewes were not fed from d 7 through 11 of their estrous cycle; on d 12, all ewes were treated with 10 mg of PGF2alpha, and fasted ewes were gvien ad libitum access to feed. For Trial 1, blood samples were collected daily through fasting and at 2-h intervals following PGF2alpha for 72 h. Serum concentrations of insulin (P < or = 0.002) and IGF-I (P < or = 0.01), but not GH (P > or = 0.60), were decreased during fasting compared with fed ewes. Serum concentrations of 29 (P = 0.02) and 34 kDa (P = 0.04) IGFBP were greater in fasted ewes at 96 h after initiation of fasting than in control ewes. Two control and four fasted ewes in Trial 1 did not exhibit a preovulatory surge release of LH by 72 h. Therefore, Trial 2 was conducted so that the timing of the LH surge could be predicted following the collection of blood samples at 2-h intervals for 112 h and then at 6-h intervals until 178 h following PGF2alpha administration and realimentation. The magnitude of the preovulatory LH surge in Trial 2 was decreased (P = 0.009) and delayed (P = 0.04), and serum concentrations of estradiol were diminished (P < or = 0.03) 12 h before the LH surge in fasted ewes. Ovulation rates were not influenced (P > or = 0.32) by fasting in Trials 1 and 2. Serum concentrations of progesterone in both Trials 1 and 2 were, however, greater (P < 0.001) in fasted than in control ewes. A third trial with ovariectomized ewes was conducted to determine whether the increased serum concentrations of progesterone observed in fasted ewes during Trials 1 and 2 were ovarian-derived. Ovariectomized ewes were implanted with progesterone-containing intravaginal implants and allotted to control (n = 5) or fasted (n = 5) treatment groups and fed as described for Trials 1 and 2. Similar to intact ewes, serum concentrations of progesterone were approximately twofold greater (P < 0.001) in fasted than in control implanted ovariectomized ewes. In summary, feed withdrawal for 5 d during the luteal phase of the estrous cycle increased serum concentrations of progesterone and evoked endocrine changes that could perturb the subsequent estrous cycle.
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Affiliation(s)
- Z Kiyma
- Department of Animal Science, University of Wyoming, Laramie 82071, USA
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Rose A, Froment P, Perrot V, Quon MJ, LeRoith D, Dupont J. The luteinizing hormone-releasing hormone inhibits the anti-apoptotic activity of insulin-like growth factor-1 in pituitary alphaT3 cells by protein kinase Calpha-mediated negative regulation of Akt. J Biol Chem 2004; 279:52500-16. [PMID: 15448167 DOI: 10.1074/jbc.m404571200] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The luteinizing hormone-releasing hormone (LHRH) receptor is a G protein-coupled receptor involved in the synthesis and release of pituitary gonadotropins and in the proliferation and apoptosis of pituitary cells. Insulin-like growth factor-1 receptor (IGF-1R) is a tyrosine kinase receptor that has a mitogenic effect on pituitary cells. In this study, we used the alphaT3 gonadotrope cell line as a model to characterize the IGF-1R signaling pathways and to investigate whether this receptor interacts with the LHRH cascade. We found that IGF-1 activated the IGF-1R, insulin receptor substrate (IRS)-1, phosphatidylinositol 3-kinase, and Akt in a time-dependent manner in alphaT3 cells. The MAPK (ERK1/2, p38, and JNK) pathways were only weakly activated by IGF-1. In contrast, LHRH strongly stimulated the MAPK pathways but had no effect on Akt activation. Cotreatment with IGF-1 and LHRH had various effects on these signaling pathways. 1) It strongly increased IGF-1-induced tyrosine phosphorylation of IRS-1 and IRS-1-associated phosphatidylinositol 3-kinase through activation of the epidermal growth factor receptor. 2) It had an additive effect on ERK1/2 activation without modifying the phosphorylation of p38 and JNK1/2. 3) It strongly reduced IGF-1 activation of Akt. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays and cell cycle analysis revealed that, in addition to having an additive effect on ERK1/2 activation, cotreatment with IGF-1 and LHRH also had an additive effect on cell proliferation. The LHRH-induced inhibition of Akt stimulated by IGF-1 was completely blocked by Safingol, a protein kinase C (PKC) alpha-specific inhibitor, and by a dominant negative form of PKCalpha. Finally, we showed that the inhibitory effect of LHRH on IGF-1-induced PKCalpha-mediated Akt activation was associated with a marked reduction in Bad phosphorylation and a substantial decrease in the ability of IGF-1 to rescue alphaT3 cells from apoptosis induced by serum starvation. Our results demonstrate for the first time that several interactions take place between IGF-1 and LHRH receptors in gonadotrope cells.
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Affiliation(s)
- Annabel Rose
- Unité de Physiologie de la Reproduction et des Comportements, Institut National de la Recherche Agronomique, 37380 Nouzilly, France
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Castilla-Cortazar I, Diez N, Garcia-Fernandez M, Puche JE, Diez-Caballero F, Quiroga J, Diaz-Sanchez M, Castilla A, Casares AD, Varela-Nieto I, Prieto J, Gonzalez-Baron S. Hematotesticular barrier is altered from early stages of liver cirrhosis: Effect of insulin-like growth factor 1. World J Gastroenterol 2004; 10:2529-34. [PMID: 15300898 PMCID: PMC4572155 DOI: 10.3748/wjg.v10.i17.2529] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: The pathogenesis of hypogonadism in liver cirrhosis is not well understood. Previous results from our laboratory showed that IGF-1 deficiency might play a pathogenetic role in hypogonadism of cirrhosis. The administration of IGF-1 for a short period of time reverted the testicular atrophy associated with advanced experimental cirrhosis. The aim of this study was to establish the historical progression of the described alterations in the testes, explore testicular morphology, histopathology, cellular proliferation, integrity of testicular barrier and hypophyso-gonadal axis in rats with no ascitic cirrhosis.
METHODS: Male Wistar rats with histologically-proven cirrhosis induced with carbon tetrachloride (CCl4) for 11 wk, were allocated into two groups (n = 12, each) to receive recombinant IGF-1 (2 μg/100 g.d, sc) for two weeks or vehicle. Healthy rats receiving vehicle were used as control group (n = 12).
RESULTS: Compared to controls, rats with compensated cirrhosis showed a normal testicular size and weight and very few histopathological testicular abnormalities. However, these animals showed a significant diminution of cellular proliferation and a reduction of testicular transferrin expression. In addition, pituitary-gonadal axis was altered, with significant higher levels of FSH (P < 0.001 vs controls) and increased levels of LH in untreated cirrhotic animals. Interestingly, IGF-1 treatment normalized testicular transferrin expression and cellular proliferation and reduced serum levels of LH (P = ns vs controls, and P < 0.01 vs untreated cirrhotic group).
CONCLUSION: The testicular barrier is altered from an early stage of cirrhosis, shown by a reduction of transferrin expression in Sertoli cells, a diminished cellular proliferation and an altered gonadal axis. The treatment with IGF-1 could be also useful in this initial stage of testicular disorder associated with compensated cirrhosis.
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Affiliation(s)
- Inma Castilla-Cortazar
- Department of Human Physiology, School of Medicine, University of Navarra, Pamplona, Spain.
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Schröder AK, Tauchert S, Ortmann O, Diedrich K, Weiss JM. Die Insulinresistenz beim polyzystischen Ovar-Syndrom. Wien Klin Wochenschr 2003; 115:812-21. [PMID: 14740344 DOI: 10.1007/bf03041041] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
With a prevalence of 5-10% the polycystic ovary syndrome (PCOS) is a common disorder of premenopausal women. According to prospective studies abnormal glucose tolerance and diabetes mellitus present in about 10.0% and 35.0% of adult women with PCOS, respectively. PCOS patients have a higher prevalence of cardiovascular risk factors such as hypertension and dyslipidaemia. The rate of spontaneous abortions as well as the risk of developing gestational diabetes is increased in PCOS. Therefore, PCOS is not only a reproductive problem, but a complex endocrine disease with important health implications. The role of glucose metabolism in PCOS, the health consequences and possible interventions are reviewed in this article.
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Affiliation(s)
- Annika K Schröder
- Klinik für Frauenheilkunde und Geburtshilfe, Universitätsklinikum Schleswig-Hostein, Campus Lübeck, Lübeck, Deutschland
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Patel K, Coffler MS, Dahan MH, Yoo RY, Lawson MA, Malcom PJ, Chang RJ. Increased luteinizing hormone secretion in women with polycystic ovary syndrome is unaltered by prolonged insulin infusion. J Clin Endocrinol Metab 2003; 88:5456-61. [PMID: 14602789 DOI: 10.1210/jc.2003-030816] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
In PCOS women with insulin resistance, hyperinsulinemia may contribute to inappropriate gonadotropin secretion. To determine whether insulin influences gonadotropin release in PCOS, pulsatile LH secretion and gonadotropin responses to GnRH were evaluated before (phase 1) and during (phase 2) insulin infusion. In phase 1, 11 PCOS and 9 normal women on separate days underwent 1) frequent blood sampling (q 10 min) for 12 h and 2) gonadotropin stimulation by successive doses of GnRH, 2 microg, 10 microg, and 20 microg, administered i.v. at 4 h intervals over a continuous 12 h. In phase 2, studies were repeated 2 h after initiation of a 12-h hyperinsulinemic-euglycemic clamp (80 mU/m(2).min). Administration of insulin to both groups failed to alter mean serum gonadotropin concentrations, LH pulse frequency, or LH pulse amplitude. Moreover, gonadotropin responses to GnRH were unchanged by insulin infusion. In PCOS and normal women, a significant reduction of serum androstenedione was associated with insulin administration, whereas no differences were noted for the remaining androgens and estrogens measured. These findings demonstrated that in PCOS women, LH secretion and gonadotropin responses to GnRH were not influenced by insulin administration. Insulin infusion had little effect on steroid hormone production with the possible exception of androstenedione. These results suggest that inappropriate LH secretion in PCOS is not a direct consequence of insulin resistance and compensatory hyperinsulinemia.
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Affiliation(s)
- Ketan Patel
- Department of Reproductive Medicine, University of California, San Diego, La Jolla, California 92093, USA
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Liu F, Austin DA, Webster NJG. Gonadotropin-releasing hormone-desensitized LbetaT2 gonadotrope cells are refractory to acute protein kinase C, cyclic AMP, and calcium-dependent signaling. Endocrinology 2003; 144:4354-65. [PMID: 12960037 DOI: 10.1210/en.2003-0204] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Sustained exposure of gonadotropes to GnRH causes a pronounced desensitization of gonadotropin release, but the mechanisms involved are poorly understood. It is known that desensitization is associated with decreased GnRH receptor and Gq/11 levels in alphaT3-1 cells, but it is not known whether downstream signaling is impaired. We have shown previously that chronic stimulation of signaling via expression of an active form of Galphaq causes GnRH resistance in LbetaT2 cells. In this study we investigated whether chronic GnRH treatment could down-regulate protein kinase C (PKC), cAMP, or Ca2+-dependent signaling in LbetaT2 cells. We found that chronic GnRH treatment desensitizes cells to acute GnRH stimulation not only by reducing GnRH receptor and Gq/11 expression but also by down-regulating PKC, cAMP, and calcium-dependent signaling. Desensitization was observed for activation of ERK and p38 MAPK and induction of c-fos and LHbeta protein expression. Activation of individual signaling pathways was able to partially mimic the desensitizing effect of GnRH on ERK, p38 MAPK, c-fos, and LHbeta but not on Gq/11. Chronic stimulation with phorbol esters reduced GnRH receptor expression to the same extent as chronic GnRH. Sustained GnRH also desensitized PKC signaling by down-regulating the delta, epsilon, and theta isoforms of PKC. We further show that chronic GnRH treatment causes heterologous desensitization of other Gq-coupled receptors.
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Affiliation(s)
- Fujun Liu
- Department of Medicine, University of California San Diego Cancer Center, San Diego, California 92093, USA
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