Luteal activity of pregnant rats with hypo-and hyperthyroidism

Journal of Ovarian Research

Rogéria Serakides¹  Natália Melo Ocarino¹  Juneo Freitas Silva¹ 

[1] Departamento de Clínica e Cirurgia Veterinária, Escola de Veterinária, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, 31270-901 Belo Horizonte, MG, Brazil

关键词: Pregnancy;    Corpus luteum;    Hyperthyroidism;    Hypothyroidism;   

Others  :  1151823
DOI  :  10.1186/1757-2215-7-75

 received in 2014-02-24, accepted in 2014-07-08,  发布年份 2014

【 摘 要 】

Background

Luteal activity is dependent on the interaction of various growth factors, cytokines and hormones, including the thyroid hormones, being that hypo- and hyperthyroidism alter the gestational period and are also a cause of miscarriage and stillbirth. Because of that, we evaluated the proliferation, apoptosis and expression of angiogenic factors and COX-2 in the corpus luteum of hypo- and hyperthyroid pregnant rats.

Methods

Seventy-two adult female rats were equally distributed into three groups: hypothyroid, hyperthyroid and control. Hypo- and hyperthyroidism were induced by the daily administration of propylthiouracil and L-thyroxine, respectively. The administration began five days before becoming pregnant and the animals were sacrificed at days 10, 14, and 19 of gestation. We performed an immunohistochemical analysis to evaluate the expression of CDC-47, VEGF, Flk-1 (VEGF receptor) and COX-2. Apoptosis was evaluated by the TUNEL assay. We assessed the gene expression of VEGF, Flk-1, caspase 3, COX-2 and PGF2α receptor using real time RT-PCR. The data were analyzed by SNK test.

Results

Hypothyroidism reduced COX-2 expression on day 10 and 19 (P < 0.05), endothelial/pericyte and luteal cell proliferation on day 10 and 14 (p < 0.05), apoptotic cell numbers on day 19 (p < 0.05) and the expression of Flk-1 and VEGF on day 14 and 19, respectively (p < 0.05). Hyperthyroidism increased the expression of COX-2 on day 19 (P < 0.05) and the proliferative activity of endothelial/pericytes cells on day 14 (p <0.05), as well as the expression of VEGF and Flk-1 on day 19 (P < 0.05).

Conclusions

Hypothyroidism reduces the proliferation, apoptosis and expression of angiogenic factors and COX-2in the corpus luteum of pregnant rats, contrary to what is observed in hyperthyroid animals, being this effect dependent of the gestational period.

【 授权许可】

   
2014 Silva et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

Figure 8.

【 参考文献 】

• [1]Bazer FW, Burghardt RC, Johnson GA, Spencer TE, Wu G: Interferons and progesterone for establishment and maintenance of pregnancy: interactions among novel cell signaling pathways. Reprod Biol 2008, 8:179-211.
• [2]Jewgenow K, Amelkina O, Painer J, Göritz F, Dehnhard M: Life cycle of feline corpora lutea: histological and intraluteal hormone analysis. Reprod Domest Anim 2012, 47:25-29.
• [3]Daya S: Luteal support: progestogens for pregnancy protection. Maturitas 2009, 65:S29-S34.
• [4]Choksi NY, Jahnke GD, Hilaire CS, Shelby M: Role of thyroid hormones in human and laboratory animal reproductive health. Birth Defects Res 2003, 68:479-491.
• [5]Shirasuna K, Nitta A, Sineenard J, Shimizu T, Bollwein H, Miyamoto A: Vascular and immune regulation of corpus luteum development, maintenance, and regression in the cow. Domest Anim Endocrinol 2012, 43:198-211.
• [6]Simpson KS, Byers MJ, Curry TE Jr: Spatiotemporal messenger ribonucleic acid expression of ovarian tissue inhibitors of metalloproteinases throughout the rat estrous cycle. Endocrinology 2001, 142:2058-2069.
• [7]Curry TE, Osteen KG: The matrix metalloproteinase system: changes, regulation, and impact throughout the ovarian and uterine reproductive cycle. Endocr Rev 2003, 24:428-465.
• [8]Stocco C, Telleria C, Gibori G: The molecular control of corpus luteum formation, function and regression. Endocr Rev 2007, 28:117-149.
• [9]Niswender GD, Juengel JL, Silva PJ, Rollyson MK, Mcintush EW: Mechanisms controlling the function and life span of the corpus luteum. Physiol Rev 2000, 80:1-29.
• [10]Sugino N, Okuda K: Species-related differences in the mechanism of apoptosis during structural luteolysis. J Reprod Dev 2007, 53:977-986.
• [11]Poppe K, Glinoer D: Thyroid autoimmunity and hypothyroidism before and during pregnancy. Hum Reprod Update 2003, 9:149-161.
• [12]Stagnaro-Green A: Overt hyperthyroidism and hypothyroidism during pregnancy. Clin Obstet Gynecol 2011, 54:478-487.
• [13]Freitas ES, Leite ED, Souza CA, Ocarino NM, Ferreira E, Cassali GD, Gomes MG, Serakides R: Histomorphometry and expressions of Cdc47 and Caspase-3 in hyperthyroid rats uteri and placentas during gestation and postpartum associated with fetal development. Reprod Fert Develop 2007, 19:498-509.
• [14]Silva JF, Vidigal PN, Galvão DD, Boeloni JN, Nunes PP, Ocarino NM, Nascimento EF, Serakides R: Fetal growth restriction in hypothyroidism is associated with changes in proliferative activity, apoptosis and vascularisation of the placenta. Reprod Fertil Dev 2012, 24:923-931.
• [15]Dalton S, Whitbread L: Cell cycle-regulated nuclear import and export of Cdc47, a protein essential for initiation of DNA replication in budding yeast. Proc Natl Acad Sci U S A 1995, 92:2514-2518.
• [16]Jänicke RU, Sprengart ML, Wati MR, Porter AG: Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis. J Biol Chem 1998, 273:9357-9360.
• [17]Ebisch IMW, Thomas CMG, Wetzels AMM, Willemsen WN, Sweep FC, Steegers-Theunissen RP: Review of the role of the plasminogen activator system and vascular endothelial growth factor in subfertility. Fertil Steril 2008, 90:2340-2350.
• [18]Reynolds LP, Borowicz PP, Vonnahme KA, Johnson ML, Grazul-Bilska AT, Wallace JM, Caton JS, Redmer DA: Animal models of placental angiogenesis. Placenta 2005, 26:689-708.
• [19]Miyamoto A, Shirasuna K, Sasahara K: Local regulation of corpus luteum development and regression in the cow: impact of angiogenic and vasoactive factor. Domest Anim Endocrinol 2009, 37:159-169.
• [20]Kosaka N, Sudo N, Miyamoto A, Shimizu T: Vascular endothelial growth factor (VEGF) suppresses ovarian granulosa cell apoptosis in vitro. Biochem Biophys Res Commun 2007, 363:733-737.
• [21]Arosh JA, Banu SK, Chapdelaine P, Madore E, Sirois J, Fortier MA: Prostaglandin biosynthesis, transport, and signaling in corpus luteum: a basis for autoregulation of luteal function. Endocrinology 2004, 145:2551-2560.
• [22]Kaczmarek MM, Schams D, Ziecik AJ: Role of vascular endothelial growth factor in ovarian physiology - an overview. Reprod Biol 2005, 5:111-136.
• [23]Sakurai T, Tamura K, Kogo H: Stimulatory effects of eicosanoids on ovarian angiogenesis in early luteal phase in cyclooxygenase-2 inhibitor-treated rats. Eur J Pharmacol 2005, 516:158-164.
• [24]Yeh J, Kim BS, Perisie J: Ovarian vascular endothelial growth factor and vascular endothelial growth factor receptor patterns in reproductive aging. Fertil Steril 2008, 89:1546-1556.
• [25]Rosato RR, Gimenez MS, Jahn GA: Effects of chronic thyroid hormone administration on pregnancy, lactogenesis and lactation in the rat. Acta Endocrinol 1992, 127:547-554.
• [26]Mattheij JA, Swarts JJ, Lokerse P, van Kampen JT, Van der Heide D: Effect of hypothyroidism on the pituitary-gonadal axis in the adult female rat. J Endocrinol 1995, 146:87-94.
• [27]Hatsuta M, Abe K, Tamura K, Ryuno T, Watanabe G, Taya K, Kogo H: Effects of hypothyroidism on the estrus cycle and reproductive hormones in mature female rat. Eur J Pharmacol 2004, 486:343-348.
• [28]Hapon MB, Simoncini M, Via G, Jahn GA: Effect of hypothyroidism on hormone profiles in virgin, pregnant and lactating rats, and on lactation. Reproduction 2003, 126:371-382.
• [29]Navas PB, Motta AB, Hapon MB, Jahn GA: Hyperthyroidism advances luteolysis in the pregnant rat through changes in prostaglandin balance. Fertil Steril 2011, 96:1008-1014.
• [30]Silva CM, Serakides R, Oliveira TS, Ocarino NM, Nascimento EF, Nunes VA: Histomorphometry and histochemistry of the ovaries, oviduct and uterus in hypothyroid rats in the metaestrus-diestrus. Arq Bras Endocrinol Metabol 2004, 56:628-639.
• [31]Serakides R, Nunes VA, Nascimento EF, Ribeiro AFC, Silva CM: Foliculogênese e esteroidogênese ovariana em ratas adultas hipertireóideas. Arq Bras Endocrinol Metabol 2001, 45:258-264.
• [32]Boeloni JN, Ocarino NM, Silva JF, Corrêa CR, Bertollo CM, Hell RC, Pereira MM, Goes AM, Serakides R: Osteogenic differentiation of bone marrow mesenchymal stem cells of ovariectomized and non-ovariectomized female rats with thyroid dysfunction. Pathol Res Pract 2013, 209:44-51.
• [33]Silva J, Ocarino N, Vieira A, Nascimento E, Serakides R: Effects of hypo- and hyperthyroidism on proliferation, angiogenesis, apoptosis and expression of COX-2 in the corpus luteum of female rats. Reprod Domest Anim 2013, 48:691-698.
• [34]Braden TB, Gamboni F, Niswender GB: Effects of prostaglandin F2 0-lnduced luteolysis on the populations of cells in the ovine corpus luteum. Biol Reprod 1988, 39:245-253.
• [35]Tsukada K, Matsushima T, Yamanaka N: Neovascularization of the corpus luteum of rats during the estrus cycle. Pathol Int 1996, 46:408-416.
• [36]Ma Y, Lovekamp-Swan T, Bekele W, Dohi A, Schreihofer DA: Hypoxia-inducible factor and vascular endothelial growth factor are targets of dietary soy during acute stroke in female rats. Endocrinology 2013, 154:1589-1597.
• [37]Oliveira-Pelegrin GR, Basso PJ, Soares AS, Martinez MR, Riester KD, Rocha MJ: Cleaved caspase-3 expression in hypothalamic magnocellular neurons may affect vasopressin secretion during experimental polymicrobial sepsis. J Neuroimmunol 2013, 258:10-16.
• [38]Araldi D, Ferrari LF, Lotufo CM, Vieira AS, Athié MC, Figueiredo JG, Duarte DB, Tambeli CH, Ferreira SH, Parada CA: Peripheral inflammatory hyperalgesia depends on the COX increase in the dorsal root ganglion. Proc Natl Acad Sci U S A 2013, 110:3603-3608.
• [39]Engstrom T: The regulation by ovarian steroids of prostaglandin synthesis and prostaglandin-induced contractility in non-pregnant rat myometrium. Modulating effects of isoproterenol. J Endocrinol 2001, 169:33-41.
• [40]Donnelly CJ, Park M, Spillane M, Yoo S, Pacheco A, Gomes C, Vuppalanchi D, McDonald M, Kim HH, Merianda TT, Gallo G, Twiss JL: Axonally synthesized β-actin and GAP-43 proteins support distinct modes of axonal growth. J Neurosci 2013, 33:3311-3322.
• [41]Macchiarelli G, Palmerini MG, Nottola SA, Cecconi S, Tanemura K, Sato E: Restoration of corpus luteum angiogenesis in immature hypothyroid rdw rats after thyroxine treatment: morphologic and molecular evidence. Theriogenology 2013, 79:116-126.
• [42]Pauli SA, Tang H, Wang J, Bohlen P, Posser R, Hartman T, Sauer MV, Kitajewski J, Zimmermann RC: The vascular endothelial growth factor (VEGF)/VEGF receptor 2 pathway is critical for blood vessel survival in corpora lutea of pregnancy in the rodent. Endocrinology 2005, 146:1301-1311.
• [43]Kashida S, Sugino N, Takiguchi S, Karube A, Takayama H, Yamagata Y, Nakamura Y, Kato H: Regulation and role of vascular endothelial growth factor in the corpus luteum during mid-pregnancy in rats. Biol Reprod 2001, 64:317-323.
• [44]Li Q, Wang H, Lin H, Shao L, Ni J, Duan E, Zhu C: Expression of vascular endothelial growth factor in rat ovary during pregnancy and postpartum. Sci China C Life Sci 2002, 45:379-387.
• [45]Bukovsky A, Caudlemr MR, Keenan JA, Wimalasena J, Upadhyaya NB, Van Meter SE: Is corpus luteum regression an immune-mediated event? Localization of immune system components and luteinizing hormone receptor in human corpora lutea. Biol Reprod 1995, 53:1373-1384.
• [46]Henkes LE, Sullivan BT, Lynch MP, Kolesnick R, Arsenault D, Puder M, Davis JS, Rueda BR: Acid sphingomyelinase involvement in tumor necrosis factor alpha-regulated vascular and steroid disruption during luteolysis in vivo. Proc Natl Acad Sci U S A 2008, 105:7670-7675.
• [47]Toft DJ, Linzer DI: Identification of three prolactin-related hormones as markers of invasive trophoblasts in the rat. Biol Reprod 2000, 63:519-525.
• [48]Hapon MB, Motta AB, Ezquer M, Bonafede M, Jahn GA: Hypothyroidism prolongs corpus luteum function in the pregnant rat. Reproduction 2007, 133:197-205.
• [49]Stocco C, Zhong L, Sugimoto Y, Ichikawa A, Lau LF, Gibori G: Prostaglandin F2α-induced expression of 20α-hydroxysteroid dehydrogenase involves the transcription factor NUR77. J Biol Chem 2000, 275:37202-37211.
• [50]Svensson EC, Markström E, Shao R, Andersson M, Billig H: Progesterone receptor antagonists Org 31710 and RU 486 increase apoptosis in human periovulatory granulosa cells. Fertil Steril 2001, 76:1225-1231.
• [51]Okuda K, Korzekwa A, Shibaya M, Murakami S, Nishimura R, Tsubouchi M, Woclawek-Potocka I, Skarzynski DJ: Progesterone is a suppressor of apoptosis in bovine luteal cells. Biol Reprod 2004, 71:2065-2071.
• [52]Young KA, Stouffer RL: Gonadotropin and steroid regulation of matrix metalloproteinases and their endogenous tissue inhibitors in the developed corpus luteum of the rhesus monkey during the menstrual cycle. Biol Reprod 2004, 70:244-252.
• [53]Carambula SF, Matikainen T, Lynch MP, Flavell RA, Gonçalves PB, Tilly JL, Rueda BR: Caspase-3 is a pivotal mediator of apoptosis during regression of the ovarian corpus luteum. Endocrinology 2002, 143:1495-1501.
• [54]Davis JS, Rueda BR: The corpus luteum: an ovarian structure with maternal instincts and suicidal tendencies. Front Biosci 2002, 1:d1949-d1978.
• [55]Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL: Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 1996, 16:4604-4613.
• [56]Wada Y, Osaki H, Abe N, Mori A, Sakamoto K, Nagamitsu T, Nakahara T, Ishii K: Role of vascular endotelial growth fator in maintenance of pregnancy in mice. Endocrinology 2013, 154:900-910.