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Journal of Assisted Reproduction and Genetics

Erschienen in:

23.01.2017 | Reproductive Physiology and Disease

Long-term effects of repeated superovulation on the uterus and mammary gland in rhesus monkeys

verfasst von: Peipei Yan, Jingyi Xu, Yan Zeng, Guoying Dong, Huarong Cao, Meimei Zheng, Hui Zhu

Erschienen in: Journal of Assisted Reproduction and Genetics | Ausgabe 4/2017

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Abstract

Purpose

The aim of this study is to evaluate the effect of repeated controlled ovarian hyperstimulation (COH) on the structure and function of the uterus and mammary gland.

Methods

Three adult female rhesus monkeys were superovulated up to four times, and three spontaneously ovulating monkeys were used as controls. After a 5-year period, the uterus and mammary gland tissue samples were collected for examination of their structure and function. Further, the expression of certain tumor markers was examined to assess the cancer risk for each organ.

Results

Expression of Wnt7a (associated with the functional/developmental status of the uterus) was significantly decreased in the uterus of superovulated monkeys, and decreased expression of proliferation marker PCNA was found in uterine cells. Meanwhile, abnormal Golgi-derived secretory vesicles with an irregular shape were observed in the mammary glands of the superovulated monkeys, and decreased PCNA expression together with increased expression of caspase-3 (an apoptosis marker) was indicated in the mammary cells. The expression of tumor molecular markers of the uterus and mammary gland was not significantly different between the two groups.

Conclusions

Repeated COH affects the expression of the uterine development-related gene several years later, and uterine cells exhibited a low proliferation status. The ultrastructure of the mammary gland epithelial cells was abnormal, and the cells exhibited both low proliferation and high apoptosis status. Cancer risk for these organs was not observed. Given that primates are the closest relatives of humans, the results obtained from this study provide more intuitive information for optimization of clinical COH.

Ge H, Tollner TL, Hu Z, Da M, Li X, Guan H, et al. Impaired mitochondrial function in murine oocytes is associated with controlled ovarian hyperstimulation and in vitro maturation. Reprod Fertil Dev. 2012;24:945–52.CrossRefPubMed

Burwinkel TH, Buster JE, Scoggan JL, Carson SA. Basal follicle stimulating hormone (FSH) predicts response to controlled ovarian hyperstimulation (COH)-intrauterine insemination (IUI) therapy. J Assist Reprod Genet. 1994;11:24–7.CrossRefPubMed

Luk J, Arici A. Does the ovarian reserve decrease from repeated ovulation stimulations? Curr Opin Obstet Gynecol. 2010;22:177–82.CrossRefPubMed

Diamond MP, DeCherney AH, Hill GA, Nero F, Wentz AC. Response to repetitive cycles of ovulation induction in the same women. J In Vitro Fert Embryo Transf. 1987;4:251–5.CrossRefPubMed

Chao HT, Lee SY, Lee HM, Liao TL, Wei YH, Kao SH. Repeated ovarian stimulations induce oxidative damage and mitochondrial DNA mutations in mouse ovaries. Ann N Y Acad Sci. 2005;1042:148–56.CrossRefPubMed

Di Luigi G, Rossi G, Castellucci A, Leocata P, Carta G, Canipari R, et al. Repeated ovarian stimulation does not affect the expression level of proteins involved in cell cycle control in mouse ovaries and fallopian tubes. J Assist Reprod Genet. 2014;31:717–24.PubMedPubMedCentral

Kalthur G, Salian SR, Nair R, Mathew J, Adiga SK, Kalthur SG, et al. Distribution pattern of cytoplasmic organelles, spindle integrity, oxidative stress, octamer-binding transcription factor 4 (Oct4) expression and developmental potential of oocytes following multiple superovulation. Reprod Fertil Dev. 2015;28:2027–2038.

Abbott DH, Foong SC, Barnett DK, Dumesic DA. Nonhuman primates contribute unique understanding to anovulatory infertility in women. ILAR J. 2004;45:116–31.CrossRefPubMed

Yang S, He X, Hildebrandt TB, Zhou Q, Ji W. Superovulatory response to a low dose single-daily treatment of rhFSH dissolved in polyvinylpyrrolidone in rhesus monkeys. Am J Primatol. 2007;69:1278–84.CrossRefPubMed

10.

Yang S, He X, Hildebrandt TB, Jewgenow K, Goeritz F, Tang X, et al. Effects of rhFSH dose on ovarian follicular response, oocyte recovery and embryo development in rhesus monkeys. Theriogenology. 2007;67:1194–201.CrossRefPubMed

11.

Dong GY, Guo YS, Cao HR, Zhou T, Zhou ZM, Sha JH, et al. Long-term effects of repeated superovulation on ovarian structure and function in rhesus monkeys. Fertil Steril. 2014;102:1452–7.CrossRefPubMed

12.

Althuis MD, Moghissi KS, Westhoff CL, Scoccia B, Lamb EJ, Lubin JH, et al. Uterine cancer after use of clomiphene citrate to induce ovulation. Am J Epidemiol. 2005;161:607–15.CrossRefPubMed

13.

Brinton LA, Scoccia B, Moghissi KS, Westhoff CL, Niwa S, Ruggieri D, et al. Long-term relationship of ovulation-stimulating drugs to breast cancer risk. Cancer Epidemiol Biomarkers Prev. 2014;23:584–93.CrossRefPubMedPubMedCentral

14.

van Leeuwen FE, Klip H, Mooij TM, van de Swaluw AM, Lambalk CB, Kortman M, et al. Risk of borderline and invasive ovarian tumours after ovarian stimulation for in vitro fertilization in a large Dutch cohort. Hum Reprod. 2011;26:3456–65.CrossRefPubMedPubMedCentral

15.

Sanner K, Conner P, Bergfeldt K, Dickman P, Sundfeldt K, Bergh T, et al. Ovarian epithelial neoplasia after hormonal infertility treatment: long-term follow-up of a historical cohort in Sweden. Fertil Steril. 2009;91:1152–8.CrossRefPubMed

16.

Dos Santos S, Wark PA, McCormack VA, Mayer D, Overton C, Little V, et al. Ovulation-stimulation drugs and cancer risks: a long-term follow-up of a British cohort. Br J Cancer. 2009;100:1824–31.CrossRef

17.

Brinton LA, Lamb EJ, Moghissi KS, Scoccia B, Althuis MD, Mabie JE, et al. Ovarian cancer risk after the use of ovulation-stimulating drugs. Obstet Gynecol. 2004;103:1194–203.CrossRefPubMed

18.

Dor J, Lerner-Geva L, Rabinovici J, Chetrit A, Levran D, Lunenfeld B, et al. Cancer incidence in a cohort of infertile women who underwent in vitro fertilization. Fertil Steril. 2002;77:324–7.CrossRefPubMed

19.

Jensen A, Sharif H, Svare EI, Frederiksen K, Kjaer SK. Risk of breast cancer after exposure to fertility drugs: results from a large Danish cohort study. Cancer Epidemiol Biomarkers Prev. 2007;16:1400–7.CrossRefPubMed

20.

Yang S, He X, Niu Y, Wang X, Lu B, Hildebrandt TB, et al. Dynamic changes in ovarian follicles measured by ultrasonography during gonadotropin stimulation in rhesus monkeys. Theriogenology. 2009;72:560–5.CrossRefPubMed

21.

Calhoun KC, Padilla-Banks E, Jefferson WN, Liu L, Gerrish KE, Young SL, et al. Bisphenol A exposure alters developmental gene expression in the fetal rhesus macaque uterus. PLoS ONE. 2014;9:e85894.CrossRefPubMedPubMedCentral

22.

Yu Y, Zhao C, Lv Z, Chen W, Tong M, Guo X, et al. Microinjection manipulation resulted in the increased apoptosis of spermatocytes in testes from intracytoplasmic sperm injection (ICSI) derived mice. PLoS ONE. 2011;6:e22172.CrossRefPubMedPubMedCentral

23.

Franco HL, Dai D, Lee KY, Rubel CA, Roop D, Boerboom D, et al. WNT4 is a key regulator of normal postnatal uterine development and progesterone signaling during embryo implantation and decidualization in the mouse. FASEB J. 2011;25:1176–87.CrossRefPubMedPubMedCentral

24.

Mericskay M, Kitajewski J, Sassoon D. Wnt5a is required for proper epithelial-mesenchymal interactions in the uterus. Development. 2004;131:2061–72.CrossRefPubMed

25.

Carta L, Sassoon D. Wnt7a is a suppressor of cell death in the female reproductive tract and is required postnatal and estrogen-mediated growth. Biol Reprod. 2004;71:444–54.CrossRefPubMed

26.

Parr BA, McMahon AP. Sexually dimorphic development of the mammalian reproductive tract requires Wnt-7a. Nature. 1998;395:701–10.

27.

Ingaramo PI, Milesi MM, Schimpf MG, Ramos JG, Vigezzi L, Muñoz-de-Toro M, et al. Endosulfan affects uterine development and functional differentiation by disrupting Wnt7a and β-catenin expression in rats. Mol Cell Endocrinol. 2016;425:37–47.CrossRefPubMed

28.

Akbas GE, Taylor HS. HOXC and HOXD gene expression in human endometrium: lack of redundancy with HOXA paralogs. Biol Reprod. 2004;70:39–45.CrossRefPubMed

29.

Xu B, Geerts D, Bu Z, Ai J, Jin L, Li Y, et al. Regulation of endometrial receptivity by the highly expressed HOXA9, HOXA11 and HOXD10 HOX-class homeobox genes. Hum Reprod. 2014;29:781–90.CrossRefPubMed

30.

Benson GV, Lim H, Paria BC, Satokata I, Dey SK, Maas RL. Mechanisms of reduced fertility in Hoxa-10 mutant mice: uterine homeosis and loss of maternal Hoxa-10 expression. Development. 1996;122:2687–96.PubMed

31.

Freeman ME, Kanyicska B, Lerant A, Nagy G. Prolactin: structure, function, and regulation of secretion. Physiol Rev. 2000;80:1523–631.PubMed

32.

Hennighausen L, Robinson GW, Wagner KU, Liu W. Prolactin signaling in mammary gland development. J Biol Chem. 1997;272:7567–9.CrossRefPubMed

33.

Aupperlee MD, Haslam SZ. Differential hormonal regulation and function of progesterone receptor isoforms in normal adult mouse mammary gland. Endocrinology. 2007;148:2290–300.CrossRefPubMed

34.

Shyamala G, Chou YC, Nandi S, Guzman RC, Smith GH, Nandi S. Cellular expression of estrogen and progesterone receptors in mammary glands: regulation by hormones, development and aging. J Steroid Biochem Mol Biol. 2002;80:137–48.CrossRefPubMed

35.

Kreizman-Shefer H, Pricop J, Goldman S, Elmalah I, Shalev E. Distribution of estrogen and progesterone receptors isoforms in endometrial cancer. Diagn Pathol. 2014;9:77.CrossRefPubMedPubMedCentral

36.

Yoo SH, Park BH, Choi J, Yoo J, Lee SW, Kim YM, et al. Papillary mucinous metaplasia of the endometrium as a possible precursor of endometrial mucinous adenocarcinoma. Mod Pathol. 2012;25:1496–507.CrossRefPubMed

37.

Yaginuma Y, Yamashita T, Ishiya T, Morizaki A, Katoh Y, Takahashi T, et al. Abnormal structure and expression of PTEN/MMAC1 gene in human uterine cancers. Mol Carcinog. 2000;27:110–6.CrossRefPubMed

38.

Cornejo KM, Kandil D, Khan A, Cosar EF. Theranostic and molecular classification of breast cancer. Arch Pathol Lab Med. 2014;138:44–56.CrossRefPubMed

39.

Zhao L, Yang X, Khan A, Kandil D. Diagnostic role of immunohistochemistry in the evaluation of breast pathology specimens. Arch Pathol Lab Med. 2014;138:16–24.CrossRefPubMed

40.

Filardo EJ, Graeber CT, Quinn JA, Resnick MB, Giri D, DeLellis RA, et al. Distribution of GPR30, a seven membrane-spanning estrogen receptor, in primary breast cancer and its association with clinicopathologic determinants of tumor progression. Clin Cancer Res. 2006;12:6359–66.CrossRefPubMed

41.

Chene G, Penault-Llorca F, Le Bouëdec G, Mishellany F, Dauplat MM, Jaffeux P, et al. Ovarian epithelial dysplasia after ovulation induction: time and dose effects. Hum Reprod. 2009;24:132–8.CrossRefPubMed

Titel: Long-term effects of repeated superovulation on the uterus and mammary gland in rhesus monkeys
verfasst von: Peipei Yan
Jingyi Xu
Yan Zeng
Guoying Dong
Huarong Cao
Meimei Zheng
Hui Zhu
Publikationsdatum: 23.01.2017
Verlag: Springer US
Erschienen in: Journal of Assisted Reproduction and Genetics / Ausgabe 4/2017
Print ISSN: 1058-0468
Elektronische ISSN: 1573-7330
DOI: https://doi.org/10.1007/s10815-017-0872-z

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Long-term effects of repeated superovulation on the uterus and mammary gland in rhesus monkeys