非人灵长类实验动物用于人类卵巢衰老研究进展

doi:10.12300/j.issn.1674-5817.2024.114

实验动物与比较医学 ›› 2025, Vol. 45 ›› Issue (1): 47-54.DOI: 10.12300/j.issn.1674-5817.2024.114

非人灵长类实验动物用于人类卵巢衰老研究进展

肖文娴¹^,²()(), 吕龙宝¹^,²^,³()()

^1.中国科学院昆明动物研究所, 昆明 650223
^2.国家非人灵长类实验动物资源库, 昆明 650223
^3.中国科学院大学, 北京 100049

收稿日期:2024-08-02 修回日期:2024-12-04 出版日期:2025-02-25 发布日期:2025-02-25
通讯作者: 吕龙宝（1974—），男，硕士，正高级工程师，研究方向：实验动物学。E-mail： lvlongbao@mail.kiz.ac.cn。ORCID： 0000-0002-8437-6333
作者简介:肖文娴（1997—），女，硕士，工程师，研究方向：实验动物学。E-mail： xiaowenxian@mail.kiz.ac.cn。ORCID： 0009-0009-8336-5649
基金资助:
国家重点研发计划“灵长类实验动物育种、繁育、SPF猴培育及资源保护研究”(2022YFF0710900);云南（昆明）院士专家工作站计划“云南（昆明）贺争鸣实验动物专家工作站”(YSZJGZZ-2022063);云南省院士专家工作站“云南省贺争鸣专家工作站”(202305AF150160)

Research Progress on Human Ovarian Aging Using Non-Human Primates as Laboratory Animals

XIAO Wenxian¹^,²()(), LÜ Longbao¹^,²^,³()()

^1.Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China
^2.National Resource Center for Non-Human Primates, Kunming 650223, China
^3.University of Chinese Academy of Sciences, Beijing 100049, China

Received:2024-08-02 Revised:2024-12-04 Published:2025-02-25 Online:2025-02-25
Correspondence to: LÜ Longbao (ORCID:0000-0002-8437-6333), E-mail: lvlongbao@mail.kiz.ac.cn

摘要/Abstract

摘要：

卵巢具有卵泡发生与激素分泌两大功能，与女性的生殖能力密切相关。卵巢衰老表现为卵巢形态改变、卵子数量减少和激素水平变化，不仅导致女性生育力下降，也被认为是多器官衰老的始动因素。此外，卵巢衰老伴随的性激素分泌紊乱还可能诱发心血管疾病、睡眠障碍、潮热等疾病和症状。由于社会压力与自身职业规划等因素的影响，现代女性的生育年龄普遍延迟，而卵巢功能的衰老进程却不会随年龄的增加而减缓。许多女性面临着想要生育时，却已错过最佳适育年龄，出现不孕不育等问题。这使人们日益关注延缓卵巢衰老的研究。非人灵长类实验动物在进化上与人类的亲缘关系最为接近，与人类基因组的序列同一性高达93%，因此在生理代谢、生殖内分泌、发育衰老等研究中具有其他模式动物无法比拟的优点，在非人灵长类实验动物上得到的研究结果转化应用到人类医学上也更为可靠。本文首先从卵巢衰老与治疗现状为切入点，概述非人灵长类实验动物作为卵巢衰老研究模式动物的优势，接着从生殖内分泌激素水平、卵巢的形态结构与功能、卵巢衰老的其他生理变化等方面。综述了非人灵长类实验动物应用于卵巢衰老研究的进展，并对存在的问题与展望进行总结，以期对读者有所帮助。

关键词: 非人灵长类实验动物, 卵巢衰老, 性激素, 卵泡

Abstract:

The ovary has two main functions: folliculogenesis and hormone secretion, both of which are closely related to female fertility. Ovarian aging is characterized by morphological changes, a reduction in follicle numbers, and fluctuations in hormone levels. It not only leads to a decline in female fertility, but is also considered to be a key driver of multi-organ aging. In addition, the disruption of sex hormone secretion associated with ovarian aging can lead to the occurrence of related diseases and symptoms, such as cardiovascular diseases, sleep disorders, and hot flashes. Due to the influence of social pressures and personal career planning, many modern women are increasingly postponing childbearing. However, ovarian aging does not slow down with advancing age. As a result, many women face issues such as infertility when they are ready to have children, having missed their optimal childbearing age. This leads to growing interest in research on delaying ovarian aging. Non-human primates share the closest evolutionary relationship with humans, with a genomic sequence identity of 93%, which grants them unparalleled advantages over other model animals in studies on physiological metabolism, reproductive endocrinology, and developmental aging. Findings obtained in non-human primates are also more reliably translatable to human medical research. This study begins by discussing the current state of ovarian aging research and treatment strategies, highlighting the advantages of non-human primates as laboratory animals for ovarian aging research. It then reviews research progress in areas such as reproductive endocrine hormone levels, ovarian morphology and function, and other physiological changes associated with ovarian aging. Furthermore, it summarizes existing challenges and future research directions, aiming to provide valuable insights for researchers.

Key words: Laboratory non-human primates, Ovarian aging, Sex hormones, Follicles

中图分类号:

R-332

肖文娴,吕龙宝. 非人灵长类实验动物用于人类卵巢衰老研究进展[J]. 实验动物与比较医学, 2025, 45(1): 47-54. DOI: 10.12300/j.issn.1674-5817.2024.114.

XIAO Wenxian,Lü Longbao. Research Progress on Human Ovarian Aging Using Non-Human Primates as Laboratory Animals[J]. Laboratory Animal and Comparative Medicine, 2025, 45(1): 47-54. DOI: 10.12300/j.issn.1674-5817.2024.114.

参考文献 61

1	HANSEN K R, KNOWLTON N S, THYER A C, et al. A new model of reproductive aging: the decline in ovarian non-growing follicle number from birth to menopause[J]. Hum Reprod, 2008, 23(3):699-708. DOI: 10.1093/humrep/dem408 .
2	DE BRUIN J P, BOVENHUIS H, VAN NOORD P A, et al. The role of genetic factors in age at natural menopause[J]. Hum Reprod, 2001, 16(9):2014-2018. DOI:10.1093/humrep/16.9.2014 .
3	GOLD E B. The timing of the age at which natural menopause occurs[J]. Obstet Gynecol Clin North Am, 2011, 38(3):425-440. DOI: 10.1016/j.ogc.2011.05.002 .
4	TAKAHASHI T A, JOHNSON K M. Menopause[J]. Med Clin North Am, 2015, 99(3):521-534. DOI:10.1016/j.mcna.2015.01.006 .
5	NELSON H D. Menopause[J]. Lancet, 2008, 371(9614):760-770. DOI:10.1016/S0140-6736(08)60346-3 .
6	WISE P M, KRAJNAK K M, KASHON M L. Menopause: the aging of multiple pacemakers[J]. Science, 1996, 273(5271): 67-70.DOI:10.1126/science.273.5271.67 .
7	WELT C K, SCHNEYER A L. Differential regulation of inhibin B and inhibin a by follicle-stimulating hormone and local growth factors in human granulosa cells from small antral follicles[J]. J Clin Endocrinol Metab, 2001, 86(1):330-336. DOI:10.1210/jcem.86.1.7107 .
8	HALL J E. Neuroendocrine changes with reproductive aging in women[J]. Semin Reprod Med, 2007, 25(5):344-351. DOI:10.1055/s-2007-984740 .
9	邓成艳, 孙爱军, 杨欣,等. 女性性激素临床应用与病例解读[M]. 北京: 中国医药科技出版社, 2021.
	Deng C Y, SUN A J, YAN X, et al. Clinical application of female sex hormones and case interpretation[M]. Beijing: China Medical Science and Technology Press, 2021.
10	GAMBRELL R D Jr. The menopause: benefits and risks of estrogen-progestogen replacement therapy[J]. Fertil Steril, 1982, 37(4):457-474. DOI:10.1016/s0015-0282(16)46149-2 .
11	JUDD H L, MELDRUM D R, DEFTOS L J, et al. Estrogen replacement therapy: indications and complications[J]. Ann Intern Med, 1983, 98(2):195-205.DOI:10.7326/0003-4819-98-2-195 .
12	ASHLEY HILL D, CRIDER M, HILL S R. Hormone therapy and other treatments for symptoms of menopause[J]. Am Fam Physician, 2016, 94(11):884-889.
13	NYSTEDT J, ANDERSON H, TIKKANEN J, et al. Cell surface structures influence lung clearance rate of systemically infused mesenchymal stromal cells[J]. Stem Cells, 2013, 31(2):317-326. DOI:10.1002/stem.1271 .
14	FISCHER U M, HARTING M T, JIMENEZ F, et al. Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect[J]. Stem Cells Dev, 2009, 18(5):683-692. DOI:10.1089/scd.2008.0253 .
15	LANKAU E W, TURNER P V, MULLAN R J, et al. Use of nonhuman Primates in research in North America[J]. J Am Assoc Lab Anim Sci, 2014, 53(3):278-282.
16	DIDIER E S, MACLEAN A G, MOHAN M, et al. Contributions of nonhuman Primates to research on aging[J]. Vet Pathol, 2016, 53(2):277-290. DOI:10.1177/0300985815622974 .
17	KUMAR S, HEDGES S B. A molecular timescale for vertebrate evolution[J]. Nature, 1998, 392(6679):917-920. DOI:10.1038/31927 .
18	GIBBS R A, ROGERS J, KATZE M, et al. Evolutionary and biomedical insights from the rhesus macaque genome[J]. Science, 2009, 316:222-234. DOI:10.1126/SCIENCE.1139247 .
19	FUJIYAMA A, WATANABE H, TOYODA A, et al. Construction and analysis of a human-chimpanzee comparative clone map[J]. Science, 2002, 295(5552):131-134. DOI:10.1126/science.1065199 .
20	ZHANG X L, PANG W, HU X T, et al. Experimental Primates and non-human primate (NHP) models of human diseases in China: current status and progress[J]. Dongwuxue Yanjiu, 2014, 35(6):447-464. DOI: 10.13918/j.issn.2095-8137.2014.6.447 .
21	雷爱华, 庞伟, 张高红, 等. 平顶猴在HIV/AIDS动物模型中的应用及研究进展[J]. 动物学研究, 2013, 34(2):77-88. DOI: 10.3724/SP.J.1141.2013.02077 .
	LEI A H, PANG W, ZHANG G H, et al. Use and research of pigtailed macaques in nonhuman primate HIV/AIDS models[J]. Zool Res, 2013, 34(2):77-88. DOI: 10.3724/SP.J.1141.2013.02077 .
22	COLMAN R J. Non-human Primates as a model for aging[J]. Biochim Biophys Acta Mol Basis Dis, 2018, 1864(9 Pt A):2733-2741. DOI: 10.1016/j.bbadis.2017.07.008 .
23	SIMMONS H A. Age-associated pathology in rhesus macaques (Macaca mulatta) [J]. Vet Pathol, 2016, 53(2):399-416. DOI:10.1177/0300985815620628 .
24	UNO H. Age-related pathology and biosenescent markers in captive rhesus macaques[J]. AGE, 1997, 20(1):1-13. DOI:10.1007/s11357-997-0001-5 .
25	WALKER M L. Menopause in female rhesus monkeys[J]. Am J Primatol, 1995, 35(1):59-71. DOI:10.1002/ajp.1350350106 .
26	GILARDI K V, SHIDELER S E, VALVERDE C R, et al. Characterization of the onset of menopause in the rhesus macaque[J]. Biol Reprod, 1997, 57(2):335-340. DOI:10.1095/biolreprod57.2.335 .
27	LANE M A. Nonhuman primate models in biogerontology[J]. Exp Gerontol, 2000, 35(5):533-541. DOI:10.1016/s0531-5565(00)00102-9 .
28	COLMAN R J, ANDERSON R M, JOHNSON S C, et al. Caloric restriction delays disease onset and mortality in rhesus monkeys[J]. Science, 2009, 325(5937):201-204. DOI:10.1126/science.1173635 .
29	RYLE M. Gonadotropins and ovarian function[J]. Acta Eur Fertil, 1973, 4(3):113-122.
30	MATTERI R L, BRIDSON W E, DIERSCHKE D J, et al. The secretion of bioactive and immunoreactive follicle-stimulating hormone (FSH) and luteinizing hormone (LH) throughout the menstrual cycle of the rhesus monkey (Macaca mulatta) [J]. Am J Primatol, 1992, 26(4):243-257. DOI:10.1002/ajp.1350260403 .
31	HILLIER S G, HARLOW C R, SHAW H J, et al. Cellular aspects of pre-ovulatory folliculogenesis in primate ovaries[J]. Hum Reprod, 1988, 3(4):507-511. DOI: 10.1093/oxfordjournals.humrep.a136736 .
32	SHIDELER S E, GEE N A, CHEN J, et al. Estrogen and progesterone metabolites and follicle-stimulating hormone in the aged macaque female[J]. BiolReprod, 2001, 65(6):1718-1725. DOI:10.1095/biolreprod65.6.1718 .
33	LUINE V N. Estradiol and cognitive function: past, present and future[J]. Horm Behav, 2014, 66(4):602-618. DOI: 10.1016/j.yhbeh.2014.08.011 .
34	PELUFFO M C, HENNEBOLD J D, STOUFFER R L, et al. Oocyte maturation and in vitro hormone production in small antral follicles (SAFs) isolated from rhesus monkeys[J]. J Assist Reprod Genet, 2013, 30(3):353-359. DOI:10.1007/s10815-013-9937-9 .
35	BETHEA C L, REDDY A P, CHRISTIAN F L. How studies of the serotonin system in macaque models of menopause relate to Alzheimer's Disease1[J]. J Alzheimers Dis, 2017, 57(4):1001-1015. DOI:10.3233/JAD-160601 .
36	CHROUSOS G P, BRANDON D, RENQUIST D M, et al. Uterine estrogen and progesterone receptors in an estrogen-and progesterone-"resistant"primate[J].J Clin Endocrinol Metab, 1984, 58(3):516-520. DOI:10.1210/jcem-58-3-516 .
37	KOHAMA S G, RENNER L, LANDAUER N, et al. Effect of ovarian hormone therapy on cognition in the aged female rhesus macaque[J]. J Neurosci, 2016, 36(40):10416-10424. DOI:10.1523/jneurosci.0909-16.2016 .
38	XU J, BISHOP C V, LAWSON M S, et al. Anti-Müllerian hormone promotes pre-antral follicle growth, but inhibits antral follicle maturation and dominant follicle selection in primates[J]. Hum Reprod, 2016, 31(7):1522-1530. DOI:10.1093/humrep/dew100 .
39	LONG H, WANG Y, WANG L, et al. Age-related nomograms of serum anti-Mullerian hormone levels in female monkeys: Comparison of rhesus(Macaca mulatta) and Cynomolgus(Macaca fascicularis) monkeys[J]. Gen Comp Endocrinol, 2018, 269:171-176. DOI:10.1016/j.ygcen.2018.09.012 .
40	DOWNS J L, URBANSKI H F. Neuroendocrine changes in the aging reproductive axis of female rhesus macaques (Macaca mulatta)[J]. Biol Reprod, 2006, 75(4):539-546. DOI:10.1095/biolreprod.106.051839 .
41	CHANNING C P, SCHAERF F W, ANDERSON L D, et al. Ovarian follicular and luteal physiology[J]. Int Rev Physiol, 1980, 22:117-201.
42	田川, 杨再玲, 朱向情,等. 猕猴从幼年到老年的卵巢组织学变化[J]. 实验动物科学, 2020,37(6):37-43. DOI: 10.3969/j.issn.1006-6179.2020.06.007 .
	TIAN C, YANG Z L, ZHU X Q, et al. Histological changes of ovaries inrhesus monkeys from juvenile to elderly[J]. Lab Anim Sci, 2020,37(6):37-43. DOI: 10.3969/j.issn.1006-6179.2020.06.007 .
43	NOZAKI M, YAMASHITA K, SHIMIZU K. Age-related changes in ovarian morphology from birth to menopause in the Japanese monkey, Macaca fuscata fuscata [J]. Primates, 1997, 38:89-100. DOI:10.1007/BF02385925 .
44	HIRAYAMA R, TAKETSURU H, NAKATSUKASA E, et al. Production of marmoset eggs and embryos from xenotransplanted ovary tissues[J]. Sci Rep, 2023, 13(1):18196. DOI:10.1038/s41598-023-45224-x .
45	NICHOLS S M, BAVISTER B D, BRENNER C A, et al. Ovarian senescence in the rhesus monkey (Macaca mulatta)[J]. Hum Reprod, 2005, 20(1):79-83. DOI:10.1093/humrep/deh576 .
46	LU H F, JING Y, ZHANG C, et al. Aging hallmarks of the primate ovary revealed by spatiotemporal transcriptomics[J]. Protein Cell, 2024, 15(5):364-384. DOI:10.1093/procel/pwad063 .
47	WANG K, YAO X, LIN S Q, et al. Cellular and molecular mechanisms of highly active mesenchymal stem cells in the treatment of senescence of rhesus monkey ovary[J]. Stem Cell Res Ther, 2024, 15(1):14. DOI:10.1186/s13287-023-03631-x .
48	TIAN C, HE J, AN Y Y, et al. Bone marrow mesenchymal stem cells derived from juvenile macaques reversed ovarian ageing in elderly macaques[J]. Stem Cell Res Ther, 2021, 12(1):460. DOI:10.1186/s13287-021-02486-4 .
49	TIAN C, AN Y Y, ZHAO J, et al. Bone marrow mesenchymal stem cells reversed ovarian aging-related m6A RNA methylation modification profile in aged granulosa cells[J]. Stem Cell Rev Rep, 2023, 19(4):953-967. DOI:10.1007/s12015-022-10485-y .
50	BROEKMANS F J, SOULES M R, FAUSER B C. Ovarian aging: mechanisms and clinical consequences[J]. Endocr Rev, 2009, 30(5):465-493. DOI:10.1210/er.2009-0006 .
51	罗爱月, 王世宣. 基于卵巢衰老理念管理绝经相关问题[J]. 实用妇产科杂志, 2020,36(9):641-644.
	LUO A Y, WANG S X. Management of menopausal related problems based on the concept of ovarian aging[J]. J Pract Obstet Gynecol, 2020,36(9):641-644.
52	杜永洪, 邹建中, 赵卫华, 等. 彩色多普勒超声在恒河猴生殖生理研究中的应用[J]. 临床超声医学杂志,2000,2(2): 65-67. DOI:10.3969/j.issn.1008-6978.2000.02.001 .
	DU Y H, ZOU J Z, ZHAO W H, et al. Color Doppler ultrasonography in the study of macaque reproductive physiology[J]. J Clin Ultrasavnd Med, 2000, 2(2):65-67, 129. DOI: 10.16245/j.cnki.issn1008-6978.2000.02.001 .
53	WANG S, ZHENG Y X, LI J Y, et al. Single-cell transcriptomic atlas of primate ovarian aging[J]. Cell, 2020, 180(3):585-600.e19. DOI:10.1016/j.cell.2020.01.009 .
54	ESTRADA A, GARBER P A, CHAUDHARY A. Current and future trends in socio-economic, demographic and governance factors affecting global primate conservation[J]. PeerJ, 2020, 8:e9816. DOI:10.7717/peerj.9816 .
55	范春梅, 王雁玲, 李志雄,等. 猕猴早期妊娠的B型超声测值[J]. 中国实验动物学杂志, 2002,12(2):102-104. DOI: 10.3969/j.issn.1671-7856.2002.02.012 .
	FAN C M, WANG Y L, LI Z X, et al. B-mode ultrasonographic measurements in early pregnant Rhesus monkey [J]. Chin J Lab Anim Sci, 2002,12(2): 102-104.DOI: 10.3969/j.issn.1671-7856.2002.02.012 .
56	范春梅, 周建华, 刘雅英. 猕猴早孕模型的建立及超声学诊断[J]. 动物学杂志, 2001,36(5):62-63. DOI: 10.13859/j.cjz.2001.05.019 .
	FAN C M, ZHOU J H, LIU Y Y. Establishment of Rhesus monkey early pregnancy model and ultrasonic diagnosis[J]. Chin J Zool, 2001,36(5):62-63.DOI: 10.13859/j.cjz.2001.05.019 .
57	李志雄, 范春梅, 周建华. 实验猕猴早早孕诊断[J]. 福建畜牧兽医, 2011,33(1):23-24. DOI: 10.3969/j.issn.1003-4331.2011.01.012 .
	LI Z X, FAN C M, ZHOU J H. Early pregnancy diagnosis in Rhesus monkey[J]. Fujian J Anim Husb Vet Med, 2011,33(1):23-24. DOI:10.3969/j.issn.1003-4331.2011.01.012 .
58	唐东红, Maria Alejandra Fuentes Priego, Maria Elena Ortiz,等. 卷尾猴的卵泡生长发育及排卵的超声监测[J]. 中国实验动物学报, 2007,15(1):25-29. DOI: 10.3969/j.issn.1005-4847.2007.01.007 .
	TANG D H, PRIEGO M, ORTIZ M, et al.Evaluation of ultrasonic monitoring follicular growth and ovulation in new world monkey Cebus apella [J].Acta Lab Anim Sci Sin, 2007,15(1):25-29. DOI: 10.3969/j.issn.1005-4847.2007.01.007 .
59	YANG S H, HE X C, HILDEBRANDT T B, et al. Superovulatory response to a low dose single-daily treatment of rhFSH dissolved in polyvinylpyrrolidone in rhesus monkeys[J]. Am J Primatol, 2007, 69(11):1278-1284. DOI:10.1002/ajp.20433 .
60	ISOLA J V V, OCAÑAS S R, HUBBART C R, et al. A single-cell atlas of the aging mouse ovary[J]. Nat Aging, 2024, 4(1):145-162. DOI:10.1038/s43587-023-00552-5 .
61	CRUZ G, FERNANDOIS D, PAREDES A H. Ovarian function and reproductive senescence in the rat: role of ovarian sympathetic innervation[J]. Reproduction, 2017, 153(2): R59-R68.DOI:10.1530/REP-16-0117 .

[1]	朱寅秋, 汪雅荻, 严国锋, 周晶, 汪静, 袁聪俐, 马政文. 不完全睡眠剥夺对青春期SD大鼠生长发育的影响[J]. 实验动物与比较医学, 2017, 37(4): 295-299.
[2]	顾艳琼, 石燕, 王健, 孙兆贵. 己烯雌酚促进实验动物卵泡发育同步化及其机制的初步研究[J]. 实验动物与比较医学, 2013, 33(2): 79-83.
[3]	王奕森1，朱萍妹2，钟高仁3，徐平4，施恩4，乔伟伟2，周光兴2. 雄性F344大鼠自发性Leydig细胞瘤的比较医学研究[J]. 实验动物与比较医学, 2007, 27(4): 230-235.
[4]	金桂枝, 章小萍. 绝经尿促性素效价测定中反应指标及计算指标的比较[J]. 实验动物与比较医学, 1995, 15(4): 213-216.
[5]	程化奇，熊舜华，殷新尤，候安继，杨勇，江仙远，夏振信，张荣，王瑞绵，戎诚兴. 大鼠更年期实验模型研究[J]. 实验动物与比较医学, 1993, 13(4): 192-196.

非人灵长类实验动物用于人类卵巢衰老研究进展

Research Progress on Human Ovarian Aging Using Non-Human Primates as Laboratory Animals

RichHTML

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

参考文献 61

相关文章 5

编辑推荐

Metrics

本文评价