Dynamics of age changes of somatotropin concentration in blood plasma and morphometric parameters of laboratory female mice ovaries

DOI: 10.29296/2618723X-2020-03-07

A.E. Katelnikova1, E.I. Trofimets1, A.A. Matichin1, N.M. Faustova2, Y.A. Gushchin3, M.N. Makarova3

1Institute of Preclinical Research,

188663, Russia, Leningradskiy region, Vsevolozhskiy district, Kuzmolovskiy, Zavodskaya st., 3-245;  

2St. Petersburg Institute of Pharmacy,

188663, Russia, Leningradskiy region, Vsevolozhskiy district, Kuzmolovskiy, Zavodskaya st., 3-245;  

3Scientific-Production Organisation «Home of Pharmacy»

188663, Russia, Leningradskiy region, Vsevolozhskiy district, Kuzmolovskiy, Zavodskaya st., 3-245

Е-mail: [email protected]

Keywords: toxicity fertility endocrine status puberty follicle

For citation:

Katelnikova A.E., Trofimets E.I., Matichin A.A., Faustova N.M., Gushchin Y.A. , Makarova M.N. Dynamics of age changes of somatotropin concentration in blood plasma and morphometric parameters of laboratory female mice ovaries. Laboratory Animals for Science. 2020; 3. https://doi.org/10.29296/2618723X-2020-03-07


Preclinical studies its a significant part of the registration dossier, formed for the purpose of state registration of a new medicinal product (MP). The assessment of the endocrine status is not significantly defined in the requirements of regulatory documents for assessing the safety of a pharmaceutical agent. However, it is important to evaluate drugs being developed for the pharmaceutical market for their potential impact on a given system and compare them with the norms described in the literature. Somatotropin (STH, growth hormone) is one of the hormones, the assessment of the effect on which is important at the stage of preclinical studies of drugs. Growth hormone is responsible for bone growth, organ development, metabolism, energy homeostasis and also one of the factors regulating puberty and fertility in men and women. However, the norms of STH in laboratory animals used in preclinical studies are very little covered. In this study we assessed the level of somatotropin in the peripheral blood of intact laboratory outbred female mice aged 2 to 8 weeks. Also, a morphometric analysis state of the ovaries in animals was carried out within of this experiment. According to the results of the study, concentration of STH in the outbred female mice blood is from 0 to 3 ng / ml. The maximum concentration of STH in female mice blood plasma was recorded at the age of 3 weeks (2.79 ± 0.34 (SD) ng / ml). The level of the hormone decreased with increasing age of the animal, and by 6 weeks ages it was 0.76 ± 0.14 ng / ml. The experimental evidence the level of STH at the onset of puberty (approximately 12 days) and the average age of onset of puberty in female mice (from 8 to 13 years) are compatible. Based on the evaluating the morphometric parameters of ovaries, puberty occur in female mice at the age of 8 weeks. At 8 weeks, against of decrease in the level of STH, antral (tertiary) follicles and yellow bodies develop in the ovaries in all animals. It will be interested evaluation hormone level in uneven-aged outbredmale mice and other animal species including non-rodents (rabbits, minipigs, dogs) for more information and development of STH reference intervals.

Full text avaliable in Russain only


The study was performed without external funding.

Autors’ contributions

A.E. Katelnikova – study concept and design, writing of the text

E.I. Trofimets – study concept and design, data collection

A.A. Matichin – study concept and design, editing of the text

N.M. Faustova – data collection and analysis

Y.A. Gushchindata collection and analysis

M.N. Makarova – idea of the research, editing of the text


  1. Organisation for Economic Co-operation and Development. Test no. 453: Combined chronic toxicity/carcinogenicity studies. – OECD Publishing, 2018.
  2. Test No. 407: Repeated Dose 28-day Oral Toxicity Study in Rodents
  3. Test No. 414: Prenatal Developmental Toxicity Study
  4. Anon. Commission Regulation (EU) No 283/2013 of 1 March 2013 setting out the data requirements for active substances, in accordance with Regulation (EC) No 1107/2009 of the European Parliament and of the Council concerning the placing of plant protection products on the market //Official Journal of the European Union L93. – 2013. – С. 1-83.
  5. Union E. Regulation (EU) No 528/2012 of the European Parliament and of the Council of 22 May 2012 concerning the making available on the market and use of biocidal products //Off J Eur Union L. – 2012. – Т. 167. – С. 1-116.
  6. Ojo O. O., Bhadauria S., Rath S. K. Dose-dependent adverse effects of salinomycin on male reproductive organs and fertility in mice //PloS one. – 2013. – Т. 8. – №. 7. – С. e69086. DOI: 10.1371/journal.pone.0069086
  7. Xiao S. et al. Doxorubicin has dose-dependent toxicity on mouse ovarian follicle development, hormone secretion, and oocyte maturation //Toxicological Sciences. – 2017. – Т. 157. – №. 2. – С. 320-329. DOI: 10.1093/toxsci/kfx047
  8. Воротникова С. Ю., Пигарова Е. А., Дзеранова Л. К. Метаболические эффекты гормона роста //Ожирение и метаболизм. – 2011. – №. 4. – С.55-59. [Vorotnikova S. YU., Pigarova E. A., Dzeranova L. K. Metabolicheskie effekty gormona rosta //Ozhirenie i metabolizm. – 2011. – №. 4. – P.55-59. (In Russ.)]
  9. Huang L., Huang Z., Chen C. Rhythmic growth hormone secretion in physiological and pathological conditions: Lessons from rodent studies //Molecular and cellular endocrinology. – 2019. – Т. 498. – С. 110575. DOI: 10.1016/j.mce.2019.110575
  10. Veldhuis J. D. et al. Differential impact of age, sex steroid hormones, and obesity on basal versus pulsatile growth hormone secretion in men as assessed in an ultrasensitive chemiluminescence assay //The Journal of Clinical Endocrinology & Metabolism. – 1995. – Т. 80. – №. 11. – С. 3209-3222. DOI: 10.1210/jcem.80.11.7593428
  11. Huang L. et al. The decline in pulsatile GH secretion throughout early adulthood in mice is exacerbated by dietary-induced weight gain //Endocrinology. – 2012. – Т. 153. – №. 9. – С. 4380-4388. DOI: 10.1210/en.2012-1178
  12. Steyn F. J. et al. Impairments to the GH-IGF-I axis in hSOD1G93A mice give insight into possible mechanisms of GH dysregulation in patients with amyotrophic lateral sclerosis //Endocrinology. – 2012. – Т. 153. – №. 8. – С. 3735-3746. DOI: 10.1210/en.2011-2171
  13. Poidvin A. et al. Risk of diabetes treated in early adulthood after growth hormone treatment of short stature in childhood //The Journal of Clinical Endocrinology & Metabolism. – 2017. – Т. 102. – №. 4. – С. 1291-1298. DOI: 10.1210/jc.2016-3145
  14. Gutefeldt K. et al. Dysregulated growth hormone‐insulin‐like growth factor‐1 axis in adult type 1 diabetes with long duration //Clinical endocrinology. – 2018. – Т. 89. – №. 4. – С. 424-430. DOI: 10.1111/cen.13810
  15. Wong J. H. et al. Sex differences in thrombosis in mice are mediated by sex-specific growth hormone secretion patterns //The Journal of clinical investigation. – 2008. – Т. 118. – №. 8. – С. 2969-2978. DOI: 10.1172/JCI34957
  16. Donahue L. R., Beamer W. G. Growth hormone deficiency in'little'mice results in aberrant body composition, reduced insulin-like growth factor-I and insulin-like growth factor-binding protein-3 (IGFBP-3), but does not affect IGFBP-2,-1 or-4 //Journal of endocrinology. – 1993. – Т. 136. – №. 1. – С. 91-104. DOI: 10.1677/joe.0.1360091
  17. Ниаури Д. А. Эффективность применения соматотропного гормона в программах ЭКО/ЭКО+ ИКСИ у женщин со «слабым» ответом яичников на стимуляцию гонадотропинами //Журнал акушерства и женских болезней. – 2015. – Т. 64. – №. 6. – С. 43–50. [Niauri D. A. Effektivnost' primeneniya somatotropnogo gormona v programmah EKO/EKO+ IKSI u zhenshchin so «slabym» otvetom yaichnikov na stimulyaciyu gonadotropinami //ZHurnal akusherstva i zhenskih boleznej. – 2015. – Vol. 64. – №. 6. – P. 43–50. (In Russ.)]
  18. HU Z. Effects of growth hormone supplementation in patients undergoing IVF/ICSI-ET with poor ovarian response to gonadotropin //Journal of Reproduction and Contraception. – 2014. – Т. 25. – №. 1. – С. 32–40. DOI: 10.7669/j.issn.1001-7844.2014.01.0032
  19. Приказ Министерства здравоохранения Российской Федерации от 01.04.2016 № 199н "Об утверждении Правил надлежащей лабораторной практики". [Prikaz Ministerstva zdravoohraneniya Rossijskoj Federacii ot 01.04.2016 № 199n "Ob utverzhdenii Pravil nadlezhashchej laboratornoj praktiki" (In Russ.)]
  20. Решение Совета ЕЭК № 81 от 03.11.16 «Об утверждении Правил надлежащей лабораторной практики Евразийского экономического союза в сфере обращения лекарственных средств». [Reshenie Soveta EEK № 81 ot 03.11.16 «Ob utverzhdenii Pravil nadlezhashchej laboratornoj praktiki Evrazijskogo ekonomicheskogo soyuza v sfere obrashcheniya lekarstvennyh sredstv». (In Russ.)]
  21. Мужикян А.А., Макарова М.Н., Гущин Я.А. Особенности гистологической обработки органов и тканей лабораторных животных // Международный вестник ветеринарии. – 2014. – № 2. – С. 103–109. [Muzhikyan A.A., Makarova M.N., Gushchin YA.A. Osobennosti gistologicheskoj obrabotki organov i tkanej laboratornyh zhivotnyh // Mezhdunarodnyj vestnik veterinarii. – 2014. – № 2. – P. 103–109. (In Russ.)]
  22. Pinter O. et al. Differences in the onset of puberty in selected inbred mouse strains //9th European Congress of Endocrinology. – BioScientifica, 2007. – Т. 14.
  23. Dutta S., Sengupta P. Men and mice: relating their ages //Life sciences. – 2016. – Т. 152. – С. 244-248. DOI: 10.1016/j.lfs.2015.10.025
  24. DiVall S. A. et al. Divergent roles of growth factors in the GnRH regulation of puberty in mice //The Journal of clinical investigation. – 2010. – Т. 120. – №. 8. – С. 2900-2909. DOI: 10.1172/JCI41069
  25. Brüning J. C. et al. Role of brain insulin receptor in control of body weight and reproduction //Science. – 2000. – Т. 289. – №. 5487. – С. 2122-2125. DOI: 10.1126/science.289.5487.2122
  26. Horikawa R. et al. Evaluation of growth hormone treatment efficacy in short Japanese children born small for gestational age: Five-year treatment outcome and impact on puberty //Clinical Pediatric Endocrinology. – 2017. – Т. 26. – №. 2. – С. 63-72. DOI: 10.1297/cpe.26.63
  27. ROSE S. R. et al. Spontaneous growth hormone secretion increases during puberty in normal girls and boys //The Journal of Clinical Endocrinology & Metabolism. – 1991. – Т. 73. – №. 2. – С. 428-435. DOI: 10.1210/jcem-73-2-428
  28. https://rzgmu.ru/images/files/c/13414.pdf
  29. Норма в медицинской практике: справ. пособие/под ред. А.В.Литвинова. –М.: МЕДпресс-информ, 2014. – 144 с. [Norma v medicinskoj praktike: sprav. posobie/pod red. A.V.Litvinova. –M.: MEDpress-inform, 2014. – 144 p. (In Russ.)]
  30. Демяшкин Г. А. Морфологическая характеристика сперматогенеза в норме и при идиопатическом бесплодии (иммуногистохимический аспект) // Вестник медицинского института "РЕАВИЗ": реабилитация, врач и здоровье. 2015. №. 4. С. 107-119. [Demyashkin G. A. Morfologicheskaya harakteristika spermatogeneza v norme i pri idiopaticheskom besplodii (immunogistohimicheskij aspekt) // Vestnik medicinskogo instituta "REAVIZ": reabilitaciya, vrach i zdorov'e. 2015. №. 4. P. 107-119. (In Russ.)]
  31. Kyrou D. How to improve the probability of pregnancy in poor responders undergoing in vitro fertilization: a systematic review and meta-analysis // Fertility and sterility. – 2009. – Т. 91. – №. 3. – С. 749–766. DOI: 10.1016/j.fertnstert.2007.12.077
  32. De Ziegler D. The value of growth hormone supplements in ART for poor ovarian responders //Fertility and sterility. – 2011. – Т. 96. – №. 5. – С. 1069–1076. DOI: 10.1016/j.fertnstert.2011.09.049
  33. Yovich J. L., Stanger J. D. Growth hormone supplementation improves implantation and pregnancy productivity rates for poor-prognosis patients undertaking IVF //Reproductive biomedicine online. – 2010. – Т. 21. – №. 1. – С. 37–49. DOI: 10.1016/j.rbmo.2010.03.013
  34. Izadyar F. Preimplantation bovine embryos express mRNA of growth hormone receptor and respond to growth hormone addition during in vitro development //Molecular Reproduction and Development: Incorporating Gamete Research. – 2000. – Т. 57. – №. 3. – С. 247-255. DOI: 10.1002/1098-2795 (200011)57:3<247::AID-MRD6>3.0.CO; 2-Q
  35. Izadyar F. Messenger RNA expression and protein localization of growth hormone in bovine ovarian tissue and in cumulus oocyte complexes (COCs) during in vitro maturation // Molecular Reproduction and Development: Incorporating Gamete Research. – 1999. – Т. 53. – №. 4. – С. 398-406. DOI: 10.1002/ (SICI)1098-2795 (199908)53:4<398::AID-MRD5>3.0.CO; 2-I
  36. Homburg R. Growth hormone facilitates ovulation induction by gonadotrophins //Clinical endocrinology. – 1988. – Т. 29. – №. 1. – С. 113-117., Owen E. J. Co-treatment with growth hormone of sub-optimal responders in IVF-ET //Human Reproduction. – 1991. – Т. 6. – №. 4. – С. 524-528. DOI: 10.1111/j.1365-2265.1988.tb00252.x

You may be interested