Accessible Unlicensed Requires Authentication Published by De Gruyter January 8, 2021

The role of makorin ring finger protein-3, kisspeptin, and neurokinin B in the physiology of minipuberty

Enver Atay, Suna Kılınç, Gozde Ulfer, Turkan Yigitbasi, Cagri Cakici, Murat Turan, Omer Ceran and Zeynep Atay

Abstract

Background

There is no data regarding the interrelationships of circulating Makorin Ring Finger Protein-3 (MKRN3), Kisspeptin (KISS1), and Neurokinin B (NKB) concentrations during minipuberty in humans.

Objective

To determine temporal changes in circulating concentrations of MKRN3, KISS1, NKB, and gonadotropins and investigate interrelationships between them in healthy full-term (FT) and preterm (PT) infants during minipuberty period.

Methods

A prospective study of 6-month follow-up performed. Eighty-seven healthy newborns, 48 FT (19 boys/29 girls), and 39 PT (21 boys/18 girls) (gestational age 31–37 weeks), were included. Blood samples were taken at 7 days (D7), 2 months (M2), and 6 months (M6) of age. Serum MKRN3, KISS1, NKB, LH, FSH, total testosterone (TT), and estradiol (E2) concentrations were measured.

Results

Seventy infants completed the study. MKRN3, KISS1, and NKB concentrations were similar in FT girls and boys. PT boys and girls also had similar concentrations of MKRN3, KISS1, and NKB. FT babies had significantly higher NKB concentrations than PT babies at D7, M2, and M6. MKRN3 and KISS1 concentrations do not differ between FT and PT babies. A strong positive correlation was found between MKRN3 and KISS1 at each time point and in all groups. FSH, LH, TT/E2 concentrations decrease while those of MKRN3 and KISS1 have a trend to increase toward the end of minipuberty. No correlation was detected between gonadotropins and MKRN3, KISS1, NKB concentrations.

Conclusion

Strong positive correlation demonstrated between KISS1 and MKRN3 suggests that interrelationship between molecules controlling minipuberty is not similar to those at puberty.


Corresponding author: Zeynep Atay, Department of Pediatric Endocrinology, Faculty of Medicine, Istanbul Medipol University, Kosuyolu Medipol Hospital, Koşuyolu Mahallesi, Harem yolu üzeri E-5, Kadıköy,34718, Istanbul, Turkey, Phone: +90 505 3945292, E-mail:

  1. Research funding: The project is funded by Istanbul Medipol University Scientific Research Support program.

  2. Author contributions: E. Atay, S. Kılınç, and Z. Atay designed and directed the project. E. Atay, S. Kılınç, and Z. Atay took the lead in preparing the draft article with medical writing assistance. All other authors contributed to data collection, participated in data analysis and interpretation, and critically reviewed the draft article.

  3. Competing interests: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

  4. Informed consent: Informed consent was obtained from all individuals included in this study.

  5. Ethical approval: The present investigation was conducted in accordance with the Declaration of Helsinki for human studies and was approved by the Swedish Ethical Review Authority (Dnr 2019-05076).

References

1. Boas, M, Boisen, KA, Virtanen, HE, Kaleva, M, Suomi, AM, Schmidt, IM, et al.. Postnatal penile length and growth rate correlate to serum testosterone levels: a longitudinal study of 1962 normal boys. Eur J Endocrinol 2006;154:125–9. https://doi.org/10.1530/eje.1.02066.Search in Google Scholar

2. Kuiri-Hänninen, T, Sankilampi, U, Dunkel, L. Activation of the hypothalamic- pituitary-gonadal axis in infancy: minipuberty. Horm Res Paediatr 2014;82:73–80. https://doi.org/10.1159/000362414.Search in Google Scholar

3. Kiviranta, P, Kuiri-Hänninen, T, Saari, A, Lamidi, ML, Dunkel, L, Sankilampi, U. Transient postnatal gonadal activation and growth velocity in infancy. Pediatrics 2016;138:e20153561. https://doi.org/10.1542/peds.2015-3561.Search in Google Scholar

4. Abreu, AP, Kaiser, UB. Pubertal development and regulation. Lancet Diabetes Endocrinol 2016;4:254–64. https://doi.org/10.1016/s2213-8587(15)00418-0.Search in Google Scholar

5. Ramaswamy, S, Seminara, SB, Ali, B, Ciofi, P, Amin, NA, Plant, TM. Neurokinin B stimulates GnRH release in the male monkey (Macaca mulatta) and is colocalized with kisspeptin in the arcuate nucleus. Endocrinology 2010;151:4494–503. https://doi.org/10.1210/en.2010-0223.Search in Google Scholar

6. Hrabovszky, E, Borsay, BA, Rácz, K, Herczeg, L, Ciofi, P, Bloom, SR, et al.. Substance P immunore activity exhibits frequent colocalization with kisspeptin and neurokinin B in the human infundibular region. PLoS One 2013;8:e72369. https://doi.org/10.1371/journal.pone.0072369.Search in Google Scholar

7. Hagen, CP, Sørensen, K, Mieritz, MG, Johannsen, TH, Almstrup, K, Juul, A. Circulating MKRN3 levels decline prior to pubertal onset and through puberty: a longitudinal study of healthy girls. J Clin Endocrinol Metab 2015;100:1920–6. https://doi.org/10.1210/jc.2014-4462.Search in Google Scholar

8. Busch, AS, Hagen, CP, Almstrup, K, Juul, A. Circulating MKRN3 levels decline during puberty in healthy boys. J Clin Endocrinol Metab 2016;101:2588–93. https://doi.org/10.1210/jc.2016-1488.Search in Google Scholar

9. Varimo, T, Dunkel, L, Vaaralahti, K, Miettinen, PJ, Hero, M, Raivio, T. Circulating makorin ring finger protein 3 levels decline in boys before the clinical onset of puberty. Eur J Endocrinol 2016;174:785–90. doi:https://doi.org/10.1530/eje-15-1193.Search in Google Scholar

10. Grandone, A, Cirillo, G, Sasso, M, Capristo, C, Tornese, G, Marzuillo, P, et al.. MKRN3 levels in girls with central precocious puberty and correlation with sexual hormone levels: a pilot study. Endocrine 2018;59:203–8. https://doi.org/10.1007/s12020-017-1281-x.Search in Google Scholar

11. Shinkawa, O, Furuhashi, N, Fukaya, T, Suzuki, M, Kono, H, Tachibana, Y. Changes of serum gonadotropin levels and sex differences in premature and mature infant during neonatal life. J Clin Endocrinol Metab 1983;56:1327–31. https://doi.org/10.1210/jcem-56-6-1327.Search in Google Scholar

12. Kuiri-Hanninen, T, Kallio, S, Seuri, R, Trvainan, E, Liakka, A, Tapanainen, J, et al.. Postnatal developmental changes in the pituitary-ovarian axis in preterm and term infant girls. J Clin Endocrinol Metab 2011;96:3432–9. https://doi.org/10.1210/jc.2011-1502.Search in Google Scholar

13. de Vries, L, Shtaif, B, Phillip, M, Gat-Yablonski, G. Kisspeptin serum levels in girls with central precocious puberty. Clin Endocrinol 2009;71:524–8. https://doi.org/10.1111/j.1365-2265.2009.03575.x.Search in Google Scholar

14. Akinci, A, Cetin, D, Ilhan, N. Plasma kisspeptin levels in girls with premature thelarche. J Clin Pediatr Endocrinol 2012;4:61–5.Search in Google Scholar

15. Pita, J, Barrios, V, Gavela-Perez, T, Martos-Moreno, GA, Munoz-Calvo, MT, Pozo, J, et al.. Circulating kisspeptin levels exhibit sexual dimorphism in adults, are increased obese prepubertal girls and do not suffer modifications in girls with idiopathic central precocious puberty. Peptides 2011;32:1781–6. https://doi.org/10.1016/j.peptides.2011.07.016.Search in Google Scholar

16. Kaya, A, Orbak, Z, Polat, H, Çayır, A, Erdil, A, Döneray, H. Plasma kisspeptin levels in newborn infants with breast enlargement. J Clin Res Pediatr Endocrinol 2015;7:192–6. doi:https://doi.org/10.4274/jcrpe.1994.Search in Google Scholar

17. Takumi, K, Iijima, N, Ozawa, H. Developmental changes in the expression of kisspeptin mRNA in rat hypothalamus. J Mol Neurosci 2011;43:138–45. https://doi.org/10.1007/s12031-010-9430-1.Search in Google Scholar

18. Heras, V, Sangiao-Alvarellos, S, Manfredi-Lozano, M, Sanchez-Tapia, MJ, Ruiz-Pino, F, Roa, J, et al.. Hypothalamic miR-30 regulates puberty onset via repression of the puberty-suppressing factor, Mkrn3. PLoS Biol 2019;7:17:e3000532.Search in Google Scholar

19. Grandone, A, Cirillo, G, Sasso, M, Tornese, G, Luongo, C, Festa, A, et al.. MKRN3 levels in girls with central precocious puberty during GnRHa treatment: a longitudinal study. Horm Res Paediatr 2018;90:190–5. https://doi.org/10.1159/000493134.Search in Google Scholar

20. Topaloglu, AK, Semple, RK. Neurokinin B signalling in human reproductive axis. Mol Cell Endocrinol 2011;22:57–64. https://doi.org/10.1016/j.mce.2011.07.014.Search in Google Scholar

21. Abacı, A, Çatlı, G, Anık, A, Küme, T, Çalan, ÖG, Dündar, BN, et al.. Significance of serum neurokinin B and kisspeptin levels in the differential diagnosis of premature thelarche and idiopathic central precocious puberty. Peptides 2015;64:29–33. https://doi.org/10.1016/j.peptides.2014.12.011.Search in Google Scholar

22. Kang, MJ, Oh, YJ, Shim, YS, Baek, JW, Yang, S, Hwang, IT. The usefulness of circulating levels of leptin, kisspeptin, and neurokinin B in obese girls with precocious puberty. Gynecol Endocrinol 2018;34:627–30. https://doi.org/10.1080/09513590.2017.1423467.Search in Google Scholar

23. Becker, M, Oehler, K, Partsch, CJ, Ulmen, U, Schmutzler, R, Cammann, H, et al.. Hormonal ’minipuberty’ influences the somatic development of boys but not of girls up to the age of 6 years. Clin Endocrinol 2015;83:694–701. https://doi.org/10.1111/cen.12827.Search in Google Scholar

24. Ernst, A, Lauridsen, LLB, Brix, N, Arah, OH, Olsen, J, Olsen, LH, et al.. Parental time to pregnancy, medically assisted reproduction and pubertal development in boys and girls. Hum Reprod 2019;34:724–32. https://doi.org/10.1093/humrep/dez008.Search in Google Scholar

25. Beydoun, HA, Sicignano, N, Beydoun, MA, Bocca, S, Stadtmauer, L, Oehninger, S. Pubertal development of the first cohort of young adults conceived by in vitro fertilization in the United States. Fertil Steril 2011;95:528–33. https://doi.org/10.1016/j.fertnstert.2010.04.057.Search in Google Scholar

Received: 2020-06-04
Accepted: 2020-11-09
Published Online: 2021-01-08
Published in Print: 2021-03-26

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