Maternal Gonadotropin-Releasing Hormone Agonist Treatment and Discontinuation: Impacts on Male and Female Offspring Voluntary Wheel Running

Curtis S. Davis¹, Kara C. Phillips¹ and David S. Hydock^1,

¹Kinesiology, Nutrition, and Dietetics, University of Northern Colorado, Greeley, USA

Cite this paper:
Curtis S. Davis, Kara C. Phillips and David S. Hydock. Maternal Gonadotropin-Releasing Hormone Agonist Treatment and Discontinuation: Impacts on Male and Female Offspring Voluntary Wheel Running. Journal of Physical Activity Research. 2026; 11(1):38-43. doi: 10.12691/jpar-11-1-5

Abstract

Despite its clinical use, the reversibility of gonadotropin-releasing hormone agonist (GnRHa) treatment after discontinuation remains poorly understood, particularly regarding offspring physical activity. Therefore, this study examined voluntary wheel-running activity as an assessment of physical activity in male and female offspring born to female rats that received GnRHa treatment early in life followed by its discontinuation. Four-week-old female Sprague-Dawley rats received either daily 100 µg subcutaneous injections of the gonadotropin releasing hormone agonist (GnRHa) triptorelin as a puberty blocker (P, n=6) or saline as a control (C, n=6) daily for 28 days. Injections then discontinued and female rats were paired with male rats for breeding. Male (M) and female (F) Offspring (O) from the P and C females were housed in cages outfitted with voluntary running wheels for 56 days (M WR (M+WR+PO, n=3; F+WR+PO, n=3; M+WR+CO, n=3; F+WR+CO, n=3). Wheel running activity was then assessed for 8 weeks. A significant main parent treatment effect (p=0.0213) and sex effect (p=0.0228) was observed for total WR distance (M+WR+PO, 158 ± 54 km; M+WR+CO, 378 ± 27 km; F+WR+PO 373 ± 58 km; F+WR+CO 738 ± 187 km), but there was no parent treatment x sex interaction (p=0.4988). No significant main effects or interactions were observed in weekly WR distances during Week 1, but significant parent treatment effects were observed in Weeks 2-5 (p=0.0157, p=0.0131, p=0.0114, p=0.0263, respectively) with significant main sex effects observed in Weeks 2, 3, and 4 (p=0.0026, p=0.0088 and p= 0.0169 respectively). No significant main effects or interactions were observed in WR distances for Weeks 6-8 (p>0.05). Male and female offspring from GnRHa treated and discontinued female rats had lower WR activity than their respective control counterparts suggesting that physical activity levels may be impacted by the temporary disruption in maternal reproductive development even after discontinuation of pubertal suppression.

Keywords:
discontinuation gonadotropin-releasing hormone agonist maternal offspring physical activity

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References:

[1]	Vukovic R, Milenkovic T, Soldatovic I, Pekic S, Mitrovic K, Todorovic S. Triptorelin-stimulated luteinizing hormone concentrations for diagnosing central precocious puberty: study of diagnostic accuracy. Endocrine. 2022; 75(3): 934-941.
[2]	Wang L, Jiang Q, Wang M, Xu J, Jin J. The effect of triptorelin and leuprolide on the level of sex hormones in girls with central precocious puberty and its clinical efficacy analysis. Transl Pediatr. 2021; 10(9): 2307-2312.
[3]	Latronico AC, Brito VN, Carel JC. Causes, diagnosis, and treatment of central precocious puberty. Lancet Diabetes Endocrinol. 2016; 4(3): 265-274.
[4]	Carel JC, Eugster EA, Rogol A, et al. Consensus statement on the use of gonadotropin-releasing hormone analogs in children. Pediatrics. 2009; 123(4): e752-e762.
[5]	Mensah FK, Bayer JK, Wake M, Carlin JB, Allen NB, Patton GC. Early puberty and childhood social and behavioral adjustment. J Adolesc Health. 2013; 53(1): 118-124.
[6]	Popovic J, Geffner ME, Rogol AD, Silverman LA, Kaplowitz PB, Mauras N, et al. Gonadotropin-releasing hormone analog therapies for children with central precocious puberty in the United States. Front Pediatr. 2022; 10: 968485.
[7]	Hembree WC, Cohen-Kettenis PT, Gooren L, Hannema SE, Meyer WJ, Murad MH, Rosenthal SM, Safer JD, Tangpricha V, T'Sjoen GG. Endocrine treatment of gender-dysphoric/gender-incongruent persons: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2017; 102(11): 3869-3903.
[8]	Brik T, Vrouenraets LJJJ, de Vries MC, Hannema SE. Trajectories of adolescents treated with gonadotropin-releasing hormone analogues for gender dysphoria. Arch Sex Behav. 2020; 49(7): 2611-2618.
[9]	Shumer DE, Nokoff NJ, Spack NP. Advances in the care of transgender children and adolescents. Adv Pediatr. 2016; 63(1): 79-102.
[10]	Chen D, Abrams M, Clark L, Ehrensaft D, Tishelman AC, Chan YM, Garofalo R, Olson-Kennedy J, Rosenthal SM, Hidalgo MA. Psychosocial characteristics of transgender youth seeking gender-affirming medical treatment: baseline findings from the Trans Youth Care Study. J Adolesc Health. 2021; 68(6): 1104-1111.
[11]	Jensen RK, Jensen JK, Simons LK, Chen D, Rosoklija I, Finlayson CA. Effect of concurrent gonadotropin-releasing hormone agonist treatment on dose and side effects of gender-affirming hormone therapy in adolescent transgender patients. Transgend Health. 2019; 4(1): 300-303.
[12]	Anacker C, Sydnor E, Chen BK, LaGamma CC, McGowan JC, Mastrodonato A, et al. Behavioral and neurobiological effects of GnRH agonist treatment in mice: potential implications for puberty suppression in transgender individuals. Neuropsychopharmacology. 2021; 46(5): 882-890.
[13]	MacKinnon KR, Kia H, Salway T, Ashley F, Lacombe-Duncan A, Abramovich A, Enxuga G, Ross LE. Health care experiences of patients discontinuing or reversing prior gender-affirming treatments. JAMA Netw Open. 2022; 5(7): e2224717.
[14]	Jones B, Hydock D. The effects of puberty blocking treatment (gonadotropin releasing hormone agonist) on reproductive function in young female rats. Arch Clin Biomed Res. 2025; 9: 552-558.
[15]	Garrido MP, Hernandez A, Vega M, Araya E, Romero C. Conventional and new proposals of GnRH therapy for ovarian, breast, and prostatic cancers. Front Endocrinol (Lausanne). 2023; 14: 1143261.
[16]	Eisenberger MA, O'Dwyer PJ, Friedman MA. Gonadotropin hormone-releasing hormone analogues: a new therapeutic approach for prostatic carcinoma. J Clin Oncol. 1986; 4(3): 414-424.
[17]	Robertson JF, Blamey RW. The use of gonadotrophin-releasing hormone (GnRH) agonists in early and advanced breast cancer in pre- and perimenopausal women. Eur J Cancer. 2003; 39(7): 861-869.
[18]	Itskovitz-Eldor J, Kol S, Mannaerts B. Use of a single bolus of GnRH agonist triptorelin to trigger ovulation after GnRH antagonist ganirelix treatment in women undergoing ovarian stimulation for assisted reproduction. Hum Reprod. 2000; 15(9): 1965-1968.
[19]	Tay CC. Use of gonadotrophin-releasing hormone agonists to trigger ovulation. Hum Fertil (Camb). 2002; 5(1): G35-G48.
[20]	Mayo Clinic. In vitro fertilization (IVF). Mayo Clinic. Published September 1, 2023. Accessed March 2026. https: // www. mayoclinic.org/tests-procedures/in-vitro-fertilization/about/pac-20384716.
[21]	Pirtea P, de Ziegler D, Poulain M, Ayoubi JM. New twists in ovarian stimulation and their practical implications. Front Med (Lausanne). 2019; 6: 197.
[22]	Kol S. Luteolysis induced by a gonadotropin-releasing hormone agonist is the key to prevention of ovarian hyperstimulation syndrome. Fertil Steril. 2004; 81(1): 1-5.
[23]	Surrey ES. GnRH agonists in the treatment of symptomatic endometriosis: a review. F S Rep. 2022; 4(2 Suppl): 40-45.
[24]	Dal Prato L, Borini A, Cattoli M, Bonu MA, Sereni E, Flamigni C. GnRH analogs: depot versus short formulations. Eur J Obstet Gynecol Reprod Biol. 2004; 115(Suppl): S40-S43.
[25]	De Sanctis V, Soliman AT, Di Maio S, Soliman N, Elsedfy H. Long-term effects and significant adverse drug reactions associated with the use of gonadotropin-releasing hormone analogs for central precocious puberty. Acta Biomed. 2019; 90(3): 345-359.
[26]	Ali M, Raslan M, Ciebiera M, Zaręba K, Al-Hendy A. Current approaches to overcome the side effects of GnRH analogs in the treatment of patients with uterine fibroids. Expert Opin Drug Saf. 2022; 21(4): 477-486.
[27]	National Institute of Diabetes and Digestive and Kidney Diseases. Gonadotropin-releasing hormone (GnRH) analogues. Published 2012. Accessed March 2026. https: // www. ncbi.nlm.nih. gov/books/ NBK547863/.
[28]	Salas-Humara C, Sequeira GM, Rossi W, Dhar CP. Gender affirming medical care of transgender youth. Curr Probl Pediatr Adolesc Health Care. 2019; 49(9): 100683.
[29]	Kim EY. Long-term effects of gonadotropin-releasing hormone analogs in girls with central precocious puberty. Korean J Pediatr. 2015; 58(1): 1-7.
[30]	Hydock DS. Sex hormone suppression and physical activity: possible implications for transgender individuals. Transgend Health. 2022; 7(1): 43-51.
[31]	Jones BC, Hydock DS. Effects of puberty blocker treatment on voluntary wheel running activity in young rats. Int J Sport Exerc Health Res. 2023; 7(2): 83-89.
[32]	US Department of Health and Human Services. Physical Activity Guidelines for Americans. 2nd ed. Washington, DC: US Dept of Health and Human Services; 2018.
[33]	Chen TJ, Whitfield GP, Watson KB, Fulton JE, Ussery EN, Hyde ET, Rose K. Awareness and knowledge of the Physical Activity Guidelines for Americans, 2nd edition. J Phys Act Health. 2023; 20(8): 742-751.
[34]	Kuriyan R. Body composition techniques. Indian J Med Res. 2018; 148(5): 648-658.
[35]	Mayo Clinic. Pubertal blockers for transgender and gender diverse youth. Mayo Clinic. Published June 14, 2023. Accessed March 2026. https: //www.mayoclinic.org/diseases-conditions/gender-dysphoria/in-depth/pubertal-blockers/art-20459075.
[36]	Vlot MC, Klink DT, den Heijer M, Blankenstein MA, Rotteveel J, Heijboer AC. Effect of pubertal suppression and cross-sex hormone therapy on bone turnover markers and bone mineral apparent density in transgender adolescents. Bone. 2017; 95: 11-19.
[37]	Neely EK, Bachrach LK, Hintz RL, et al. Bone mineral density during treatment of central precocious puberty. J Pediatr. 1995; 127(5): 819-822.
[38]	Tanner MK, Hohorst AA, Mellert SM, Loetz EC, Baratta MV, Greenwood BN. Female rats are more responsive than males to the protective effects of voluntary physical activity against the behavioral consequences of inescapable stress. Stress. 2023; 26(1): 2245492.
[39]	Mathis V, Wegman-Points L, Pope B, Lee CJ, Mohamed M, Rhodes JS, Clark PJ, Clayton S, Yuan LL. Estrogen-mediated individual differences in female rat voluntary running behavior. J Appl Physiol. 2024; 136(3): 592-605.
[40]	Capra L, Tezza G, Mazzei F, Boner AL. The origins of health and disease: the influence of maternal diseases and lifestyle during gestation. Ital J Pediatr. 2013; 39: 7.
[41]	Kartchner LC, Dunn A, Taylor KH, et al. Lifestyle modifications prior to pregnancy and their impact on maternal and perinatal outcomes: a review. J Clin Med. 2025; 14(18): 6582.
[42]	Johnson K, Posner SF, Biermann J, et al. Recommendations to improve preconception health and health care—United States. MMWR Recomm Rep. 2006; 55(RR-6): 1-23.