Daily GnRH agonist treatment delays the development of reproductive physiology and behavior in male rats

Guarraci, Fay A.; Davis, Lourdes K.; Henneman, Elizabeth L.; Toro, Erin; Odell, Shannon E.; Le, Nathan N.; Navarro, J. M.; Valdivia, Hannah S.; Williams, Ian H.; Credeur, Matthew; Gore, Andrea C.

doi:10.1016/j.yhbeh.2021.104982

Cited by 3 publications

(4 citation statements)

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“…Similar to our initial findings [9], daily leuprolide treatment disrupted the development of male copulatory behavior and the expression of sexual motivation. Specifically, exposure to leuprolide reduced the frequency of copulatory behaviors and the time spent with a female stimulus rat.…”

Section: Male Ratssupporting

confidence: 89%

“…In the current study, daily leuprolide administration at a dose of 50 µg/kg delayed the onset of puberty by an average of 6 days in male rats. This delay in preputial separation is about two days longer than what we reported in our previous study [9]. The difference between our two studies is likely a function of administering a higher dose in the present experiment (50 μg/kg here vs. 25 μg/kg previously).…”

Section: Male Ratscontrasting

confidence: 67%

“…Although we did not measure serum testosterone at the end of the present experiment, we had previously found that approximately 4 weeks after leuprolide treatment ended, serum testosterone levels increased beyond control levels, probably representing an overshoot as the hypothalamic-pituitary-gonadal axis became activated [9]. Similarly, approximately 3 weeks after serum leuprolide levels neared zero following subcutaneous microcapsule injections, testosterone concentrations attained control levels in male rats [28].…”

Section: Male Ratsmentioning

confidence: 71%

“…Only a few preclinical studies have tested the effects of blocking puberty in animals to model the use of GnRH agonists to halt pubertal progression in adolescents questioning their gender identity. For instance, in male rats, daily leuprolide treatment during the periadolescent period delayed puberty, as well as the development of copulatory behavior and sexual motivation when preference for a sexual partner was tested within 3 days of treatment termination [9]. Similarly, male mice exposed to leuprolide for 6 weeks in late adolescence spent less time investigating a female stimulus, but more time investigating a male stimulus compared to saline controls [10].…”

Section: Introductionmentioning

confidence: 99%

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Chronic periadolescent leuprolide exposure affects the development of reproductive physiology and behavior of female and male rats differently, but both mature after treatment termination

et al. 2023

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Background GnRH agonists have been used to halt the development of puberty in children with precocious puberty since the 1980s. Recently, drugs like Lupron Depot® (leuprolide acetate), have been used to suppress pubertal progression in adolescents who are questioning their gender identity. However, few preclinical studies have been conducted to investigate potential effects of using GnRH agonists in this context. Methods The present study tested the effects of daily leuprolide treatment (50 µg/kg, postnatal day (PD) 25–50) on pubertal onset in female (i.e., vaginal opening) and male (i.e., preputial separation) Long-Evans rats. The first estrous cycle immediately after vaginal opening was also measured. Sexual behavior and sexual motivation were tested using the partner-preference paradigm. Female rats were tested during the first behavioral estrus after treatment ended (between PD 51–64). Male rats were tested weekly for four consecutive weeks starting three days after treatment ended (PD 53). Results Consistent with previous findings, leuprolide significantly delayed pubertal onset in both female and male rats. In addition, the first estrous cycle during the treatment period was disrupted by leuprolide, as indicated by a failure to cycle into estrus after vaginal opening until treatment ended. However, leuprolide affected neither sexual motivation nor fertility when female rats were tested within 14 days of leuprolide treatment ending. In contrast, the development of copulatory behavior and sexual motivation was significantly delayed by leuprolide in male rats; however, mature reproductive behavior was observed by the fourth week post-treatment. Conclusions Taken together with previous findings, the present results indicate that male rats may be more sensitive to periadolescent leuprolide administration, taking longer to overcome the effects of leuprolide than female rats. Nevertheless, not long after leuprolide treatment is discontinued, sex-typical reproductive physiology and behavior emerge fully in female and male rats, indicating that the drug’s effects are not permanent. If translatable to humans, leuprolide may be a reversible option to give adolescents more time to consider their gender identity with minimal long-term effects on sexual development.

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