Daily GnRH agonist treatment effectively delayed puberty in female rats without long-term effects on sexual behavior or estrous cyclicity

Guarraci, Fay A.; Avendano, Layla; Kelly, Megan; Estoestra, Cler; Frohock, Brooke; Candelario, Isabel; Davis, Lourdes K.; Oevermann, Matthew; Sencherey, Bernard; Toro, Erin; Valdivia, Hannah S.; Gore, Andrea C.

doi:10.1016/j.physbeh.2022.113879

Cited by 2 publications

(7 citation statements)

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“…In the current study, daily leuprolide administration at a dose of 50 µg/kg delayed the onset of puberty by an average of 7 days in female rats. These results are consistent with our previous findings in female rats using the same dose [11]. Nevertheless, most of the female rats treated with leuprolide showed physiological signs of pubertal onset during the treatment period, suggesting that this dose of leuprolide is not able to indefinitely suppress puberty in female rats.…”

Section: Physiological Effects Of Leuprolide Female Ratssupporting

confidence: 93%

“…Therefore, full recovery from leuprolide treatment can take place within a week of treatment termination in female rats. These results are consistent with our previous study, which also found no evidence that leuprolide affected fertility within two months of treatment termination [11]. However, in our previous study not all female rats received an ejaculation, so we were not able to thoroughly evaluate fertility [11].…”

Section: Physiological Effects Of Leuprolide Female Ratssupporting

confidence: 92%

“…These results are consistent with our previous study, which also found no evidence that leuprolide affected fertility within two months of treatment termination [11]. However, in our previous study not all female rats received an ejaculation, so we were not able to thoroughly evaluate fertility [11]. It is unlikely that there are any lasting effects of leuprolide on fertility once treatment ends.…”

Section: Physiological Effects Of Leuprolide Female Ratssupporting

confidence: 92%

“…Kisspeptin expressing neurons in the Nevertheless, despite observing a delay in vaginal opening and a persistent disruption of cyclicity during treatment in the present study, our current study found that within a week of leuprolide treatment termination (PD 51-57), the majority of leuprolide-treated female rats (5 of 8) entered estrus and were sexually receptive. Furthermore, our previous study found that regular estrous cyclicity was observed 2 weeks after leuprolide treatment ended [11]. Together these results indicate that leuprolide may be useful to indefinitely suppress LH, but within days of discontinuing treatment, regular ovarian cyclicity occurs.…”

Section: Physiological Effects Of Leuprolide Female Ratsmentioning

confidence: 68%

“…In contrast, leuprolide seems to have no effect on sociosexual behavior in female rodents. For example, we failed to find any long-term effects of daily periadolescent leuprolide administration on sexual behavior or sexual motivation when preference for a sexual partner was tested in female rats two months after leuprolide treatment ended [11]. Nor did we find any lasting effects of leuprolide on estrous cyclicity when measured for a month, starting two weeks after leuprolide exposure ended [11].…”

Section: Introductionmentioning

confidence: 67%

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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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Section: Physiological Effects Of Leuprolide Female Ratssupporting

confidence: 93%

Section: Physiological Effects Of Leuprolide Female Ratssupporting

confidence: 92%

Section: Physiological Effects Of Leuprolide Female Ratssupporting

confidence: 92%

Section: Physiological Effects Of Leuprolide Female Ratsmentioning

confidence: 68%

Section: Introductionmentioning

confidence: 67%

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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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Androgen Inhibition of Reproductive Neuroendocrine Function in Females and Transgender Males

Kauffman

2024

Endocrinology

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Ovarian function is controlled by pituitary secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH), which in turn are governed by gonadotropin releasing hormone (GnRH) secreted from the brain. A fundamental principle of reproductive axis regulation is negative feedback signaling by gonadal sex steroids back to the brain to fine-tune GnRH and gonadotropin secretion. Endogenous negative feedback effects can be mimicked by exogenous steroid treatments, including androgens, in both sexes. Indeed, a growing number of clinical and animal studies indicate that high levels of exogenous androgens, in the typically male physiological range, can inhibit LH secretion in females, as occurs in males. However, the mechanisms by which male-level androgens inhibit GnRH and LH secretion still remain poorly understood, and this knowledge gap is particularly pronounced in transgender men (individuals designated female at birth but identifying as male). Indeed, many transgender men take long-term gender-affirming hormone therapy that mimics male-level testosterone levels. The impact of such gender-affirming testosterone on the reproductive axis, both at the ovarian and neuroendocrine level, is a long-understudied area that still requires further investigation. Importantly, the few concepts of androgen actions in females mostly come from studies of polycystic ovary syndrome, which does not recapitulate a similar androgen milieu or a pathophysiology of inhibited LH secretion as occurs in testosterone-treated transgender men. This review summarizes clinical evidence indicating that exogenous androgens can impair neuroendocrine reproductive function in both female individuals and transgender men and highlights emerging experimental data supporting this in recently developed transgender rodent models.

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Daily GnRH agonist treatment effectively delayed puberty in female rats without long-term effects on sexual behavior or estrous cyclicity

Cited by 2 publications

References 40 publications

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

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

Androgen Inhibition of Reproductive Neuroendocrine Function in Females and Transgender Males

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