The GnRH Antagonist Degarelix Suppresses Gonadotropin Secretion and Pituitary Sensitivity in Midgestation Sheep Fetuses

Abstract

The specific role of GnRH on brain sexual differentiation remains unclear. To investigate whether gonadotropin and, in turn, testosterone (T) secretion is regulated by GnRH during the critical period for brain differentiation in sheep fetuses, we attempted to selectively suppress pituitary-testicular activation during midgestation with the long-acting GnRH antagonist degarelix. Fetuses received subcutaneous injections of the antagonist or vehicle on day 62 of gestation. After 2 to 3 weeks we examined consequences of the intervention on baseline and GnRH-stimulated plasma LH and T levels. In addition, we measured the effect of degarelix-treatment on mRNA expression for the pituitary gonadotropins and key gonadal steroidogenic enzymes. Baseline and GnRH-stimulated plasma LH levels were significantly suppressed in degarelix-treated male and female fetuses compared to control values. Similarly, T concentrations were suppressed in degarelix-treated males. The percentage of LHβ-immunoreactive cells colocalizing c-fos was significantly reduced by degarelix treatment indicating that pituitary sensitivity was inhibited. Degarelix treatment also led to the significant suppression of mRNA expression coding for the pituitary gonadotropin subunits and for the gonadal enzymes involved in androgen synthesis. These findings demonstrate that pharmacologic inhibition of GnRH early in gestation results in suppression of LH secretion and deficits in the plasma T levels of male lamb fetuses. We conclude that GnRH signaling plays a pivotal role for regulating T exposure during the critical period of sheep gestation when the brain is masculinized. Thus, disturbance to gonadotropin secretion during this phase of gestation could have long-term consequence on adult sexual behaviors and fertility.

Association between the prevalence rates of circadian syndrome and testosterone deficiency in US males: data from NHANES (2011–2016)

“…Shift workers, people who stay up late, and people who sleep little are more prone to circadian rhythm disorders and TD (24, 25). Recent rat experiments support that short sleep can induce an intense alternation in the hypothalamic-pituitary-adrenal axis, resulting in elevated serum cortisol levels and reduced testosterone levels (26,27). In detail, the increased cortisol content significantly decreases testosterone levels via direct access (e.g., its receptors in Leydig cells) or by inducing Leydig cell apoptosis (28, 29).…”

“…Testosterone secretion mainly depends on the hypothalamus-pituitary-gonadal (HPG) axis. Gonadotropin-releasing hormone (GnRH), at the upstream of the HPG axis, is produced in the hypothalamus and stimulates testosterone production ( 30 ). In addition, the release of GnRH is closely related to hypothalamic N-peptide kisspeptin encoded by the KISS1 gene and kisspeptin receptor on GnRH neurons.…”

“…In addition, the release of GnRH is closely related to hypothalamic N-peptide kisspeptin encoded by the KISS1 gene and kisspeptin receptor on GnRH neurons. Research focusing on TD indicates that the transmission of blocked kisspeptin signaling plays a critical role in GnRH release ( 30 ). For obese people with CircS, increased adipokine secretion (adiponectin, leptin) can block kisspeptin signaling and inhibit GnRH release, leading to decreased testosterone secretion ( 31 , 32 ).…”

Systematic review of hormonal strategies to improve fertility in rams

“…However, a drawback of these GnRH agonists is that with continuous administration, the receptors become obstructed and unresponsive, resulting in the suspension of FSH and LH secretion ( Adams, 2005 ). However, GnRH antagonists are more directly inhibitory in their effect as they block the receptor immediately upon binding ( Amodei et al, 2022 ; Hitesh and Kansal, 2022 ; Hashem et al, 2023 ). Moreover, in goat and sheep production systems, farm productivity must be based on the continuity of kidding and lambing throughout the different seasons.…”