Effects of Long-Term Flutamide Treatment During Development on Sexual Behaviour and Hormone Responsiveness in Rams

Area of Science:

• Reproductive biology
• Neuroendocrinology
• Developmental biology

Background:

• Prenatal testosterone exposure is crucial for male sexual differentiation in sheep.
• Testosterone acts via androgen receptors (AR) or after aromatization to oestradiol and oestrogen receptors.

Purpose of the Study:

• To investigate the role of androgen receptor (AR) activation in male sexual differentiation in sheep.
• To determine if blocking AR activation prenatally affects male sexual behaviors and neuroanatomy.

Main Methods:

• Administered the AR antagonist flutamide (Flu) to sheep from days 30-90 of gestation.
• Compared Flu-exposed rams to control rams and ewes regarding external genitalia, reproductive organs, sexual behaviors, and brain anatomy (ovine sexually dimorphic nucleus).

Main Results:

• Flutamide-exposed rams had female-like external genitalia, undescended testes, impaired androgen secretion, and were azospermic.
• Flu rams displayed male-typical mounting behaviors but lacked a penis, preventing intromission and ejaculation.
• The ovine sexually dimorphic nucleus volume in Flu rams was intermediate between control rams and ewes.

Conclusions:

• Prenatal anti-androgen exposure does not completely block male sexual differentiation in sheep.
• Compensatory mechanisms likely ensure adequate androgen stimulation during critical developmental periods.
• AR activation is essential for typical male genital development and reproductive organ structure.