UC San Diego

Testosterone replacement therapy (TRT) is a critical part of gender affirming care for many transgender men (assigned female at birth). However, TRT, which produces circulating testosterone in the male physiological range, also results in irregular menstrual cycles, diminished reproductive hormone levels, and infertility. This mechanism for the reproductive inhibition by TRT is poorly understood. High doses of dihydrotestosterone, a non-aromatizable androgen, inhibit pulsatile secretion of luteinizing hormone (LH) in females of several animal models including mice; however, it is not well examined if male levels of testosterone, such as those resulting from TRT, will obstruct other aspects of female reproductive hormone secretion such as the preovulatory LH surge which triggers ovulation. To investigate this, we implanted adult female mice with male level testosterone, then ovariectomized them and treated with elevated estradiol known to induce an LH surge. All control mice, without testosterone treatment, showed an LH surge while the testosterone treated mice did not have an LH surge. This indicated that their reproductive axis was inhibited. We next examined the brains of control females or females treated with testosterone and determined that RP3V kisspeptin neurons, known to stimulate the LH surge, had reduced activation in the latter group. Our findings suggest that elevated, male level testosterone in TRT possibly disrupt fertility in females by blocking the LH surge, perhaps by inhibiting kisspeptin neurons. Further research will elucidate the mechanism by which testosterone inhibits the LH surge, which could lead to a therapeutic target to reverse testosterone’s inhibition of female fertility.