However, it is important to note that given the complex nature of the positive and negative feedback mechanisms regulating estradiol, progesterone, FSH, and LH release (Kubota et al., 2016), all hormone manipulation models are confounded by unintended effects on hormone levels and hormone-dependent behaviors (i.e., anxiety and depression; Azizi-Malekabadi et al., 2015). The gene discussed is PLOD1; the disease is major depressive disorder.