PLOD1 and depressive disorder: 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).