Progesterone and Its Metabolites Play a Beneficial Role in Affect Regulation in the Female Brain

Premenstrual dysphoric disorder is a female affective disorder that is defined by mood symptoms. The condition is linked to unstable progesterone concentrations. Progestin supplementation is given in cases of threatened or recurrent miscarriage and for luteal phase support. Progesterone is essential for implantation, immune tolerance, and modulation of uterine contractility. For a long time, the administration of progestins was associated with an unfavorable impact on mood, leading to negative affect, and, therefore, was contraindicated in existing mood disorders. Establishing the role of the natural progesterone derivative allopregnanolone in advances in the treatment of postpartum depression has shed new light on the general pathophysiology of mood disorders. Allopregnanolone directly interacts with gamma-aminobutyric acid type A (GABA-A) receptors even at nanomolar concentrations and induces significant anti-depressant, anti-stress, sedative, and anxiolytic effects. Postpartum depression is caused by a rapid drop in hormones and can be instantly reversed by the administration of allopregnanolone. Premenstrual dysphoric disorder can also be considered to result from insufficient neuroactive steroid action due to low progesterone derivative concentration, unstable hormone levels, or decreased receptor sensitivity. The decrease in progesterone levels in perimenopause is also associated with affective symptoms and an exacerbation of some psychosomatic syndromes. Bioidentical progesterone supplementation encounters several obstacles, including limited absorption, first-pass effect, and rapid metabolism. Hence, non-bioidentical progestins with better bioavailability were widely applied. The paradoxical, unfavorable effect of progestins on mood can be explained by the fact that progestins suppress ovulation and disturb the endocrine function of the ovary in the luteal phase. Moreover, their distinct chemical structure prevents their metabolism to neuroactive, mood-improving derivatives. A new understanding of progesterone-related mood disorders can translate the study results from case series and observational studies to cohort studies, clinical trials, and novel, effective treatment protocols being developed.