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Mood Disorders
Published in Vincenzo Berghella, Maternal-Fetal Evidence Based Guidelines, 2022
Madeleine A. Becker, Tal E. Weinberger, Leigh J. Ocker
Brexanolone, a soluble IV formulation of the neuroactive steroid allopregnanolone, is the first medication approved by the FDA specifically for the treatment of postpartum depression. Allopregnanolone, a progesterone metabolite, is a potent allosteric modulator of GABAa receptors and has been shown to have significant effects on anxiety and depression in animal models. Allopregnanolone levels change in parallel with progesterone, reaching highest concentrations in the third trimester and decreasing abruptly after childbirth [128, 129]. Brexanolone dosing was designed to be comparable to allopregnanolone levels in the third trimester. Brexanolone is administered as a continuous 60-hour infusion, with a gradual decrease in dose until the infusion is stopped, allowing for a slow rather than abrupt decrease in allopregnanolone levels in a population which may be vulnerable to rapid hormonal fluctuation.
Clinical Endocrinology of Pregnant Mares
Published in Juan Carlos Gardón, Katy Satué, Biotechnologies Applied to Animal Reproduction, 2020
On the other hand, the concentration of these steroids in maternal and umbilical circulation is variable and changes as the time of delivery approaches. This is related to the maintenance of uterine quiescence during this period, during which uterine stress related to increased fetal size may stimulate myometrial contractility. Thus, 5αDHP is found primarily at the uterine level during mid-gestation, but as labor approaches, its distribution changes and is predominantly in fetal circulation. Additionally, this metabolite is an immediate precursor of allopregnanolone, a potent gamma-aminobutyric acid receptor agonist with activity on myometrial relaxation in other species (Holtan et al., 1991; Scholtz et al., 2014; Conley, 2016; Wynn et al., 2018a). Serum levels of allopregnanolone increase similarly to its precursor, reaching maximum values at middle of gestation (16 ng/mL) and a term (20 ng/mL) (Legacki et al., 2016). However, both P4 and DHP prevent weakly myometrial contractions induced by oxytocin in vitro, suggesting the intervention of the other hormones in the maintenance of uterine quiescence (Ousey et al., 2000). On the other hand, an umbilical increase of P4 after 300 days of gestation has been described, related to a greater expression in the trophoblast of the enzyme 3β-HSD, necessary for the conversion of P5 into P4 (Ousey et al., 2003).
Serotonin Metabolism in Functional Somatic Illness
Published in Peter Manu, The Psychopathology of Functional Somatic Syndromes, 2020
Patients with premenstrual syndrome had significantly higher levels of allopregnanolone than those recorded for the control group. The intergroup difference was statistically significant (p < 0.001) both at baseline (2.6 versus 1 ng/mL) and after stressful tasks (2.3 versus 1.2 ng/mL). Compared with the baseline value, the poststress allopregnanolone level increased in 83 percent of the control subjects and 42 percent of the premenstrual syndrome patients. Patients with greater premenstrual anxiety had significantly lower levels of allopregnanolone than the remainder of the group (p < 0.01), and a similar trend was noted for premenstrual irritability (p = 0.08) and depression (p = 0.09). The cortisol levels were lower in the premenstrual group (p < 0.05). A negative correlation between cortisol and allopregnanolone levels was demonstrated for both baseline and poststress conditions in the premenstrual syndrome group (p < 0.05). The findings were interpreted to indicate that premenstrual syndrome is associated with higher levels of allopregnanolone, which inhibit the function of the hypothalamic-pituitary-adrenal axis. They also postulated that the hormone alters the receptor sensitivity of neurotransmitters that modulate the anxiety, irritability, and depression of patients with this condition, but direct evidence for this type of effect was not obtained in the study.
The pharmacotherapeutic management of premenstrual dysphoric disorder
Published in Expert Opinion on Pharmacotherapy, 2023
Nancy Ciccone, Maya B. Kovacheff, Benicio N. Frey
Extensive research showing that PMDD symptoms are triggered by hormonal fluctuations, and the fact that five placebo-controlled trials have demonstrated efficacy of OCPs in the management of PMDD, suggests that the use of OCPs should be more in the forefront of options in the management of this condition. Unfortunately, the use of OCPs to treat a mental health condition is also not consistently disseminated in psychiatry or primary care training. While there is some evidence that trials with shorter placebo breaks (four vs seven days) may be more beneficial, quite often experts in the field use off-label continuous daily OCPs with no breaks for 3–4 months with success. This is a real research gap that needs to be addressed by future controlled trials. Similarly, there is a lack of controlled trials using leuprolide in those who did not respond or could not tolerate antidepressants and OCPs, although anecdotal use suggests benefit from leuprolide in severe, treatment-resistant cases. There is a clear need to find alternative treatments for this recurrent condition. Recent preliminary studies targeting neurosteroids, in particular allopregnanolone, are promising. Preclinical studies investigating the mechanisms of action of chasteberry extract can also shed a light of potentially unexplored mechanisms for drug discovery.
Allopregnanolone and reproductive psychiatry: an overview
Published in International Review of Psychiatry, 2019
Katherine McEvoy, Lauren M. Osborne
As progesterone changes dramatically across pregnancy and after childbirth, so does allopregnanolone. ALLO levels rise steadily through pregnancy (produced primarily by the placenta) until shortly before delivery, when the ratio of ALLO to its precursor progesterone begins to drop. Both then drop precipitously immediately after childbirth. These rising levels of ALLO across pregnancy may lead to a down-regulation of receptors, which then fail to recover appropriately in women who develop symptoms in the postpartum (Gilbert Evans, Ross, Sellers, Purdy, & Romach, 2005; Maguire & Mody, 2008; Osborne et al., 2017). Knockout mice who were unable to downregulate the delta sub-unit of the GABAA receptor during pregnancy or to upregulate it postpartum developed depressive and anxiety-like behaviours in the postpartum. These symptoms were specific to the postpartum and did not occur when the mice were given an inhibitor that replaced the activity of the knocked out gene (Maguire & Mody, 2008). Similarly, an inability to recover receptor concentration postpartum has been associated with PPD (Gilbert Evans et al., 2005). Mood symptoms may, therefore, be arising either as a direct effect of changing hormone levels; as an indirect effect due to changes in receptor concentration or configuration; or as a result of mediating factors such as the immune system or HPA axis changes.
Evidence on the use of progesterone in menopausal hormone therapy
Published in Climacteric, 2018
Progesterone is converted to allopregnanolone in the mammalian brain, which has been shown to induce GABAergic effects and promote sleep. Sleep parameters improved in several trials of P4-containing HT, with some showing better improvements when P4 vs. MPA was used. A polysomnography study of 21 menopausal women found that 0.625 mg CEE with cyclic 200 mg/day P4, but not with cyclic 5 mg/day MPA, significantly improved sleep efficiency and decreased time spent awake after sleep onset from baseline, with similar improvements in other subjective sleep indices in both groups46. In another small, cross-over, polysomnography study (n = 10), 300 mg P4 alone for 21 days significantly reduced time spent awake and increased rapid eye movement sleep in the first third of the night vs. placebo49. Continuous CEE 0.3 mg/day with P4 100 mg also provided significantly better sleep outcomes than CEE/MPA 2.5 mg47. The REPLENISH trial showed improved sleep parameters (Medical Outcomes Study – Sleep Scale) with various continuous E2/P4 doses at week 12 and months 6 and 1250, consistent with a reduction in hot flushes.