Medroxyprogesterone acetate positively modulates specific GABAA-receptor subtypes - affecting memory and cognition

Das, Roshni; Ragagnin, Gianna; Sjöstedt, Jessica; Johansson, Monika; Haage, David; Druzin, Michael; Johansson, Staffan; Bäckström, Torbjörn

doi:10.1016/j.psyneuen.2022.105754

Cited by 6 publications

(9 citation statements)

References 55 publications

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“…Besides, the signal of decreased appetite was detected in depot progestin users in this study. Since progestin metabolites have been reported to modulate GABA-A receptors directly rather than lowering estrogen levels to regulate appetite and mood, 45 exact mechanisms behind the effect of progestins remain to be further investigated.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Adverse Events and Medical Errors in Long-Term Hormone Treatments for Endometriosis: A Study Based on the US Food and Drug Administration Event Reporting System

Zhang¹,

Zhu²,

Sun³

2022

IJWH

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Purpose To investigate adverse events and medical errors, as well as their possible risk factors, of combined oral contraceptives and progestins used in patients with endometriosis. Patients and Methods Reports between January 1, 2014 and September 30, 2021 about patients with endometriosis in US Food and Drug Administration Adverse Event Reporting System were analyzed. Disproportional analysis was performed with the Gamma-Poisson Shrinker model to detect overreported drug-event pairs. Logistic regression analysis was utilized to explore potential risk factors. Results There were 823 reports on long-term hormone treatments and 6247 reports on other drugs after removing duplicates, most of which were reported by consumers and were from the United States. Procedural complications and product issues were common among long-term hormone treatment users, while some other new adverse events emerged in subgroup analysis of different dosage forms of progestin. Polytherapy was negatively associated with off label use (adjusted OR = 0.47, 95% CI 0.22–0.94) and product use in unapproved indication (adjusted OR = 0.36, 95% CI 0.15–0.76) for combined oral contraceptive users. Combined oral contraceptive users aged greater than or equal to 30 were less likely to have product use issue (adjusted OR = 0.33, 95% CI 0.12–0.82) but were at higher risk of pulmonary embolism (adjusted OR = 4.04, 95% CI 1.35–17.43). Conclusion Long-term hormone treatment products in this study are generally safe for endometriosis, while newly detected signals need to be validated by further exploration. Patients’ tolerance and fertility desire should be considered when preparing treatment plans.

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Section: Discussionmentioning

confidence: 99%

Analysis of Adverse Events and Medical Errors in Long-Term Hormone Treatments for Endometriosis: A Study Based on the US Food and Drug Administration Event Reporting System

Zhang¹,

Zhu²,

Sun³

2022

IJWH

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“…MPA also showed its direct effect without adding GABA in rat hypothalamic cells. These results demonstrate that MPA is a positive allosteric modulator of GABA‐A receptor subtypes α5β3γ2L and α2β3γ2S, and influences cells taken from the hypothalamic preoptic area [80].…”

Section: Mpa Is a Positive Gaba‐a Modulator (Pam)mentioning

confidence: 99%

“…There is a lack of knowledge about MPA effects on subtypes of GABA-A receptors involved in cognition and mood. We have therefore performed studies of MPA on recombinant human GABA-A receptors [80]. Our studies in human embryonic kidney 293 cell lines permanently expressing the α1β2γ 2L, α5β3γ 2L, or α2β3γ 2S subtypes-using electrophysiological patch-clamp technology-examined MPA compared to well-known steroid-PAMs such as THDOC and ALLO.…”

Section: Mpa Is a Positive Gaba-a Modulator (Pam)mentioning

confidence: 99%

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The GABA system, a new target for medications against cognitive impairment—Associated with neuroactive steroids

et al. 2023

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The prevalence of cognitive dysfunction, dementia, and neurodegenerative disorders such as Alzheimer's disease (AD) is increasing in parallel with an aging population. Distinct types of chronic stress are thought to be instrumental in the development of cognitive impairment in central nervous system (CNS) disorders where cognitive impairment is a major unmet medical need. Increased GABAergic tone is a mediator of stress effects but is also a result of other factors in CNS disorders. Positive GABA‐A receptor modulating stress and sex steroids (steroid‐PAMs) such as allopregnanolone (ALLO) and medroxyprogesterone acetate can provoke impaired cognition. As such, ALLO impairs memory and learning in both animals and humans. In transgenic AD animal studies, continuous exposure to ALLO at physiological levels impairs cognition and increases degenerative AD pathology, whereas intermittent ALLO injections enhance cognition, indicating pleiotropic functions of ALLO. We have shown that GABA‐A receptor modulating steroid antagonists (GAMSAs) can block the acute negative cognitive impairment of ALLO on memory in animal studies and in patients with cognitive impairment due to hepatic encephalopathy. Here we describe disorders affected by steroid‐PAMs and opportunities to treat these adverse effects of steroid‐PAMs with novel GAMSAs.

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“…However, the endogenous metabolites bind to the GABA A receptor at specific neurosteroid binding sites, which differs from that of the exogenous GABA A receptor active compounds mentioned above [7,8]. AP and THDOC modulate the post-synaptic GABA A receptor activity in several different aspects [7][8][9]: (1) by prolonging the decay time of spontaneous inhibitory post-synaptic currents (sIPSCs) [10,11] and (2) by causing a direct receptor opening effect (a shift in baseline holding current), especially on extra-synaptic receptors [12,13]. AP also increases the frequency of presynaptic GABA release [10].…”

Section: Introductionmentioning

confidence: 99%

Extra-Synaptic GABAA Receptor Potentiation and Neurosteroid-Induced Learning Deficits Are Inhibited by GR3027, a GABAA Modulating Steroid Antagonist

Bengtsson,

Sjöstedt,

Malinina

et al. 2023

Biomolecules

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Objectives In Vitro: To study the effects of GR3027 (golexanolone) on neurosteroid-induced GABA-mediated current responses under physiological GABAergic conditions with recombinant human α5β3γ2L and α1β2γ2L GABAA receptors expressed in human embryonic kidney cells, using the response patch clamp technique combined with the Dynaflow™ application system. With α5β3γ2L receptors, 0.01–3 μM GR3027, in a concentration-dependent manner, reduced the current response induced by 200 nM THDOC + 0.3 µM GABA, as well as the THDOC-induced direct gated effect. GR3027 (1 μM) alone had no effect on the GABA-mediated current response or current in the absence of GABA. With α1β2γ2L receptors, GR3027 alone had no effect on the GABA-mediated current response or did not affect the receptor by itself. Meanwhile, 1–3 µM GR3027 reduced the current response induced by 200 nM THDOC + 30 µM GABA and 3 µM GR3027 that induced by 200 nM THDOC when GABA was not present. Objectives In Vivo: GR3027 reduces allopregnanolone (AP)-induced decreased learning and anesthesia in male Wistar rats. Rats treated i.v. with AP (2.2 mg/kg) or vehicle were given GR3027 in ratios of 1:0.5 to 1:5 dissolved in 10% 2-hydroxypropyl-beta-cyclodextrin. A dose ratio of AP:GR3027 of at least 1:2.5 antagonized the AP-induced decreased learning in the Morris Water Mase (MWM) and 1:7.5 antagonized the loss of righting reflex (LoR). GR3027 treatment did not change other functions in the rat compared to the vehicle group. Conclusions: GR3027 functions in vitro as an inhibitor of GABAA receptors holding α5β3γ2L and α1β2γ2L, in vivo, in the rat, as a dose-dependent inhibitor toward AP’s negative effects on LoR and learning in the MWM.

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Medroxyprogesterone acetate positively modulates specific GABAA-receptor subtypes - affecting memory and cognition

Cited by 6 publications

References 55 publications

Analysis of Adverse Events and Medical Errors in Long-Term Hormone Treatments for Endometriosis: A Study Based on the US Food and Drug Administration Event Reporting System

Analysis of Adverse Events and Medical Errors in Long-Term Hormone Treatments for Endometriosis: A Study Based on the US Food and Drug Administration Event Reporting System

The GABA system, a new target for medications against cognitive impairment—Associated with neuroactive steroids

Extra-Synaptic GABAA Receptor Potentiation and Neurosteroid-Induced Learning Deficits Are Inhibited by GR3027, a GABAA Modulating Steroid Antagonist

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