Medroxyprogesterone acetate impairs memory and alters the GABAergic system in aged surgically menopausal rats

Abstract

In women, medroxyprogesterone acetate (MPA) is the most commonly used progestin component of HT. In vitro, MPA negatively impacts markers of neuronal health and exacerbates experimentally-induced neurotoxicity. There is in vitro evidence that these factors are driven by GABAergic and neurotrophic systems. Whether these effects translate to a negative impact on brain function has not been tested in vivo, clinically or preclinically. Here we evaluate the mnemonic and neurobiological effects of MPA in the surgically menopausal rat. Aged ovariectomized (OVX) rats were given subcutaneous vehicle, natural progesterone, low-dose MPA or high-dose MPA. Multiple cognitive domains were analyzed via the water radial-arm maze (WRAM), and Morris maze (MM). Cognitive brain regions were assayed for changes in the GABAergic system by evaluating GAD protein, the synthesizing enzyme for GABA, and neurotrophins. On the WRAM, both progestin types impaired learning. Further, high-dose MPA impaired delayed memory retention on the WRAM, and exacerbated overnight forgetting on the MM. While neurotrophins were not affected by progesterone or MPA treatment, both progestin types altered GAD levels. MPA significantly and progesterone marginally decreased GAD levels in the hippocampus, and both MPA and progesterone significantly increased GAD levels in the entorhinal cortex. These findings suggest that MPA, the most commonly used progestin in HT, is detrimental to learning and two types of memory, and modulates the GABAergic system in cognitive brain regions, in aged menopausal rats. These findings, combined with in vitro evidence that MPA is detrimental to neuronal health, indicates that MPA has negative effects for brain health and function.

Sex Hormones and Cognition: Neuroendocrine Influences on Memory and Learning

“…MPA in combination with 17β-estradiol treatment impairs spatial reference memory relative to 17β-estradiol treatment alone or progesterone plus 17β-estradiol treatment in aged ovariectomized rats (107). In spatial working memory tasks, MPA-associated impairments were greater with higher levels of working memory load both in young and older ovariectomized adult rats (76,77). MPA administration may have long-term effects on spatial working memory beyond the time frame of administration, as MPA administered in either young adulthood, or middle age, impaired water radial-arm maze and Morris water maze performance when measured in middle age (76), with more pronounced effects seen with MPA administration in both young and middle adulthood.…”

“…Some studies [e.g., (384)] use retired breeders or oral administration of hormone, which is metabolized differently and poses challenges for dosage control. Further, natural versus synthetic progestins have different effects on cognition in rats depending on task type, with more negative outcomes associated with use of synthetic progestins such as medroxyprogesterone acetate (MPA) [e.g., (76,77,107,384)]. For example, tonic MPA impairs memory retention after a delay on the water radial arm maze, and exacerbates overnight forgetting on the spatial reference memory Morris water maze (77).…”

“…Further, natural versus synthetic progestins have different effects on cognition in rats depending on task type, with more negative outcomes associated with use of synthetic progestins such as medroxyprogesterone acetate (MPA) [e.g., (76,77,107,384)]. For example, tonic MPA impairs memory retention after a delay on the water radial arm maze, and exacerbates overnight forgetting on the spatial reference memory Morris water maze (77). MPA in combination with 17β-estradiol treatment impairs spatial reference memory relative to 17β-estradiol treatment alone or progesterone plus 17β-estradiol treatment in aged ovariectomized rats (107).…”

The Effects of Progesterone Selection on Psychological Symptoms in Hormone Replacement Therapy

“…In another in vitro study, it was demonstrated that medroxyprogesterone acetate and metabolites influenced memory, learning and other cognitive functions unfavorably through the GABA-ergic system, and could cause neuronal toxicity, this effect was not clearly revealed in in vivo clinical and preclinical studies [18].…”

Evaluating the Role of Hormone Therapy in Postmenopausal Women with Alzheimer’s Disease

“…MPA is a synthetic analogue of progesterone and acts like an agonist at progesterone receptors, but it also binds to androgen and glucocorticoid receptors, respectively [91,92]. A recent study found that MPA administered without estrogen impaired the performance of rats in the water radial arm maze and the spatial water maze tests [93].…”