Pathogenesis in Menstrual Cycle‐Linked CNS Disorders

Abstract

That 3alpha-hydroxy-5alpha/beta-pregnane steroids (GABA steroids) have modulatory effects on the GABA-A receptor is well known. In behavioral studies in animals high exogenous dosages give concentrations not usually reached in the brain under physiological conditions. Animal and human studies show that GABA-A receptor-positive modulators like barbiturates, benzodiazepines, alcohol, and allopregnanolone have a bimodal effect. In pharmacological concentrations they are CNS depressants, anesthetic, antiepileptic, and anxiolytic. In low dosages and concentrations, reached endogenously, they can induce adverse emotional reactions in up to 20% of individuals. GABA steroids can also induce tolerance to themselves and similar substances, and rebound occurs at withdrawal. Menstrual cycle-linked disorders can be understood by the concept that they are caused by the action of endogenously produced GABA-steroids through three mechanisms: (a) direct action, (b) tolerance induction, and (c) withdrawal effect. Examples of symptoms and disorders caused by the direct action of GABA steroids are sedation, memory and learning disturbance, clumsiness, increased appetite, worsening of petit mal epilepsy, negative mood as tension, irritability and depression during hormone treatments, and the premenstrual dysphoric disorder (PMDD). A continuous exposure to GABA steroids causes tolerance, and women with PMDD are less sensitive to GABA-A modulators. A malfunctioning GABA-A receptor system is related to stress sensitivity, concentration difficulties, loss of impulse control, irritability, anxiety, and depression. An example of withdrawal effect is "catamenial epilepsy," when seizures increase during menstruation after the withdrawal of GABA steroids. Similar phenomena occur at stress since the adrenals produce GABA steroids during stress.

Progesterone selectively increases amygdala reactivity in women

“…[47][48][49] Low doses of allopregnanolone increase aggressive behavior in mice, whereas higher doses decrease aggression. 50 Moreover, the addition of a low dose of progesterone to the treatment with estradiol during hormonal replacement therapy increases negative mood, but higher doses do not.…”

Progesterone, progestins and psychosomatic health of women

“…In a further publication, Bäckström et al (5) concluded that in ''hysterectomized women only estrogen replacement is strictly necessary. Indeed, there is no imperious need for administrating progesterone/synthetic progestins other than for preventing the risk of endometrial hyperplasia and/or cancer''.…”

Extrasynaptic GABAA receptors in the crosshairs of hormones and ethanol

“…Present treatment of PMDD is mainly limited to SSRI such as Zoloft, in spite of the fact that there seems to be no serotonergic abnormality in affected women (Freeman 2004). GABAergic mechanisms are much more likely to be involved (Smith 2001;Backstrom et al 2003;Sundstrom-Poromaa et al 2003), but there are few experimental studies on the subject.…”

“…The prevalence of PMDD is 2-8% of women and a less severe phenotype of PMS is present in 15-25% of women (Wittchen 2002;Chawla et al 2002;Backstrom et al 2003;Halbreich et al 2003). Despite the high prevalence of PMDD, the World Health Organization (WHO) did not include PMDD or PMS in the comprehensive report regarding the economic burden of mental health disorders.…”

“…The disorders associated with the menstrual cycle in women share patterns of symptom manifestation worsening during the luteal phase, occurring just prior to or during menses, and/ or at the time of ovulation (Smith 2001;Backstrom et al 2003;Sundstrom-Poromaa et al 2003). The prevalence of PMDD is 2-8% of women and a less severe phenotype of PMS is present in 15-25% of women (Wittchen 2002;Chawla et al 2002;Backstrom et al 2003;Halbreich et al 2003).…”