Pathogenesis in menstrual cycle-linked CNS disorders.
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.
Umeå Neurosteroid Research Center, Department of Clinical Sciences, Obstetrics and Gynecology, Norrlands University Hospital, SE-901 85 Umeå, Sweden. Torbjorn.Backstrom@Obgyn.umu.se
Torbjörn
T
Bäckström
Agneta
A
Andersson
Lotta
L
Andreé
Vita
V
Birzniece
Marie
M
Bixo
Inger
I
Björn
David
D
Haage
Monica
M
Isaksson
Inga-Maj
IM
Johansson
Charlott
C
Lindblad
Per
P
Lundgren
Sigrid
S
Nyberg
Inga-Stina
IS
Odmark
Jessica
J
Strömberg
Inger
I
Sundström-Poromaa
Sahruh
S
Turkmen
Göran
G
Wahlström
Mingde
M
Wang
Anna-Carin
AC
Wihlbäck
Di
D
Zhu
Elisabeth
E
Zingmark
D000339:Affect / Q000502:physiology; D000818:Animals; D005260:Female; D006801:Humans; D008597:Menstrual Cycle / Q000502:physiology*; D019964:Mood Disorders / Q000209:etiology* / Q000503:physiopathology / Q000523:psychology; D011280:Pregnanolone / Q000502:physiology; D011293:Premenstrual Syndrome / Q000209:etiology* / Q000503:physiopathology / Q000523:psychology; D011963:Receptors, GABA-A / Q000502:physiology
D011963:Receptors, GABA-A; D011280:Pregnanolone