Estrogen Makes the Brain a Sex Organ

B R A I N S T O R M S Clinical Neuroscience Update

Stephen M. Stahl, M.D., Ph.D. © Copyright 1997 Physicians Postgraduate Press, Inc. Issue: The explanation of neurobiological actions of estrogen and other sex hormones on the brain is strengthening the link between reproductive hormones and behavior. Estrogen receptors in the brain are quite different from neurotransmitter receptors and appear to influence mood, cognition, and synaptogenesis.

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s estrogen a sex hor- quential intracellular riders. The last membrane, and connects to its estro- mone or a neurotransmit- rider is a transcription factor that de- gen receptors right in the cell I ter? Estrogen has well- livers the information directly to nucleus, next to the DNA. No need documen-ted actions on several neuro- genes, basically telling them to turn for the pony express here, for estro- transmitter systems, including on or to turn off. gen is itself the transcription factor.3 serotonergic, adrenergic, and cholin- Estrogen bypasses this process and When genes are activated, all sorts ergic pathways and receptors.1 How- places a direct call to the genome. of events can occur in a cell. The ef- ever, recent advances from molecular That is, it floats directly through the fects of estrogen on gene expression neuroscience reveal that estrogen does neuronal membrane and the nuclear have been most extensively studied not appear to act like a traditional neurotransmitter. Recall that chemical neurotransmission occurs in the synapses be- Take-Home Points tween cells and at receptors within 2 neuronal membranes. Information is Although the effects of estrogen on bone, breast, uterus, then relayed from the external mem- and the cardiovascular system are well-known, recent brane to cellular headquarters, namely the DNA in the cell nucleus. Neuro- advances are now clarifying our understanding of the transmitters relay their messages via a influence that sex hormones can have on the brain as well chemical pony express of many se- Receptors for estrogen are present in the cell nucleus of

BRAINSTORMS is a monthly section of The certain neurons, where they can directly influence the Journal of Clinical Psychiatry aimed at providing expression of genes in the central nervous system updates of novel concepts emerging from the neurosciences that have relevance to the practicing psychiatrist. Estrogen can exert profound cyclical influences upon From the Clinical Neuroscience Research Center in San Diego and the Department of synapses in certain neurons during the menstrual cycle, Psychiatry at the University of California San with early-cycle estrogen erecting synapses and late-cycle Diego. Reprint requests to: Stephen M. Stahl, M.D., estrogen withdrawal dismantling them Ph.D., Editor, BRAINSTORMS, 8899 University Center Lane, Suite 130, San Diego, CA 92122.

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Dendrite Axon

Synaptic Estrogen Destruction

Glutamate release

Progesterone One personal copy may be printed

No Estrogen

Excitotoxicity Synaptogenesis

in tissues traditionally thought to be more incredibly, the withdrawal of es- mental health practitioners approach the primary targets of this hormone, trogen not only stops further synapse normal behavior and the treatment of namely, the reproductive organs, formation, but apparently activates psychiatric illness across the life bone, and, indirectly, the cardiovascu- the genetic machinery necessary for cycle. Certainly, the brain is a very lar system. tearing apart synapses, perhaps via an important sex organ. Since the consequences of gene ex- excitotoxic mechanism with gluta- pression take a while to develop, the mate.5 effects of estrogen are long term and Exactly how such actions of estro- REFERENCES not immediate. One of the best ex- gen alter neurotransmission or behav- amples of delayed gene expression is ior is the subject of intense current re- 1. Jensvold MF, Halbreich U, Hamilton JA, eds. how estrogen can dramatically alter search activity. Could direct calls to Psychopharmacology and Women: Sex, Gen- der and Hormones. Washington, DC: Ameri- the cellular machinery for both con- the genome from the transcription can Psychiatric Press; 1996 structing and dismantling synapses in factor estrogen interact with the de- 2.Stahl SM. Essential Psychopharmacology. response to changes in estrogen lev- layed arrival of psychotropic drugÐ New York, NY: Cambridge University Press; 4 1996 els. The building up and tearing induced pony express transcription 3. de Cupis A, Favoni RE. Oestrogen/growth down of these synapses take time, but factors? Would such interaction alter factor cross-talk in breast carcinoma: a spe- occur within the time course of a individual responses to psychophar- cific target for novel antioestrogens. Trends Pharmacol Sci 1997;18:245Ð251 single menstrual cycle (see Figure). macologic treatments? Better under- 4. Woolley CS, Gould E, Frankfurt M. Naturally The presence of estrogen thus standing of the molecular mecha- occurring fluctuations in dendritic spine den- triggers the genetic machinery neces- nisms of action of estrogen at its CNS sity on adult hippocampal pyramidal neurons. J Neurosci 1990;10:4035Ð4039 sary to build synapses. Perhaps even receptors may ultimately impact how 5. Stahl SM. Excitotoxicity and neuroprotection. J Clin Psychiatry 1997;58:247Ð248 J Clin Psychiatry 58:10, October 1997 421422