Vol 4 n° 2 - Cerebral aspects of reproductive endocrinology
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hroughout the life span, the brain continues to be shaped and modified by the external world acting through the release and actions of circulating hor- mones and endogenous growth factors and neurotrans- mitters. Hormone effects on behavior were recognized as long ago as 1849 in the experiments of A.A. Berthold1; and yet it was only in the 1960s that receptors for steroid hormones and thyroid hormone were discovered and recognized as regulators of transcription of the genetic code in eukaryotic cells.2 Besides helping catalyze the discovery of other transcription regulators,3 the steroid- thyroid hormone family of receptors has provided an important  tool  for  elucidating  the  sites  and  cellular mechanisms by which circulating hormones exert per- manent developmental effects (eg, sexual differentiation) and reversible and often cyclic effects on the mature brain.4 Recent research is showing that the brain is more wide- ly  responsive  to  gonadal  hormones  than  previously thought. That is, not only is the hypothalamus affected by circulating estrogens and androgens, but also struc- tures like the hippocampus undergo sexual differentia- tion and are hormone responsive in maturity.5 Even the cerebellum is sensitive to estrogens.6-9 Moreover, major projecting neurons,  such as cholinergic,  serotonergic, noradrenergic, and dopaminergic systems, are responsive to gonadal hormones.5,10,11 In addition, one of the most striking effects of ovarian steroids is the cyclic induction of synapses not only in the hypothalamus, but also in the hippocampus of female rats, and studies of this process have revealed new aspects of steroid hormone action involving the interactions between cells and between steroid hormones and neurotransmitters. Finally, there B a s i c   r e s e a r c h 1 6 3 Basic neurobiology of ovarian steroids: clinical implications Bruce S. McEwen, PhD Keywords: estrogen; hippocampus; cognitive function; synaptogenesis; Alzheimer’s disease; neuroprotection; memory

Author affiliations: Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, Rockefeller University, New York, NY, USA

 Address for correspondence: Bruce S. McEwen, PhD, Harold and Margaret Milliken Hatch, Laboratory of Neuroendocrinology, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA (e-mail:mcewen@rockefeller.edu T Ovarian  steroids  have  numerous  effects  on  the  brain, beginning during gestation and continuing throughout the life span. Besides affecting the hypothalamus related to reproduction, they have widespread effects through- out the brain on many neurotransmitter systems, includ- ing the basal forebrain cholinergic system and the mid- brain raphe serotonin system. Ovarian steroids regulate the formation of synapse turnover in the CA1 region of the hippocampus in the female rat. Formation of new excitatory synapses is induced by estradiol and involves N-methyl-D-aspartate (NMDA) receptors, whereas down- regulation of these synapses is induced by progesterone. Many of these ovarian steroid actions occur by a combi- nation  of  genomic  and  nongenomic  mechanisms  and include cell membrane actions as well as many second- messenger   systems.   There   are   developmentally   pro- grammed  sex  differences.  Because  of  the  widespread influences  of  these  various  neuronal  systems,  ovarian steroids have measurable effects on affect as well as on cognition,   and   have   neuroprotective   effects   toward dementia and stroke damage. Dialogues Clin Neurosci. 2002;4:163-175.