Ovarian hormones act as a central governor of neuronal excitability, synaptic function, and structural remodeling in the brain. Receptors for estrogen and progesterone are widely distributed in various regions of the central nervous system. These ovarian hormones alongside other neurosteroids interact both directly and indirectly with brain structures and signaling pathways to influence its activity and organization. As hormones fluctuate throughout the menstrual cycle and life in general, so do the neural circuits upon which they act. Neuronal firing and network activity as well as synaptic plasticity and behavior adapt based on levels of circulating estrogen and progesterone, translating into alterations in behavior, mood, and cognition.
In the hypothalamus, ovarian hormones regulate neuronal excitability and firing patterns, thereby directly affecting how the brain processes stimuli. In the hippocampus, an area responsible for learning and memory, estrogen orchestrates changes in neuronal excitability and plasticity. Estrogen also influences neuronal activity and communication in the medial prefrontal cortex, and dopamine neuron excitability in the ventral tegmental area of the midbrain. Collectively, estrogen not only alters firing rates but reorganizes the extracellular matrix and reconfigures network dynamics.
Estrogen and progesterone essentially behave as tuning nobs, impacting how neurons communicate with one another. Ovarian hormones shape the way the brain adapts by modulating synaptic plasticity and potentiation. These effects inform structural changes in the brain. Research is elucidating a broader mode of action of hormones that extends beyond gene transcription. Hormones directly interact with membrane receptors and microglia, triggering signaling pathways involved in synaptic and circuit plasticity. Furthermore, ovarian hormones participate in the remodeling of brain structures such as dendritic spines. This reorganization subsequently modifies how information is transmitted.
Neurosteroids synthesized within the brain include allopregnanolone, pregnenolone, dehydroepiandrosterone, and locally produced estrogen. They work in complement with ovarian hormones to orchestrate plasticity. Neurosteroids act directly to modulate receptors, and also selectively curate neural pathways and associated adaptations to ensure preservation of normal communication. Neurosteroids thus behave as higher order regulators, imposing secondary control points of plasticity. Neurosteroids additionally exhibit neuroimmune capacity, dampening inflammatory cascades that would otherwise impair requisite rewiring that confers memory and learning. The brain’s ability to manufacture its own neurosteroids as opposed to waiting on peripheral hormones explains how identical circulating hormones do not always elicit the same outcomes.
As hormones decline with reproductive aging, there is a notable loss of volume and cortical thickness in certain brain regions that correlate with inferior executive function and memory consolidation. The longer the brain is exposed to robust hormone levels, the better preserved brain volume and memory performance seem to be. More research is needed to elucidate how restoration of hormonal signaling and neurosteroid activity might delay brain aging and the associated cognitive deficits that drastically compromise quality of life.
Sasaki T, Nwaigwe C, Inoue S. Neural plasticity across hormonal states in females: From modulator to dynamic regulator. Curr Opin Neurobiol. 2026;98:103180. doi:10.1016/j.conb.2026.103180