Sex and sex hormone differences in hippocampal neurogenesis and their relevance to Alzheimer’s disease

Longitudinal 7T MRI reveals volumetric changes in subregions of human medial temporal lobe to sex hormone fluctuations

“…We were especially interested in CA1 and Area 35 given previously observed selective patterns of neuronal vulnerability to memory impairment in CA1 (41) and Area 35 (45)(46)(47)(48)(49), as women are more likely to suffer from cognitive impairment when ovarian hormones rapidly fluctuate, such as during perimenopause (50)(51)(52). The hypothesized interaction in CA1 is in line with previous animal work, showing that estradiol enhances synaptogenesis, spine density, and synaptic protein levels in CA1, while subsequent increases in progesterone seem to inhibit this effect (3,5,8,(42)(43)(44).…”

“…Therefore, future studies should test whether these hormone-induced changes in MTL subregions are further exacerbated during times of more profound neuroendocrine change, and whether there are behavioral consequences for patient populations. Recent work does suggest that early changes in neuropsychiatric and neurodegenerative disease are better detected in smaller subregions of the MTL rather than with whole structure analysis (46)(47)(48)72), and women are at increased risk for such disorders following ovarian hormone fluctuations, such as depressive disorders (73)(74)(75)(76)(77), multiple sclerosis (78-80), dementia (50,52), and other inflammation-related disorders (81) during the premenstrual phase (73-75, 78, 81), postpartum period (73,76,79), and following perimenopause (50,52,73,77,80). Given the essential role of the MTL in adult synaptic plasticity and the differential contributions of MTL subregions to cognitive functions (40,(82)(83)(84)(85)(86), this information may be particularly relevant for plasticity-related disorders such as depression and dementia.…”

“…This region is clinically relevant with regards to aging and disease, with previous work showing that neurodegeneration and atrophy in this region is associated with early stages of dementia and cognitive decline (45)(46)(47)(48)(49). Given the increasing focus on the interplay between endogenous hormone fluctuations, the MTL, and the disproportionate risk for Alzheimer's disease in women (51,52), we hypothesized that estradiol fluctuations would be associated with Area 35 volumetric changes. The observed progesterone association is a novel finding, as the majority of related literature on hippocampal structural plasticity has thus far focused on estradiol relative to progesterone, and the CA1 and dentate gyrus relative to other MTL regions.…”

“…Another region of key interest is perirhinal Area 35, corresponding to the transentorhinal region and medial perirhinal cortex (31,45), in which atrophy has been associated with cognitive decline as well as early stages of dementia (45)(46)(47)(48)(49). While this subregion has received little attention in regards to endogenous hormone fluctuations, women have greater risk of developing Alzheimer's disease relative to men, particularly following periods of more pronounced hormone fluctuations later in life, such as after perimenopause (50)(51)(52). Thus, understanding how subtle hormone fluctuations may influence CA1 and Area 35 volume in young women would potentially provide insight into underlying mechanisms of risk for cognitive decline in women.…”

Association of infertility and recurrent pregnancy loss with the risk of dementia

“…In this process, synapses, neuronal axons, and white matter are compromised, leading to cognitive impairment [27]. Meanwhile, oestrogen and progesterone are fundamental regulators of mitochondrial function and neuroplasticity in the female central nervous system [32,33]. Women with pregnancy loss may have inadequate level of oestrogen or progesterone.…”