G‐protein coupled estrogen receptor, estrogen receptor α, and progesterone receptor immunohistochemistry in the hypothalamus of aging female rhesus macaques given long‐term estradiol treatment

Abstract

Steroid hormone receptors are widely and heterogeneously expressed in the brain, and are regulated by age and gonadal hormones. Our goal was to quantify effects of aging, long-term estradiol (E2) treatment, and their interactions, on expression of G protein-coupled estrogen receptor (GPER), estrogen receptor α (ERα) and progesterone receptor (PR) immunoreactivity in two hypothalamic regions, the arcuate (ARC) and the periventricular area (PERI) of rhesus monkeys as a model of menopause and hormone replacement. Ovariectomized (OVX) rhesus macaques were young (~11 years) or aged (~25 years), given oil (vehicle) or E2 every 3 weeks for 2 years. Immunohistochemistry and stereologic analysis of ERα, PR, and GPER was performed. More effects were detected for GPER than the other two receptors. Specifically, GPER cell density in the ARC and PERI, and the percent of GPER-immunoreactive cells in the PERI, were greater in aged than in young monkeys. In addition, we mapped the qualitative distribution of GPER in the monkey hypothalamus and nearby regions. For ERα, E2 treated monkeys tended to have higher cell density than vehicle monkeys in the ARC. The percent of PR density in the PERI tended to be higher in E2 than vehicle monkeys of both ages. This study shows that the aged hypothalamus maintains expression of hormone receptors with age, and that long-term cyclic E2 treatment has few effects on their expression, although GPER was affected more than ERα or PR. This result is surprising in light of evidence for E2 regulation of the receptors studied here, and differences may be due to the selected regions, long-term nature of E2 treatment, among other possibilities.

Estrogen Effects on Cognitive and Synaptic Health Over the Lifecourse

“…Nuclear ER ␣ immunoreactivity is sparse in the hippocampus and cortex, although it is located both pre-and postsynaptically in the PFC of young and aged monkeys (143) (FIGURE 2). A recent study demonstrated that the hypothalamus in aged rhesus monkeys retained youthful expression levels of ER ␣, GPER1, and progestin receptor (PR) protein and neuronal levels of these receptors were responsive to estradiol treatment in both young and aged monkeys (151). In ovariectomized female monkeys, estradiol treatment along with the presence of postsynaptic ER ␣ improved cognitive performance (222), supporting a role of ER ␣ in tasks mediated by the PFC.…”

Perimenopause as a neurological transition state

“…However, many women do not choose this treat ment, because the data on the benefits and risks of estro gen replacement therapy are complicated, controversial and confusing. 51,52 Many factors contribute to this con founding state, including unresolved issues regarding the timing of intervention, hormone formulation, dose and route of administration. Optimizing and personalizing hormone therapy remains an unmet need in women's health but is a central issue for precision medicine to treat neurological symptoms that develop during, and persist beyond, the perimenopause.…”

“…While the complete distribution of ER-α and ER-β remains to be completely mapped in humans, in rats the location of these receptors is well documented. [45][46][47][48][49][50][51][52][53] Dysregulation of estrogen signalling, either through changes in estrogen concentration or through modifications of estrogen receptor, will affect neural circuit activation and, thus, neurological function. Abbreviations: ER, estrogen receptor; GPER, G protein-coupled estrogen receptor.…”

“…[45][46][47][48][49][50][51][52] To date, three distinct estro gen receptors have been identified: estrogen receptor 1 (ESR1; commonly known as ERα), estrogen recep tor 2 (ESR2; co mmonly known as ERβ) and Gprotein coupled estrogen receptor 1 (GPER; formerly known as GPR30). For estrogen to be a regulator of the neurologi cal systems that generate the symptoms associated with perimenopause, the locations of estrogen receptors need to be coincident with the relevant neuro anatomical regions.…”

Sexual attractiveness: a comparative approach of morphological, behavioral neurophysiological signaling in women and nonhuman primate females

“…The houmonal tueatment did mimic theuapeutic supplements in peui-menopausal women. Suupuisingly, old macaque females maintain ueceptou expuession, and long-teum estuadiol supplementation mauginally influenced the ueceptou density (Naugle et al, 2014).…”