Research progress on FSH-FSHR signaling in the pathogenesis of non-reproductive diseases

Abstract

Follicle-stimulating hormone (FSH), a glycoprotein hormone synthesized and secreted by the anterior pituitary gland, plays a critical role in reproductive development and regulation by binding to FSH receptor (FSHR). Beyond reproductive tissue, FSHRs have been identified in various non-reproductive tissues, indicating broader functions. FSH levels chronically rise during menopause and remain elevated in postmenopausal life. This increase in FSH level has been indicated to be associated with heightened risk of several non-reproductive diseases, including osteoporosis, hypercholesterolemia, type 2 diabetes mellitus, obesity, cardiovascular disease, Alzheimer's disease, and certain cancers. In this review, we will examine the role of FSH-FSHR signaling in the pathogenesis of these non-reproductive diseases and explore therapeutic strategies targeting FSH-FSHR signaling pathways.

Keywords: FSH; FSHR; menopause; non-reproductive diseases; reproduction.

FIGURE 1

Beige adipose tissue activation under different stimuli. This figure compares the intracellular activities of beige adipose tissue in response to cold exposure (left panel) and elevated follicle-stimulating hormone (FSH) levels (right panel). Under cold exposure, norepinephrine activates β-adrenergic receptors associated with Gαs, stimulating an increased cyclic adenosine monophosphate (cAMP) level which activates protein kinase A (PKA). This pathway upregulates uncoupling protein-1 (UCP1) in mitochondria, promoting lipolysis, ATP production, fatty acid oxidation, and the differentiation of preadipocytes into brown adipose tissue (BAT). Conversely, with elevated FSH levels, FSH binds to follicle-stimulating hormone receptor (FSHR), coupled with Gαi proteins, leading to decreased cAMP levels and reduced PKA activity. This inhibition reduces UCP1 activation, decreasing mitochondrial function and energy expenditure, thereby increasing fat storage and reducing thermogenesis. Created in BioRender. gN, fh. (2024) BioRender.com/d80o007.

FIGURE 2

The role of FSH-FSHR signaling in Alzheimer’s disease pathogenesis. This figure illustrates the signaling pathways activated by FSH in neurons located within the cortex and hippocampus. This sequence of molecular events contributes to the neurodegenerative processes that are indicated to cause Alzheimer’s disease (AD), highlighting a novel mechanism by which follicle-stimulating hormone (FSH) could influence AD pathology independent of its canonical reproductive roles. In this pathway, FSH activates follicle-stimulating hormone receptor (FSHR) coupled with Gαi, which downstream phosphorylate CCAAT/Enhancer binding protein alpha (C/EBPβ) and stress-activated protein kinase (SRPK2). These two molecules subsequently enhance the expression and effect of asparagine endopeptidase (AEP), leading to an increased cleavage of amyloid precursor protein (APP) and Tau protein. This pathway ends with the formation of neurodegenerative hallmarks amyloid-β (Aβ) and Tau368. Created in BioRender. gN, fh. (2024) BioRender.com/s03s437.

FIGURE 3

FSH signaling pathways involved in various mechanisms of ovarian cancer pathogenesis. Key molecules, extracellular signal-regulated kinase (ERK) (orange), octamer-binding transcription factor 4 (OCT4) (red), Snail (purple), and Survivin (blue), are highlighted to clearly delineate their downstream signaling roles in promoting tumor growth, metastasis, and anti-apoptosis. This figure illustrates the complex interactions between FSH receptors (FSHR1 and FSHR3) and various downstream effectors, leading to distinct cellular responses that contribute to the progression of ovarian cancer. Specifically, it showcases the roles of the mitogen-activated protein kinase (MAPK)/ERK pathway, OCT4 overexpression in epithelial-mesenchymal transition and cancer stem cell maintenance, Snail activation in metastasis, and Survivin-mediated resistance to apoptosis.