Menopause Alters Gene Expression Within and Beyond the Reproductive Tract in Both Humans and Rhesus Macaques

Jordana C. B. Bloom^1,2, Tiffany Pham¹, Ricki Colman³, David C. Page^1,2,4

< !1. Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA

< !2. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA

< !3. Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin 53715, USA

< !4. Howard Hughes Medical Institute, Cambridge, MA 02142, USA

Abstract Text:

Menopause onset is the major determinant of reproductive lifespan in women and its impact across the body is a critically understudied aspect of women’s health. Earlier age of menopause onset is associated with numerous comorbidities, including increased risk of dementia, cardiovascular disease, and osteoporosis.  To better understand the connection between these conditions and menopause, we conducted a systems-level analysis of reproductive aging on tissues throughout the human body using bulk RNA-sequencing data from 31 tissues collected by the Genotype-Tissue Expression (GTEx) project.  We identified menopause-associated gene expression changes in thousands of genes across the tissues and determined that variation in the number of responsive genes correlates with each tissue’s sex hormone receptor levels.  To determine the evolutionary conservation of the body-wide expression changes we identified, we performed bulk RNA-sequencing of the ovary and 10 non-reproductive tissues from pre-, peri- and post-menopausal rhesus macaque donors.  Modeling gene expression as a function of estradiol, progesterone, luteinizing hormone (LH), follicle stimulating hormone (FSH), anti-mullerian hormone (AMH) and testosterone serum concentrations in the macaque has allowed us to define which sex hormones drive conserved reproductive aging-associated gene expression changes across tissues.  Altogether, findings from this work provide novel mechanistic insights into how reproductive aging contributes to global differences in gene expression throughout the body.