A recent study by researchers at the University of California, Riverside, has identified the biological mechanism underlying premature ovarian failure (POF): a mutation in the Fragile X messenger ribonucleoprotein 1 (FMR1) gene. The FMR1 mutation is most commonly associated with Fragile X Syndrome, a leading genetic cause of intellectual impairment and autism spectrum disorder. But this new study determined that FMR1 mutations also contribute to POF, a reproductive disorder that can lead to early menopause and infertility. Researchers hope that a better understanding of how the FMR1 gene affects this disease will lead to improved treatment outcomes for women with POF and related reproductive disorders.
The Connection Between an Autism Gene and Fertility
The FMR1 gene produces FMRP, a protein necessary for brain development. For those with Fragile X syndrome (FXS), an FMR1 mutation prevents the production of FMRP. FXS, which can cause developmental delays, social or behavioral difficulties, and learning challenges, also has a high association with both intellectual disabilities and autism spectrum disorder.
Along with autism and intellectual disabilities, FXS is associated with premature ovarian failure (POF), which causes infertility and early menopause in adult women. But while researchers have observed that the FMR1 mutation is associated with a 25-fold increased risk of POF, the reasons behind the link were previously unclear.
A New Research Method
Previous research examining the link between FMR1 and reproductive disorders like POF exclusively analyzed these disorders from an endocrine perspective, looking at the changes in hormone levels that occur in these disorders and the way that endocrine cells function in the ovaries.
The UC Riverside team used a different approach, working from the hypothesis that reproduction-regulating neurons were affected by the FMR1 mutation, causing a change in hormone levels.
For their research, a team led by Djurdjica Coss, professor of biomedical sciences at the UC Riverside School of Medicine, compared control mice to transgenic mice lacking the FMR1 gene, which accurately emulated the FMR1 mutation. In comparing the two, the team found that in the Fmr1-knockout (KO) mouse model, reproduction-regulating neurons in both the ovaries and the brain functioned differently than in the control mouse model.
The team observed that the change in neuron functioning in the Fmr1-KO mice first caused female mice to secrete hormones rapidly, and then later, it led to an early stop to their reproductive ability, just as in women with FMR1 mutations.
After that, in order to see how the FMR1 mutation affected brain neurons alone, the researchers removed the ovaries from both groups of mice.
Coss explains that doing so “allowed us to determine that these neurons in the brain, called gonadotropin-releasing hormone neurons, show changes in connectivity that affect how they function. The increased number of synapses causes them to be faster and have more pulses of hormone secretion.”
The team further observed that in the Fmr1-KO mouse model, ovary-innervating neurons were more prevalent than in control mice, further supporting the hypothesis that it is ovarian innervation — instead of an increase in hormone-producing cells — that is to blame for increases in ovarian hormone levels that occur in conditions like POF.
Looking to the Future
The team’s next step is to investigate if partially inhibiting neurons in the ovaries could alleviate the effects of the FMR1 mutation. The hope, Coss says, is that this “may normalize ovarian hormone levels, possibly allowing for a physiological reproductive lifespan.”
This is significant, as POF and related reproductive disorders account for some of the nearly 20 percent of heterosexual couples in the United States who are experiencing or will experience infertility. And that number is likely to rise as more couples are choosing to wait longer to try to have children. With the median age for first-time mothers steadily on the rise, so too is the risk for infertility.
But even for women not planning on having children, premature menopause is a health concern that expands beyond fertility, as it is also linked to higher risks for osteoporosis and cardiovascular disease. The study’s findings have significant implications for understanding the reasons behind reproductive disorders and eventually finding treatments.
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