When I was an endocrinology fellow, my mentor was invited to a symposium at the Bronx Zoo. We were a little unsure about the invitation, but she returned from her morning at the zoo excited — about ferrets. She was surprised to hear that people keep ferrets as pets, and she was even more surprised to learn that when female ferrets were spayed, they developed problems with their adrenal glands.
One of the presenters told her that they had figured out why this happened. Ferrets have receptors for follicle-stimulating hormone (FSH) outside the ovaries, including in the adrenal glands. My mentor wondered aloud whether women also had FSH receptors outside of their ovaries. If so, what effects did FSH have on those other glands? It turns out that she was onto something.
What is FSH and how does it impact perimenopause?
Follicle-stimulating hormone is a hormone that is made in the pituitary gland. It travels to the ovaries, where it stimulates an egg to mature, and it tells the ovaries to make estrogen. As we approach perimenopause, the eggs left in our ovaries are the last ones left, and often the quality isn’t so great. As a result, it takes more FSH to get these eggs ready to ovulate. FSH levels rise from less than 8 mIU/mL during the reproductive years to as high as 70 mIU/mL or more as we progress toward menopause. Add to that, FSH levels aren’t stable — with ovulation they will plummet, and then after a period they will start skyrocketing again.
Why is the idea that there might be FSH receptors elsewhere in the body important?
Let’s quickly recap Biology 101. (Stick with me for a moment.) It’s easy to think that hormones take a direct route to their target, that FSH makes a beeline straight from the pituitary gland to the ovary without any detours. In reality, the pituitary gland makes FSH and releases it into the blood. Once FSH is circulating in the blood, it travels all over the body.
Some of it ends up binding to receptors in the ovaries and causing an egg to mature and the ovaries to make estrogen. And some FSH never circulates to the ovaries but just gets broken down by enzymes in the blood and recycled. However, if there are FSH receptors in other parts of the body, FSH that passes through those tissues may bind to those receptors as well.
When any molecule binds to a receptor in a cell, including FSH, it signals to that cell to behave in a certain way. It might open or close a channel in the cell wall, it might tell the cell to make something, or it might tell the cell to release something. If there are FSH receptors in tissues outside the ovaries, what changes occur in those tissues when FSH binds to those receptors?
During the reproductive years, FSH levels are typically relatively low, but during the perimenopausal transition and menopause, those levels skyrocket. All that FSH is circulating in the blood and can act on receptors all over the body, not just in the ovaries. In recent years, researchers have started to explore how high FSH levels might be responsible for some of the changes that occur in women’s bodies during perimenopause and menopause.
Where have we found FSH receptors so far?
Historically, we thought only the ovaries had FSH receptors. That meant the rising FSH levels seen during perimenopause and menopause wouldn’t have much effect on our bodies once the ovaries were out of eggs and were no longer pumping out estrogen. We attributed all the symptoms of menopause to dropping estrogen levels. We had never looked for FSH receptors beyond the ovaries until recently.
Adrenal glands
Doctors have observed for decades that during perimenopause and menopause, women gain fat in their midsection. While we attributed the changes in women’s body composition to falling estrogen levels, it was clear that giving estrogen in the form of hormone replacement therapy does not prevent these changes in body composition. Studies have also shown that high FSH is associated with increased fat mass. And giving estrogen in the doses typically used in hormone therapy doesn’t lower FSH levels significantly. However, the link between FSH and increased fat mass has not been fully understood.
It turns out there is actually some evidence that women are like ferrets. We may have FSH receptors in our adrenal glands, specifically in the cells that make and release the stress hormone cortisol. In research on cells grown in the lab, FSH binds to these cells and increases their production of cortisol. In mouse studies, high FSH levels are also associated with higher cortisol levels. The researchers gave the mice estrogen but kept FSH levels high, and still the mice had high cortisol levels, suggesting that it is the high FSH and not the low estrogen levels that lead to higher cortisol levels.
We know that increased cortisol can cause muscle loss and increased fat mass. Cortisol raises blood sugar levels too and makes our body more resistant to insulin. And cortisol raises blood pressure and cholesterol levels. These are all metabolic changes we often see in women during perimenopause and menopause.
It may be that FSH acting in the adrenal glands and raising cortisol levels is responsible for many of the metabolic changes associated with perimenopause and menopause.
Bone
We have attributed the bone loss women experience in menopause to low estrogen levels alone. However, more recently, high FSH levels have also been linked to low bone mass. In a study of more than 600 women, researchers looked at the association between bone density in the hip and FSH levels. They found that the women with higher FSH levels had, on average, lower bone density.
We know that hormone therapy containing estrogen improves bone density. The women in the study who currently took hormone therapy or had taken hormone therapy in the past did have higher bone density than those who did not. When the authors controlled for estrogen levels, though, high FSH was still associated with lower bone density.
Another study looked at women who were given the medication leuprolide. Leuprolide tells the pituitary gland not to make FSH. When FSH levels are low, there is no signal to tell the ovaries to make estrogen. The results showed that women taking leuprolide have low estrogen and low FSH. In those women, no changes were seen in blood markers of bone loss even though estrogen levels were low, further supporting the idea that low estrogen levels are not the only factor in perimenopausal bone loss. High FSH plays a role too.
Again, it may be that FSH, and not just estrogen, is acting directly on the bones, causing bone loss that can lead to osteoporosis and fracture.
Cardiovascular system
Women develop cardiovascular disease at a later age than men. Their risk for heart attack and stroke increases about 10 years after menopause. Dropping estrogen levels have been thought to make women vulnerable to cardiovascular disease after menopause, but FSH may be involved as well. In a subanalysis of data from 856 participants in the Study of Women’s Health Across the Nation (SWAN), researchers found that rising FSH levels were associated with thickening of the walls of the arteries — a marker of developing plaque in the arteries. Another study of 126 women found that women with high FSH levels were more likely to have high levels of calcium in the arteries in their heart, another marker of plaque in the arteries.
Studies in mice have found that special white blood cells called monocytes have FSH receptors. Monocytes stimulated by FSH enter plaques in the arteries. This causes the plaques to become unstable. Unstable plaques can rupture and block arteries in the heart, causing a heart attack.
This means that FSH may be having direct effects on the plaques on the blood vessels, leading to an increased risk of heart attack and stroke.
Why is understanding FSH’s activity outside the ovaries important?
For a long time, researchers have wondered why giving women estrogen did not help with all the health issues that arise in perimenopause and menopause. Could high FSH levels be the answer? The current research regarding FSH and FSH receptors outside the ovaries is in its infancy. Many of the studies I have referenced are in mice or measure changes that are associated with outcomes we are interested in, not the outcomes themselves. That means that right now, we can describe how FSH might play a role in many of the health problems women are at risk for in perimenopause and menopause. However, there are as yet no treatments targeted to prevent the effects of rising FSH.
Gaining a better understanding of how our bodies function in all their complexity can lead to future targets for medications. I can imagine a time when I might be prescribing my patients a medication that treats a whole host of health problems by blocking FSH from acting on FSH receptors all over their body.
The bottom line
- In recent years, follicle-stimulating hormone has been recognized as having important effects outside the ovaries.
- High FSH levels are associated with increased fat mass and decreased muscle, bone loss, and formation of plaques in the arteries that are early signs of cardiovascular disease.
- Each of these changes seem to result from the direct effects of FSH on the adrenal glands, bone, and white blood cells.
- A better understanding of how FSH acts on the body tissues could result in future treatments that directly target FSH or its receptors.
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This is really interesting, thank you– but I’m surprised to hear that giving estrogen doesn’t lower FSH meaningfully; I thought that during IVF an estrogen patch is often used to suppress FSH before the stimulation cycle, in order to prevent the rise of FSH from leading to the formation of a dominant follicle too early. (Maybe I misunderstood that?) I also have seen very low day 3 FSH in perimenopause while using transdermal estradiol replacement and assumed the FSH was low (below 5) due to the supplemental estradiol. Hm.
Thanks for your comment! It is true that higher doses of estrogen, like the doses seen in birth control pills can suppress FSH especially in younger women with lower FSH levels. Estrogen in the doses typically used for hormone replacement therapy don’t significantly lower FSH especially once FSH levels are stably elevated nearer to menopause.
This is such powerful news, if not for me then at least, I hope, my niece and younger women. I hope someday this leads to doctors doing and saying more than “You just need to adjust your diet and exercise more.” And it absolutely astounds me that the effects of perimenopause and menopause have been afflicting women for millennia and we’re *just now* figuring out that we have FSH receptors elsewhere in the body.