To Dr. Kara Goldman, the ovary serves as more than a vehicle for women’s fertility — it also provides insights into female longevity and overall health. As Associate Professor of Reproductive Endocrinology and Infertility at Northwestern University Feinberg School of Medicine, Dr. Goldman has dedicated her career to enhancing and supporting her patients’ fertility needs. She has also explored the role the regulator mTOR serves in the ovary and in healthy aging.
“We need better biomarkers, we need earlier intervention, and we need to view the ovary as not just a window into systemic health decline, but a therapeutic opportunity to promote health span,” she says.
Hear more from Dr. Goldman and her research in our video of her talk from DOC 2025’s “The Science of Women’s Health” session, or read our lightly edited transcript below.
TRANSCRIPT:
Dr. Kara Goldman
Thank you very much. Transport yourself for a moment to a fertility center at a major academic medical center in Chicago. We meet a 30-year-old woman. She’s smart, she’s proactive. She’s health conscious. She has done everything right. She and her partner have been trying for a year to get pregnant, unsuccessfully. We talk about her biology, and she realizes she knows nothing except how not to get pregnant.
We review her lab results. We discuss her AMH level anti-Müllerian hormone. It’s the best marker we have of ovarian reserve. It’s the quantity of eggs remaining. It is not a perfect test, but the best we have. She learns in that moment that her number is exceptionally low. Not only does this predict a poor response to medications that we use in in-vitro fertilization, there is a clear correlation between AMH and time to menopause. She is aghast that the first time she is hearing this is in the context of inability to conceive, and not years earlier. Because you see the ovary is a window into systemic health, and we are only looking through it at the time of infertility. But we should be looking so much earlier. Think about all of these earlier opportunities. Here we are meeting the patient at 30 years old. But what about six years earlier when she had severe pelvic pain? She was started on a birth control pill to control her pain. But maybe that pain represented endometriosis and endometriosis. There is a 7- to 9-year diagnostic delay. It’s no surprise it wasn’t diagnosed immediately, but there is an association with accelerated ovarian aging.
What if she will go through menopause early, and what could we have done differently? And what about when she was ten years old? Her mom went through menopause at the age of 40. But our patient didn’t know that because they never had that conversation. And it was only until we had a visit. And I said, when did your mom go through menopause, and she texted her mother, and this happens in every single consult, and that’s when she found out. Why is this conversation not happening earlier? When we know that that relationship between a mom’s age of menopause and a daughter’s is really clear. And if that same patient had gone through chemotherapy for cancer or had a genetic predisposition to low ovarian reserve like a BRCA1 mutation, Fragile X mutation, Turner syndrome, these are all opportunities that we could have intervened.
And in utero, we know that the majority of egg cells are lost in utero. There are 6 to 7 million eggshells at 20 weeks of gestation. By birth, 1 million remain. By puberty, 300,000 remain. By menopause, 1000. The vast majority is follicles, serve an endocrine function, not a fertility function, and we are only watching as that decline has already happened, rather than prospectively.
What I’m really worried about with this patient, she’s worried about her fertility. I’m particularly worried about what’s going to happen when she completes her family, and we then have decades remaining. She, if she goes through menopause early, will have an earlier risk of cognitive decline. So significantly greater risk of Alzheimer’s and vascular dementia. If she goes through menopause early every one year earlier of menopause is going to correlate to a 3% greater risk of incident cardiovascular disease. Every one year earlier of menopause increases her risk of fracture by 2%. And if she goes through menopause before the age of 45, she has a 50 to 100% greater risk of hip fracture, with significant morbidity and increased risk of mortality, and all cause mortality is greater with early menopause. For every one year earlier of menopause, there’s a one year shortening of lifespan.
So let’s dive into the biology of the ovary to understand what we can be targeting here. So the ovary has all of the egg cells it will have at birth. They sit in little primordial follicles that surround the edge of the ovary. This is where there’s dormant egg cells that are dormant at prophase of meiosis 1, Follicles activated to become a growing follicle. Once that follicle is activated it is lost. This activation is critical. And this is the key to maintaining follicles in this dormant pool.
Let’s take ourselves to Easter Island for a second. Everyone in this room is very familiar with rapamycin and mTOR. We know that mTOR activation is associated with age-related diseases, and it’s a very attractive target to promote longevity. But it also plays a critical role in the ovary. And mTOR is critically involved in that activation from primordial follicle to primary follicle.
This is an opportunity to harness that ovary and harness the potential that of those follicles. We return to our clinical console room. We have in front of us our patient. Let’s think about the different ways that we can utilize the biology of the ovary to potentially protect the ovary and protect her future health span.
So first, the acute consult. I have a young patient in front of me who has a new diagnosis of breast cancer. She will be faced with significantly anatoxic chemotherapy that will either render her ovaries completely dysfunctional post-treatment or, severely, suboptimal. But there’s a higher risk of ovarian insufficiency after chemotherapy. The only option that we can offer her right now is we can freeze eggs and we can freeze embryos. That is certainly only viewing her ovary through the lens of fertility. But we can do nothing to protect her ovaries from the long-term risks and consequences of ovarian insufficiency. In a mouse model, my question was can we look at mTOR inhibitors to protect those primordial follicles and maintain follicles in that state to protect ovarian function. In mice it was absolutely effective. So we administered cyclophosphamide, a very toxic agent, to the ovary alongside mTOR inhibitors everolimus, INK128, and primordial follicles were protected and fertility was protected.
What we didn’t expect to find is that even without treatment, and we were just looking at mTOR inhibitors alone, there was a significantly greater pool of primordial follicles. So these follicles were protected, and, and potentially this has an implication for ovarian, reserve, long term and reproductive longevity and ovarian function long term. What we did was we mated mice at a young age, after exposing them to mTOR inhibitors and looked at their reproductive function over the course of many months. At a very, advanced age, saw that the mice that were exposed to these drugs had significantly improved reproductive function, which, of course, looking at fertility, it’s not just a proxy for the ovarian function, but improved ovarian function over time. We are now translating this in other and other models. I’m partnering with Oregon Primate Center, who have treated rhesus macaques with rapamycin and caloric restriction. We’re studying their ovaries, and what we really need to do is if we are going to translate this to humans, we need to understand how these drugs interface with the ovary in humans.
There’s a population of patients who take these medications, takes relevance for lymphoma angio mitosis. We’re studying the ovaries of these women. They are young, they have ovaries. They are on single agent treatment, and evaluating what do these drugs do to these patients’ ovarian reserve, and what could this mean for other patients if we were to consider this as an intervention.
In my clinical space, I take care of women who are going through infertility, egg freezing. In the embryology laboratory, we have access to a tremendous rich opportunity to study ovaries. In young women who are freezing eggs, we can remove the cells from the outside of the egg that would otherwise be discarded and study markers that may be promoting aging. And the same for our older patients who are 44 years old going through IVF, we can study those cells. In fact, the heat map that you see, it’s a representative heat map. The red indicates upregulation of kinases. These are proteins that modify other proteins. We’re seeing this upregulation in these older patients potentially targets that we can look at that are associated with aging in the ovary and thus would have implications for the health of the ovary and health span.
Ultimately, if we are going to think about translating this to humans, we need to understand dose, duration, timing. How would this actually work in practice? Would we take care of women at 30 and administer a medication and try to protect their ovaries, not just from a fertility standpoint, but from an ovarian health and longevity standpoint? My area of focus is on follicle activation. But there are so many other targets within the ovary. We focus on the cells surrounding the ovary, and we can focus on the vasculature within the ovary. We know that vascular decline is of course a critical part of aging. Systemically, we don’t understand what that looks like in the ovary. We have so many opportunities, and we need to harness these opportunities to protect women. Because the ovary is so much more than fertility. The ovary is heart, brain, bone, and every other organ system.
We return to our clinical setting with our patient in front of us. She has completed her family. Hopefully she has been successful with in vitro fertilization or whatever tools we have. She wants to know how can she support her ovaries moving forward. We need better biomarkers, we need earlier intervention, and we need to view the ovary as not just a window into systemic health decline, but a therapeutic opportunity to promote health span. Thank you.