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Melanie Cole, MS (Host): Welcome to UF Health MedEd Cast with UF Health Shands Hospital. I'm Melanie Cole. And today, we are highlighting obesity-associated endometrial cancer. And joining me is Dr. Kaitlin Nicholson. She's a Clinical Assistant Professor of Gynecologic-Oncology in the Department of Obstetrics and Gynecology at the University of Florida College of Medicine.

Dr. Nicholson, thank you so much for joining us today. As we're learning more and more about obesity-related cancers and diseases, describe a little bit about the current landscape of endometrial cancers and how the obesity epidemic has shifted that epidemiology of this disease. Do we know about the causal link between obesity and these types of cancers?

Dr. Kaitlin Nicholson: Absolutely. Thank you so much for having me. I'm really happy to be here today. So, we know that endometrial cancer is the fourth common cause of cancer in females in the United States. And we know that the incidence of endometrial cancer is increasing, and we think that this is probably related to a variety of factors. But sort of at the forefront is the increasing obesity prevalence and, with this, diabetes and other comorbidities, possibly changes in reproductive behaviors. But it has been shown that patients with obesity have higher levels of estrogen due to the conversion of the active form of estrogen, estradiol, in our fat cells.

Melanie Cole, MS: Well, this is such an interesting relationship. We're learning so much more about it. And one of the things I think that so many people wonder about is the hormonal and metabolic pathways. As we know Dr. Nicholson, that obesity can cause metabolic disorders of many different types, also so many shifts in our hormones, particularly estrogen, insulin resistance. We know diabetes type 2 has been on the rise, inflammation. So, tell us a little bit about our latest understanding of how adipose tissue influences that tumor development and progression based on some of the hormonal and metabolic pathways that we're learning more and more about.

Dr. Kaitlin Nicholson: Sure. So, it all is sort of related to excess estrogen. And so, we know that, as I said, our fat cells convert androgens into estradiol. And so, patients with increased fat cells related to obesity will therefore have increased levels of circulating estrogen. At the same time, patients with insulin resistance or diabetes. They will have impaired ability to bind this active estrogen. So, it's sort of a twofold mechanism of increasing circulating estrogen.

And so, the way I sort of describe it to patients is I use a lawnmower and fertilizer analogy And so, during a normal menstruation and before menopause, there's sort of this ebb and flow of estrogen and progesterone that are responsible for ovulation and subsequent onset of menses. And so, estrogen acts as the fertilizer on the lining of the uterus and progesterone acts like the lawnmower.

And so, really after menopause, the ovarian production of estrogen and progesterone is almost entirely diminished. And so, the lining of the uterus really should be thin without the estrogen or the fertilizer acting on it. And so, because we have this peripheral version of the active form of estrogen in our fat cells, women with excess fat cells have this unopposed estrogen acting on the lining of the uterus without the progesterone to sort of act as the lawnmower to keep it in I balance. Therefore, patients can have overgrowth of the lining of the uterus and overgrowth in the form of pre-cancer cells or cancer cells in the endometrium.

Melanie Cole, MS: Wow, that's so interesting. And I love the way that you described that. And I think in this day, we think of hormone replacement, we think of all the different ways that women approach perimenopause and postmenopause. How is the presence of obesity influencing how you clinicians approach that risk stratification and certainly early detection, but also in our comorbid situations that we think about in postmenopausal women as we lose our estrogen. Tell us how that all ties together and how clinicians are putting that together to work with us.

Dr. Kaitlin Nicholson: Well, I say, menopause is having a moment, and I think there's more and more providers every day who are certified by the National Menopause Society to really feel comfortable about talking to patients about hormone replacement therapy. And so, the big take-home is that patients with a uterus should not have unopposed estrogen. And so, if you are thinking about giving hormone replacement therapy to a patient with a uterus, you really need to give them some sort of progesterone, whether it's oral or in the form of an IUD to protect them from that excess estrogen.

So in terms of risk stratification and early detection of endometrial cancer, really the first clinical indicator to alert a provider about possible endometrial cancer or pre-cancer is postmenopausal bleeding or abnormal uterine bleeding. And a lot of patients will say, "Well, there's just a little pink spot" or "It happened once and I really didn't think anything of it." So, it's really something that patients after menopause should be asked about at every primary care visit. It's a great way to screen for endometrial cancer and sort of trigger any additional imaging or endometrial sampling.

And then, for premenopausal women, it's a little bit more challenging because a lot of women, especially in that perimenopause phase can have abnormal uterine bleeding. So, really having a low threshold to screen patients with a transvaginal ultrasound and/or an endometrial biopsy, especially if these patients have increased risks for endometrial cancer, such as obesity, polycystic ovarian syndrome or anovulation, never being pregnant, having their periods early, or going through menopause at a later age, or having a strong family history. Those all play into the risks of endometrial cancer.

Melanie Cole, MS: When we think of the treatments, Dr. Nicholson, and obesity, I mean, we know that if somebody who is living with obesity has any kind of surgical needs, whether it's a knee replacement or a hip replacement, there's always going to be just a little bit of extra thinking and planning on the surgeon's part. So, how does that impact surgical management, both in terms of that technical difficulty and postoperative outcomes when we think of hysterectomies, when we think of tumor removal? Tell us a little bit about what goes into that planning.

Dr. Kaitlin Nicholson: The standard care of surgical management typically involves a total hysterectomy and removal of the ovaries, fallopian tubes, uterus, cervix, and lymph node sampling. And we try to do this when possible through small incisions, minimally invasive surgery, robotically or traditional laparoscopy.

Patients with obesity often will have multiple medical comorbidities-- heart disease, kidney disease, liver disease, maybe structural issues like large hernias that may make them less ideal candidates for surgery. And some patients might not be eligible at all for this sort of standard of care. And we may need to pivot to other clinically proven, efficacious, but not standard of care alternatives such as hormonal therapy with either oral or intrauterine progesterone, or sometimes even primary radiation.

But in those patients that we are going to try to get to surgery, we typically have to put them in deep Trendelenberg in order to get all of the bowel out of the pelvic field in order to be able to operate safely in the pelvis. And adding that excess adiposity onto the patients chest can make it really difficult to ventilate. And so, oftentimes they'll have a hard time with anesthesia and may not be able to complete the case. Postoperatively, they could have increased risk of bleeding, infection, delayed wound healing blood clots, especially if they're sedentary, and possibly even cardiovascular complications.

Melanie Cole, MS: Wow. So much to think about. Now, when we talk to our patients, weight loss, lifestyle interventions are always certainly recommended. But how effective do you see that they might be in reducing that risk or recurrence in endometrial cancers? What do we know about the role of certain weight loss interventions such as bariatric surgery or medical interventions. You know, there's Ozempic, there's all these things now. Do we put that association in a lower risk now?

Dr. Kaitlin Nicholson: Clinically, absolutely. Scientifically, there's not as much robust research in this area, but it's very much a research interest of mine. And so, there are some prospective studies looking at this. I think the long of the short of it is that, yes, we know that weight loss can lower the risk of endometrial cancer and the risk of recurrence in those who are already diagnosed with it. But it's unclear how effective weight loss and lifestyle interventions are and which is more effective than the other.

But as I mentioned, there are clinical trials. There's one, I believe, it's out of Memorial Sloan Kettering looking at the use of GLP-1 receptor agonists in patients who are undergoing surveillance for endometrial cancer to see if the usage will decrease the risk of recurrence. And so, more to follow on that.

Melanie Cole, MS: Well, this is really such an interesting topic and really an exciting time in your field as we're learning so much more. But one of the more important things is that multidisciplinary approach and collaboration. So, how do gynecologic oncologists collaborate with primary care, endocrinology team, nutrition, dietetics? There's so many different areas of specialties that could work together for these women.

Dr. Kaitlin Nicholson: Oftentimes, especially where we practice a lot of patients coming from rural areas, sometimes a new diagnosis of endometrial cancer or pre-cancer is the reentry point into the medical system for some patients. And so, it really offers a unique opportunity for GYN oncologists to partner with primary care or endocrinologists to help patients address other potential comorbidities associated with obesity and really help the patients in the full spectrum of their health to get a handle on everything.

So, I would encourage folks to seek out primary care physicians and obesity specialists in the area and really develop a partnership. I've developed a partnership with one of the obesity specialists here at UF, Dr. Amy Sheer. And we've really established a multidisciplinary approach to addressing both obesity and endometrial cancer. We're starting a clinical trial that is looking at GLP-1 receptor agonists in patients who are not candidates for that standard of care surgery. And I think through opportunities like this, you really can reach a lot of patients.

Melanie Cole, MS: I agree. And this is such an interesting conversation, and there's so much more we could discuss because it's so far-reaching as we look at this obesity epidemic, Dr. Nicholson. But as we wrap up, what areas of research do you feel are most promising for unraveling this connection? How do you envision AI, precision medicine, metabolic targeted therapies reshaping the management in the next decade? And if you want other providers to take-home a key message about reframing obesity, not just as a risk factor, but as a modifiable, biologically active disease process that could intersect with cancer care, what would you tell them? It's a big ask, but I know you can do it.

Dr. Kaitlin Nicholson: As clinicians, we have this opportunity to move toward a model that treats obesity with the same seriousness, compassion, and scientific rigor that we apply to every other chronic disease, including cancer care. And I think educating patients and colleagues about how adiposity drives inflammation, hormonal signaling, immune changes, all of which can accelerate carcinogenesis and affect disease processes.

I think acknowledging that by improving metabolic health, we can enhance treatment tolerance and possibly reduce risk of recurrence and really focus on improvements of quality of life. I think we're lucky at this institution to have a lot of really smart scientists who are interested in, you know, exercise physiology and obesity medicine. And so, I've reached out to several colleagues. And we're trying to look at it from multiple different angles, whether it's exercise interventions and in patients who are survivors, or as I mentioned before, the partnership with Dr. Sheer. So, there's really a lot of opportunity with AI. I think different modes like apps and things like that to really be able to help engage patients, I think, is going to be huge for this.

Melanie Cole, MS: I agree with you. And thank you so much for such an enlightening discussion, Dr. Nicholson, and for joining us today. And to learn more, you can visit ufhealth.org/gynecologicalcancer, or to learn more about this in other healthcare topics at UF Health Shands Hospital, you can always visit innovation.ufhealth.org. That concludes today's episode of UF Health MedEd Cast with UF Health Shands Hospital. I'm Melanie Cole.