about in women with GYN cancers, just in the interest of time, I can always talk another time about those at high risk for it. So why do we care? Sorry, okay. The reason why I wanted to present this, because in talking to Linda, I wasn't sure how much of hormones and hormone replacement therapy the fellows in Da Nang get, because I know it was certainly something that I felt I was lacking a little bit in my fellowship too. And so I just wanted to talk about the hormonal changes of menopause, much of which we induce in our patients and understand how we can safely use hormone replacement therapy in women with gynecologic malignancies. So just a brief history of menopause, it was considered to be a form of neurosis resulting from the loss of femininity. And until 1980, menopause was actually included among the criteria defining psychosis in the DSM, which is the manual of mental disorders that's used for psychiatric diagnoses. 1980 wasn't that long ago. So menopause is defined as the permanent cessation of menstruation that occurs after loss of ovarian activity. And it really can't be determined to have occurred until one year after the last menstrual period. In North America, the median age is 51 years. And I apologize that I do not know the median age in Vietnam for menopause. So there's also this perimenopausal or climacteric or menopausal transition period where physiologic changes begin to occur in the years preceding the final menstrual period. And it's marked by fluctuations in hormone levels as ovarian function begins to decrease. So it leads to a decrease in serum estradiol and progesterone levels leading to a subsequent increase in FSH levels. And the hormonal changes include vasomotor symptoms. So 87% of women say that they have symptoms daily. There's also the genitourinary syndrome of menopause where 10 to 40% of women will experience symptoms of vaginal atrophy, which can present as dryness, discharge, itching, or dyspareunia. And importantly, there's also adverse effects on cardiovascular health, bone health, and memory and cognition. And so I just wanna take a little trip down memory lane for everybody to think about where they were in July of 2002. In the U.S. at least, there was still like post 9-11 effects. Were internationally Serena Williams, Venus Williams for her first Wimbledon singles title. And really why we're talking about it here is that an announcement came out that would have enduring effects on the health and quality of life of women. And I'm talking about the Women's Health Initiative. The July 2002 announcement that estrogen and progestin therapy was being halted prematurely due to safety concerns. So before we get into what those ramifications were and why it's relevant to our patients, let me just briefly tell you what the Women's Health Initiative was or is. It's a long-term national health study in the United States that started in the 1990s. And it's important for focusing on strategies for a lot of really important things. So preventing heart disease, breast cancer, colorectal cancer, osteoporosis, and postmenopausal women. And the original study actually had three parts, a clinical trial, an observational study, and a community prevention study. And the data collection was completed in 2005. And through all that data that was collected, the Women's Health Initiative continues to contribute to the science of women's health because there's a bunch of extension and ancillary studies coming out of it. But why is it important? Because after that July 2002 announcement, menopausal hormone therapy initiation dropped from 8.6% to 2.8% post-WHI. And so the decrease in continuation, so women who had already been on menopausal hormone, menopausal hormone therapy, and how many of them actually continued, that also dropped from 84% to 62%. And what was really important is that we saw a large decline in subgroups for whom it was still recommended, including younger women and those with vasomotor symptoms. And recent WHI findings show that there's actually no hormone therapy related difference in long-term all-cause mortality. But the harm has kind of been done, was already done almost 20 years ago now. So what about patients with gynecologic cancers? The Women's Health Initiative specifically excluded women who had any type of invasive cancer in the past 10 years. They excluded women with endometrial cancer at any stage at any time if they had endometrial hyperplasia at baseline biopsy or an ultrasound had a thickness of the endometrium of greater than five millimeters. They were not included in this study. And so just in terms of background, 40% of women with GYN cancers are pre or perimenopausal at the time of diagnosis. And as I mentioned earlier, a lot of the therapies that we use often result in induced menopause, which is defined as stopping of menstruation after either bilateral oophorectomy or if we've ablated their ovarian function with chemo or with radiation. And what's important is that there's a more rapid onset of menopause or this hypoestrogenic state and more severe menopausal symptoms and a higher negative impact on quality of life than if the woman had gone through natural menopause. And we know that systemic and local hormone therapy are effective treatments, but we persistently underutilize them in GYN cancer patients. So in terms of cervical cancer, I'm just gonna kind of go over the different GYN cancers and whether or not they're safe and why or why not, what data we have. So in cervical cancer survivors, the short version is that hormone therapy is safe in women with cervical cancer. 40% of women diagnosed with cervical cancer are under the age of 45. It is not a hormonally responsive cancer. And actually ovarian conservation is recommended in women with squamous cell cancer of the cervix to prevent this induced menopause. The incidence of ovarian metastases in women with squamous cell cancer of the cervix is less than 2%. Combination estrogen and progesterone therapy. This is a Bezodoxifen is kind of off the mark, is not really used and it's not technically off the market, but it's not really used much. So really you should use estrogen progesterone therapy in women who were treated with primary chemo radiation, but who still have a uterus in place. In uterine cancer survivors, a quarter of patients are premenopausal at the time of diagnosis. I know I've mentioned this before, but the BMI say we're 18 and 20. I operated to be a patient with a BMI of 56. So I'm just astounded at the, this is why we've got all these uterine cancer patients who are premenopausal in the U.S. with our obesity epidemic. But endometrial cancer we know is commonly estrogen receptor positive. So there's this hesitancy among docs to prescribe hormone therapy. Not so much amongst GYN oncologists any longer, but even some of the medical oncologists that I work with, there's still some hesitancy among them to prescribe hormone therapy. And so there was actually a prospective double-blind randomized controlled trial, the GOG was running the 137A in stage one to two endometrial cancer to figure out whether or not it was safe to use hormone therapy in these women. It enrolled over 1,000 patients and they were followed for almost three, a median of about three years after being treated with a hysterectomy and BSO. And if you see 2% of patients who are assigned to hormone therapy recurred and about 2% of patients assigned to placebo recurred. And you can see that the confidence interval crossed one, but unfortunately this study was also a victim of the WHI. It was closed prematurely without meeting its target of accrual because of the WHI announcement. And so the authors of the study put out this statement that said, although this incomplete study cannot conclusively refute or support the safety of estrogen with regard to risk of endometrial recurrence, it's noteworthy that the absolute recurrence rate and the incidence of new malignancy were low. So there were other studies, there was a meta-analysis on the effects of hormone therapy that included this GOG 137A data as well as five observational studies also did not show a significant increase in risk of endometrial cancer recurrence. A Cochran review stated that there was insufficient high quality evidence to inform decisions, but what we do know, or the data we do have did not appear to suggest significant harm on these early stage low risk patients. So what the SGO recommends is that the use of estrogen therapy in patients with early stage, so stage one or two endometrial cancer is reasonable and should be individualized in patients, especially in women who have undergone early bilateral ophrectomy and are at higher risk of adverse health consequences related to estrogen loss, specifically those effects on cardiovascular health, bone health, and brain health. In fact, they go on to say that ovarian preservation at the time of hysterectomy for presumed stage one endometrial cancer had no effect on cancer specific or overall survival in serodata analysis. And the NCCN guidelines state that ovarian conservation may be safe in select women with early stage endometrioid cancer. Unfortunately, in stages three and four endometrial cancer, there's no data supporting hormone use, so we do not recommend it currently, and we recommend non-hormonal therapies for vasomotor symptoms and prevention of bone loss. In terms of uterine sarcomas, we know that leiomyosarcoma and endometrial stromal sarcoma often express ER and PR, estrogen and progesterone receptors, and that we use anti-estrogen therapies for these cancers. So given any lack of data regarding the safety of hormone therapy, in patients with uterine sarcomas that express hormone receptors, hormone therapy is not recommended. And again, it's not because of data showing harm, it's because of just lack of data. And finally, in ovarian fallopian tube and primary peritoneal cancer patients, there are multiple randomized and observational studies that now dispel any concern regarding oncologic safety of systemic hormone therapy in ovarian cancer patients. In fact, it was shown that there was improved overall and relapse-free survival in ovarian cancer patients who were randomized to estrogen therapy versus routine care. And that was 150 patients followed for a median of 19 years and included all histologies. So based on these data, estrogen therapy can be prescribed for women with epithelial ovarian cancer. However, in low-grade serous and endometrioid ovarian cancers, again, similar to the uterine sarcomas, those are patients that we treat with anti-estrogen therapies. So we don't recommend hormone therapy in those subsets. And with borderline tumors, there's insufficient data. So you discuss the risks and benefits with the patient, determine how old they are, whether they were perimenopausal or truly just premenopausal at the time of orophrectomy, and discuss the adverse health effects with the patient. So this is just a summary, and this came from a review article in GYN Oncology, but basically the green boxes are where hormone therapy is acceptable, and the red arrows show where hormone therapy is not recommended. So early-stage endometrial cancer, high-grade serous ovarian cancer, and cervical cancer hormone therapy is acceptable, and some of the references to support that are here. And then the advanced-stage endometrial cancers, the uterine sarcomas, and low-grade serous and endometrioid ovarian cancers, it's not recommended. And the reason I want to discuss this also is because a lot of times women are cured of their cancers, but we've really done a disservice to them in terms of their quality of life by putting them into premature menopause. So I think it's just important that we're able to counsel patients appropriately as to what their risk is, because patients are deathly afraid of doing anything that would potentially increase their risk of the cancer coming back, and now we have data showing that for many of the cancers, hormone therapy is safe. That's what I had in the interest of time. I can talk another time about those women who are just at high risk and haven't been diagnosed with cancer. But any questions?

hormone replacement therapy

gynecologic malignancies

menopause

Women's Health Initiative study

counseling patients