Episode 6.11 Vaginal Estrogen and More!
In this episode, we discuss several new articles related to treatment of vaginal atrophy or genitourinary syndrome of menopause, including literature that clarifies the role of vaginal estrogen cream. Plus, we discuss the role of washings at the time of management of adnexal masses. We also discuss new literature about the true impact of oxytocin on postpartum hemorrhage risk and examine a paper that claim that female gynecologists receive lower patient satisfaction scores than males. Finally, we discuss the true rate of pregnancy loss.
00:00:02 Peritoneal Washings in OBGYN Surgery
00:52:11 The True Rate of Pregnancy Loss
Effect of Fractional Carbon Dioxide vs Sham Laser on Sexual Function in Survivors of Breast Cancer Receiving Aromatase Inhibitors for Genitourinary Syndrome of Menopause: The LIGHT Randomized Clinical Trial
What are we thinking about on today’s episode?
Well, we’re going to talk a lot about vaginal estrogen, mainly for postmenopausal symptoms, but also for some other things, and then just throw in a few other papers that we’ve been meaning to talk about but haven’t gotten a chance yet. But first, what’s the thing we do for no reason?
All right. Well, how about getting perineal washings for management of simple ovarian cysts, or just routinely at the time of bilateral salpingo-oophorectomy, or just whenever there might be a concern for malignancies?
Okay, I remember this coming up in my training and I think sometimes residents are taught that every time they manage any adnexal pathology surgically then they should collect peritoneal washings for cytology, just in case there is a cancer, because the presence of cancerous cells in those washings would change the stage of cancer and is part of a staging evaluation for ovarian cancer. And maybe people take this approach in every single routine case or have a low threshold to do it, thinking it’ll benefit the rare patient that doesn’t look like she has cancer but then has a microscopic cancer and then they think, well, better safe than sorry for those patients.
Yeah, a lot of better safe than sorry in OBGYN. So exactly, the truth is, every time we do any gynecologic surgery there could be an occult cancer awaiting us. An early ovarian cancer or tubal cancer or something could be present at any salpingectomy or oophorectomy, or a uterine cancer might be present at the time of any hysterectomy. But we have to limit on where we do these extra procedures. They aren’t necessarily benign and they could at least cost time and money and add to the complexity and expense of the case.
So we already previously talked with our Gyn-Onc friend, Stuart on a previous episode about when would be appropriate to refer patients with adnexal masses to a Gyn-Oncologist, and I think that if the risk of cancer especially if the adnexa is high enough that you would be preemptively planning to do washings during the surgery, then you probably should already be considering just referring them to the GYN oncologist. Anyway, you have to have some process for determining in your mind what do you think the risk is going into the surgery. I think it’s a totally different scenario if you go into a routine benign case and then when you get in you unexpectedly see obvious abnormal masses or carcinomatosis or something, in which case you would want the washings as well as maybe a tissue biopsy if possible. So we’re talking about routine cases where you’re planning to get washings anyway.
And probably in the case at that point, and send them off. We call that a peak and treat.
But yeah, in the academic programs where an oncologist might be available to come in and case, something happens. Well, that changes your thought process quite a bit. Now you and I both work in places where we don’t have the luxury of having a steward any time we have a problem. So we have to be thoughtful about which cases we do and which cases we send away. And the comments may not always see that distinction, depending on where they train. But it’s not like those washings are going to reveal a cancer mid-surgery and then you’re going to call the Gyn-Onc awaiting in the wings in or anything like that.
Yeah, it’s not like frozen washings or anything. It takes several days to get the answer back. So, outside of doing cancer surgeries as a trainee with my gynecology attendings, I think I can probably count on one hand the number of times I’ve gotten washings and benign cases, and I’ve gotten them for all very specific reasons. But let’s see if maybe those were even the correct reasons. So let’s talk about when we should get them.
Well, I think the answer is simple you should get washings anytime there is a clinical suspicion of malignancy, which again means for me that I’m not going to get into a case with a plan to get washings because I have a clinical suspicion of malignancy. Before I do the case and I’ve already would have sent that patient to a gynecological oncologist. Of course I could discover something, as you said, the peak and shriek and what I thought was going to be a benign case, and then I might get washings and get a biopsy and in fact close them and send them off. But we certainly shouldn’t be getting washings for things other than where there is not a clinical suspicion of malignancy, like managing simple ovarian cysts or ovarian cysts of a known etiology, like an endometrioma, for example. When I manage an endometrioma I don’t have suspicion of malignancy, not that it’s impossible, but I don’t have suspicion of malignancy. If I take care of a simple cyst that’s already been characterized by ultrasound, I don’t have clinical suspicion of malignancy.
Yeah, and, as you said, theoretically it’s possible that anyone could have a hidden cancer, but the risk is so low in someone who has benign imaging and the mass has certain characteristics or maybe they don’t even have a mass. But I imagine that on some oncology rotations that people go through, residents are just doing cancer cases and then even those they’re catching, those rare ones that get referred to them and they might start to see virtually every single surgery as a possible malignancy and just get into this mindset of starting out all cases with washings. But just because anyone could have a cancer doesn’t mean we refer every single patient to a Gyn-Onc. We just don’t do that. So we do the low-risk cases.
We should also point out that FIGO has de-emphasized the role of peritoneal washings in management of ovarian malignancies and you also run the risk of false positive washings when you do these, especially on the low-risk patients. We can link to an article that discusses some of these issues, but there is some controversy about how these washings actually change anything for the patient. It’s not that getting them when you don’t necessarily need to is associated with worse outcomes, but it is that false positive rate that can occur that might either upstage them inappropriately or might give someone a significant scare and an extensive workup that doesn’t even have cancer. But the cells came falsely malignant and while true positive malignant cells on washings are associated with the worst prognosis and do require generally more aggressive treatment, you usually have other things besides the washings that are telling you that the patient is at risk for a worse prognosis. So again, effectively it may not really be the crucial piece of information that changes their management and either way, like I said, it’s not currently a point of emphasis in the management guidelines.
So this gets back to the concept of pretest probability In this case.
If you’re collecting washings on someone who has a simple 8-centimeter system ultrasound, then your expectation of cancer is so low that if you saw something abnormal in those washings, it likely would be a false positive, and now you’ve harmed the patient with that test. There are some studies that look at this and I’ll put a link to a paper in the British Journal from 2011 that looked at 409 women who are under went laparoscopic salpingo-oophorectomy by a group of Gyn-Onc, and these were surgeries being done for things like risk-reducing salpingo-oophorectomy or surgeries performed as part of breast cancer management, like for women with progesterone receptor positive but premenopausal breast cancers. So 113 women of the 409 had risk-reducing surgeries, 103 is part of their breast cancer management, 59 were for simple ovarian cysts, 111 were for complex ovarian cysts and 23 were for some other reason. So it’s a pretty broad range of patients and included some patients that I might have just sent out to a gynecologic oncologist in the first place and of course, that’s who did the surgeries in this series of patients.
All right. So what did they find?
Well, of the 409 women, 11 of them did have a discovery of an occult malignancy on pathology, and three of those women also had positive peritoneal washings. One of those was from breast cancer metastasis, so their conclusion was essentially that the washings didn’t pick up any additional cancers and that the practice shouldn’t be routinely performed even in that panel of patients, which is comparatively high risk compared to many of the cases that you might normally do.
Well, I think that paper and others like it we’ll just discuss hopefully at least one other one are part of, as we said, a deemphasis on washings and the treatment and management of ovarian cancer patients. The question would be did the management of any of them change due to also having that positive cytology? And it seems like the answer is no. Well, I have not been in the mindset ever to get washings for all routine and benign appearing cases or really for any of them, but I still at least consider it. I usually get them for certain situations where I think there’s a higher risk, where Even this paper is saying they’re not necessary. So in BRCA positive or maybe even Lynch syndrome risk reducing cases where everything the imaging is negative. Or if we got tumor markers and they’re negative. Or, for example, if I’m removing a moderately complex mass and again the tumor markers were negative and no signs of invasive disease on imaging or asides or anything. That’s when I’ve been getting washings. And as another example, I have encountered patients in my current practice setting where Gyn-Oncs were consulted and they said they didn’t think they needed to take on someone with that. This is a real example of a 20 centimeter multi-loculated ovarian mass because the tumor markers were negative and there were no signs of metastases or asides on imaging and at a young age. So those are the scenarios where I’m thinking, okay, well, I think it’s a little bit higher chance than just the simplest. So I’ll do it if you say it’s okay, but I’ll get washings.
And I’m stuck on doing washings in those cases because I remember being taught the still current Figo ovarian cancer staging criteria from 2014, which this was before I started my own oncology rotations say that 1A 1B specifies that there’s no tumor on the ovarian surface and that washings are negative. So it requires negative washings to say that. And 1C1 has three 1C1 is 1C 2 spill. is tumor present on or outside of the surface of the ovary before surgery, if the tumor had spontaneously ruptured before the surgery began 1C3 And then specifically is malignant asides or peritoneal washings without any further criteria to meet stage two or above. And I remember being taught very emphatically by at least one oncology attending that the 1C for is so different from the treatment of one A or one B and it’s the washings that help differentiate that. And they also implied don’t be the sad surgeon that causes surgical spill of 1A 1B cancer and then turns it iatrogenically into a 1C .
Well, that later point may be why some gynecologists are too quick to do a complete oophorectomy for benign masses like dermoids, for example, rather than a cystectomy with ovarian conservation. You essentially have to accept some amount of risk and the consequences of spilling when you do a cystectomy, because shelling out a big but thin walled cyst intact is hard to do, especially endoscopically. But you would only be conserving the ovary if there was nothing suspicious on imaging to suggest cancer anyway. So there shouldn’t be any cancer morbidity concerns related to spillage in those cases and you should leave their ovary whenever you can, especially if they’re young.
But, yeah, if it’s a complex enough cyst, that there’s some suspicion for maybe an early malignancy and for some reason you’re the benign gynecologist who’s removing it. I know you used to practice somewhere where the patient literally had to get a plane ticket to see a gynecologist, and there are probably many other settings where there’s just not a quick availability or access to Gyn-Onc and you’re truly limited to referring confirmed cancers to them, not these suspicious cases. So especially in those sorts of cases, you’d remove the whole ovary and very carefully remove it in an intact way without spillage, and that’s usually a situation where you can put the specimen in a bag endoscopically before you’ve completed the dissection. So if it does rupture, at least it’s already contained. It helps you take it out endoscopically anyway, and in those cases it may also be reasonable to get peritoneal washings.
But regarding your first point about BRCA risk reducing surgeries, I’ll put a link to another paper from 2016 that looks specifically at getting peritoneal washings in women who had either a BRCA one or two gene mutation or otherwise had some hereditary breast or ovarian cancer syndrome and were undergoing risk reducing salpingo-oophorectomy.
Now this was a group of women from the Netherlands and they had 471 patients who underwent risk reducing surgery, and 267 of them had washings performed. Four of those were positive and indeed all four women were diagnosed with ovarian and or fallopian tube cancer on pathology. There was a fifth patient who didn’t have washings performed but went on to develop primary peritoneal cancer 80 months after the surgery. But their conclusion was that the study failed to show that the washings were of any value during risk reducing surgery in detecting primary peritoneal cancer or a one C tubal ovarian cancer, even though 36% of the patients who already had ovarian or fallopian tube cancer did have positive cytology. And they concluded that routine sampling wasn’t found useful in detecting subsequent primary peritoneal cancers and, again, it didn’t change the management of those patients.
Yeah, I read this. This was a very interesting paper and it’s definitely getting me reconsidering my practice. So just to give some further details, they excluded anyone who had an elevated CA125 or any suspicious mass on imaging, of course. So this truly was just cases where there was no signs of cancer going into the surgery. It was meant to be risk reducing and not a staging or treatment, in other words, something appropriate for a general gynecologist to do. You don’t have to refer these benign, risk reducing cases to Gyn-Oncs.
But in their intro of this paper they said that historically there’s a wide range, but up to about 25% of even those types of patients can still have an occult ovarian or tubal cancer on their final pathology, which is one reason that you ask the pathologist to process the tubes in a very specific way that they wouldn’t do for the specimens from average risk patients, and I think 25% is a pretty high number for a general gynecologist to still be taking to the OR, although what they had in their final numbers was quite a bit lower.
So they had 267 patients who had washings done at the time of their risk reducing salpingo-oophorectomy and of those, 11 had occult cancer on the tubes or ovaries, and of those, four of them had positive cytology on washings and then the other seven had benign washings. So 11 out of 267 is a 4% rate of cancer, which still probably is higher than many of the other cases a benign gynecologist would do, even for a dermoid or simple cyst or endometriosis. But regardless, what they’re saying is that even though those washings technically could have upstaged those four patients, compared to if they didn’t get washings, and that information wasn’t known, it ultimately didn’t affect those patients’ outcomes or management.
Right. But it’s because none of them were stage ones to begin with. They were already stage two or three and they didn’t need the washings to demonstrate that. They knew whether other biopsies were also collected. But stage two or three means extension of the cancer beyond one organ. So there’s a good chance there was some visible cancer in those patients. And they did also have one false positive where the initial read on washing said cancer but the tissue said no cancer. They did a reanalysis on the washings and determined it was actually endometriosis and not cancer cells. People sometimes forget that pathology can be falsely positive and the one patient who later developed primary peritoneal cancer had no cancer in her ovaries or tubes initially. This is just part of the known baseline risk of still developing a BRCA-related cancer even after a risk-reducing surgery. It doesn’t make it 0%. We can’t prophylactically remove a patient’s peritoneum.
Right and yeah, they’re implying that very likely I believe she didn’t have washings done, but very likely they would have been benign for her to not develop it for another 80 months.
The one thing they unfortunately didn’t talk about were those other seven patients who had cancer on pathology but had benign washings.
I’m assuming they were mostly lower stage, probably all stage one, but it would have been nice just to demonstrate the comparison between those cases and the positive washings patients.
This paper, I think, still does leave open the theoretic possibility theoretic but likely, rare that a patient could have an otherwise occult-contained cancer but then still have positive washings that then get upstage based on the washings alone, and maybe we should try to have Dr Winkler back on to discuss how feasible that even is. I thought there’s never encountered that specific example, whereas they did encounter that completely false positive result. So on the whole, this study really does seem to give a strong case against getting washings, at least for the BRCA and probably the other hereditary breast or ovarian cancer risk-reducing surgeries and definitely for anyone else who’s even lower risk of having an occult cancer because again we said there’s in this study was 4%. Historically it’s been higher, but usually the risk is even lower if you’re just going for a dermoid or something and there are no other studies out there at least that we’ve found that do show value in getting washings for those types of patients.
All right agreed.
All right. Well, so that’s the thing we do for no reason. Let’s get into our main topics. I know we’ve talked before about the risk of postpartum hemorrhage with prolonged oxytocin exposure in labor, but there’s a new paper in the Gray Journal from August 2023 that looked at the risk of postpartum hemorrhage for women who were augmented with oxytocin compared to those who were not, and I think it adds a lot to our knowledge on the subject.
Yeah, and the title to the paper is really all you need to know. The title is Oxytocin is not associated with postpartum hemorrhage and labor augmentation, and this was a retrospective cohort study that was done in the United States.
Well, right off the bat you have to. You always have to wonder is there any bias? But read the paper. It sounds pretty self-explanatory though, doesn’t it Brevity?
is a solo wit. Yeah, and before we talk about the paper, I would make a point that if you read the title of paper and it uses qualifying words like may or might or could, then it’s likely that the finding of the paper is not definitive but preliminary or not certain. But this paper says plainly is not, may not, so they aren’t hedging. If you pay attention to a lot of news headlines where you see papers reported with some new novel association, they often will say something like increased exposure to something may be associated with some cancer or some other outcome. But the emphasis is on the word may because the finding is not definitive and is merely preliminary and has a high level of uncertainty associated with it. But people read those as if they are definitive. But this headline for this paper is definitive Oxytocin is not associated with postpartum hemorrhage and labor augmentation.
Yeah, at least not in this retrospective cohort study, but it’s a pretty big one. They looked at almost 21,000 women in the United States who had spontaneous labor onset and they were cared for in the Intermountain Healthcare System in Utah, which has among the lowest rates of cesarean in the US. So they do a lot of work in active management of labor to achieve that low rate. So you might expect that they start a lot of oxytocin on women who present in labor to augment their labor and I looked in this study to see if that was associated with an increased risk of postpartum hemorrhage and when they rigorously controlled for potential confounders, especially for different labor patterns, they found that it was not.
Right, and I think that that last part isn’t the important part here.
It’s true to say that if a woman receives oxytocin then she’s at an increased risk of postpartum hemorrhage compared to a woman who does not receive oxytocin, and I’ll explain that in a minute.
But because of that people become afraid of doing things like using pitocin for augmentation, or they may only stick to lower dose protocols, less oxytocin, which tends to drag out their labor course, and ironically, doing that may lead to a higher rate of cesarean delivery, where there’s definitely a greater risk to the mother of greater blood loss.
But the thing that people miss in all of those studies about the risk of hemorrhage with oxytocin is that the women who need oxytocin or more oxytocin are different than the women who do not need more oxytocin, and the more oxytocin they need to achieve an adequate labor pattern, the more different they are.
And what I mean specifically is their tissues may not be as sensitive on a receptor level to oxytocin as women who don’t need as much oxytocin or don’t need any oxytocin, so it’s not the oxytocin exposure that desensitizes them and affects their hemorrhage risk. They likely have fewer upregulated oxytocin receptors or just less activity to begin with. So the fact that you’re going to have to give them more oxytocin is a sign that there’s already an underlying problem, but you still need to give them the oxytocin to treat it. Then, when they finally deliver, that same issue will lead to inadequate contractility of the uterus and therefore more blood loss. So it’s an example of an association that doesn’t equal causation. The increased oxytocin doesn’t cause hemorrhage, but it can be a sign that that patient has an increased risk for hemorrhage due to inadequate oxytocin receptor activity.
Yeah, and that’s exactly what this paper was able to demonstrate without having to do uterine tissue studies on this women, and I think that really would be just an impossible study design anyway, because here they chose to augment some women with oxytocin and when that practice of active management of labor essentially was compared to women who didn’t get augmented, maybe some women declined it or they just wanted to sit, wait and see and the abnormal labor patterns were adjusted for. In both cases then there was not an increased risk of hemorrhage. So just using oxytocin in and of itself doesn’t increase the risk of hemorrhage and probably if you have a patient on oxytocin and then you’re going to take him back for a C-section, you probably don’t need to stop it and wait for the oxytocin to wash out so the receptors can come back.
Please don’t do that.
Yeah, that’s not how it works, but that’s, I think, how a lot of people understand it. I think it’s the oxytocin that caused that, and we’ve talked about that whole hemorrhage risk association before. People really should not be afraid of oxytocin, at least in terms of that aspect. But if you’re having to use high doses of it and someone’s just not responding well, they don’t have a regular or adequate contraction pattern then you can predict they might also have a higher rate of at any after delivery because they just aren’t sensitive to oxytocin as much as another patient might be. So in those cases, instead of backing off on oxytocin or trying to let it wash out for 90 minutes or however long, you have to titrate it as needed, get them delivered and then be prepared for additional uterotonic measures in the third stage.
Yeah, and we can’t emphasize enough that association doesn’t equal causation. But also, when you read headlines or titles of papers, keep in mind that there is a difference between using that sort of conditional subjunctive tense versus the indicative tense.
Are we getting a grammar lesson?
Yes, well, I guess that would probably generate too much hate mail. But anyway, when a title says may or something, you could just as easily substitute the word may not and try that in your mind when you read titles that say may or could, just though it not in there, it’s equally true based on what they found. So do that as an exercise. But you can’t. Change is to is not without contradicting the author’s message.
All right. Well, let’s move on to some vaginal estrogen. There’s a lot of papers on this. There was a nice systematic review in the September Green Journal of non-estrogen therapies for treatment of genitourinary syndrome of menopause. There was also a really good November Green Journal review on compounded bioidentical menopausal hormone therapy. I don’t know if we’ll get to that one today, but that was a really good read and I especially found those quite valuable because I’m seeing a lot more of this now than I ever did in the past when I was previously in the military setting.
You just didn’t have a lot of both menopausal patients, and one thing we are learning more of in the literature with great confidence is that there’s really not a lot of reasons to avoid vaginal estrogen cream or tablet or any other vaginal estrogen for the treatment of genitourinary syndrome of menopause. Some of the normal reasons to avoid estrogen, like with birth control for example, just are not relevant to vaginal use. So some common examples are thromboembolic disorders or breast cancer. But people have been very uncomfortable with using estrogen cream where contraindications to systemic estrogen might be applicable. So this is a nice review of other therapies to try besides estrogen.
Well, let’s quickly just summarize some of those therapies that they discussed and this is in September, this article and what the evidence is. It’s referred to this for more detailed references to the studies. For sure, I’ll note that for many of these items there are no head-to-head trials comparing estrogen and vaginal cream to the product or procedure, but they do look at vaginal DHEA cream, vaginal hyaluronic acid, fractional CO2 laser, the erbium-yag laser, ospimefine or osphena, polycarbophyl-based vaginal moisturizers, vaginal testosterone and tibolone.
Yeah, so lots of options out there. They did find that vaginal DHEA improved symptoms of vaginal dryness, dyspareunia and sexual dysfunction. But, as you said, no comparative trials between this and estrogen. And of course, when DHEA is absorbed through the mucosa some of it gets converted to estrogen. So, knowing that, it doesn’t necessarily make sense to me to choose DHEA cream over estrogen, maybe from the fact that it is an androgen and the thought that it could give some kind of advantage for patients with low libido. But that outcome has not been compared with vaginal estrogen and it hasn’t been found to increase circulating androgen levels above normal physiologic ranges either. So I don’t think vaginal DHEA would be equivalent to using any kind of transdermal androgen, and the November review article discusses that a little bit further. So really I can’t think of any valid reason that vaginal DHEA should be superior to vaginal estrogen. But at any rate it is better than placebo or a lot of non-hormonal moisturizers.
Yeah, and that’s the general theme of a lot of the products that we’re going to talk about and are the drugs we’re going to talk about. It’s not enough to have a placebo-controlled trial. Most of these things are better than placebo. You start with that so you can see if it does something at all. But then the question is does it have efficacy against the gold standard? And the gold standard here is definitely vaginal estrogen cream. So you really have to ask yourself why you’re trying to avoid vaginal estrogen cream in the first place for a particular patient, before you might even consider an alternate therapy that hasn’t been proven superior. But the next one thing they looked at was vaginal hyaluronic acid, and there actually are comparative trials for this product to vaginal estrogen cream, and in this case vaginal hyaluronic acid was no better than placebo and definitely was not comparable in head-to-head trials to estrogen for treatment of dryness and dyspareunia, so probably not something to use.
Yeah, they spend a lot of time talking about the two types of laser treatments as well, which, of course, are non-hormonal. We’ve discussed some of those before. I think we’ve discussed them a lot offline and maybe a little bit less on this podcast, but there have been some safety warnings come out regarding these quote vaginal rejuvenation laser treatments. So these are not lasers for treatment of lesions like pre-cancerous lesions, these are just for basically postmenopausal symptoms. But the important thing is neither laser product was better than vaginal estrogen cream. So again, it makes no sense to use an expensive and potentially dangerous device when it doesn’t improve outcomes any better than the gold standard. And I think it’s still an open question about whether those lasers are even better than placebo or not.
I have had one patient who told me that she had it done and it really helped her and she just insisted on getting that done and I went ahead and referred her because I don’t offer them. But that’s one patient I’ve ever come across. But by nature of these laser products it’s hard to do a placebo-controlled trial. You have to do some kind of sham laser and in the best quality studies they’re just not effective. So on the whole, I would still regard these as experimental and risky, both medically to the patient and also financially to the patient and the practice. Who’s offering it?
Yeah, they’re very expensive and, of course, a lot of products are sold out of fear-mongering to estrogen, and things do have a placebo benefit, so you’re going to find patients who swear by them. That’s why products like this rely on testimonials only. Remember that seeing that you’re better than placebo though even if such a study existed, shouldn’t get you many points, particularly when it’s hard to design, as you said, for this, a placebo-controlled or sham-controlled study. You need to be better than the gold standard and also, hopefully, safer, and that’s simply not the case for the laser treatments. Even if it’s equal to the gold standard, the safety concerns and the cost of the product in its use don’t justify utilization of this.
Now, moving on to ospemefine, or osphena is easier to see. Of course, this does work better than placebo it’s FDA approved for this but it also may increase the rate, paradoxically, of vasomotor symptoms, ease infection and endometrial thickness in patients who use it. It’s also very cost prohibitive for a lot of patients. Now, this is an oral selective estrogen receptor modulator designed for vaginal symptoms and menopause, and of course, there’s no head-to-head comparison, once again with vaginal estrogen cream, and really think about it. There should be no advantage in terms of side effects. I suppose it’s less messy because you take an oral tablet rather than use a cream in the vagina, but all the same, concerns regarding estrogen risks also apply to this thromboembolic risk, hepatic dysfunction and, of course, estrogen-related breast cancers.
Yeah, I’ve never prescribed this product, nor have I been asked by any patient to prescribe it, and I don’t see that changing anytime soon based on this review. So let’s move on to the next product, the polycarbophil-based vaginal moisturizers. So these form a film over the vagina so that the moisturizer stays more adherent than other moisturizers would. And again, they do improve symptoms of dryness, which you would expect. In comparative trials, it was still inferior to estrogen cream.
Okay, and then that gets us to testosterone products. There are comparative trials of testosterone to estrogen, as well as to lubricants and to placebo, and the data here is weaker than for some of the other things we’ve talked about so far. A lot of these studies look at changes in vaginal pH as a surrogate marker, but not necessarily at the patient’s actual symptoms and complaints. To summarize, testosterone might be slightly better than a lubricant, but still inferior to estrogen. Vaginal cream.
Yeah, it seems like vaginal testosterone may be a fair consideration for someone who is adamantly wanting to avoid estrogen, despite its good safety profile. But I think the problem, at least in the US, is access, because there’s no FDA-approved testosterone formulation for cisgendered women in the US. So you’d have to either send them to a compounder, which the November article talks about a lot there’s really no guarantees of the quality of that or have them use a tiny fraction of some male testosterone medication dose that’s not meant to go in the vagina, using an off-label way and likely either way paying out of pocket. We’ve seen some pharmacokinetic studies on vaginal testosterone where, even though their serum levels of testosterone did increase, there were no reported changes in sexual response in various parameters that were measured. So again, it may not actually help with libido issues that a lot of postmenopausal women have, at least when given by this route. So again, really not a lot of advantage here over estrogen.
And finally we’ll mention Tibolone. This was in the review article as well, but it’s not available in the US. It’s another selective estrogen activity regulator. It is used in other countries as a hormone replacement product, also to treat osteoporosis and endometriosis, and this was found to be similar to estrogen for many of the outcomes in the comparative studies, but unfortunately it’s just not available in the US. So it does sound like it could be a decent alternative that some patients in the US might be interested in, but I’m sure it’s a whole another can of worms as to why we can’t get it here that I don’t really have insight into.
Well, the bottom line is that estrogen is still the gold standard, so you really should be asking why you’re deviating from the gold standard. The question still would be is there a reason to avoid vaginal estrogen in a particular patient? And the most common ones we see that you mentioned earlier are patients with a history of thromboembolism, patient with a history of breast cancer and, specifically, estrogen receptor positive breast cancer.
And that doesn’t cover every possible scenario or condition a patient might have, but there have been some more recent studies to help answer this question.
Yeah, actually, there is a paper in November 2023’s JAMA Oncology which followed 55,000 women in two cohorts. Now, 5% of those women did use vaginal estrogen cream and they found no evidence of increased early breast cancer specific mortality compared with patients who did not use hormone replacement therapy. Now, none of these women use systemic hormones. When I say hormone replacement, I just mean vaginal estrogen.
I’ll also put a link to a study in JAMA Open Network from earlier this year that looked at the use of laser versus sham in postmenopausal women who were on aromatase inhibitors, and they found that the laser was no better than sham therapy. So there’s certainly no evidence that using these lasers in that particular population is effective, and there’s also no evidence that using vaginal estrogen cream is harmful in that population. Now, more to the point, there was a similar article in the September 2023 Green Journal examining the safety of vaginal estrogen therapy for women with genitourinary syndrome of menopause who have a personal history of breast cancer. So these researchers identified 42,000 women who had a diagnosis of GUS after a breast cancer diagnosis, and about a fourth of them were estrogen receptor positive. In that group, 3.9% of the patients received vaginal estrogen cream treatment, compared to 5% overall in the group, but in any event they found no increased risk of breast cancer or breast cancer recurrence within five years for those women who did that.
Yeah, so from that perspective, really we should not be concerned anymore about prescribing it, even for patients with ER positive breast cancer. We need to remember that hormone replacement therapy is not the same as birth control. Those doses are significantly lower. So many risk factors that would be contraindications to certain hormonal birth control pills, especially the DVT risk and history of ER positive breast cancer, do not apply to transdermal or transvaginal menopausal hormone replacement doses.
Yeah, for DVT in particular, I’ll put a link to a 2021 study that looked at this, and the bottom line is they found no increased risk of thromboembolism with use of vaginal estrogen cream and no increased risk even in women with prior thromboembolism who were on vaginal estrogen cream. Now there are probably still some exceptions, but this is mainly in the name of caution due to limited data, For example, data on endometrial cancer survivors, who are very. That data is very limited but surprisingly favorable towards using the estrogen cream in the setting of debilitating menopausal symptoms. But if you have a patient with a prior endometrial stromal sarcoma or granulosa cell tumor, there’s definitely not much data, but there is a huge theoretic risk to them, and so we just don’t know enough to have that kind of reassurance. So, similarly, we don’t know enough about the effects on various liver diseases either, although, depending on the specific condition, it may be reasonable to monitor liver function imaging while on vaginal estrogen cream and then reassess accordingly.
We could also make similar case by case assessments for patients with some of the other systemic HRT contraindications, like uncontrolled hypertension or severe dyslipidemia, or history of stroke or heart attack. But as a general rule, besides keeping these rare and extreme exceptions in mind, we really should be using vaginal estrogen cream as first sign therapy in everyone with genital urinary syndrome of menopause until we have evidence that an alternative therapy is more effective and safer.
Okay, well, let’s stay on topic. There’s another trial relative to this in the September 2020 Gray Journal. That was a double-blinded, sham-controlled trial of the vaginal epithelium histology before and after fractional CO2 laser treatment in postmenopausal women, and a lot of the studies that were reviewed in the article we were just talking about are small and low-quality studies, often with some bias, directed by funding sources, because they were mostly paid for by the companies that make them. But this is a trial that may help us more definitively answer some of the claims made about vaginal lasers and its effect on the histology of the vaginal epithelium.
Okay, what are they? Fine?
Well, they found that fractional CO2, laser and sham have the same effect on the epithelium and they actually conclude that it should not be recommended for clinical use for postmenopausal vaginal symptoms.
All right. Well, that’s quite a bit more negative than what we read in that other systematic review that we just discussed a few minutes ago and other reviews out there about vaginal laser.
Yeah, it is, but when you look at the quality trials, this is consistent with those. It just doesn’t work and, given the cost and the risks associated with it that have been shown in excellent studies, it’s just not efficacious and it’s a real stretch to justify using it clinically outside of some research protocol. Not only are most of the studies that exist funded by the companies that make the lasers or sell the devices, but they’re just small and designed in a way to find some benefit.
All right, so another point for vaginal estrogen. It is.
And in that same edition of the Gray Journal there were a couple of other interesting articles. I thought One was a paper from the Society of Gynecologic Surgeons meeting recently entitled women physicians receive lower Press-Ganey patient satisfaction scores in a multicenter study about patient gynecology care and they concluded that women gynecologists are 18% less likely to receive top patient satisfaction scores compared to men in the study.
All right. Well, if someone doesn’t send us hate mail about this, I’m gonna write hate mail myself.
You said controversy sales okay.
Well, that’s true. I suppose We’ve talked about studies similar to this, that well, we’ve talked about studies that say women are better surgeons than men. So I guess it’s fair to balance it out and talk about women cause less patient satisfaction. Yeah, cause less patient satisfaction.
Fair enough. We did do an episode about gender bias and OBGYN in terms of the profession and folks can refer back to that one, but my thoughts about this study is that it is what it is. I’m not sure that the difference here is entirely explainable by gender. This just highlights a problem of selecting one criteria among many different potential confounders and not selecting for other things. They did adjust for age in the study, but there are a ton of other factors that might impact these results that are not accounted for, like how long has a doctor been taking care of patients? For decades or a few visits or less? Are these OBGYNs who also delivered the patient’s babies, or are they GMI and only doctors? We’re seeing a bunch of studies like this that break down very broadly different outcomes of whether, like you said, surgeries or patient ratings or whatever it is, and then, based on just a couple of demographic factors, they find some difference, and I think that’s almost always a mistake. There are just too many unknown variables between those groups.
Okay, so it sounds like you’re defending the women here.
I always defend women. All of my physicians are women. You know that.
Well, yeah, it’s nice to know that if you needed a gynecologist, he would still prefer a female, despite what this study suggests 100% and I may need one, so Okay.
the other interesting thing was they concluded that the scores should be adjusted this was the author’s conclusion should be adjusted by 18%, because the difference in scores must be due to gender bias, and I think that’s a conclusion not supported by the data. You have to be careful making such broad, sweeping conclusions without a methodology that specifically tests that hypothesis. Now, interestingly, in the same study, physicians who were from historically underrepresented races or ethnicities she received the highest number of top box scores, while white physicians received the lowest number of top box scores. So does that mean we can conclude that’s also due to bias and if so, does that mean that white women, who are the lowest, should receive some kind of adjustment for bias in their Press-Ganey evaluations to account for that bias?
Well, like you said, there’s tons of possible confounders here, and they didn’t interview the patients or get other qualitative types of information. So I think they have to prove that there is a bias against women to begin with if they’re gonna make this claim that we need to adjust the results for bias. So I think it would be wrong to jump to the conclusion. No-transcript. There’s some kind of racial disadvantage among women physicians against white women that we also have to correct. For you can disagree if you’d like, but these sorts of data mining studies are hypothesis generating, not hypothesis confirming or negating, so it really is inappropriate for them to make conclusions about what this data might mean. Instead, they should use this data to inform a prospective trial or maybe some other kind of like a qualitative study or something that better answers their questions of what physician qualities lead to higher patient satisfaction.
Okay, well, there’s one more article in the Gray Journal, that same edition, that relates to vaginal estrogen cream, so let’s not neglect it.
Okay, yeah, this was a study on the effects of preoperative intravaginal estrogen on pelvic floor disorder symptoms in postmenopausal women with pelvic organ prolapse. So it was randomized controlled trial in which women who were scheduled for prolapse surgery were given more than five weeks’ worth of preoperative vaginal estrogen cream and then also continued on this twice weekly for a whole year after their surgery. Well that sounds exciting.
There may already be a lot of physicians out there who will routinely delay surgery just so patients can use vaginal estrogen cream in advance of their pelvic organ prolapse surgeries. And I’m betting a lot more surgeons also will still pack the vagina after they make repairs with a gauze that’s been soaked with usually primer and estrogen cream, and that’s a very expensive practice with no known benefit, and in fact it’s unusual that packing in general has any benefit after doing these vaginal repairs. But what did they find in this study about the preoperative use of estrogen?
Well they didn’t find benefit to using. On average it was six or seven weeks’ worth of preoperative vaginal estrogen cream. The estrogen and placebo groups were similar in all of the variables that they measured.
Okay, and I believe that’s consistent with other studies that have looked at this in the past. It’s a tough thing because patients often in that age group do benefit from vaginal estrogen cream, but I think the deliberate practice of having the patient use it for pre and post-op or delaying their surgery just so they can use it beforehand is probably of no value. Okay, and one more article from that issue of the Grey Journal that I thought was interesting was a study where they assessed patient satisfaction with home versus office and dwelling catheter removal. So this was in the setting of bladder rest for urinary retention after some of these pelvic floor surgeries.
A percentage of patients after surgeries that I do as outpatient surgeries won’t be able to urinate before they go home. So it’s common that I have maybe I don’t know, one in 10 or one in 15 patients go home with an indwelling catheter overnight and come to the office the next day for a bladder trial and then removal. I can’t remember the last time that someone who did that didn’t pass their bladder trial the next day. So you are given to wonder sometimes if they could have just taken it out themselves, and occasionally I’ll have somebody asked to do that, often to nurse.
Well, they did exactly what you’re interested in this study. They had some patients come to the office and have a bladder trial, like you are used to doing, and then they had other patients just stay home. They sent them home with a syringe and they instructed the patient on how to take it out themselves, and they also gave them a hat to measure their urine. And then they called the patients later that afternoon, on post op day one, to ask them how forceful their stream was and how much they had urinated.
And they found no difference in patient satisfaction. There were some other differences, however. The home group was much more likely to rate it as convenient to do at home rather than come to the office, but they were also much less likely to have urinary tract infections, which makes some sense due to the invasiveness of a bladder trial that was being done to the patients in the office. They were also more likely to endorse outpatient removal as a way to go and overall 84% of the patients who removed the catheters at home had no retention afterwards.
So this seems like it could be a good thing. It could work well, as long as the patients could come back to the office later that day, if they did have retention and be taught maybe to self-cath or have another indwelling catheter put back in.
Yeah, and I also think it’s interesting that only 73% of the office group had no retention, which implies that the voiding trial may be over sensitive to diagnosing retention, and that means that the more folks in the office trial had to undergo self-catheterization or prolonged indwelling catheterization for a few more days, which may also be why you saw an increased rate of urinary tract infections. We’re increasingly learning that bladder trials are just not necessary after most of these surgeries.
So are you gonna start to change how you do this for your patients?
Well, like I said, I have done this a couple of times and I think it’s a good idea. I may have problems, though, just pragmatically operating on Thursdays and not working Friday afternoon in the office about getting patients back before the weekend. So it may be a pragmatic problem, but it’s a good idea.
All right, well, let’s try and do a couple more. There were some articles from the August 2023 grade journal. One of these comes back to our theme on vaginal estrogen cream. It was a study assessing the efficacy of vaginal estrogen for preventing recurrent UTIs in women who were hypoestrogenic. It was a multi-center retrospective review over a 10 year period of women who had recurrent UTIs defined as three or more positive urine cultures within a 12 month period, and among women who were given vaginal estrogen cream, the rate of recurrent UTI was decreased by 50%.
Yeah, that’s another great platitude, I think, for vaginal estrogen cream. If you look at the literature on things that are commonly used to prevent recurrent in your retract infections, they’re very meager in terms of potential benefit compared to this 50% reduction that they found.
Yeah, so that would be things like methenamine salts or cranberry supplements.
Yeah, methenamine salts like Hyprex or Cystex or a couple of brand names. These are converted to ammonia and formaldehyde, which then denature bacterial proteins in the bladder. Methenamine is actually fairly effective, though its ability to reduce UTI is not quite 50%. It varies widely in various studies. As far as cranberry, the data is much more mixed. Most studies lack efficacy and a few focus on extracts, with some barely positive data. I’ll put a link to a recent review of cranberry as well as D-mannose and vitamin C that essentially say these supplements are not effective.
All right, so another win for vaginal estrogen.
Yeah, and if you were gonna use any of these other remedies, you should definitely consider vaginal estrogen first. Also, it’s much better tolerated than methenamine and has no contraindications with ring and pyramid like methenamine does.
Yeah, and you can use it just once or twice a week for maintenance, rather than two to four times a day. So that’s nice. Well, let’s maybe try to do one more from that issue and then maybe wrap up.
Okay, well, there was a perspective piece called gestation versus pregnancy that I thought was interesting. This comments on the fact that the rate of spontaneous abortion or miscarriage that we frequently discuss with patients is around 15%. Of course, that varies somewhat by age, so your population may be north or south of that number depending on age and other demographic characteristics. But, as they point out, that number only includes known pregnancies, or how many pregnancies are lost after you’ve had a positive test.
Right. Many embryos never implant or are lost very soon after implantation. One study estimated that half of all conceptions are lost very early on and of course most of these are due to severe genetic abnormalities or chromosomal issues. That usually are random events. We also hear about implantation failure in the infertility population, especially because they know when an embryo is going in like a fertilized egg and even when it’s presumably been tested to be genetically normal, and so they know when that goes in and then they fail to get a positive pregnancy test.
So for any IVF patient, the expected outcome on average is that about half of transferred embryos will implant. The other half won’t even implant and of those that did implant and resulted in a positive HCG, about half of those will still miscarry. And that’s normal numbers. And of course those could still be due to unknown genetic problems, because the pre-implantation genetic testing actually is pretty limited. So there’s a lot of things that might not be catching. But there are plenty of IVF patients in whom this failure to implant or then early miscarriage happens much more often than those expected rates and in those cases it’s often difficult to determine why. But regardless, the average normal human fecundity rate, which is what’s the chance you’ll get pregnant and produce a living newborn from any one menstrual cycle with regular intercourse is somewhere between 14% and, at best, 31%.
Yeah, and I think historically we think of that as, oh, it took us three or four months of trying to get pregnant, when in reality pregnancy may have occurred in each cycle, but the loss rate is high and though a conception or implanted or a fertilized embryo or something occurred, a pregnancy occurred, gestation meaning implanted, and having a positive pregnancy test did not.
Yeah, and I guess that’s where this article is getting into, with the semantics of that Establishing an ongoing gestation, that, especially one that it’s gonna result in a live born baby, is difficult.
Right. And so they conclude that it’s likely that half of all early embryos are lost and then, after an established gestation is identified with the detectable level of HCG, another 15% or so are lost. That 15% we think about.
Yeah, and the authors here propose calling that first phase pregnancy, where there’s a fertilized egg, and the second phase, gestation, where there’s also a not just a fertilized egg but a positive pregnancy test, to at least distinguish those two in the scientific literature.
I think knowing this changes your perspective a bit about miscarriage. If you understand that by the time you even have an opportunity to have a miscarriage after you’ve had a positive pregnancy test, you’ve already lost at least one other pregnancy, statistically speaking, and maybe more if you’re older. If patients better understood that the majority of pregnancies are lost, I think they would recontextualize our and failed treatment approaches for prevention and miscarriage or understanding vitro fertilization differently. Things like that Maybe have less self-blame or less belief that something like progesterone may help them, despite decades of scientific evidence that says it doesn’t work. People do any kind of weird treatments or progesterone therapy or things like that because they don’t really appreciate. I think that embryonic wastage rates are very high and that all of those are do almost exclusively to genetic or chromosomal problems.
Yeah, I’ve read about a lot of other kind of more experimental things, especially within IVF message boards, that have to do with different endometrial treatments that are meant to improve implementation rates, but obviously very experimental. None of these came up in my own treatment course either.
Well, and the point is, as of now, they don’t work. We’re not seeing evidence that these things work. They’re not ready for prime time, at least because we’re not seeing benefit. And again, the fact that you made the embryos in a Petri dish doesn’t exclude you from the fact that what half of embryos don’t implant in nature?
Antonia 58:35 Yeah, all right. Well, I think we can wrap it up for the day. So the Thinking About OBGYN website will have links to the studies we talked about, and we’ll be back in a couple of weeks.