Gynecological Potpourri

Yet another study on the laser. Does Duavee work? Endometriosis and MHT.

It’s time for another potpourri post. No, not herbs for “vaginal steaming” or who knows what, but a collection of things I’ve read this week or questions that have come up a few times in the comments. Think Gyno Jeopardy Potpourri. 

Yet ANOTHER Study Shows the Vaginal Laser is Ineffective for Vaginal Symptoms of Menopause

How many well-done studies do we need to prove a procedure doesn’t work? Because as far as the vaginal fractional carbon dioxide laser for genitourinary syndrome of menopause, or GSM, is concerned (the Mona Lisa is the most widely marketed), I think we’re there. In fact, I’m wondering if we are veering into the realm where it may not even be ethical to do more research because study after study after study shows it’s no better than a sham (i.e., placebo) procedure. 

This latest study (Li 2023) randomized 49 women to receive laser therapy or a sham procedure. The researchers reported on vaginal biopsies taken before and after the laser therapy. For the laser to be considered effective therapy by the hypothesized mechanism, we want to see changes under the microscope in vaginal tissue that look like those we see when estrogen is used. Surprise! The before and after laser biopsies were not “significantly different” from the sham procedure.  

This is no shocker because this is now the THIRD study to show no beneficial changes in the biopsy of vaginal tissues after the laser compared with a sham procedure, hence my comment above about the ethics of continuing to study laser for vaginal GSM. How can we ask women to have vaginal biopsies when we now have THREE STUDIES showing that biopsies before and after the laser show no change compared with sham procedure? (Yes, I’m a little shouty). 

In addition, several high-quality sham-controlled trials evaluating the impact of the laser on symptoms like pain or dryness show no benefit. The only data that shows benefit are lower quality studies, most not sham-controlled. 

None of this is any surprise because when you look back at the original reports back in 2015 that claimed the laser created beneficial remodeling in vaginal tissue, what was being reported as remodeling was more consistent with the body's normal injury and repair function. This means the tissue was subjected to a thermal injury (laser) and healed itself (expected) with no magical reversal of changes related to menopause. 

How the vaginal laser went from a hypothesis (with apparently not even any animal data showing it worked, see why I am shouty?) to something offered as almost a menopause miracle is a story I am definitely interested in telling. My range compels me. So stay tuned. 

Is Duavee Going to Help My Symptoms?

There have been several questions about the potential effectiveness of Duavee, the combination of conjugated equine estrogens (Premarin) 0.45 mg and bazedoxifene, a selective estrogen receptor modulator, and whether it will work as well as estradiol as menopause hormone therapy. I’m guessing this is related, at least in part, to how successful the messaging has been about transdermal estradiol being the first-line therapy for MHT. 

Premarin or CEE, the estrogen in Duavee, was the gold standard for years, and all of the data we have from the WHI is with Premarin. We also know that, like Premarin, bazedoxifene is also good for bones. The data tells us that Duavee works well for hot flashes and night sweats, can help with sleep impacted by night sweats, and prevents osteoporosis. In addition, the expert speaking on Duavee at the Menopause Society meeting gave us this reassuring data about the impact on lipids (decreasing LDL and increasing HDL). 

Estrogens are rarely studied head-to-head, so there is no good data we can use to make claims about one estrogen being superior to the other for managing symptoms, but there is no reason to suspect Duavee is inferior to either transdermal or oral estradiol for symptom control in menopause or for osteoporosis prevention. As someone who prescribed a lot of Premarin back in the day, I’d say it works great.

The biggest issue with Duavee is whether someone is a candidate for oral estrogen. And if they are, they should be comforted in knowing that Duavee is an excellent choice. 

MHT and Endometriosis

I haven’t found anything regarding risks of hormone therapy with a history of endometriosis. Have you seen research on this?

Question via The Vajenda

The concern with MHT for people with endometriosis is the estrogen could make endometriosis grow, even potentially resurrecting endometriosis that hasn’t been active for years. This is more than a theory because there are reports of this happening, although whether this is a sporadic occurrence versus something that is often missed is unknown, meaning predicting who this will happen to isn’t possible

If someone has had issues with active endometriosis during their menopause transition or if that was the reason for having their ovaries removed, then for hormone therapy, a discussion about progesterone vs. progestins needs to happen, even when they don’t have a uterus. This is because progestins are better at suppressing both endometrial tissue and endometriosis tissue than progesterone. We may even recommend people who had a hysterectomy take a progestin because microscopic endometriosis implants could remain even after a surgery that removed the uterus and both ovaries. 

At the Menopause Society Meeting (September 2023), one of the speakers mentioned Duavee for endometriosis. Bazedoxifene is very effective at suppressing endometrium, and the belief is that it may also be very effective at suppressing endometriosis; after all, it was designed specifically with the idea of counteracting estrogen’s effects on the endometrium. As an aside, this is the power of synthetic medications; they can be designed to work in specific ways that suit specific medical needs. 

I took a look to see what data we had. There are animal data using bazedoxifene as well as CEE plus bazedoxifene to treat endometriosis (just a reminder about animal data being important before we move to human use) and several case reports of Duavee to treat endometriosis (several before menopause and one who was in menopause). With this in mind, I think Duavee may be an alternative to estradiol plus a progestin for MHT for someone with a history of endometriosis. 

Based on what we know about progesterone, progestins, and bazedoxifene, the latter two seem like better options for suppressing endometriosis after menopause. There is, unfortunately, very little research here, so we don’t have data to guide the best decisions. It wouldn't be wrong if someone wanted to take progesterone instead of a progestin or Duavee. If someone had a hysterectomy and their ovaries removed, and there was no evidence of active endometriosis, it might, in some cases, be reasonable just to use estrogen for MHT. This is a discussion that requires an excellent knowledge of someone’s medical history, how they may have felt while taking hormone therapies previously, and what they feel comfortable with treatment-wise. I suspect we will see more research soon with Duavee and endometriosis, and I am excited about it.

References

1. Li FG, Fuchs T, Deans, r, et. al. Vaginal epithelial histology before and after fractional CO2 laser in postmenopausal women: a double-blind, sham-controlled randomzied trial. A J Obstet Gynecol 2023;229:278-279.

2. The NAMS 2020 GSM Position Statement Editorial Panel. The 2020 genitourinary syndrome of menopause position statement of the North American Menopause Society. Menopause. 2020;27(9):976-992. doi:10.1097/ GME.0000000000001609

3. Preti M, Vieira-Baptista P, Digesu GA, et al. The clinical role of LASER for vulvar and vaginal treatments in gynecology and female urology: an ICS/ISSVD best practice consensus document. Neurourol Urodyn. 2019;38(3):1009-1023. doi:10.1002/nau.2393

4. Li FG, Maheux-Lacroix S, Deans R, et al. Effect of fractional carbon dioxide laser vs sham treatment on symptom severity in women with postmenopausal vaginal symptoms: a randomized clinical trial. JAMA. 2021;326(14): 1381-1389. doi:10.1001/jama.2021.14892.

5. Mension E, Alonso I, Anglès-Acedo S, et al. 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. JAMA Netw Open. 2023;6(2):e2255697. doi:10.1001/jamanetworkopen.2022.55697.

6. Gemmell LC, Webster KE, Kirtley S, Vincent K, Zondervan KT, Becker CM. The management of menopause in women with a history of endometriosis: a systematic review. Hum Reprod Update. 2017 Jul 1;23(4):481-500. doi: 10.1093/humupd/dmx011. PMID: 28498913; PMCID: PMC5850813.

7. Kulak J Jr, Fischer C, Komm B, Taylor HS. Treatment with bazedoxifene, a selective estrogen receptor modulator, causes regression of endometriosis in a mouse model. Endocrinology. 2011 Aug;152(8):3226-32. doi: 10.1210/en.2010-1010. Epub 2011 May 17. PMID: 21586552; PMCID: PMC3138238.

8. Flores, Valerie A. MD; Stachenfeld, Nina S. PhD; Taylor, Hugh S. MD. Bazedoxifene–Conjugated Estrogens for Treating Endometriosis. Obstetrics & Gynecology 132(2):p 475-477, August 2018. | DOI: 10.1097/AOG.0000000000002739

9. Snyder BM, Beets JW, Lessey BA, Horton SRW, Abrams GA. Postmenopausal Deep Infiltrating Endometriosis of the Colon: Rare Location and Novel Medical Therapy. Case Rep Gastrointest Med. 2018 Feb 14;2018:9587536. doi: 10.1155/2018/9587536. PMID: 29666722; PMCID: PMC5832128.