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There’s a concept called diagnostic bias that I read about in a recent review on pelvic congestion syndrome (Krambeck et al., Journal of Clinical Medicine, 2026). When a patient presents with chronic pelvic pain and endometriosis is on the differential or even when it has been proven through excision to be endometriosis, we tend to chalk everything up to the endo and we don’t go much further. But in this article, the review’s authors argument is that focusing only on endometriosis increases the risk of missing pelvic venous disease, and that risk is made worse by how often the two conditions occur together in the same patient.

How to actually identify it

PeVD doesn’t have one clean test the way for example, an endometrioma, shows up on ultrasound. It’s identified by a symptom pattern plus a few specific findings, most of which are accessible in a regular gynecology visit. Pelvic varices show up in up to 10% of the general population and only about 40% of those women go on to develop symptoms. Also, a dilated vein on a scan is not an automatic diagnosis, because the patient must also have the symptoms and functional findings to make the case.

Start with the symptom pattern. Classic PeVD pain is dull, aching, and worsens with prolonged standing or sitting, with intercourse, after orgasm, and in the days before menses. Post-coital ache in particular is one of the more specific findings. On its own that’s not enough to separate it from endometriosis, since both conditions cause dyspareunia and premenstrual pain. What differs is that endo pain tends to be sharp, deep, and tightly cyclic, tracking the menstrual cycle closely while PeVD pain tends to be duller, less tied to the cycle, and more tied to posture and time of day. Pain that goes away when a patient lies down is also the hallmark of PeVD.

Do the bimanual exam with this in mind. One older study found that side-specific adnexal tenderness on bimanual exam, combined with a history of post-coital ache, identified PeVD with 94% sensitivity and 77% specificity. That’s a strong combination for something without requiring imaging at all. On inspection, we look for vulvar or vaginal varices (bluish, dilated veins), along with hemorrhoids or lower-extremity varicose veins, since PeVD is linked with venous disease elsewhere in the body. Polycystic-appearing ovaries are also seen in over 40% of PeVD patients, an association nobody fully understands but that’s worth noting and asking patients about in their medical histories.

Then move to transvaginal ultrasound, done differently. TVUS is the recommended first-line imaging tool. Another older study (Park et al., 2004) defines PeVD by a dilated, “tortuous parauterine vein over 4mm, slow flow at or under 3 cm/s, and a dilated vein in the myometrium crossing the midline,” though that vein finding alone is only about 25% sensitive despite being 91% specific. A more recent approach (Szkodziak et al.) uses a higher diameter cutoff, ovarian vein dilation over 6 to 8mm, flow under 3 cm/s, reflux lasting more than 1 second, and myometrial vein dilation over 5mm, and reports much higher sensitivity, up to 100% when all four criteria are visualized.

There’s an important point to make about both of these studies and definititions. Vein diameter alone is a not a good predictor of whether reflux is actually present. The Society of Interventional Radiology’s own consensus statement says diameter shouldn’t be used to rule PeVD in or out when other findings point toward it. So the functional finding and retrograde flow on Doppler matters more than how big the vein measures.

One real limitation of TVUS specifically for this dual workup. While it’s good at catching PeVD, its sensitivity for other causes of pelvic pain, endometriosis included, is limited. So a TVUS ordered and read specifically for venous findings doesn’t guarantee a good look at endo, even though both conditions technically fall within the same scan’s reach. The order needs to be very specific to say you have to look for both.

This isn’t the same exam as a lower-extremity venous duplex either, which is a different study on a different body part using an external probe on the legs, typically ordered to rule out a DVT or map leg varicosities. What you want for PeVD is a TVUS specifically performed or re-ordered with Doppler assessment of the pelvic veins, sometimes described as a pelvic venous duplex, but it needs to be requested as that, not assumed to be part of a standard scan.

Rule out the structural mimics. The two anatomic conditions that can produce a nearly identical clinical picture but need a completely different treatment are nutcracker syndrome, where the left renal vein is compressed between the aorta and the superior mesenteric artery, and May-Thurner configuration, where the left common iliac vein is compressed by the right common iliac artery. Both cause pelvic venous congestion from obstruction rather than valve failure, and both need the obstruction addressed, sometimes with a stent. Nutcracker syndrome also tends to come with its own symptoms, like hematuria, proteinuria, or flank pain, while May-Thurner more often shows up as thrombosis than as isolated pain (so we often only find it when someone has a blood clot).

Know what goes after TVUS. MRI and MR venography (MRV) add detail on venous anatomy and collateral pathways and are preferred over CT in premenopausal women because there’s no radiation exposure, though a supine position during scanning can under-detect congestion that would be more visible standing. A good MRI can evaluate for PeVD, structural causes like nutcracker or May-Thurner, and endometriosis or adenomyosis all in the same study, which is the closest thing to a single comprehensive look available aside from invasive testing. Laparoscopy, despite being the default next step for unexplained pelvic pain, is a not a good tool for PeVD specifically; supine positioning and the pressure from CO2 compress the very veins we’re trying to see, and its sensitivity for PeVD runs around 40%. Catheter venography remains the actual gold standard, but it’s invasive and reserved for cases moving toward intervention, not first-line diagnosis.

The takeaway is that you can screen for this in the office with history, bimanual exam, and a properly performed TVUS specifically looking for venous findings, without needing to reach for anything invasive first, and without assuming a normal vein diameter rules the condition out.

The number that gets cited most is 80%, referring to women with endometriosis who also have dilated pelvic or ovarian veins. The original paper (Pacheco & Fortes de Oliveira, Annals of Vascular Surgery, 2016) says: 48 women studied in Rio de Janeiro, 25 with endometriosis (confirmed surgically and histologically in 15, by MRI in 10) and 23 controls with no endometriosis and no chronic pelvic pain symptoms. Ovarian varices, defined in this study as 5mm or more of dilation on transvaginal ultrasound, showed up in 80% of the endometriosis group versus 26.1% of controls.

Separately, a 2026 retrospective imaging study out of São Paulo came at it from the other direction. In women who already had confirmed pelvic varicosities on MR venography, 61.5% of them (32 of 52) also had radiological findings consistent with endometriosis (95% CI 47.0 to 74.5%).

The studies are small with only 48 patients and 52 patients. The two papers also use different diameter thresholds to define a varix: 5mm or more in the 2016 study, versus 7 to 8mm in more recent ultrasound criteria elsewhere in this literature. A lower threshold identifies more positive cases so these numbers aren’t strictly comparable.

Why are these two connected?

The Krambeck review lays out two potential theories.

Estrogen exposure. The ovaries sit in a local estrogen concentration roughly a hundred times higher than what other veins in the body are exposed to. Animal studies, specifically in female rats, have shown estrogen-receptor-mediated relaxation of venous tissue. The hypothesis is that the same hormonal environment that helps drive endometriotic tissue growth may also be part of why pelvic veins in particular, as opposed to veins anywhere else, become dilated and incompetent. This tracks with the clinical picture too: PeVD shows up almost exclusively in premenopausal women and declines sharply after menopause, the inverse of what happens with venous insufficiency everywhere else in the body, where age is the main driver.

Vascular inflammation and tissue remodeling. Veins affected by PeVD show increased expression of enzymes that break down collagen and smooth muscle, which is thought to contribute to endothelial damage and localized inflammation in the vessel wall. That sounds familiar if you’ve spent any time thinking about endometriosis as an inflammatory disease rather than just an anatomic one.

Oxidative stress and abnormal blood vessel formation. The Pacheco & Fortes de Oliveira paper adds a third thread, distinct from the two above. Both endometriotic implants and varicose veins depend on angiogenesis, or new blood vessel growth, and both show elevated VEGF (vascular endothelial growth factor), the main driver of that process. The authors’ proposal is that oxidative stress inside a varix sitting next to the ovary may itself disrupt the ovary’s local blood flow, contributing to the same dysfunction that helps endometriosis take hold. It’s the same logic that’s been studied in varicoceles in men, where oxidative stress from dilated veins is linked to impaired organ function nearby.

Sadly, none of these three theories is proof that one condition causes the other. The Krambeck review is explicit that evidence on correlation is limited, and the Pacheco paper is not a demonstrated pathway. But if pelvic tissue and pelvic vasculature are both responsive to the same hormonal, inflammatory, and angiogenic signals, then congestion isn’t some random unrelated finding that happens to show up in the same patients. It’s plausibly part of the same terrain, the same way I think about MCAS, POTS, and hEDS showing up together in this populationas several systems that share a vulnerability, expressing it in different tissues.

Telling them apart at a glance

Between the identification criteria above and the mechanism section below, most of the differentiating detail is already on the table. As a quick reference, endo pain is cyclic and tied to menses, with exam findings in the posterior fornix (uterosacral nodularity, a fixed or retroverted uterus). PeVD pain is non-cyclic, worse with standing and after sex, with exam findings, when present, showing up as vulvar or vaginal varices, hemorrhoids, or other signs of venous disease.

The overlap is real at least in our small clinic, and there’s a plausible shared mechanism worth taking seriously. If you take one thing from this, let it be permission to ask the question at your next appointment!

New documents are being added to the reference guide link, you can sign up here

Come see us! www.washgyn.com, www.washingtonendometriosis.com

References

• Krambeck C, Tesch K, Watrowski R, Maass N, Alkatout I. Pelvic congestion syndrome: the gynecological perspective. J Clin Med. 2026;15:1655.

• Pacheco KG, Fortes de Oliveira MR. The prevalence of ovarian varices in patients with endometriosis. Ann Vasc Surg. 2016;34:135-143.

• Bookwalter CA, VanBuren WM, Neisen MJ, Bjarnason H. Imaging appearance and nonsurgical management of pelvic venous congestion syndrome. Radiographics. 2019;39:596-608.

• Zlotnik M, Messina ML, Vieira TDR, et al. High prevalence of endometriosis in women with chronic pelvic pain and confirmed pelvic varicosities: a multiparametric MRI study. Clinics (Sao Paulo). Published online March 3, 2026. doi:10.1016/j.clinsp.2026.100895

In a recent lecture by Michael Lewiecki, MD, one of the country’s leading osteoporosis experts, about prevention of osteoporosis, he presented thoughts about how to prevent osteoporosis instead of waiting for it to happen. One thing he talked about was the role of FSH and I went on a little bit of a deep dive.

We don’t typically order an FSH since it can fluctuate cycle to cycle and may not settle into a stable postmenopausal range until three to six years after the final period. At that point the diagnosis is obvious. There are some exceptions (suspected premature ovarian insufficiency under 40, or confirming early menopause between 40 and 45 with two FSH values above 30 IU/L, four to six weeks apart), but for the average perimenopausal patient, it usually isn’t all that helpful.

But what I learned this weekend was that even though FSH may not be a test to diagnose menopause, it may be a marker that tells us when the body is entering one of its most important transitions.

The “transmenopausal” window and FSH

Bone loss during the menopause transition isn’t a slow, uniform drift, it accelerates sharply in a defined window, starting about a year before the final menstrual period (FMP) and continuing for around two years after it. If there are predictors of this accelerated window that can be identified before they happen, we have an opportunity to intervene early rather than waiting for a DXA scan later.

The SWAN study showed that trabecular bone score (TBS), a measure of bone microarchitecture and an independent predictor of fracture risk, begins to decline approximately 1.5 years before the final menstrual period. The decline is the fastest during the menopausal transition (Lewiecki calls it “transmenopause”), and averages about 1.16% per year until two years after the final menstrual period when it slows to approximately 0.89% per year. This means that bone density is already deteriorating before the last period arrives.

So if the fastest period of bone loss begins before the final menstrual period, waiting until menopause is officially diagnosed means we've already missed part of the opportunity to prevent it. Lewiecki highlighted one of the earliest SWAN bone studies, a 2003 analysis of more than 2,300 pre- and perimenopausal women. After adjusting for race, BMI, physical activity, and other variables, FSH, not estradiol, testosterone, or SHBG, was the hormone most strongly associated with lumbar spine bone density.

That doesn’t mean FSH diagnoses menopause better than estrogen. It suggests that FSH may help identify the narrow window when bone loss is about to accelerate, while there is still time for prevention.

This is different than “test FSH to diagnose menopause,” which the guidelines reject. It’s closer to: FSH may be one of the few available signals for a narrow, high-stakes window of accelerated bone loss, and if predictors like TBS and FSH can be validated together, prevention could start before the fracture-risk clock starts ticking.

Beyond the founding study

Later SWAN analyses kept arriving at basically the same conclusion. Using different statistical approaches, FSH consistently outperformed estradiol as a predictor of both baseline bone density and future bone loss.

That doesn’t prove FSH causes bone los, but it raises an interesting possibility: maybe rising FSH isn’t only reflecting ovarian aging, maybe it’s actually signaling a distinct phase of the transition that has its own biology.

There is also a reason researchers became interested in FSH in the first place. FSH receptors have been identified directly on osteoclasts, the cells responsible for breaking down bone. Experimental studies suggest FSH can stimulate osteoclast formation and activity independent of estrogen, making it plausible that FSH could play a more direct role than previously assumed.

When Drake and colleagues suppressed FSH by about 86% in postmenopausal women while keeping estrogen levels stable, markers of bone resorption didn’t change. If FSH were independently driving bone loss, this was the type of experiment that should have demonstrated it; it didn’t.

But - the counterargument is that GnRH agonists suppress LH and other pituitary hormones too, confusing things, and that aromatase inhibitors have their own skeletal effects, may explain the results. As of my most recent review, though, no human study has isolated FSH cleanly enough to settle the question.

The fat and brain data extend the same pattern

What makes this even more interesting is that the same rising-FSH window has been linked to changes in body fat distribution and, more recently, cognitive aging. In mouse models, blocking FSH with an antibody doesn’t just spare bone, it induces “beiging” of white adipose tissue, increases mitochondrial density, and reduces body fat, apparently having nothing to do with estrogen levels. Human data shows rising FSH tracking with gains in total and subcutaneous fat mass over time.

The brain research is the newest, and probably the most headline-grabbing part of this. FSH receptors have been found on brain cells in regions affected by Alzheimer’s disease. A 2022 Nature paper showed that when FSH binds to these receptors, it seems to trigger a chain reaction that produces the two proteins associated with Alzheimer’s: amyloid plaques and tau tangles. Blocking FSH reversed this process in the mouse model used. A 2023 follow-up from the same group found that FSH seems to team up with the ApoE4 genotype to drive the same pathway, and that anti-FSH antibody treatment eased AD-like pathology in ApoE4-carrying female mice - a possible reason why ApoE4 raises Alzheimer’s risk more in women than in men.

In actual patients, higher FSH levels have been linked to more amyloid buildup on brain scans and faster cognitive decline in people already showing early signs of memory trouble, while estradiol didn’t show the same association. Another study also reported a statistically significant causal estimate linking genetically predicted FSH to Alzheimer’s risk, though the effect size was very small.

Zaidi and colleagues have proposed a theory that the late-perimenopausal FSH surge, which is happening while estrogen is often still largely intact, may be hitting bone, fat, and brain simultaneously through FSH receptors in each tissue.

There’s now a lead candidate antibody that selectively blocks FSH at the receptor without touching estrogen or LH. It’s been through primate safety and other work and is ready for first-in-human testing, but has not, as of this writing, been through a human trial. If it works the way the animal data suggests, it would be a single therapy addressing osteoporosis, visceral fat, and possibly Alzheimer’s risk through one mechanism.

The clinical takeaway, for now

I've stopped thinking of FSH as a laboratory value that is either "useful" or "useless." It’s not a great test to diagnose menopause. But the the rise in FSH during late perimenopause may turn out to be one of the earliest (measurable) signals that the body is entering a period of accelerated change, not just in bone, but potentially in fat metabolism and brain aging as well.

I don’t think we’re anywhere close to screening or treating around FSH outside its current indications. But if even part of the proposed bone-fat-brain axis holds up in human interventional studies, it could fundamentally change how we think about the menopausal transition. Instead of waiting until disease is established, we may eventually recognize a biologic window where prevention begins much earlier.

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References

1. Crandall CJ, Mehta JM, Manson JE. Management of Menopausal Symptoms: A Review. JAMA. 2023.

2. Hamoda H, Moger S, Morris E, et al. Menopause practice standards. Clinical Endocrinology. 2024.

3. Sowers MR, Finkelstein JS, Ettinger B, et al. The association of endogenous hormone concentrations and bone mineral density measures in pre- and perimenopausal women of four ethnic groups: SWAN. Osteoporos Int. 2003;14:44–52.

4. Sowers MR, Jannausch M, McConnell D, et al. Hormone predictors of bone mineral density changes during the menopausal transition. J Clin Endocrinol Metab. 2006;91:1261–1267.

5. Crandall CJ, Tseng CH, Karlamangla AS, et al. Serum sex steroid levels and longitudinal changes in bone density in relation to the final menstrual period. J Clin Endocrinol Metab. 2013.

6. Shieh A, Greendale GA, Cauley JA, et al. Estradiol and follicle-stimulating hormone as predictors of onset of menopause transition-related bone loss in pre- and perimenopausal women. J Bone Miner Res. 2019.

7. Greendale GA, Huang M, Cauley JA, Liao D, Harlow S, Finkelstein JS, Hans D, Karlamangla AS. Trabecular bone score declines during the menopause transition: the Study of Women’s Health Across the Nation (SWAN). J Clin Endocrinol Metab. 2020;105(4):e1872–82.

8. Ramírez Stieben LA, Brun LR, Pustilnik E, et al. Beyond estrogen deficiency: the independent role of FSH in site-specific bone loss in midlife women. Calcif Tissue Int. 2025. [Threshold value not independently re-verified in this pass.]

9. Chin KY. The relationship between follicle-stimulating hormone and bone health: alternative explanation for bone loss beyond oestrogen? Int J Med Sci. 2018.

10. Khosla S. Estrogen versus FSH effects on bone metabolism: evidence from interventional human studies. Endocrinology. 2020.

11. Drake MT, McCready LK, Hoey KA, Atkinson EJ, Khosla S. Effects of suppression of follicle-stimulating hormone secretion on bone resorption markers in postmenopausal women. J Clin Endocrinol Metab. 2010;95(11):5063–5068.

12. Liu P, Ji Y, Yuen T, et al. Blocking FSH induces thermogenic adipose tissue and reduces body fat. Nature. 2017.

13. Mattick LJ, Bea JW, Singh L, et al. Serum follicle-stimulating hormone and 5-year change in adiposity in healthy postmenopausal women. J Clin Endocrinol Metab. 2022.

14. Xiong J, Kang SS, Wang Z, et al. FSH blockade improves cognition in mice with Alzheimer’s disease. Nature. 2022;603(7901):470–476. doi:10.1038/s41586-022-04463-0.

15. Xiong J, Kang SS, Wang M, et al. FSH and ApoE4 contribute to Alzheimer’s disease-like pathogenesis via C/EBPβ/δ-secretase in female mice. Nat Commun. 2023;14:6577.

16. Ding et al. Potential causal association between follicle-stimulating hormone and Alzheimer’s disease: genetic loci study and Mendelian randomization study. Ann Hum Genet. 2025.

17. Zaidi M, Lizneva D, Kim SM, et al. FSH, Bone Mass, Body Fat, and Biological Aging. Endocrinology. 2018;159(10):3503–3514. doi:10.1210/en.2018-0060.

18. Pallapati AR, Korkmaz F, Rojekar S, et al. Efficacy and safety of a therapeutic humanized FSH-blocking antibody in obesity and Alzheimer’s disease models. J Clin Invest. 2025.

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In our practice we’ve been seeing more and more patients who turn out to have pelvic venous disease (PeVD) in addition to endometriosis, and what strikes me every time is how obvious it looks when you ask about certain symptoms or on imaging when someone knows what to look for. The veins are right there; obviously they’ve always been right there, but we just haven’t been looking.*

That has sent me down a rabbit hole and I started reading the PeVD literature. I posted something on a listserv that I am on and got a very strongly worded email from an interventional radiologist whose (very) strongly held position is that GYN providers aren’t considering pelvic venous disease in our diagnostic algorithms, that we are misdiagnosing a lot of women as a result, and that those women are suffering, sometimes for decades, because of it.

I’ve had some back and forth with him. He is not subtle! But I took his argument seriously enough to go looking for myself, and what I found when I went to our own guidelines surprised me enough that I wanted to write about it here.

This is not instead of endometriosis

This isn’t a claim that endometriosis has been overdiagnosed or unnecessarily treated. What I’m actually seeing in my practice is coexistence and patients with confirmed, surgically diagnosed endometriosis, appropriately excised, who still have pain afterward. When we image them, so many also have PeVD.

There is data discussed below that hints at this. Endometriosis and pelvic congestion showed up in roughly equal proportions in the cohort that was studied, and both conditions in the same patient were documented in 12 %.

I’m going to keep digging into what’s known about that connection and write more on it, but the practical point is this: if a patient has had appropriate excision and still hurts, venous disease should be somewhere on the differential before we send her back to the OR.

So let me tell you what the interventional radiologist (I am going to keep his name out of it for now!) is saying, what the evidence actually shows, and what I think about it.

What he’s is arguing

His core claim is straightforward and kind of uncomfortable. Pelvic venous disease, which he defines as chronic pelvic pain of venous origin caused by reflux in the ovarian veins, engorgement of pelvic varicosities, or outflow obstruction at the level of the iliac veins, is present in roughly 30 to 43 % of women with chronic pelvic pain. That figure comes from the only study he knows of where every patient with chronic pelvic pain was evaluated for every possible cause using both venography and laparoscopy. Soysal and colleagues, writing in Human Reproduction in 2001, prospectively evaluated 148 women and found endometriosis in 39 %, pure pelvic congestion in 31 %, and concomitant venous changes alongside other pathology in another 12 %. Venous disease and endometriosis were present in roughly equal proportions.

Laparoscopy, the procedure we use to evaluate endometriosis, is performed with the patient in Trendelenburg position (where the patient’s head is lower than their feet) and under abdominal inflation to make it easier to see. Pelvic veins decompress and collapse in that position, even massively dilated varicosities can be completely invisible during a laparoscopy. Endometriosis, which is visible, gets diagnosed and becomes the answer. The veins above the uterus are not seen because no one is looking, and in Trendelenburg they wouldn’t be visible even if someone tried (at least during surgery).

He also argues, with considerable force, that vulvodynia as a diagnostic category is in large part a reflection of an incomplete workup. Vulvodynia is defined as vulvar pain without identifiable organic cause. But if the workup that precedes that diagnosis doesn’t include vascular imaging, then the definition is circular. You haven’t ruled out organic causes, you’ve only ruled out the organic causes you looked for. He presented data at the Cardiovascular and Interventional Radiological Society of Europe in 2023 showing that after pelvic vein embolization or stenting, pain with intercourse improved in 86 % of patients, vaginal pressure and burning in 83 %, and lasting pain after intercourse in 80 %. He is not claiming that all vulvodynia is venous, but he is claiming that a substantial fraction of it is, and that we are offering vestibulectomy to women whose veins have never been imaged.

In an email he sent me, he wrote: “the word vein does not appear in the JAMA review on chronic pelvic pain. It does not appear in the state of the science article on vulvodynia. The Vulvodynia Society has no information about veins.”

He asked whether I thought that was acceptable and honestly I didn’t have a good answer given what I have been seeing lately.

So I went to look

I went to the guidelines to look to see if he was right.

The 2021 JAMA review on chronic pelvic pain in women, written by Lamvu and colleagues, a past president of the International Pelvic Pain Society among them, is comprehensive. It covers musculoskeletal pain, central sensitization, endometriosis, irritable bowel syndrome, bladder pain syndrome, pudendal neuralgia, psychosocial factors, vulvodynia. The word vein does not appear once.

The 2020 ACOG Practice Bulletin on chronic pelvic pain lists an extensive differential: adenomyosis, endometriosis, leiomyoma, ovarian remnant syndrome, adhesions, vulvodynia, irritable bowel syndrome, interstitial cystitis, fibromyalgia, myofascial pain, neuralgias. Pelvic venous disorders are not on that list.

The 2015 ISSVD, ISSWSH, and IPPS consensus terminology and classification of persistent vulvar pain, which is the foundational document our field uses to define and categorize vulvodynia, lists the associated factors: genetics, hormonal influences, inflammation, neurologic mechanisms, musculoskeletal factors, psychosocial factors, structural defects. No vascular category.

The 2026 Krapf et al. executive summary of the Vulvodynia Therapeutic Research Summit, published in Obstetrics and Gynecology this year, the most current document our field has produced on this topic. Also not mentioned.

Five documents and a decade of consensus work across every society relevant to our practice in the world of pelvic pain. Pelvic venous disease does not appear as a diagnostic consideration, an exclusion criterion, or a research priority in any of them.

What the evidence actually shows

His argument sounds pretty radical. The evidence base behind it is more modest than he lets on, but it is not nothing, and it is stronger than I expected when I started looking.

The foundational study is Soysal et al., published in Human Reproduction in 2001. It is a single center study from Turkey, 148 women with chronic pelvic pain, and every patient underwent both venography and laparoscopy. The method that is chosen matters because it means the investigators were actually looking for venous disease rather than discovering it by accident. What they found was that pure pelvic congestion was present in 31 % of patients and venous changes were present in an additional 12 %, putting the total somewhere between 30 and 43 %. Endometriosis was present in 39 %. Those two conditions were running neck and neck in the same population. The study has not been replicated at scale in a Western population, which is of course a real limitation, but it is the only study where someone looked for all causes of chronic pelvic pain in the same patients using the same protocol.

In a 2023 BJOG case control study, three hundred and twenty eight premenopausal women, 164 with chronic pelvic pain and 164 matched asymptomatic controls, all evaluated with transvaginal duplex ultrasound by blinded vascular scientists using a standardized protocol. PeVD was found in 62 % of women with chronic pelvic pain compared with 19 % of asymptomatic patients. Pelvic varices showed an even stronger association, present in 26 % of chronic pelvic pain cases versus 2 % of controls. The paper also explicitly confirms what our interventional radiologist says about laparoscopy: pelvic veins empty when patients are supine and in Trendelenburg position, which is why the standard diagnostic procedure for pelvic pain misses this.

The same group published the first randomized controlled trial of pelvic vein embolization for chronic pelvic pain in BJOG in 2023. Sixty women with confirmed pelvic vein incompetence were randomized to coil embolization versus sham venography, with patients blinded to their allocation. At twelve months the treated group had a median pain score of 2 compared with 9 in controls on the McGill Pain Rating Index, and a VAS score of 15 compared with 53 in controls, both statistically significant. Quality of life improved significantly in the treatment arm and no major complications were reported. The trial was stopped early by COVID before reaching its planned enrollment of 100, so it is a single center study of 30 patients per arm with twelve month follow up. So that is a positive result from a small trial, but not a definitive answer.

The field knows it needs more. The EMBOLIZE trial, a multicenter sham controlled randomized trial funded by the Society of Interventional Radiology Foundation, is currently enrolling at five sites with results pending. More to come on that soon, I think.

On the stenting side, Villalba and Larkin published five year follow up data in the Journal of Vascular Surgery Venous and Lymphatic Disorders in 2025 showing approximately 98 % of patients had significant pain relief after iliac vein stenting with 73 % achieving complete resolution. Gavrilov and colleagues published prospective cohort data in 2025 suggesting stenting may be better than embolization alone in patients with significant iliac vein compression, which Santoshi and colleagues have estimated may be present in approximately 80 percent of PeVD patients. These are observational data, not randomized trials, but they are consistent with what our expert is saying.

What about vulvodynia specifically, and what about vestibulectomy?

This is where his argument gets most provocative and where I think the most important questions arise for those of us practicing sexual medicine.

Vulvodynia is defined as vulvar pain of at least three months duration in the absence of a recognized underlying cause. It is a diagnosis of exclusion. The 2015 ISSVD, ISSWSH, and IPPS consensus statements list the factors we consider: genetics, hormonal influences, inflammation, neurologic mechanisms, musculoskeletal factors, psychosocial factors, structural defects. Vascular disease is not on that list and has never been on that list, which means the exclusion process that precedes this diagnosis has never included vascular imaging.

The CIRSE 2023 data showed that after pelvic vein embolization or stenting, pain with intercourse improved in 86 % of patients, vaginal pressure and burning in 83 %, and lasting pain after intercourse in 80 %. That is a striking number, honestly. He is not claiming all vulvodynia is venous, but he IS asking whether we know it isn’t, and the honest answer is that we don’t, because we haven’t looked.

There is one documented case in the peer reviewed literature of treatment persistent vulvodynia that turned out to be caused by nutcracker syndrome driving ovarian vein reflux and pelvic varicosities in a 25 year old woman with left sided vaginal wall pain, itching, dyspareunia, muscle tension, and a chronic vaginal ulceration. The veins were invisible on speculum exam. After vascular treatment her symptoms resolved. This is only one patient of course, but it happened, and nobody had found it until someone looked at the veins.

The connection to the nervous sysyem is pure speculation but not out of the realm of possibility. Venous congestion in the pelvis generates substance P and CGRP through inflammation. Gavrilov and colleagues showed in 2024 that embolization significantly reduces both neuropeptide levels leading to pain relief. Vestibular biopsies in vulvodynia patients show neuroproliferation and inflammatory infiltrates in the same area. CGRP has been identified in vestibular nociceptors. Nobody has asked whether the environment driving vestibular neuroproliferation could be result of venous congestion rather than a primary process.

Which brings me to vestibulectomy

I want to be careful here because vestibulectomy works. The systematic review by Saçıntı and colleagues published in 2024 covering 29 studies found success rates ranging from 52 to 93 % depending on how success was defined and how long patients were followed. For patients with confirmed neuroproliferative vestibulodynia vestibulectomy may be the right answer and possibly even first line treatment.

But a floor of 52 % success means up to 48 % of patients in some studies didn’t have any relief. Rettenmaier and colleagues reported 30 % symptom recurrence within two years of modified vestibulectomy. Eanes and colleagues found only 22 % of patients pain free at four to ten year follow up. And the preoperative workup required before offering vestibulectomy, per ACOG Committee Opinion 673, is failure of conservative treatment, pain localized to the vestibule, and evaluation for vaginismus. No imaging, no vascular assessment, no requirement to have asked whether the pain might have an upstream cause.

So why do vestibulectomies work if some of this pain is venous? Probably because the population is mixed. Some patients have primary neuroproliferative disease with no venous component and surgery is exactly the right treatment. Others may improve because excising hyper-innervated tissue reduces the pain signal regardless of what generated the neuroproliferation in the first place, even if the underlying venous environment remains unchanged. That could also explain recurrence; if congested veins continue to drive inflammation in the healing tissue, pain comes back. We don’t know because nobody has looked at the venous status of vestibulectomy patients who fail or recur.

That is the specific question I think needs to be asked - not whether vestibulectomy should stop, but whether we should know more about our patients’ veins before we offer it.

What should we actually do with this?

I am not saying we should stop doing vestibulectomies or abandon the neuroproliferative model. I am saying that before we offer a surgical procedure on the vestibule, we should probably know whether the patient’s veins have been evaluated. Right now, we don’t require that because our guidelines don’t ask for it.

The clinical picture of venous pain is actually easily recognizable once you know what you’re looking for:

Beard and colleagues showed in 1988 that the combination of adnexal point tenderness, found by palpating at the junction of the upper and middle third of the line between the navel and the anterior superior iliac spine, and a history of post-coital ache is 94 % sensitive and 77 % specific for venous origin pain - a two minute history and one palpation point.

There are also physical findings worth knowing:

The imaging with highest sensitivity is MRV directed specifically at the pelvic veins or transvaginal duplex ultrasound performed by someone trained in the protocol. Standard pelvic ultrasound ordered the usual way will miss this so the request has to be specific (one example of protocols here)

I was searching to see if there were some good patient testimonials about what this means for our patients. I found an article about a patient named Nichole Vollmer, whose story was published in Endovascular Today in 2022. Nichole had pelvic venous disease for twenty-two years before anyone found it. In that time she had eighteen CT scans, twenty-two emergency room visits, and twelve surgeries. She stopped looking for a diagnosis when she got pregnant with her first child and was eventually diagnosed by accident, when she interviewed for a job that happened to focus on venous disease.

Before her procedure she told her doctor (Dr. Brooke Spencer) that she was nervous - not about the procedure itself, but about the possibility that she would wake up and hear what she had heard for two decades: “we couldn’t find anything wrong”or “everything is normal.” Our patients hear this a lot.

I don’t know how many of my patients with vulvodynia or chronic pelvic pain have a venous etiology. What I know is that our guidelines don’t ask us to look and that the evidence suggests we probably should start. We also need to figure out why this is so prevalent in our endo community and figure out how best to help these patients who sometimes seem to just accept the fact that they will always be in chronic pain.

*I understand that I am maybe just speaking for myself and maybe everyone is looking! In which case please feel really good about yourself! :)

Come see us! Appointments here.

www.washingtonendometriosis.com

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References:

1. Soysal ME, Soysal S, Vicdan K, Ozer S. A randomized controlled trial of goserelin and medroxyprogesterone acetate in the treatment of pelvic congestion. Hum Reprod. 2001;16(5):931-939.

2. Hansrani V, Riding D, Seif MW, et al. Pelvic vein incompetence and chronic pelvic pain: a case-control study. BJOG. 2023;130(8):941-948.

3. Hansrani V, Riding D, Seif MW, et al. Transvenous occlusion of incompetent pelvic veins to treat chronic pelvic pain in women: a randomised controlled trial. BJOG. 2023;130(8):949-956.

4. Winokur RS, Salazar G, Gibson K, Meissner MH, Machan L, Khilnani NM. Randomized controlled, single-blinded, parallel-group trial of ovarian vein and pelvic vein embolization in women with chronic pelvic pain and pelvic varices (EMBOLIZE trial). J Vasc Interv Radiol. 2026;37(3):107880.

5. Villalba L, Larkin T. Iliac venous stenting provides long-term relief from chronic pelvic pain. J Vasc Surg Venous Lymphat Disord. 2025;13(1):101993.

6. Santoshi RKN, Lakhanpal S, Satwah V, Lakhanpal G, Malone M, Pappas PJ. Iliac vein stenosis is an underdiagnosed cause of pelvic venous insufficiency. J Vasc Surg Venous Lymphat Disord. 2018;6(2):202-211.

7. Gavrilov SG, Lebedev IS, Vasilyev AV, Churikov DA, Mishakina NY, Alenichev AV. Prospective cohort study of a treatment strategy for a combination of left common iliac vein compression stenosis and pelvic venous insufficiency. J Endovasc Ther. 2025;32(2):363-373.

8. Gavrilov SG, Karalkin AV, Moskalenko YP, Alenichev AV. Effects of venoactive drug therapy and ovarian vein interventions on vasoactive neuropeptide and cytokine levels in patients with pelvic venous disorders. Ann Vasc Surg. 2024;108:466-474.

9. Lamvu G, Carrillo J, Ouyang C, Rapkin A. Chronic pelvic pain in women: a review. JAMA. 2021;325(23):2381-2391.

10. Committee on Practice Bulletins—Gynecology. Chronic pelvic pain: ACOG Practice Bulletin, Number 218. Obstet Gynecol. 2020;135(3):e98-e109.

11. American College of Obstetricians and Gynecologists’ Committee on Gynecologic Practice. Persistent vulvar pain: ACOG Committee Opinion No. 673. Obstet Gynecol. 2016;128(3):e78-e84.

12. Bornstein J, Goldstein AT, Stockdale CK, et al. 2015 ISSVD, ISSWSH, and IPPS consensus terminology and classification of persistent vulvar pain and vulvodynia. J Sex Med. 2016;13(4):607-612.

13. Krapf JM, Yong PJ, Berke MD, et al. Executive summary of the vulvodynia therapeutic research summit. Obstet Gynecol. 2026;147(2):266-276.

14. Saçıntı KG, Razeghian H, Bornstein J. Surgical treatment for provoked vulvodynia: a systematic review. J Low Genit Tract Dis. 2024;28(4):379-390.

15. Tomalty D, Giovannetti O, Magliocchetti S, et al. Characterizing the innervation of the vulvar vestibule and the immunohistochemical features of neuroproliferative vestibulodynia. J Sex Med. 2023;20(6):716-731.

16. Bohm-Starke N, Hilliges M, Falconer C, Rylander E. Neurochemical characterization of the vestibular nerves in women with vulvar vestibulitis syndrome. Gynecol Obstet Invest. 1999;48(4):270-275.

17. Tympanidis P, Terenghi G, Dowd P. Increased innervation of the vulval vestibule in patients with vulvodynia. Br J Dermatol. 2003;148(5):1021-1027.

18. Altshuler PC, Garland BT, Jorgensen ME, Gerig NE. Treatment-refractory vulvodynia from nutcracker syndrome: A case report. Case Rep Womens Health. 2018;19:e00071. Published 2018 Jun 30. doi:10.1016/j.crwh.2018.e00071

19. Beard RW, Reginald PW, Wadsworth J. Clinical features of women with chronic lower abdominal pain and pelvic congestion. Br J Obstet Gynaecol. 1988;95(2):153-161.

20. Harlow BL, Stewart EG. A population-based assessment of chronic unexplained vulvar pain: have we underestimated the prevalence of vulvodynia? J Am Med Womens Assoc. 2003;58(2):82-88.

One of the patterns I keep seeing in endometriosis patients is that certain co-occurring conditions are consistently missed. When a patient comes back in pain after surgery, the reflex is almost always to look for what was missed surgically, when sometimes the more important question is whether there is something else entirely running alongside the endo that nobody has thought to look for.

There are three conditions that I think should be part of the standard workup for the perimenopausal endo patient who is still in pain. Not because the biology is the most complicated, but because these conditions are actually findable with tools that already exist, and finding even one of them can completely change the trajectory of a patient who has been told, explicitly or implicitly, that there is nothing left to do.

I also want patients to read this, because if these conditions are present and nobody is looking for them, it often falls to the patient to ask the right questions, and I want to give you some questions you can ask to do that.

POTS

POTS is not a fringe diagnosis. It has consensus diagnostic criteria from the Heart Rhythm Society, the American Autonomic Society, the Canadian Cardiovascular Society, and NIH, and it is diagnosed at Mayo Clinic, Cleveland Clinic, and Johns Hopkins. The reason it has a reputation for being fringe is because 77% of patients with POTS were told they had anxiety or a psychiatric disorder before their diagnosis, which is a statistic that should make us all feel a little uncomfortable, because what it means is that we are systematically misattributing a very real condition to a psychological one in exactly the population that is also most likely to have endometriosis and have already been gaslight 1000 times.

The symptoms of POTS - flushing, palpitations, lightheadedness, brain fog, fatigue, exercise intolerance - may seem like anxiety, and in the perimenopausal endo patient they also look exactly like menopause, and exactly like an endo flare, often all three at the same time. The problem is that you can’t tell from the symptom picture alone which one you are dealing with, but you can tell from orthostatic vitals, which is something that can be checked in any clinical office today.

Why does POTS seem to be common in endo? We don’t have a direct study specifically quantifying the rate of POTS in endometriosis patients, but what we do have is a growing body of indirect evidence pointing in a consistent direction. For example, a prospective cohort of over 7,600 women found that endo patients had significantly higher odds of palpitations, which is a cardinal symptom of orthostatic intolerance, compared to women without endo (aOR 1.77, Gete et al., 2023), and a large Danish registry study of over 60,000 endo patients found significantly higher rates of arrhythmia more broadly (aHR 1.21, Havers-Borgersen et al., 2024). These are not POTS studies, but they are enough to justify routine screening in this population.

Why these conditions may appear together connects directly to what I covered in Issue 3. This doesn’t establish MCAS as the cause of POTS, but it does support the idea that mast cells may contribute to symptoms in a substantial subset of patients. We also know that mast cell activation episodes often worsen premenstrually, suggesting that the same estrogen-sensitive mast cell biology that appears to drive pain in endometriotic lesions may also contribute to autonomic dysregulation (Kohno et al., 2021; Bryarly et al., 2019; McCallion et al., 2022). There are no studies testing this directly in patients with endometriosis, but each part is supported by peer-reviewed evidence, and together they provide a biologically plausible framework for why these conditions may cluster in some patients.

Important: Blitshteyn’s 2026 paper on POTS specifically in perimenopausal women found that transdermal estrogen with micronized progesterone was better tolerated than oral formulations, which is the same in the endo recurrence literature and in the mast cell biology which is a convergence I mentioned in Issue 2.

If POTS is identified and treated, it changes the trajectory of a patient’s care in ways that go beyond the autonomic symptoms themselves, because the formulation and route of MHT she is on needs to account for her autonomic function - oral estrogen can worsen orthostatic symptoms - and that is a clinical consideration that most providers are not currently thinking about.

IC/BPS

Interstitial cystitis and bladder pain syndrome is the co-occurring condition with the strongest biological overlap with endometriosis, and it is also the one most likely to be misattributed to endo itself, which means that the patients who have both conditions are being treated for one of them while the other goes unrecognized and untreated. The co-occurrence data here is actually some of the strongest in the pelvic pain literature. A systematic review of nine studies cited in the ACOG Practice Bulletin on Chronic Pelvic Pain found a mean co-occurrence rate of 48% between IC/BPS and endometriosis, a 2026 consensus paper puts the overlap from prospective studies at approximately 65%, and a population-based study using Taiwan’s National Health Insurance database found that women with endometriosis were nearly four times more likely to develop IC/BPS within three years, even after adjusting for 17 comorbidities (adjusted HR 3.74, Wu et al., 2018).

The clinical problem is that urinary urgency and frequency in a perimenopausal endo patient almost always gets attributed to bladder endometriosis. Sometimes that is right, but in a very significant proportion of cases it is IC/BPS impacting the same mast cell-nerve sensitization mechanism I described in Issue 3, just in a different organ. If IC/BPS is part of the picture, endometriosis treatment alone may not be enough to improve bladder symptoms, since both conditions need to be evaluated and treated separately. The biology of this connection is actually better established for IC/BPS than for endo, because the mast cell-nerve sensitization loop I described in Issue 3 as animal data in endo is actually established in IC/BPS in humans.

The symptoms pointing toward IC/BPS rather than endo on the bladder include urgency and frequency without infection on culture, bladder pain that worsens as the bladder fills and improves temporarily after voiding, and worsening with certain foods including coffee, alcohol, citrus, and spicy food. An important clinical point from the 2026 consensus is that endometriosis should not be used as an exclusion to diagnosing IC/BPS, meaning that when bladder symptoms do not improve with optimized hormonal management or after surgical treatment of endo, IC/BPS needs its own workup and its own treatment rather than being attributed to inadequate endo management (Sullivan et al., 2026).

There is also an interesting finding from the treatment literature that connects back to Issues 2 and 3: a study of women with both IC and endometriosis found that hormonal suppression - leuprolide or oral contraceptives - improved bladder symptoms even in women who did not have endometriosis, suggesting that the improvement was not from treating endometriotic lesions specifically but from targeting shared estrogen-dependent mechanisms that underlie both conditions (Lentz et al., 2002).

Pelvic Venous Disease

Pelvic venous congestion and the compression syndromes that cause it, including May-Thurner and Nutcracker syndrome, deserve more than a paragraph here so I wrote a separate piece on it a couple of weeks ago. The short version is that this is frequently overlooked in patients with chronic pelvic pain, particularly in those with endometriosis. Standard history-taking often misses it.

Patients undergoing endometriosis excision surgery may have pelvic venous disease missed because surgical positioning can compress pelvic veins, and MR venography, the imaging most likely to identify it, is not routinely included in standard endometriosis workups.

If a patient’s pelvic pain is worse through the day and improves when lying down, if she has vulvar varicosities or leg heaviness, or if recovery after surgery did not go as expected, pelvic venous disease should be on the differential.

Read the full piece here

What this looks like when all of it is running at once

We are missing the perimenopausal patient with endo history and post-surgical pain that hasn’t resolved, who also has dizziness when she stands up, a burning quality to her pain, GI symptoms, urinary urgency, food reactivity, and pain that is worse by evening and better when she lies down. For some patients, this may not be a single condition with many symptoms. Instead, it may be several disorders that all need to be addressed. When everything gets attributed to endometriosis, the other contributing conditions risk never being identified or treated.

Some patients in this picture have hypermobile Ehlers-Danlos syndrome, which is now recognized in AGA guidelines as part of a broader comorbidity cluster that includes dysautonomia and mast cell activation (Collins Hutchinson et al., 2025; Aziz et al., 2025). The relationship between hypermobile Ehlers-Danlos syndrome and endometriosis is more complex than a simple association. Rates of endometriosis in hEDS patients appear lower than would be expected based on symptom burden, though it is unclear whether this reflects underdiagnosis or true differences in disease prevalence.

Some patients in this pattern also have symptoms of mast cell activation, which is often seen with dysautonomia and contributes to multisystem involvement in some patients.

Questions to bring to your appointment

• Have I ever had my orthostatic vitals? Can you screen me for POTS, because the symptoms overlap completely with menopause and endo flares I am having and I want to know whether that’s part of what’s happening.

• My urinary symptoms haven’t improved with endo treatment, is it possible this is interstitial cystitis rather than endometriosis on my bladder, and if so what would that workup look like?

• My pain is worse as the day goes on and better when I lie down, have we ever considered pelvic venous disease, and would a pelvic MRV be possible given that pattern?

• Is it possible that more than one condition is contributing to my pain, and if so are we treating all of them or only the endometriosis?

So what is actually true?

POTS is well established, has consensus diagnostic criteria, and remains under-recognized, mostly when it comes to women with overlapping symptoms. While we don’t (yet) have a direct study in endo patients specifically, the indirect evidence and the biological mechanism both show that there may be strong connection that we should be routinely screening for. We can also say that IC/BPS co-occurs with endometriosis in 48 to 65% of patients depending on the study, that women with endo are nearly four times more likely to develop it, and that it shares biological mechanisms with endo but requires its own diagnosis and its own treatment, and that endometriosis is not an exclusion to diagnosing it. And we can say that pelvic venous disease is real, is extremely common in this population, is missed by laparoscopy the vast majority of the time for a specific and fixable reason, and responds well to treatment when it is actually found.

The point isn’t that every patient with persistent pain has POTS, IC/BPS, or pelvic venous disease. Many have persistent or recurrent endometriosis. These diagnoses are not mutually exclusive. Endometriosis doesn’t prevent other conditions from developing, but identifying one diagnosis should NOT stop the evaluation when the clinical picture isn’t obvious.

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www.washingtonendometriosis.com

make an appointment

References

1. Blitshteyn S. Postural orthostatic tachycardia syndrome, menopause and hormone replacement therapy. J Clin Med. 2026;15(4):1477. doi:10.3390/jcm15041477

2. Spencer JB, et al. POTS and pelvic venous compression in approximately 400 patients. eClinicalMedicine. 2026. [Disclosed conflict of interest with device manufacturers. Verify full citation before publishing.]

3. Gete DG, Doust J, Mortlock S, Montgomery G, Mishra GD. Associations between endometriosis and common symptoms. Am J Obstet Gynecol. 2023;229(5):536.e1-536.e20. doi:10.1016/j.ajog.2023.07.033

4. Havers-Borgersen E, Hartwell D, Ekelund C, et al. Endometriosis and long-term cardiovascular risk: a nationwide Danish study. Eur Heart J. 2024;45(44):4734-4743. doi:10.1093/eurheartj/ehae563

5. Kohno R, Cannom DS, Olshansky B, et al. Mast cell activation disorder and postural orthostatic tachycardia syndrome. J Am Heart Assoc. 2021;10(17):e021002. doi:10.1161/JAHA.121.021002

6. Bryarly M, Phillips LT, Fu Q, Vernino S, Levine BD. Postural orthostatic tachycardia syndrome: JACC focus seminar. J Am Coll Cardiol. 2019;73(10):1207-1228. doi:10.1016/j.jacc.2018.11.059

7. McCallion A, Nasirzadeh Y, Lingegowda H, et al. Estrogen mediates inflammatory role of mast cells in endometriosis pathophysiology. Front Immunol. 2022;13:961599. doi:10.3389/fimmu.2022.961599

8. Collins Hutchinson ML, Liang E, Fuster E, Blitshteyn S. Autonomic symptom burden, comorbidities and quality of life in women with hEDS/HSD. Auton Neurosci. 2025;262:103356. doi:10.1016/j.autneu.2025.103356

9. Aziz Q, Harris LA, Goodman BP, Simrén M, Shin A. AGA clinical practice update on GI manifestations and autonomic or immune dysfunction in hEDS. Clin Gastroenterol Hepatol. 2025;23(8):1291-1302. doi:10.1016/j.cgh.2025.02.015

10. Committee on Practice Bulletins—Gynecology. Chronic pelvic pain: ACOG practice bulletin, number 218. Obstet Gynecol. 2020;135(3):e98-e109. doi:10.1097/AOG.0000000000003716

11. Sullivan ME, El Haraki A, Padoa A, et al. Role of gynecologic findings in interstitial cystitis/bladder pain syndrome: a consensus. Neurourol Urodyn. 2026;45(1):39-45. doi:10.1002/nau.70099

12. Wu CC, Chung SD, Lin HC. Endometriosis increased the risk of bladder pain syndrome/interstitial cystitis: a population-based study. Neurourol Urodyn. 2018;37(4):1413-1418. doi:10.1002/nau.23462

13. Lentz GM, Bavendam T, Stenchever MA, Miller JL, Smalldridge J. Hormonal manipulation in women with chronic, cyclic irritable bladder symptoms and pelvic pain. Am J Obstet Gynecol. 2002;186(6):1268-1271. doi:10.1067/mob.2002.123729

14. American Urological Association. Diagnosis and treatment of interstitial cystitis/bladder pain syndrome. Available at auanet.org.

15. Taylor HS, Kotlyar AM, Flores VA. Endometriosis is a chronic systemic disease. Lancet. 2021;397(10276):839-852. doi:10.1016/S0140-6736(21)00389-5

16. Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain. 2011;152(3 Suppl):S2-S15. doi:10.1016/j.pain.2010.09.030

Society for Vascular Surgery pelvic venous embolization guidelines: vascular.org. This newsletter is written by a clinician for educational purposes and does not substitute for care from a provider who knows your history.

There is a pattern that I am seeing in endometriosis patients after (successful) surgeries, and once you see it, it seems to be everywhere. Not in every patient, obviously, but often enough that it is hard to ignore. A subset of patients come to our office with leg pain, or back pain, or pelvic pain that does not fit the expected recovery curve, or hematuria, or they can’t get out of bed without being in significant pain. We have one patient who is literally so debilitated she is in a wheelchair, and another that has to crawl to the bathroom during her period. The reflex is to look for residual or recurrent endometriosis, and sometimes that is the answer. But sometimes, and more often than most of us have been trained to consider, the answer is in the veins.

The most interesting part of what we are seeing is that every patient we are diagnosing with pelvic venous disorder is also an endometriosis patient. This may be because they are coming to our office because they have endo, or it may be a coincidence, but either way, we are seeing and diagnosing it more often than I ever thought we would. Just this week, four patients had imaging come back showing some kind of venous compression. Four. In one week. That is not a coincidence, and it is not a rare finding, it’s just rarely identified.

Vascular compression syndromes happen when blood vessels get squeezed between anatomic structures, and the ones most relevant to endometriosis patients are May-Thurner syndrome, nutcracker syndrome, and median arcuate ligament syndrome. May-Thurner is the one most clinicians have heard of - it’s when the right iliac artery compresses the left iliac vein against the lumbar spine. It presents in young women after surgery or peripartum, which is exactly the population we operate on the most, but importantly it also presents in perimenopausal women, which means it does not conveniently age out of your differential.

Nutcracker syndrome is less familiar but may be just as important in this population. The left renal vein gets compressed between the aorta and the superior mesenteric artery, which backs up venous pressure all the way down through the gonadal (ovarian) veins into the pelvis. The classic presentation includes left flank pain, blood in the urine, pain that worsens with standing, dyspareunia, and varicosities in the vulvar area or inner thigh. In an endometriosis patient, every one of those symptoms has an obvious other explanation, which is exactly why it gets missed.

Median arcuate ligament syndrome is the one that causes post-meal GI pain, nausea, and weight loss, which in a patient with known bowel endometriosis is almost impossible to attribute to the right thing without specifically looking for it. It is also more prevalent in women, more common in patients with low BMIs, and overlaps with connective tissue disorders and POTS, both of which show up disproportionately in the endometriosis population.

It is worth being clear about what is actually happening in the veins. Compression syndromes obstruct venous outflow, which forces blood to back up into the pelvic reservoir and creates congestion. But congestion can also exist without any compression at all - driven by valve failure in the gonadal or internal iliac veins, where blood simply flows the wrong direction and pools. Both can coexist in the same patient, which is what makes the diagnostic picture so complicated and why the sequence of treatment matters so much.

What makes this even more complicated is that these syndromes do not tend to show up alone. A 2025 study of women with pelvic congestion syndrome found that more than half had both May-Thurner and nutcracker syndrome at the same time. This makes sense once you understand that these compressions all involve the same vascular territory, and that when one pathway is blocked, pressure is redistributed somewhere else, which can unmask or even worsen a compression that previously was asymptomatic. Nutcracker forces blood through the gonadal veins into the pelvis; May-Thurner blocks the outflow from the pelvis through the iliac veins. Together they create a venous pressure situation that pelvic surgery - with its immobilization, tissue trauma, and inflammatory response - can push from a silent anatomic variant into a clinical emergency.

There is also a diagnostic problem, because endometriosis and pelvic congestion syndrome co-occur so frequently and their symptoms overlap so much that a 2026 review specifically warned about “diagnostic bias,” meaning the tendency to attribute everything to the diagnosis you already know about and miss the one you have not considered. And the standard diagnostic tool for endometriosis, laparoscopy, has notably limited sensitivity for pelvic venous pathology, because the way the procedure is done with CO2 and Trendelenburg positioning actively compresses the pelvic veins and makes them appear normal. A study of women with chronic pelvic pain found pelvic vein incompetence in 62% of them, compared to 19% of women without pain. Again, these are not rare findings.

So what do we actually do with this?

The first thing is to think about the full picture when a patient is not recovering the way we expect. Left-sided leg swelling, flank pain, hematuria, or pelvic pain that changes character after surgery are the signals. Standard duplex ultrasound frequently misses iliac vein compression; MR venography (MRV) is what you need. For pelvic congestion specifically, a transvaginal ultrasound that is specifically looking for venous insufficiency, ovarian vein diameter, flow velocity, vein dilation, will give you information that a standard pelvic ultrasound report will not include unless someone asks for it.

The second thing is that when obstruction and reflux are both present, the obstruction has to be treated first. Embolizing an ovarian vein that is working as a pathway for a blocked renal vein makes things worse, not better, so the sequence is important.

And the third thing is that patients need to know enough to ask about this. If you have endometriosis and your recovery has not gone the way you expected, or you have leg heaviness or vulvar varicosities or pain that is worse with standing and better when you lie down, you are not imagining something. You are describing a pattern that has a name and a treatment pathway. You are allowed to ask your clinician whether your veins have been looked at, and what kind of imaging was actually done, because a normal pelvic ultrasound and a normal laparoscopy do not answer that question.

We are seeing this so much more than we expected, and my guess is that if most practices start looking for pelvic venous disease in their endo patients they will find the same thing.

Come see us @www.washgyn.com or www.washingtonendometriosis.com

If you would like an appointment with me, you can schedule online here.

References

1. Under Pressure: A Head-to-Toe Review of Vascular Compression Syndromes. Nadim B, Alizada S, Gupta S, et al. Clinical Radiology. 2024;79(10):722-735. doi:10.1016/j.crad.2024.07.006.

2. Pelvic Congestion Syndrome Due to Central Venous Outflow Obstruction: A Single-Center Experience With May-Thurner and Nutcracker Syndromes. Wu WC, Hsu WH, Chang TC, Huang LW. International Journal of Gynaecology and Obstetrics: The Official Organ of the International Federation of Gynaecology and Obstetrics. 2025;. doi:10.1002/ijgo.70268.

3. Nutcracker Syndrome in 2026: A Nephrologist-Oriented Diagnosis and Management. Mačionienė E, Kerpauskienė A, Žakauskienė U, et al. Clinical Kidney Journal. 2026;19(5):sfag124. doi:10.1093/ckj/sfag124.

4. Contemporary Management of Nutcracker Syndrome: A Systematic Review. Sarikaya S, Altas O, Ozgur MM, et al. Annals of Vascular Surgery. 2025;:S0890-5096(25)00538-2. doi:10.1016/j.avsg.2025.07.043.

5. Median Arcuate Ligament Syndrome—Review of This Rare Disease. Kim EN, Lamb K, Relles D, et al. JAMA Surgery. 2016;151(5):471-7. doi:10.1001/jamasurg.2016.0002.

6. Median Arcuate Ligament Syndrome and Its Associated Conditions. Huynh DTK, Shamash K, Burch M, et al. The American Surgeon. 2019;85(10):1162-1165.

7. Pelvic Congestion Syndrome: The Gynecological Perspective. Krambeck C, Tesch K, Watrowski R, Maass N, Alkatout I. Journal of Clinical Medicine. 2026;15(4):1655. doi:10.3390/jcm15041655.

8. Pelvic Vein Incompetence and Chronic Pelvic Pain: A Case-Control Study. Hansrani V, Riding D, Seif MW, et al. BJOG : An International Journal of Obstetrics and Gynaecology. 2023;130(11):1355-1361. doi:10.1111/1471-0528.17485.

9. Imaging Appearance and Nonsurgical Management of Pelvic Venous Congestion Syndrome. Bookwalter CA, VanBuren WM, Neisen MJ, Bjarnason H. Radiographics : A Review Publication of the Radiological Society of North America, Inc. 2019 Mar-Apr;39(2):596-608. doi:10.1148/rg.2019180159.

There is so much evidence now about endo and menopause (I have given up on “menendo” and now call it “endopause”) that clinicians really don’t have much of a basis to continue to tell patients that symptoms will get better after menopause. Because it turns out that endometriosis may not actually stop at menopause.

The disease can persist and it can reactivate. And when it does, it looks nothing like what most clinicians are trained to recognize, which means it gets missed, attributed to something else, and left untreated in women who have often, as we know, already spent years being dismissed and undertreated.

Two papers published this spring give even more info than we already had. The first, by Ketenci Gencer and colleagues in the European Journal of Obstetrics and Gynecology, synthesized 64 studies on endometriosis at the two ends of reproductive life. The second, an editorial by Apelian, Chedraui, and Hugh Taylor in Climacteric, published in April, makes the same argument from a different angle, and adds some things the review doesn’t cover.

In postmenopausal women with a history of endo, it’s not cyclic pelvic pain or heavy bleeding. Instead, patients report bowel symptoms, urinary complaints, things that get diagnosed as IBS, aging, stress, honestly anything except endometriosis. Across the studies reviewed, pelvic pain was reported in only roughly 18 to 25 percent of postmenopausal cases and GI symptoms in 30 to 40 percent. The symptoms are completely not what we are used to and no one has taught anyone to look for it.

The biology of endo lesions changes how we should be thinking about the postmenopausal patients. After menopause, systemic estrogen drops, but as we have talked about before, the lesions themselves can keep producing estrogen locally. Endometriotic tissue overexpresses aromatase, which is an enzyme that converts androgens into estrogen, so it’s basically making its own estrogen having nothing to do with the ovaries.

There is another cause of endo in postmenopausal women. Work by Flores, Sahin, and Taylor published in 2025 identified a group of lesions with reduced progesterone receptor expression. These low-PR lesions don’t respond well to progestin-based therapy, and post-treatment lesion size was sixfold larger in low-PR lesions than high-PR lesions after MPA.

The potential for malignancy in patients with an endometriosis history is important. Endometriosis-associated ovarian cancer is a well-documented risk that does not go away after menopause. One cohort study cited in the Ketenci Gencer review found a cumulative ovarian cancer incidence of approximately 2.5 percent over roughly 13 years of follow-up among women with ovarian endometrioma. A separate study found ovarian cancer in 39 percent of surgically confirmed postmenopausal endometriosis cases though this was from a highly non-randomized surgical population, it explains why we need to exclude malignancy first in this age group.

Extra-ovarian malignant transformation, while rare, appears to be more common in postmenopausal women. The symptoms to watch for are new-onset or rapidly progressive pain, vaginal bleeding, dyspareunia, and imaging findings with atypical or solid components. Any new or enlarging pelvic mass in a woman with a history of endometriosis requires careful evaluation (but then what postmenopausal mass doesn’t??).

So what do we do with all of this??

The hormone therapy question is the one that makes everyone uncomfortable because everyone has been told to stay away from estrogen if you have endo. If the patient has a history of endometriosis and is on MHT, the formulation matters a lot. The 2025 EMAS clinical guide is explicit that estrogen-only MHT should be avoided even in hysterectomized women with endometriosis history because of recurrence risk and the potential for malignant transformation of any residual disease. Continuous combined estrogen-progestin is considered safer than sequential or estrogen-only regimens. Tibolone is another option, though it is not available in the US.

Though one systematic review found that both combined and sequential MHT regimens carried some risk of reactivation, the absolute risk was small and the data was mostly observational. This is not a reason to withhold MHT; we know what happens when patients are denied MHT and the overall health consequences, but it is a reason to individualize the regimen and monitor her.

The next step is imaging, and this is where postmenopausal endometriosis differs fundamentally from reproductive-age disease. ACOG recommends transvaginal ultrasonography as the initial modality, with MRI for further characterization of deep disease. Any new or enlarging pelvic mass, solid or vascularized adnexal lesion, or rising CA-125 warrants surgical exploration (obviously).

When symptoms are significant, surgery is still generally considered first-line. The EMAS guide recommends it as the preferred option since it reduces pain, provides a histologic diagnosis, and decreases malignancy risk. Medical treatment is second-line, for recurrence after surgery or when surgery is contraindicated or declined.

For women who cannot undergo surgery, decline surgery, or have recurrent disease after surgery, aromatase inhibitors are probably the most biologically rational option we have. GnRH agonists do not work well after menopause because there is no ovarian function left to suppress. AIs target the local aromatase activity in the lesions themselves and the peripheral conversion of androgens in adipose tissue, which is exactly where the estrogen is coming from in this population. Rotenberg and colleagues published a case in Climacteric of a postmenopausal patient with deep infiltrating endometriosis involving the rectum and urinary tract who had already failed Lupron and Depo-Provera. She had a marked clinical response to letrozole 2.5 mg daily; the rectal mass resolved completely on colonoscopy, the hydro-ureter resolved, and her bleeding stopped. The overall evidence base is still small and mostly case reports, no RCTs. In postmenopausal women, AIs can be used as monotherapy, no add-back needed.

If you use an AI, monitor bone density. Baseline DXA before starting, calcium and vitamin D throughout, consider a bisphosphonate if T-score is already low, repeat DXA at 12 to 24 months. Same approach used in breast cancer patients on AIs.

There is no reliable way to identify low-PR lesions clinically before treatment fails. Progesterone receptors on surgical specimens do show strong predictive value but this requires tissue, which means it only helps after surgery. We do not yet know whether AIs would be effective in this subgroup either, since those lesions are less estradiol-dependent for growth. If the standard approach is not working, that may be part of the reason.

The more I read this literature, the more I think menopause doesn’t end the story of endometriosis, it just changes the story. The problem is that many of us are still looking for the reproductive-age version of the disease, and we miss what it becomes later in life. The evidence is still evolving, but there is already enough here to change how we think about these patients.

Come see us @washington-gyn.com; make an appointment!

Ketenci Gencer et al., European Journal of Obstetrics and Gynecology and Reproductive Biology, 324 (2026), 115217. DOI: 10.1016/j.ejogrb.2026.115217

Apelian S, Chedraui P, Taylor HS. Endometriosis beyond menopause: a call for greater clinical awareness. Climacteric. 2026. DOI: 10.1080/13697137.2026.2658790

Flores VA, Sahin C, Taylor HS. Progesterone receptor status predicts aggressiveness of human endometriotic lesions in murine avatars. F S Sci. 2025;6(1):65–72. DOI: 10.1016/j.xfss.2024.10.004

Rotenberg O, Kuo DYS, Goldberg GL. Use of aromatase inhibitors in menopausal deep endometriosis: a case report and literature review. Climacteric. 2022;25(3):235–239. DOI: 10.1080/13697137.2021.1990259

Reference Guides Link

Just some of the guides I have been adding….

Pelvic venous disorders are the second most common cause of chronic pelvic pain after endometriosis. And yet routine laparoscopies can miss 80 to 90 percent of cases. That is a near-complete miss, and it happens because the procedure was not designed to find vein problems in the first place - it is to look for endo.

The diagnosis is not complicated, but it requires asking the right questions and ordering the right imaging. The symptom pattern is actually almost obvious once you know what you are looking for - pain that builds through the day and is better when the patient lies down, a feeling of heaviness that worsens with prolonged standing, aching after sex that doesn’t go away for hours or days, varicosities that keep coming back. When you see that pattern, ordering a pelvic venous ultrasound and specifying venous insufficiency or an MRV, is not complicated, and it is the step that can genuinely change someone’s pain trajectory.

For patients, I want you to know that bringing this possibility up to your provider is reasonable. You can ask whether a vein problem could be contributing to your symptoms or whether your imaging actually evaluated the pelvic veins or was focused on something else entirely. And if the symptom pattern fits, you can ask for a referral to someone with expertise in this area. These are thoughtful questions, not difficult ones.

There is a patient guide and a clinician reference to make both of those conversations easier. They are linked below. I hope they help someone get an answer they have been waiting too long for. They are meant to educate and are not a replacement for medical advice.

And here are the other updates I have added over the past month or so as I have been reading and collecting evidence/ info:

Website/ spreadsheet

• Added a new section framing endometriosis as a systemic inflammatory disease, with an evidence table covering central sensitization, local aromatase activity, progesterone resistance, mast cell density in lesions, immune dysregulation, and elevated cardiovascular risk - each with evidence grade and clinical implication

• Added a dedicated section on the perimenopausal endo patient, covering earlier ovarian reserve loss, the progesterone-first decline sequence, estradiol fluctuation as MCAS trigger, and co-occurring conditions surfacing at perimenopause

• Expanded the diagnosis section to include MCAS testing criteria and the ovarian cancer risk data (Barnard JAMA 2024)

• Replaced the basic treatment ladder with a detailed one including LNG-IUD mast cell evidence (Engemise 2011), norethindrone-to-estrogen conversion warning (Chu JCEM 2007), MHT guidance with the three-stream rationale for micronized progesterone, aromatase inhibitor use with bone density warning, and a full mast cell-targeted options table (LNG-IUD, antihistamines, cromolyn, ketotifen, PEA) with evidence grades for each

• Added a non-hormonal adjunct section covering LDN, pentoxifylline, cabergoline, and metformin — all marked off-label with evidence grades (thank you drjordanemont for your amazing substack!)

New — PeVD Patient Guide A plain-language guide for patients exploring whether their symptoms might be caused by a pelvic venous disorder. Covers how to recognize the symptom pattern, what the different conditions mean in plain terms, how diagnosis works, what treatment looks like, and questions to bring to appointments. Available as a PDF.

New — PeVD Clinician Reference A clinical reference covering updated PeVD terminology and background, pathophysiology (reflux and obstruction mechanisms), anatomical zones, compensated vs. uncompensated presentations, the four clinical presentations, the PIOG escape point system, the adnexal point exam, PeVD–POTS overlap, history-taking elements, the full diagnostic pathway with ordering and coverage guidance, conservative compression framework, interventional treatment options, post-procedure expectations including post-embolization syndrome, periprocedural MCAS considerations, and selected references.

Website here and appointments here (come see me!)

⚕️ Disclaimer - Not Medical Advice

The content provided in all of these posts and apps is intended solely for medical education and informational purposes.

The materials presented reflect current evidence, clinical guidelines, and expert opinion where applicable; however, they are not intended to replace independent clinical judgment. Clinical decisions must be individualized to each patient’s unique medical history, presentation, comorbidities, and preferences.

This resource does not establish a standard of care, nor does it create a physician–patient relationship. Recommendations may evolve as new research emerges. Clinicians are responsible for verifying medication dosages, contraindications, and regulatory approvals in their own jurisdiction.

This reference includes adapted and compiled material derived from established clinical frameworks and other third-party sources. It is not presented as wholly original work, and users should consult the underlying primary literature, source guidelines, and official prescribing information where relevant.

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This is one reason why endometriosis pain can be so relentless

One of the most common questions I get from patients who’ve had endometriosis excision surgery is why they are still in pain even though they were told that the surgery was successful. This piece is about what the biology actually says, and why that question has a better answer than most patients have ever been given.

Something we know from the research literature that still hasn't fully reached the endo conversation is that disease stage and pain don't track together the way we expect. The staging system we use - Stage I through IV, based on lesion size and location - doesn't seem to predict how much pain a patient is actually experiencing. A woman with Stage I disease can be completely incapacitated while a woman with Stage IV can have mild symptoms or none at all. We've known this for a long time, but I don't think we've fully figured out what it means and how to talk to patients about their disease, what we tell them to expect after surgery, and whether we're asking the right questions when they come back still in pain.

The lesion is not the whole story, because if it were, stage would predict pain and it doesn’t. It seems from the literature (which hasn’t been studied much) that there are two explanations: the immune environment around the lesion and the nervous system that has been processing pain signals from it sometimes for years.

First, the nervous system

There is a phenomenon in pain medicine called central sensitization. Here is what it means in plain terms: when the nervous system is exposed to persistent pain signals for long enough, it starts to amplify. Pain spreads beyond the original site, and stimuli that shouldn’t hurt start to hurt. The nervous system has been completely reset by the experience of chronic pain - and it doesn’t automatically recalibrate back.

This is not a psychological observation - it is measurable. Clifford Woolf at Harvard has spent decades documenting it, and his 2011 paper in Pain is one of the foundational texts in this field (Woolf, 2011). Central sensitization has been documented in fibromyalgia, IBS, interstitial cystitis, chronic pelvic pain, and postsurgical pain - conditions that tend to travel together, likely because they share this common mechanism.

Mast cell mediators correlate with pain severity - not with lesion size, not with disease stage. Anaf et al., Fertil Steril 2006, McCallion et al., Front Immunol 2022

In endometriosis specifically, researchers found that women with endo have lower pain thresholds not just in their pelvis - but at their thumb and forearm, sites that have nothing to do with endometriosis (As-Sanie et al., 2016). Brain imaging has shown actual structural changes, for example, reductions in gray matter volume in pain-processing regions. These are objective, measurable findings.

And in a subset of patients, those nervous system changes persist after their lesions are removed, which can be confusing, because even though the peripheral source of pain signals is gone, the central amplification continues.

Surgery may remove the lesions but it does not reset a nervous system that has been running in a sensitized state for years. Those are two completely different problems, both of which need to be addressed in many patients.

This is one of the most important things I can tell a post-surgical endo patient. When she comes back six months after surgery with clear imaging and she is still in significant pain, the reflex is to wonder if something was missed, or to question whether her pain is real. The central sensitization research gives us a different explanation entirely. Her nervous system may have just kept going. That is neurobiological. It is not in her head.

It also means that surgery is not always the right next step when she comes back in pain. If the primary driver at that point is a sensitized nervous system rather than active lesion burden, another laparoscopy doesn’t fix the thing that needs fixing. That’s a hard conversation because people want to believe surgery can fix them and no one has ever mentioned that endo may not be just one thing.

Now the immune piece - mast cells

Most people know mast cells from allergic reactions. They’re the immune cells that fire when you’re exposed to something you’re allergic to, releasing histamine and causing the symptoms you recognize. But their role is much broader than allergy, and in endometriosis two things about them have been well documented in human tissue.

Mast cells are found in significantly higher numbers in endometriotic lesions than in normal tissue, replicated across multiple histological studies (Anaf et al., 2006; McCallion et al., 2022). Those mast cells are clustered right next to nerve fibers, within approximately 25 micrometers, which is about the width of a human hair. This is especially in deep infiltrating endometriosis, which also has the highest mast cell density and the worst pain scores (Anaf et al., 2006).

And here is the finding that is the most interesting. The chemicals mast cells release - histamine, tryptase - correlate with pain severity in the peritoneal fluid of endo patients. There is no correlation with lesion size or disease stage, only with how much our patient hurts.

This is one biological explanation for something we’ve observed for decades. Stage doesn’t predict pain. Mast cell mediators do.

What this establishes is that mast cells are elevated, activated, and positioned next to nerve fibers in a way that could be driving pain. What it does not establish is whether they are the primary driver, or one piece of a broader inflammatory picture. These are associations and the histological finding doesn’t prove causation. The field is appropriately more cautious about that claim than it was ten years ago, and I think that is smart.

How estrogen fits in and what this has to do with perimenopause

Most of what follows is animal and lab data and has not been confirmed in prospective human studies. The biology is coherent and has been replicated by multiple research groups, but animal data is not human data, which is obviously important to keep in mind.

Mast cells have estrogen receptors. Research in animal models suggests that estrogen fluctuations can activate them directly with no allergen needed, just the hormone. There appear to be two pathways: a slower pathway involving changes in gene activity that promotes inflammation and fibrosis (Guo et al., 2021), alongside a faster non-genomic pathway that directly sensitizes nearby nerve fibers (Xu et al., 2023). And then there's a feedforward loop (see the figure at the beginning of this article): activated mast cells increase local estrogen production in the surrounding tissue, which activates more mast cells and becomes a self-sustaining cycle that may not need systemic hormone levels to keep running. [Animal / lab data only]

A 2025 paper in the FASEB Journal identified a more specific piece of this puzzle - a receptor called MRGPRX2 on mast cells that, when activated, triggers a chain reaction leading directly to nerve sensitization. Blocking it reduced pain behavior in mice. And an antihistamine - desloratadine - reversed the nerve sensitization in lab studies. Specific and interesting but still animal and lab data. [Animal / lab data only]

Here is why all of this matters for perimenopause specifically. Progesterone - which in lab studies appears to act as a brake on mast cell activity - declines first, years before estrogen does. Then estrogen surges erratically before it eventually falls. If the animal data translates to humans, you have a system where the brake disappears and the activator is misfiring in a patient whose nerve fibers are already sensitized from years of disease. It hasn’t been confirmed in a prospective human study but the pieces fit in a way that I think is worth paying attention to.

This is further complicated by the fact that roughly one in three people with endometriosis show progesterone resistance, meaning the brake may be partially or fully absent even before perimenopause begins (Taylor et al., 2021). This is thought to involve downregulation of progesterone receptors in the lesions themselves. What isn't known is whether this resistance extends to mast cell behavior specifically. If it does, that brake may be impaired or absent, which would mean perimenopause isn't introducing a new vulnerability so much as compounding an existing one, and so we have to look at other ways to suppress the lesions. But that connection hasn't been studied directly, it's only a reasonable inference from what we know, not an established finding.

So what does the evidence actually say about treatment?

I want to be precise here because the evidence varies a lot depending on what you’re asking about. These are not all the same category of evidence, and treating them as equivalent would be a mistake.

PEA/transpolydatin - the only one with actual human data in endo

Palmitoylethanolamide - PEA - is a naturally occurring compound that acts as a mast cell modulator. It doesn’t block mast cells entirely; it turns down their activity, reducing the inflammatory signals they send to nerve fibers. The most studied formulation pairs PEA 400mg with transpolydatin 40mg, twice daily.

Two small human studies in endometriosis patients showed significant pain reduction - one of them a randomized controlled trial (Giugliano et al., 2013; Cobellis et al., 2011). These are small trials and haven’t been replicated at scale. But this is actual human data in endo patients, which puts PEA in a completely different category from everything else on this list. Available as a supplement in many countries. Formulation matters - ultra-micronized PEA is absorbed better. And it should sit alongside optimized hormonal management, not replace it.

Ketotifen

Ketotifen is an antihistamine that also stabilizes mast cells. It has good evidence in animal endo models and positive randomized trial results in IBS, which shares overlapping biology. No human trials in endometriosis exist and in the US it requires a compounding pharmacy for oral use (strangely you can get it in an FDA-approved eye drop). Some clinicians use it because they have seen it work in patients with strong histamine-type symptoms like flushing with pain, food reactivity, reactions to wine or aged cheese. That’s off-label since the evidence comes from IBS, not from endo, but the underlying biology is close enough that it seems reasonable. Of course we have to explain that this is off-label and not FDA-approved. [Animal data / IBS RCTs only]

Antihistamines

H1 antihistamines - cetirizine, loratadine, the kind available over the counter - have a more specific biological rationale than they did before based on the 2025 MRGPRX2 receptor research (Mao et al., 2025). It is low risk and widely available but there are no clinical trials that have been done in endometriosis. Some clinicians use them in patients with histamine-type symptoms alongside their pain because - as with ketotifen - they have seen success with other patients and there are few side effects.

One important note: not all antihistamines carry the same risk. First-generation antihistamines like Benadryl have a well-documented association with dementia risk with long-term use. The second-generation options - cetirizine, loratadine, fexofenadine - do not carry that same risk (especially important in women already worried their brain fog is dementia!). (Gray et al., JAMA Intern Med, 2015)

So what is actually true?

I think we can say all of this with confidence:

(1) Mast cells are elevated in endo lesions and clustered next to nerve fibers (Anaf et al., 2006; McCallion et al., 2022).

(2) Mast cell mediators correlate with pain severity, not lesion size.

(3) Central sensitization is real, measurable, and documented in endo patients in human studies (Woolf, 2011; As-Sanie et al., 2016). And in a subset of patients it persists after surgery.

All of that is established.

The estrogen-mast cell activation loop (Guo et al., 2021; Xu et al., 2023), the progesterone brake, the feedforward cycle - makes sense biologically and is replicated in animal models, but not yet confirmed in prospective human studies. Worth watching but not yet worth prescribing from.

PEA has small human RCT data in endo (Giugliano et al., 2013; Cobellis et al., 2011). Ketotifen has compelling animal data and IBS evidence. H1 antihistamines have a plausible mechanism and very low risk. Dedicated mast cell stabilizers as a treatment for endo pain have zero human trials.

All of those things are true.

None of this contradicts the rest of what we’ve covered in this series. The hormone question from my last piece, the mast cell biology, the missed diagnoses coming next - these are not competing explanations. They are overlapping, and the patient who is still in pain after surgery may be dealing with more than one of them at the same time.

What this means if you’re the patient

If you’ve had surgery and you’re still in pain and your imaging is clear, you are not imagining it and to be honest it’s not much of a mystery. The central sensitization research gives us a strong biological explanation for exactly that scenario (Woolf, 2011). Your nervous system may have kept working even after the lesions were removed and it points toward a different kind of management than another surgery.

If you have strong histamine-type symptoms alongside your pain - flushing, food reactivity, reactions to wine or fermented foods, urticaria during flares - the mast cell connection may be relevant to your picture. That’s a conversation absolutely worth having with your clinician.

And if perimenopause made everything worse, the hormonal research gives us a biologically good explanation for why, even if the prospective human study confirming it hasn’t been done yet (Taylor et al., 2021). Your perimenopausal symptoms may be worse than your friends without a history of endometriosis because your system is responding to a specific transition in a way that makes complete sense given everything else that has happened.

What’s coming in Issue 4

Next issue: the conditions that travel with endo and almost nobody checks for. POTS, interstitial cystitis, and pelvic venous congestion - all real, all diagnosable, all frequently missed. I want to talk specifically about pelvic venous congestion because it is the one I most want clinicians to walk away thinking about. It is extremely common, almost universally missed, entirely reversible in many patients, and almost never included in a standard endo or even pelvic pain workup. The reason it gets missed is specific and fixable. More on that next issue.

References

1. Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain. 2011;152(3 Suppl):S2-S15. doi:10.1016/j.pain.2010.09.030

2. As-Sanie S, Kim J, Schmidt-Wilcke T, et al. Functional connectivity is associated with altered brain chemistry in women with endometriosis-associated chronic pelvic pain. J Pain. 2016;17(1):1-13. doi:10.1016/j.jpain.2015.09.008

3. Anaf V, Chapron C, El Nakadi I, De Moor V, Simonart T, Noël JC. Pain, mast cells, and nerves in peritoneal, ovarian, and deep infiltrating endometriosis. Fertil Steril. 2006;86(5):1336-1343. doi:10.1016/j.fertnstert.2006.03.057

4. McCallion A, Nasirzadeh Y, Lingegowda H, et al. Estrogen mediates inflammatory role of mast cells in endometriosis pathophysiology. Front Immunol. 2022;13:961599. doi:10.3389/fimmu.2022.961599

5. Guo X, Xu X, Li T, et al. NLRP3 inflammasome activation of mast cells by estrogen. Front Immunol. 2021;12:749979. doi:10.3389/fimmu.2021.749979

6. Xu X, Wang J, Guo X, et al. GPR30-mediated non-classic estrogen pathway in mast cells in endometriosis pain. Front Immunol. 2023;14:1106771. doi:10.3389/fimmu.2023.1106771

7. Mao X, Wang J, Ding S, et al. MRGPRX2 mediates mast cell-induced endometriosis pain via histamine/HRH1/TRPV1 signaling. FASEB J. 2025;39(13):e70778. doi:10.1096/fj.202501493R

8. Giugliano E, Cagnazzo E, Soave I, et al. The adjuvant use of N-palmitoylethanolamine and transpolydatin in endometriotic pain. Eur J Obstet Gynecol Reprod Biol. 2013;168(2):209-213. doi:10.1016/j.ejogrb.2013.01.009

9. Cobellis L, Castaldi MA, Giordano V, et al. Effectiveness of micronized N-palmitoylethanolamine-transpolydatin in chronic pelvic pain related to endometriosis. Eur J Obstet Gynecol Reprod Biol. 2011;158(1):82-86. doi:10.1016/j.ejogrb.2011.04.011

10. Taylor HS, Kotlyar AM, Flores VA. Endometriosis is a chronic systemic disease. Lancet. 2021;397(10276):839-852. doi:10.1016/S0140-6736(21)00389-5

11. As-Sanie S, Mackenzie SC, Morrison L, et al. Endometriosis. JAMA. 2025;334(1):64-78. doi:10.1001/jama.2025.2975

12. Mao X, et al. MRGPRX2 Mediates Mast Cell-Induced Endometriosis Pain Through the Sensitization of Sensory Neurons via Histamine/HRH1/TRPV1 Signaling Pathway. FASEB J. 2025

13. Gray SL, Anderson ML, Dublin S, et al. Cumulative use of strong anticholinergic medications and incident dementia. JAMA Intern Med. 2015;175(3):401-407. doi:10.1001/jamainternmed.2014.7663

This newsletter is written by a clinician for educational purposes and does not substitute for care from a provider who knows your history.

This is the crux: Whether testosterone is higher than estrogen in women really depends on what you are actually measuring and when.

I do think it is worth pointing out that the data referenced in our article and in this substack comes from peer-reviewed research that has been examined, challenged, and tested by experts before publication. Peer review does not make something perfect, but it does mean the data has been scrutinized and the conclusions have been held to a standard. There is a big difference between saying something on social media and publishing it in a peer-reviewed journal.

Also, our paper addresses testosterone’s physiologic role across the female lifespan and isn’t a simple head-to-head comparison of blood levels. And even if it were, the science is not as straightforward as saying one number is higher than another and calling it a day. Testosterone and estrogen are not measured the same way, they don’t behave the same way in the body, and circulating blood levels are only a piece of a much more complex picture.

First, a little history

For many years when researchers measured testosterone levels in women’s blood they used tests called immunoassays. The problem with this type of testing is that the results were picking up the wrong thing. They were supposed to measure testosterone, but they were also including other hormones floating around in the blood - particularly DHEA, made by the adrenal glands. So the testosterone readings looked much higher than they actually were. It took us a while to figure that out and correct it (Stanczyk FZ, Vesper H. Menopause 2025).

Modern testing - called liquid chromatography tandem mass spectrometry, or LC-MS/MS - fixed this. It measures testosterone specifically without picking up everything else. This matters a lot for understanding what the research actually shows.

What the blood tells us

With modern testing, circulating estradiol (the most biologically active estrogen) is higher than testosterone in the bloodstream of premenopausal women. Research from Skiba and colleagues using LC-MS/MS in a large cohort of women confirmed this clearly (Skiba MA et al. J Clin Endocrinol Metab 2019). And when you add in all the other estrogens women produce - estrone and estriol - total circulating estrogens are substantially higher than testosterone in premenopausal women.

So if someone tells you circulating estrogen is higher than testosterone in premenopausal women they are correct. That is what the blood shows with modern testing. But what is circulating in the blood is only one part of the story. What the body produces, converts, and uses throughout the day is another.

Both of these statements are true. We just keep measuring what is in the blood at a moment in time and calling that the whole story, and of course it is not.

The blood level is just a snapshot

We all know that a blood test only shows you what is circulating at one moment in time, which is why we don’t recommend hormone testing in perimenopause. Your body is constantly producing hormones, converting them into other hormones, using them in tissues throughout the body. What shows up in a blood draw is just a small part of what is actually happening.

When researchers measured daily hormone production rates using a completely different methodology called isotope dilution studies, which were not affected by the old immunoassay problems, they found that daily testosterone production in reproductive-aged women exceeds estradiol production. Estimates vary depending on the method used to measure it, and that variation is a perfect example of the larger point - how you measure hormones shapes what the result is (Burger HG et al. Recent Prog Horm Res 2002).

That production estimate is also likely conservative. It does not fully account for all the androgen precursors - hormones like DHEA and androstenedione - that are constantly being converted into testosterone in your tissues, your fat cells, your muscles, and your brain throughout the day (Goldman AL et al. Endocr Rev 2017).

The same logic applies to both sides

When researchers argue that total estrogens are higher than testosterone - by including estrone and estriol alongside estradiol - they are making a valid point. But the same logic can apply to testosterone.

Testosterone has its own family of precursor hormones that convert into testosterone throughout the body. Just like total estrogens exceed estradiol alone in the blood, total androgens significantly exceed what you see as testosterone in a single blood test. Both hormone families are being underrepresented by any one measurement (Goldman AL et al. Endocr Rev 2017).

We all know that the way we measure testosterone and estradiol are with different units. Testosterone operates at nanomolar concentrations in women compared to the picomolar concentrations of estradiol (Davis SR, Wahlin-Jacobsen S. Lancet Diabetes Endocrinol 2015). A nanomole is a thousand times larger than a picomole. These are very different orders of magnitude - both documented in the peer reviewed literature - and they help us understand hormone activity in the body.

What the data looks like over a lifetime

The figure below from Mauvais-Jarvis and Lindsey published in the Journal of Clinical Investigation in 2024 shows circulating testosterone and estradiol in males and females across the entire lifespan - measured in the same units using gold standard LC-MS/MS testing on CDC NHANES data from over 14,000 people.

Figure 2 from Mauvais-Jarvis F, Lindsey SH. J Clin Invest. 2024;134(17):e180073. Panel A shows concentrations in pg/mL across the lifespan. Panel B shows the ratio of testosterone to estradiol across the lifespan in both sexes.

A few important points about these graphs. First - both hormones are measured in the same units using the same (gold standard) methodology. This is not an apples to oranges comparison. Second, this figure compares testosterone to estradiol alone, not total estrogens. When you include estrone and estriol, total circulating estrogens exceed testosterone in premenopausal women, consistent with the Skiba data. Third, Panel B shows the testosterone to estradiol ratio across the lifespan. Even in women that ratio is consistently above zero, meaning testosterone is always present and measurable.

The authors state directly in the Mauvais-Jarvis article that testosterone is the most abundant circulating active sex steroid in females across the lifespan and may circulate at concentrations roughly 5–50 times higher than estradiol depending on the life stage being evaluated. That range makes sense when you think about it - estradiol drops dramatically after menopause while testosterone declines more gradually, so which hormone appears higher really depends on which women you are measuring and when.

So what is actually true?

I think we can say that all of this is true.

Circulating estrogens are higher than testosterone in the bloodstream of premenopausal women when you use the right testing (Skiba MA et al. J Clin Endocrinol Metab 2019).

Daily testosterone production significantly exceeds estradiol production in reproductive aged women - though how much depends on how you measure it (Burger HG et al. Recent Prog Horm Res 2002).

The total amount of androgens (not just testosterone) in your blood is much higher than what shows up on a testosterone blood test - just like total estrogens are larger than estradiol alone. Also true (Goldman AL et al. Endocr Rev 2017).

And over the female lifespan, including post-menopause, testosterone is the most abundant circulating active sex steroid, running 5 to 50 times higher than estradiol (Mauvais-Jarvis F, Lindsey SH. J Clin Invest 2024).

None of these findings contradict each other; they are just answering different questions.

What really matters

Here is what we should actually be focusing on: in a recent analysis of over 33,000 women aged 18 to 70 years diagnosed with hypoactive sexual desire disorder only 850 were ever prescribed testosterone, which is less than 3 percent (Agrawal P et al. J Sex Med 2024). Even accounting for prescriptions not captured in that data, that gap is just not acceptable.

Part of what drives that gap is confusion about what testosterone is, what it does, and what the research actually shows. We need to give our patients more than just a conclusion, so women don’t lose the ability to have informed conversations with their clinicians and miss out on treatment.

The bottom line

The next time you see testosterone and estrogen described in absolute terms - one higher, one lower, case closed - ask what is actually being measured. Blood levels or production rates? Estradiol alone or total estrogens? Testosterone alone or the full androgen pool?

The answer to each of those questions is different and all of them are correct. We just have to be very careful to understand that things aren’t always black and white.

References

Agrawal P, Singh SM, Hsueh J, et al. Testosterone therapy in females is not associated with increased cardiovascular or breast cancer risk: a claims database analysis. J Sex Med 2024;21:414–9.

Burger HG, Dudley EC, Robertson DM, et al. Hormonal changes in the menopause transition. Recent Prog Horm Res 2002;57:257–75.

Davis SR, Wahlin-Jacobsen S. Testosterone in women — the clinical significance. Lancet Diabetes Endocrinol 2015;3(12):980–92.

Goldman AL, Bhasin S, Wu FCW, et al. A reappraisal of testosterone’s binding in circulation: physiological and clinical implications. Endocr Rev 2017;38(4):302–24.

Lanoff J, Simon JA. Testosterone in women: clinical evidence and practice guidelines. Obstet Gynecol Clin N Am 2026. https://doi.org/10.1016/j.ogc.2026.03.003

Mauvais-Jarvis F, Lindsey SH. Metabolic benefits afforded by estradiol and testosterone in both sexes: clinical considerations. J Clin Invest 2024;134(17):e180073.

Skiba MA, Bell RJ, Islam RM, et al. Androgens during the reproductive years: what is normal for women? J Clin Endocrinol Metab 2019;104(11):5382–92.

Stanczyk FZ, Vesper H. Challenges in developing accurate assays for the measurement of estradiol and testosterone in postmenopausal women. Menopause 2025;32(12):1149–56.

Testosterone is one of the most misunderstood and unstudied hormones in women’s health - dismissed, underprescribed, and a mess of regulatory confusion. This article is our attempt to cut through the noise and examine the evidence.

Here are some of the highlights….

Testosterone isn’t just a “male hormone”

One of the first things we wanted to establish is something many people don’t realize: in reproductive-aged women, daily testosterone production is estimated to be three to four times higher than estradiol. It plays a role in sexual motivation, genital sensitivity, bone metabolism, and more. It’s not a fringe therapy - it’s a hormone that belongs in the conversation about women’s health across the lifespan.

The gap between evidence and practice is striking

This is a number that made me need a couple deep breaths. In a study of over 33,000 women with a diagnosis of hypoactive sexual desire disorder (HSDD), only 850 were prescribed testosterone.

HSDD - persistent low sexual desire accompanied by personal distress - is the only evidence-based, guideline-supported indication for testosterone therapy in postmenopausal women. And yet, even for this indication, testosterone is incredibly underprescribed. That gap reflects real barriers: no FDA-approved formulation for women in the US, diagnostic complexity, and variable clinician comfort. Our article addresses all three.

What the evidence actually says

We reviewed the data across multiple organ systems. Here’s the quick picture:

Sexual function (HSDD): This is obviously where the evidence is strongest. Multiple randomized controlled trials, including the INTIMATE SM phase III trials, have demonstrated meaningful improvements in sexual desire and satisfying sexual events. The ISSWSH guidelines recommend testosterone for postmenopausal HSDD, and our article walks through exactly how to implement that in practice.

Cardiovascular safety: Reassuring. RCTs and observational data consistently show no adverse effects on blood pressure, lipid profiles, or insulin sensitivity when testosterone stays within physiologic ranges - particularly with transdermal delivery, which avoids the hepatic first-pass metabolism that makes oral formulations problematic.

Bone health: This is one of the areas I find to be pretty persuasive, even though we’re not yet at a clinical recommendation. A large retrospective analysis of over 600,000 patients found a significantly lower incidence of hip fractures among those prescribed testosterone replacement - and this is supported by good evidence. Androgen receptors sit on osteoblasts and osteocytes, and testosterone also aromatizes to estradiol, which suppresses bone resorption. Early small studies showed improvements in bone mineral density when testosterone was combined with estrogen. I’m watching this space closely. The evidence isn’t there yet to justify prescribing testosterone for osteoporosis prevention, but I’d be surprised if future well-designed trials don’t move the needle.

Musculoskeletal strength, cognition, mood: Mixed results across the board but to be honest most are generally positive. Current evidence doesn’t support prescribing testosterone for these indications but again, I would be surprised if we didn’t see more and more evidence of positive outcomes.

Dry eye disease and bladder health: Two emerging areas I find early data on actually exciting - even if we have to be honest that they’re still investigational. Androgen receptors are present in the meibomian and lacrimal glands, and a multicenter RCT found that testosterone eye drops markedly improved gland function, with complete symptom resolution occurring frequently. For bladder health, NHANES data suggest women with lower testosterone levels have significantly higher odds of overactive bladder. The biology is really persuasive, the early signals are there - now we need the trials to match.

The regulatory landscape is the real problem

Of course as we all know, no testosterone product is FDA-approved for use in women in the United States.

AndroFeme - a 1% transdermal testosterone cream - is the only regulatory-approved formulation for women globally, available in Australia, New Zealand, South Africa, and (as of July 2025) the UK. In the US, clinicians are left choosing between off-label use of male-formulated products at roughly one-tenth the male dose, or compounded preparations with variable quality.

This isn’t a just an inconvenience, it influences prescribing behavior, creates dosing inconsistencies, and leaves patients without consistent, well-studied options. The FDA has declined to approve a testosterone patch for women despite clinical trial evidence of efficacy. Our article discusses this history and what it means for how we practice.

Practical guidance: what every clinician should know

A major goal of this article was to give clinicians a clear, actionable framework. Some key takeaways:

• Use LC-MS/MS, not immunoassays, for measuring testosterone in women - accuracy matters, especially post-menopause

• Total testosterone is your most reliable marker - the evidence for free testosterone as the “active” form is weaker than commonly assumed

• Target physiologic levels - generally ≤90–100 ng/dL. Don’t push above physiologic range to “overcome” elevated SHBG

• Transdermal is the preferred route - oral and pellet formulations are discouraged and not as safe

• Assess clinical response by 12 weeks, with a go/no-go decision at 6 months

• Base treatment decisions on symptoms and distress, not labs alone

We included a detailed monitoring protocol table, a formulation comparison table, and a “what every clinician should know” summary box in the article - resources I really hope clinicians will use.

Why this matters

Low sexual desire is common - affecting roughly 27% of premenopausal women and over 50% of naturally and surgically postmenopausal women in partnered relationships. And the numbers are likely much higher. But these symptoms of low desire, distress, and treatment is still too often dismissed or undertreated.

Testosterone therapy, used appropriately, is safe, evidence-based for HSDD, and potentially beneficial across multiple other systems. The field is moving. Formulations designed for women are gaining approval internationally. Long-term safety registries are being called for. And the research questions - around cognition, bone, bladder, ocular health - are actively being pursued.

I hope this article helps clinicians feel more confident having these conversations, and helps patients feel seen.

The article is available now as an article in press in Obstetrics & Gynecology Clinics of North America (2026). DOI: https://doi.org/10.1016/j.ogc.2026.03.003

Free access (no login required, available until July 2, 2026):

Have questions or want to discuss a case? I’d love to hear from you.

www.washgyn.com

Make an appointment here and we will ACTUALLY listen to you.

Jennifer Lanoff, WHNP-BC, JD
Washington Women’s Health and Complex Gynecology

These take me a long time to write so thank you for being patient!

A patient comes in. She has endo history and had surgery that was reportedly successful and the path showed DIE (deep infiltrating endo). She’s 44, her cycles are irregular, she’s not sleeping, her pain is back (or worse than before), she has hot flashes and brain fog and her libido is gone. This patient is presenting with a classic perimenopausal presentation on top of a disease that already made everything harder.

When I ask about hormone therapy, she says: “I can’t take estrogen - it’ll make the endo come back.” She’s been told this by more than one provider and so often that she doesn’t even ask anymore.

That advice isn’t wrong, it’s just incomplete, and the gap is doing real harm.

So what is the actual risk?

The concern about estrogen in endo patients is supported by from the evidence. Women with both deep infiltrating endometriosis and ovarian endometriomas have nearly ten times the ovarian cancer risk of women without endo. That data has been shown, most recently from an article by Barnard et al. in JAMA 2024 in a large, well-designed study. So of course that is a very real and serious finding.

Residual lesions - even microscopic ones, even ones that don’t show up on imaging - can be reactivated by estrogen, and it happens even after hysterectomy if ectopic tissue remains.

Because of this, estrogen-only hormone therapy - estrogen without a progestogen to oppose it - is genuinely problematic for this patient. That concern is legitimate and should absolutely inform clinical decision-making.

But “estrogen-only therapy is risky for her” became “she can’t take hormones at all.” Those are not the same statement, and we are conflating them constantly.

The EMAS clinical guide - updated in 2025 - is explicit: menopausal hormone therapy is indicated for women with endometriosis history. Not contraindicated. Indicated. The preferred formulation is continuous combined therapy: estrogen plus a progestogen together, continuously, not cyclically. At that level, recurrence rates run around three percent. There is no documented increase in malignancy risk over six years with combined regimens.

So here is the actual risk picture, sorted out clearly:

Avoid:

• Estrogen-only MHT - even post-hysterectomy in endo patients

• Can reactivate residual lesions. Real risk. Guideline-level recommendation.

Indicated:

• Continuous combined MHT - estrogen plus progestogen together

• ~3% recurrence rate. No increased malignancy risk at 6 years. See EMAS 2025.

Real risk:

• DIE + endometrioma: 9.66x elevated ovarian cancer risk

• Barnard et al., JAMA 2024. This warrants close monitoring, NOT treatment avoidance.

Another real risk:

• Untreated estrogen deficiency in a woman with elevated cardiovascular baseline

• Nurses’ Health Study: endo carries HR 1.14–1.30 for CVD. Undertreating makes it worse.

That last point is the one that keeps getting left out of the conversation - even when we are practicing shared decision making. The patient already carries elevated cardiovascular risk - that’s established in the Nurses’ Health Study data. She already has compromised bone density trajectory because of the disease and possibly the GnRH agonists she’s been on. She already has cognitive and sexual function consequences from her pain and disrupted sleep. Letting her estrogen deficiency go unmanaged doesn’t protect her; it increases harm from a baseline that was already elevated.

We’re not choosing between a risky option and a safe one, we’re choosing between risks, but doing nothing actually IS NOT the safer option.

Why the progestogen choice matters more in this patient than in most

If continuous combined MHT is the right framework; the next question is which progestogen. And this is where it gets super interesting - because the answer matters more for this patient than for almost anyone else, and it’s rarely discussed.

Here’s the pharmacology problem first. Norethindrone acetate - a commonly prescribed synthetic progestin - partially converts to ethinyl estradiol at clinical doses. This is established, confirmed by Chu and colleagues in the Journal of Clinical Endocrinology and Metabolism in 2007. At 10mg, it produces plasma ethinyl estradiol levels around 58 pg/mL. At 20mg, around 178 pg/mL. This is a significant estrogen level. In a patient where the explicit goal is to avoid unopposed estrogen-driven activity in residual lesion tissue, that’s a problem. We’re trying to oppose estrogen with a progestogen that is itself contributing estrogen.

But looking at the progestogen question across the literature, in three completely separate bodies of research - from different clinical domains, using different methodologies, asking different questions - all arrived at the same answer: micronized progesterone, or progesterone-derived progestins like dienogest or drospirenone.

Does this prove micronized progesterone is 100% the right choice? No. The head-to-head comparative trial in endo patients does not exist. The mast cell biology is animal data and has not been confirmed in prospective human studies. When three completely separate lines of research land in the same place, that seems important. Especially when one of those pieces of evidence - the pharmacology of norethindrone acetate conversion - is established human pharmacology.

A recent publication (published since my lecture last month) by Apelian, Chedraui, and Taylor (the same Hugh Taylor whose 2021 Lancet paper is the foundation for this whole series) raises something worth paying attention to, even if the evidence behind it is still early. Based primarily on case reports and small series, they describe the possibility that a subset of endometriotic lesions persisting into or presenting after menopause may carry reduced progesterone receptor expression, more aggressive behavior, and less responsiveness to progesterone. If that's right, it means some postmenopausal lesions may not respond to progestogen-containing MHT the way you'd expect, and that GnRH antagonist resistance has been observed in some of these cases as well. The authors are careful to frame this as a hypothesis that needs prospective study, not an established finding. We really don't yet know how to identify these patients before treatment, and the evidence on how to manage them is limited. But it's a reason to keep this in mind, individualize the approach, and not assume that adding a progestogen solves the problem in every case.

Route of administration is not a minor detail

The route matters - and again, it matters more for this patient than for most. Transdermal estrogen bypasses first-pass liver metabolism, which gives it a much better cardiovascular and thrombotic risk profile than oral estrogen. For a patient who already carries elevated cardiovascular risk, this is is a really important distinction.

And for patients who have POTS - postural orthostatic tachycardia syndrome, which I wrote about in Issue 1 and will go into more in Issue 4 - oral estrogen can worsen orthostatic symptoms. Blitshteyn’s 2026 paper on POTS and menopause specifically recommends transdermal formulations. If the patient has POTS and you give her oral estrogen, you may be making one problem better while making another worse.

The aromatase problem

One thing that doesn’t get talked about enough: endo lesions can produce their own estrogen locally via aromatase. So even a patient whose serum estradiol looks low or who is clinically postmenopausal may have endo lesions that are still running their own local estrogen supply. This is why some women have active symptoms and inflammatory activity even when their labs suggest they should be in a hypoestrogenic state. The lesion microenvironment can sustain itself. This is documented in the Taylor Lancet 2021 review and it explains a lot of the clinical scenarios that can be confusion for both clinicians and patients.

There’s also that newer 2026 editorial (Apelian, Chedraui, Taylor) that complicates this and adds something important here: in postmenopausal women, peripheral conversion of androgens in adipose tissue can also provide enough estrogen to maintain or reactivate lesions - independently of ovarian function and independently of whether she’s on MHT. This means the aromatase problem doesn’t go away at menopause. It just changes shape. For some patients, the source shifts from the lesion itself to systemic adipose conversion, and the lesion keeps going regardless. This is one reason why a group of women are diagnosed with endometriosis for the first time after menopause - the disease was running quietly on non-ovarian estrogen sources the whole time.

And this is exactly why the postmenopausal presentation gets missed so often. The classic symptoms that lead to a diagnosis in the first place, like cyclical pain, painful periods, are gone, because she's had a hysterectomy, or because she isn’t getting her period anymore. What's left is non-cyclical pelvic pain, maybe an adnexal mass on imaging, maybe GI or urinary symptoms that get a GI or urology work up. The 2026 article is explicit about this: the clinical picture in postmenopausal women differs significantly from the reproductive-age presentation, so clinicians are less likely to include endometriosis in the differential for pelvic pain in this population. The disease didn’t change but how we diagnose it did. And that gap between a disease that's still running plus symptoms that no longer look like endometriosis is where women fall through the cracks.

Questions to bring to your next appointment

If you are a patient reading this: you are allowed to be specific. “Can I take hormones?” isn’t specific enough to get a helpful answer. Here are the questions that actually are important to the conversation:

• Is the concern estrogen-only therapy, or all hormone therapy? Because those carry different risks.

• Would continuous combined MHT be appropriate for me? What would you need to feel confident recommending it?

• Which progestogen would you use, and why that one specifically?

• Should I be using transdermal rather than oral estrogen given my history?

• What is the cost of not treating my menopause - cardiovascular, skeletal, cognitive given that I already carry elevated baseline risk from the endo?

If your clinician can’t answer those questions specifically, or if the answer is still just “it’s too complicated” or “better not to risk it” without that level of detail, it may be time for a second opinion from someone who specializes in endometriosis or menopause medicine. Not because your provider is wrong to be careful but because you deserve the actual answer, not the cautious one.

So this part has covered the framework and the hormone question. The next issue goes into the biology that explains why the patient deteriorates at 43 even when imaging looks fine, and this is where I will discuss the mast cell connection, what the research actually shows, and where it’s genuinely compelling versus where it’s still animal data we may be getting a little too excited about. It’s the most complex part of this problem and honestly, the most interesting.

If someone you know is this patient, please share this with them. The information exists, it just isn’t reaching the people who need it!

Menopause + endometriosis is more nuanced than “no estrogen.” There are ways to treat symptoms safely and we should be having that conversation.

www.washgyn.com

Make an appointment here

References

1. Barnard ME, Farland LV, Yan B, et al. Endometriosis Typology and Ovarian Cancer Risk. JAMA. 2024;332(6):482-489. doi:10.1001/jama.2024.9210

2. EMAS (European Menopause and Andropause Society). Clinical guide: MHT in women with endometriosis history. 2025. Available at emas-online.org.

3. Chu MC, Zhang X, Gentzschein E, Stanczyk FZ, Lobo RA. Formation of ethinyl estradiol in women during treatment with norethindrone acetate. J Clin Endocrinol Metab. 2007;92(6):2205-2207. doi:10.1210/jc.2007-0044

4. Taylor HS, Kotlyar AM, Flores VA. Endometriosis is a chronic systemic disease: clinical challenges and novel innovations. Lancet. 2021;397(10276):839-852. doi:10.1016/S0140-6736(21)00389-5

5. Blitshteyn S. Postural orthostatic tachycardia syndrome, menopause and hormone replacement therapy: clinical decisions in times of uncertainty. J Clin Med. 2026;15(4):1477. doi:10.3390/jcm15041477

6. Raffi F, Metwally M, Amer S. The impact of excision of ovarian endometrioma on ovarian reserve: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2012;97(9):3146-3154. doi:10.1210/jc.2012-1558

7. Apelian S, Chedraui P, Taylor HS. Endometriosis beyond menopause: a call for greater clinical awareness. Climacteric. 2026. doi:10.1080/13697137.2026.2658790

This is written by a clinician for educational purposes, is not medical advice, and does not substitute for care from a clinician who knows your history.

This was the topic of a talk I gave earlier this week, and I want to write some more about it because this is a population of patients that no one is thinking about, except to tell them estrogen will bring their endo back (note: this is not true). I see these patients all the time in our clinic.

The patient has endometriosis. It was confirmed - pathology, surgery, a real diagnosis from a real surgeon who knew what they were doing. She followed up and managed it. But now, somewhere in her early forties, something has shifted. Her cycles are weird, her pain has come back or has gotten worse, or changed. She’s exhausted and can’t get enough sleep no matter what. And on top of that she’s got new symptoms she can’t explain - bladder pain, GI issues, dizziness when she stands up, a kind of full-body pain that is new.

So the patient goes back to her surgeon convinced the endo is back. Maybe she gets another surgery or is told to try a different pill. Maybe she gets told that she cannot take estrogen OR that she can’t possibly have pain because her endo surgery was a success. So she just has to get through perimenopause without the best treatment there is for perimenopausal and menopausal symptoms.

So this is what she does, because she’s been managing this for years and that’s what you do when you have chronic pain.

Why this specific patient deserves her own framework

I want to make the case for why the perimenopausal endo patient isn’t just an endo patient who got older. Because once you see her as a distinct clinical picture, a lot of things that seemed confusing start to make sense.

Three things make these patients different:

They hit menopause earlier and harder. Women with endometriosis have significantly reduced ovarian reserve compared to their peers - that’s established, replicated research. Every surgery on an endometrioma accelerates that decline further. So by the time perimenopause starts, the patient is already behind. The transition that’s hard for everyone is harder for her and it starts sooner.

By their early forties, their pain may not be primarily coming from the lesions anymore. This is what I really want to emphasize and what I find so interesting. A landmark 2021 review in The Lancet made the case that endometriosis is a chronic systemic disease, not a pelvic pain disease. It changes the nervous system. And brain imaging studies have documented actual structural changes - reductions in gray matter volume in pain-processing regions - in women with endo. Research on pain thresholds has found that women with endo are more sensitive to pain at their thumb and forearm - sites that have nothing to do with pelvic pain but with their nervous system. And the clinical consequence is that while surgery removes the lesion, it does not reset a nervous system that has been running in a sensitized and inflammatory state for years. So after another surgery that doesn’t make her better, and imaging that looks completely clear, the reflex is to wonder if something was missed, or to start thinking the pain is psychological rather than physical. But the neuroscience gives us a different explanation - her nervous system stayed in a sensitized state. That is biological, measurable, and very much not in her head.

These patients have elevated cardiovascular risk - and undertreating their menopausal symptoms makes it worse. This piece often gets left out of endo conversations. The Nurses’ Health Study data is clear that surgically confirmed endometriosis is associated with significantly higher cardiovascular disease risk. When estrogen deficiency goes unmanaged - which happens constantly, because of that “just don’t give her hormones” is the default - she accumulates cardiovascular, skeletal, and cognitive risk on top of a baseline that was already elevated. So doing nothing is not a safe choice, it’s actually its own kind of harm.

Why perimenopause is the worst possible moment for her system

Perimenopause isn’t simply “estrogen levels dropping.” The hormonal sequence is more chaotic than that, and it matters enormously for this patient.

Progesterone declines first - five to seven years before menopause, erratically, long before most clinicians start thinking about the menopausal transition. Then estrogen goes haywire: not a steady decline, but unpredictable fluctuations and frequent surges to supraphysiologic levels before it eventually drops.

Now add what we know about endo biology. There is a growing body of research - though most of it in animal models - suggesting that progesterone acts as a kind of brake on inflammatory signaling in endometriotic tissue, and that estrogen fluctuations are recognized triggers for immune activation in those same lesions. The immune cells involved - mast cells, which are found in elevated numbers in endo lesions, clustered right next to nerve fibers - appear to be one of the mechanisms linking hormonal chaos to pain. And here’s the finding that keeps showing up in this research: the chemical mediators those immune cells release correlate with pain severity, not with lesion size. So not with what’s visible on imaging but with how much the patient hurts. This is the biological explanation for something clinicians have observed forever - that disease stage doesn’t predict pain.

There’s one more layer. Endometriotic lesions produce estrogen locally - via aromatase activity - independently of what’s happening systemically. So even a post-menopausal patient whose labs look hypoestrogenic may have lesions that are still running their own local estrogen supply. The disease can sustain itself even when the systemic numbers suggest it shouldn’t be active.

So a summary: the progesterone brake disappears first, then estrogen surges. Local production may still be running in the lesion. And the patient’s nervous system is already sensitized from years of disease. That’s why she deteriorates at 43. That’s the specific, mechanistic reason perimenopause is so hard for this patient - not only because it’s hard for everyone, but because the hormonal sequence lands on a system that was already used to exactly this kind of chaos and chronic inflammation.

The estrogen question - and why the answer the patient gets is incomplete

Honestly this shapes everything. The patient was told she can’t take estrogen. That advice came from a real place with all the right intentions. Women with deep infiltrating endometriosis and ovarian endometriomas have significantly elevated ovarian cancer risk - nearly ten times higher, according to a 2024 JAMA study. Estrogen-only hormone therapy, without a progestogen to balance it, can reactivate residual lesions. That concern is legitimate and should absolutely inform clinical decision-making.

But “estrogen-only therapy carries specific risks for this patient” somehow became “this patient cannot have hormones” somewhere along the way. And those are not the same statement.

The actual guideline position - from EMAS, updated in 2025 - is that menopausal hormone therapy is indicated for women with endometriosis history. Not contraindicated. but actually indicated. The preferred approach is continuous combined therapy: estrogen plus a progestogen together (even if the patient has had a hysterectomy). At these low levels, recurrence rates are around three percent, and there’s no documented increased malignancy risk over six years with combined regimens.

The evidence says we have to choose the right formulation very carefully, not withhold treatment. We are conflating those two things constantly, and our patients are paying the price.

The progestogen choice also matters more in this patient than in most - and that’s something I’ll go deep on in a future issue. The short version is that three completely independent bodies of research, coming from different clinical directions, converge on the same practical preference.

What I am going to try to cover

I am going to write a couple of pieces so I can focus on each piece of this patient’s picture. Some will be deep dives into the biology, some will be practical, like here’s what to ask your clinician, here’s what the workup actually looks like, here’s what the research says about X. Of course I will be honest about where the evidence is thin and the field is still figuring it out.

Issue 1 - you are here

The framework: who she is and why she’s different

Issue 2 - coming next

The estrogen question, fully answered

Issue 3

The mast cell connection: inflammation, nerves, and pain

Issue 4

POTS, IC/BPS, and the conditions traveling with her endo

A note on evidence: I’m a clinician and I read the primary literature, and I will always make sure to distinguish between what’s established in human studies, what’s animal or lab data, and what’s still too early to say. I won’t oversell the science but I also won’t undersell it.

The questions I want to answer

These are some of the questions that keep me reading and that I’m going to try to answer here.

• Why does our patient deteriorate at 43 when imaging shows nothing new? And what are we missing when we treat that as a mystery?

• If central sensitization persists after surgery - and the research says it does, in a meaningful subset of patients - what does good post-surgical care actually look like?

• How many women are walking around with undiagnosed POTS, pelvic venous disease, or interstitial cystitis that’s being attributed to endo when it needs its own treatment?

• Is the mast cell research in endometriosis going to produce anything clinically useful - and how far away are we from knowing?

• What does it actually mean to treat her menopause well, given everything else that’s going on?

This is a hard patient and the literature is all over the place. I’m going to do my best to make it accessible!

www.washgyn.com

Appointments here

References:

• Taylor HS, Kotlyar AM, Flores VA. Endometriosis is a chronic systemic disease: clinical challenges and novel innovations. Lancet. 2021;397(10276):839-852. doi:10.1016/S0140-6736(21)00389-5

• As-Sanie S, Kim J, Schmidt-Wilcke T, et al. Functional connectivity is associated with altered brain chemistry in women with endometriosis-associated chronic pelvic pain. J Pain. 2016;17(1):1-13. doi:10.1016/j.jpain.2015.09.008

• Barnard ME, Farland LV, Yan B, et al. Endometriosis and risk of ovarian cancer by histologic subtype. JAMA. 2024.

• Anaf V, Chapron C, El Nakadi I, De Moor V, Simonart T, Noël JC. Pain, mast cells, and nerves in peritoneal, ovarian, and deep infiltrating endometriosis. Fertil Steril. 2006;86(5):1336-1343. doi:10.1016/j.fertnstert.2006.03.057

• Engemise SL, Willets JM, Emembolu JO, Konje JC. The effect of the levonorgestrel-releasing intrauterine system, Mirena®, on mast cell numbers in women with endometriosis undergoing symptomatic treatment. Eur J Obstet Gynecol Reprod Biol. 2011;159(2):439-442. doi:10.1016/j.ejogrb.2011.09.007

• McCallion A, Nasirzadeh Y, Lingegowda H, et al. Estrogen mediates inflammatory role of mast cells in endometriosis pathophysiology. Front Immunol. 2022;13:961599. doi:10.3389/fimmu.2022.961599

• Xu X, Wang J, Guo X, et al. GPR30-mediated non-classic estrogen pathway in mast cells participates in endometriosis pain via the production of FGF2. Front Immunol. 2023;14:1106771. doi:10.3389/fimmu.2023.1106771

• Raffi F, Metwally M, Amer S. The impact of excision of ovarian endometrioma on ovarian reserve: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2012;97(9):3146-3154. doi:10.1210/jc.2012-1558

• Erel CT, Nigdelis MP, Ozcivit Erkan IB, et al. Endometriosis and menopausal health: An EMAS clinical guide. Maturitas. 2025;202:108715. doi:10.1016/j.maturitas.2025.108715

So here it is!

We talk a lot about blood sugar and BMI when it comes to metabolic health in midlife women. And those things absolutely matter. But what this new study looks at is something we’re largely not measuring: fasting insulin. Specifically, what your fasting insulin levels in perimenopause are doing to your hot flashes, your night sweats, and your hormones.

The short answer? A lot more than we realized. And most of us are not checking it.

What the study found

Researchers analyzed data from over 700 women in the SWAN cohort - one of the most rigorous long-term datasets we have on women across the menopausal transition. They measured fasting insulin at age 47 and followed those women for up to a decade. The results:

Women with higher fasting insulin had hot flashes that started earlier and lasted longer.

We’re talking about a 14% higher hazard of hot flashes per standard deviation rise in insulin - and that held up even after controlling for BMI and fasting glucose.

Insulin was doing this independently. Not as a proxy for weight. On its own.

Why insulin? Here’s the biology

The authors explain that insulin isn’t just a blood sugar regulator - it acts on the brain, including the hypothalamus, which controls body temperature. There’s research showing insulin can directly suppress the heat-sensitive neurons that are already being destabilized by falling estrogen during perimenopause. So elevated insulin may be actively narrowing that thermoneutral zone - making hot flashes more likely, more intense, and longer lasting.

The hormone picture gets a lot more interesting too. The study found that higher BMI was linked to slower estrogen decline and a blunted FSH rise - probably because fat tissue produces estrogen that partly buffers the transition. But higher insulin told a completely different story: a steeper rise in testosterone around menopause. That carries its own risks for cardiovascular health.

The gap we need to close

Here’s what frustrates me about all of this. A standard metabolic panel includes fasting glucose. It does not normally include fasting insulin. Which means a woman could walk into your office with perfectly normal blood sugar and completely elevated insulin - and we are missing it entirely. Fasting insulin plus fasting glucose gives you a far more sensitive early marker of metabolic dysfunction. It’s one extra line on a lab order. We should be doing this for perimenopausal women routinely.

Here’s the good news

Insulin is modifiable - and often more responsive to intervention than weight is. Aerobic and resistance exercise both lower fasting insulin independently of weight loss. Insulin reductions tend to come before changes on the scale, not after. Reducing refined carbs, improving sleep, managing stress - these move the needle on insulin in ways that matter for symptom burden, not only for future diabetes risk.

This reframes the conversation in a way we can all find useful day to day. It’s NOT “lose weight to have fewer hot flashes.” It’s: your metabolic health right now - specifically your insulin - is shaping your perimenopause experience. And patients have more agency over that than you (and they) might think.

Bottom line

• Ask about fasting insulin, not just fasting glucose - especially for women in their 40s

• Higher fasting insulin at 47 predicts earlier, longer hot flashes - independent of weight

• Insulin and BMI affect the transition differently: insulin drives testosterone rise, BMI blunts estrogen decline

• Exercise lowers insulin even without weight loss - and that matters for symptoms

• Hyperinsulinemia can precede insulin resistance and obesity - catching it early is the whole point

Perimenopause is not just a reproductive event. It’s a metabolic one. And the more we treat it that way - in the clinic and in the conversation - the better we can actually serve the women going through it.

The research comes from the SWAN study (Study of Women’s Health Across the Nation), one of the most rigorous long-term datasets we have on women’s health across the menopausal transition. Researchers looked at fasting insulin levels in 704 women (so not huge…) at age 47, then followed them for up to a decade. What they found was actually pretty striking.

Women with higher fasting insulin had hot flashes that started earlier - about a year sooner - and lasted significantly longer. That association held up even after accounting for BMI and fasting glucose. This tells us that this isn’t just a weight story. Insulin is doing something here on its own.

Why insulin ?

Most of us think of insulin purely as a blood sugar regulator. But it’s a lot more than that. Insulin acts on the brain — including the hypothalamus, the region responsible for regulating body temperature. Research in rodents has shown that insulin can directly suppress the heat-sensitive neurons that keep your thermostat stable. When those neurons are already being destabilized by falling estrogen during perimenopause, elevated insulin may be making things worse.

There’s also a hormone angle that goes beyond hot flashes. The study found that higher insulin at 47 was linked to a steeper rise in testosterone across the menopausal transition. Higher BMI, by contrast, was more closely associated with slower estrogen decline and a blunted FSH rise - a different pattern entirely. Insulin and body weight are related, but they’re telling different biological stories here.

The gap in standard care

Here’s the frustrating part. A standard metabolic panel — the bloodwork most women get at an annual physical — includes fasting glucose. It does not routinely include fasting insulin. So you could have completely normal glucose and still have insulin levels that are quietly elevated and already shaping your perimenopause experience.

Fasting insulin combined with fasting glucose gives you HOMA-IR, a much more sensitive early marker of metabolic dysfunction. It requires one extra line on a lab order. We should be doing this routinely for women in their 40s, and we’re largely not. That’s a gap worth closing.

The part that’s actually hopeful

Unlike some risk factors, insulin is genuinely modifiable — and often more responsive to lifestyle change than weight is. Both aerobic exercise and strength training lower fasting insulin independently of weight loss. In fact, research consistently shows that insulin reductions tend to come before changes on the scale, not after. If you’ve ever wondered why exercise seems to make you feel better even when your weight hasn’t budged, this might be part of the answer.

Diet matters too — reducing refined carbohydrates, prioritizing protein and fiber, improving sleep quality, managing chronic stress. None of this is revolutionary advice. But framing it specifically around insulin — and specifically around protecting your perimenopause experience — might make it land differently. This isn’t about aesthetics. It’s about how the next decade of your life feels.

What to take away from this

• Ask your doctor for a fasting insulin test, not just fasting glucose — especially if you’re in your 40s

• Higher fasting insulin at 47 predicts earlier onset and longer duration of hot flashes, independent of weight

• Insulin and BMI affect the menopausal transition differently — this is more nuanced than a weight story

• Exercise lowers insulin even without weight loss — and that matters for symptom burden

• Elevated insulin is linked to testosterone rise around menopause, with downstream cardiovascular implications

The menopausal transition is inevitable. How hard it hits is not entirely fixed. Metabolic health in your 40s, and insulin specifically, is one of the levers we actually have access to. The earlier we pay attention to it, the more we can shape what comes next.

Worth acting on.

www.washgyn.com

Make an appointment!

Semaglutide and tirzepatide have truly changed medicine. For millions of people, these drugs are life-changing.

But here’s a question I get a lot: What is that much weight loss doing to my bones?

Losing weight is hard on bone. Your skeleton is a load-bearing structure. When you weigh less, your body responds with less bone mass. Studies show that weight loss of around 7–10% or more increases bone breakdown and also reduces bone mineral density - mostly at the hip. This happens with diet alone and happens after bariatric surgery (fracture risk rises starting around three years post-surgery).

So the more weight you lose, the more this matters. Which means the drugs working best really can actually carry the greatest consequences.

We do have some randomized controlled trial data looking at semaglutide and bone. A (small) trial enrolled 64 adults at elevated fracture risk (mostly women, average age 63) and randomized them to once-weekly semaglutide 1mg or placebo for 52 weeks. Semaglutide produced an average weight loss of 9.4%. BUT it also produced:

• A 2.1% decrease in lumbar spine bone mineral density

• A 2.6% decrease in total hip bone mineral density

• A 54.8% greater increase in CTX - the most important marker of bone breakdown - compared to placebo

This is similar to what we see with caloric restriction, so the effect here may be actually driven more by weight loss itself.

This is interesting, though. There was also another analysis looking at liraglutide (same class) with and without exercise after a low-calorie diet. They compared liraglutide alone, exercise alone, both together, and placebo. Liraglutide alone decreased hip and spine bone density. When combined with resistance exercise, bone density was preserved.

In 2025, the SELECT trial found that among women, hip and pelvic fractures occurred in 1.0% of those on semaglutide versus 0.2% on placebo. In participants aged 75 and older, fracture rates were 2.4% versus 0.6%. However, this trial wasn’t really designed to detect fractures, so we need to view these results in context.

So it seems like based on what we currently know, the people with the most reason to think carefully about bone health before and during GLP treatment are:

• Postmenopausal women. Hopefully we all know by now that bone loss accelerates around menopause - lumbar spine density can fall nearly 2.5% per year during the menopausal transition. Adding weight loss on top of that is not a small thing, especially for women who haven’t had a baseline bone density scan.

• Adults over 65. Older adults also have less bone reserve to lose and are at higher baseline fracture risk.

• Anyone already diagnosed with osteopenia or osteoporosis. If your T-score is already borderline, a 2–3% drop in hip or spine density matters. This population may need bone-protective treatment alongside weight loss therapy.

• People losing very large amounts of weight. Around 7–10% weight loss for has significant bone effects.

+++

The good news is that there are concrete, evidence-based steps that appear to lessen bone loss during GLP-1 treatment:

Resistance training. This is the intervention with the clearest evidence and may actually be protective. The combination of liraglutide plus resistance exercise preserved bone density where liraglutide alone did not.

Calcium and vitamin D. When you eat less, you absorb less. Aim for around 1,200mg of calcium daily, and please try to focus on dietary sources (dairy, fortified plant milks, sardines, leafy greens) and supplementing the gap. Keep vitamin D levels above 30 ng/mL.

Get a DXA scan. If you are postmenopausal, over 50, or have other risk factors, establish your baseline bone density before or shortly after starting treatment. A 2% drop means something different if you’re starting at a T-score of -1.0 versus -2.3.

Talk to your doctor about your fracture risk specifically. FRAX (the standard fracture risk calculator) and DXA results together can help determine whether you need bone-protective medication alongside weight loss treatment.

Don’t stop moving. Weight-bearing exercise is bone-protective beyond its effects on muscle. The sedentary weight loss that some people experience on GLP-1 drugs (less hunger, less energy sometimes) may paradoxically worsen bone outcomes even as the scale improves.

The bottom line

Semaglutide and tirzepatide are amazing drugs for the right patients. The benefits are real. But populations most likely to benefit from aggressive weight loss overlap substantially with those most vulnerable to fracture.

As always, we need more data, particularly from tirzepatide at obesity doses, and particularly with fractures and not just bone density as an endpoint. Until that data exists, we need to make sure to talk to patients about their risks when they start these meds.

Come see me to talk bone health!

www.washGYN.com

Make an appointment here

Karam S, et al. Effects of GLP-1 receptor agonists on bone metabolism and fracture risk. Osteoporos Int. 2025.

Anastasilakis AD, et al. GLP-1 receptor agonists and skeletal health: clinical implications. Diabetes Obes Metab. 2025.

Tsai JN. Women’s Health and Menopause lecture. Massachusetts General Hospital/Harvard Medical School; March 2026.

Kushner RF, et al. Safety outcomes of semaglutide in obesity: results from the SELECT trial. Obesity (Silver Spring). 2025.

I’ve made a few updates - both to the content and how access works - and wanted to walk through it clearly.

Soon will be adding a primer to help explain pelvic venous congestion to your patients.

A reminder - the information provided in these materials is intended for medical education and to support clinical decision-making. It does not replace independent clinical judgment.

What’s changed

I’ve simplified how access works and moved everything to a more reliable system.

You can still choose between:

• Annual payment

• Monthly subscription

Hopefully this allows for a much cleaner and more stable experience going forward.

How to access

You can get access here:

GUIDE LINK

After purchase, you’ll receive immediate access with instructions about how to access but NO sign in.

For previous subscribers

If you were previously subscribed, you’ll need to re-sign up using the links above. I am sorry!

The previous system has been retired as part of this transition.

I really appreciate your support in the earlier version - this update is meant to make access simpler and more reliable going forward.

What’s included

This is a curated set of practical, evidence-informed tools I use for clinical guidance - especially for patients who don’t fit neatly into a single diagnosis.

The focus is on structure, pattern recognition, and decision-making - not just information.

Here is a list of what’s up so far (and they are constantly being updated!)

Pelvic Pain & Inflammatory Conditions

• Pelvic Pentad: Endometriosis as an Inflammatory Disorder

• Endometriosis & Pelvic Pain + MCAS / POTS / EDS (comprehensive + quickstart)

• Pelvic Pain Diagnostic Flowchart

• Vulvodynia Clinical Guide

• Vaginitis Clinical Guide

Hormone & Menopause Medicine

• AUB Risk Assessment & Endometrial Screening Tool

• Bone Health & Osteoporosis (patient guide + clinician pearls)

Sexual Medicine

• Treatment Options for Anorgasmia: A Clinical Guide

Tools

• Spreadsheet + interactive symptom checker

Patient Education Resources

A full set of patient-facing guides covering:

• Pelvic pain & vulvovaginal conditions

• Vaginal health & vaginitis

• Sexual medicine (arousal and orgasm support)

• Hormone therapy and menopause

• Bone health

• Sleep optimization

• Bladder pain and urinary symptoms

Coming soon

• Counseling framework for gene-positive results

• Menopausal hormone therapy in patients with gynecologic oncology histories

Don’t forget the apps!

Pelvic Pain & Sexual Health

Pelvic Pain Pentad

A quick note

All materials are derived from published literature, clinical guidelines, and expert consensus, with references cited where applicable. Clinical decisions must be individualized based on each patient’s history, presentation, comorbidities, preferences, and applicable standards of care.

Clinicians are responsible for verifying medication dosing, contraindications, and regulatory considerations prior to implementation.

These are intended to support clinical thinking - not to replace independent clinical judgment.

This is very much an evolving resource, and I’ll continue to update it as I refine how I approach these patients.

If you’ve been using these already, thank you - your feedback has shaped a lot of what’s here.

Message washgynoffice@gmail.com

Check out my website or make an appointment!

Some of the conditions I treat have a reputation problem - and if you’ve taken care of menopausal patients, you’ve seen a version of this before - even 5 years ago very few clinicians would even TALK to their patients about MHT. The patients know exactly what is going on and by the time they get to me, usually have spent years trying to understand what’s happening in their own bodies. The skepticism tends to come more from clinicians, from institutions that decide what gets studied and taught, and, if I’m being honest, from some colleagues who might read this and change their opinion of me for even entertaining what they’d consider fringe.

I understand that reflex, because I’ve definitely had it myself. But instead of trying to argue about what the evidence is, I’ve been more interested in understanding where that knee-jerk response actually comes from. Medicine is really good at things it can see and measure - RTCs, labs, imaging. That’s what gives something credibility, and what we mean when we say we’re practicing “evidence-based medicine.” When a condition fits neatly into that model, it gets studied and treated. When it doesn’t, it tends to get labeled instead as functional, idiopathic, or psychosomatic - which often says more about the limits of our research than the patient, not to even mention how we’ve historically valued research on women.

By the time most of my patients find me, they’re exhausted in a way that goes way beyond their symptoms. They’ve seen the gynecologist who reassured them that painful periods are normal or prescribed the pill, the GI who called it IBS and recommended fiber, the urologist who told them everything looked fine. Some have had endo surgery - sometimes with successful excision of lesions - and still don’t feel better, and have no real explanation why. Many have also been referred to therapy for the “psychological component” of pain - not always said outright, but often enough that the message is clear.

Endometriosis is a good example because it doesn’t fit neatly into that model. We know it’s associated with lesions and inflammation, but what you see doesn’t reliably match how someone feels. Patients with minimal disease can have severe pain, while others with more extensive disease have very few symptoms. A lot of what likely drives that difference isn’t something we can easily see or measure in clinic.

And that’s really the issue. When something is biologically real but hard to measure, patients end up in that gap. Pelvic pain has always lived in that gap which is part of why it’s been so uncomfortable for medicine to manage. These conditions are underfunded, harder to study, and slower to develop clear diagnostic tools, so patients wait years for answers and often end up doing their own research in the meantime.

Clinicians who tend to do well in this space are the ones who are willing to listen to those patterns and then look for the underlying biology, even when the tools are still catching up. From the outside, that can get labeled as fringe, but a lot of the time it just means the science hasn’t fully made its way into clinical practice yet.

What I tell my patients is that their experience - including the time it took to be believed - is not unusual and doesn’t reflect a problem with them. There is science that helps explain what they’re feeling, even if we don’t have perfect ways to measure it yet. We work with what we know, stay honest about what we don’t, and try not to turn uncertainty into dismissal – that is when we do harm. In a space like this, that’s honestly what makes the care evidence-based.

ALSO for those of you looking to get into the guides - I am fixing it asap!

Find me here.

Come see me! I love the medical mysteries. Appointments here.

This was not something I ever planned on doing and honestly still feels like overkill, but here we are. Also will never do this again (I learned things about Xcode I am trying to forget as quickly as possible!)

These are essentially a streamlined version of my websites - same frameworks, just less text-heavy and easier to use on the go.

They’re not treatment protocols and they’re not meant to replace clinical judgment and I have tons of references listed. They’re really just a way to organize complexity so you’re not constantly starting from scratch with patients. Most of the time there is a pattern - hormonal shifts, neuroinflammation, pelvic floor compensation, mast cell activity - but it’s easy to miss how those pieces are interacting when you’re looking at them one at a time.

This is my attempt to put those pieces in the same place so we can get these patients some relief.

If you’re seeing patients where things aren’t adding up or aren’t responding the way you expect, this is probably relevant to you. If everything in your practice is straightforward and resolves exactly as it should, then you definitely don’t need this and I’m happy for you.

If you do end up using them, I’m genuinely interested in what’s helpful and what isn’t since I update them almost daily.

I am also adding a patient checklist to the website that you can hand to patients so that they know what they are doing.

Come see us! Make an appointment here

Check out my website

BUT when you scroll past the marketing and read the actual ingredient list, you find something that is not estrogen, was never estrogen, and cannot legally be estrogen sold over the counter without a prescription.

What the label says vs. what’s in the bottle

None of those ingredients are estrogen. They are phytoestrogens — plant compounds that can weakly bind to estrogen receptors in the body. That sounds similar. It isn’t.

Phytoestrogens are not estrogen

This distinction matters enormously, and the supplement industry is banking on most consumers not knowing it.

What the science actually shows

Bioidentical estrogen

Chemically identical to estradiol produced by your ovaries. Decades of clinical evidence. Requires a prescription. The gold standard for treating vasomotor symptoms of menopause.

Phytoestrogens

Plant compounds that loosely mimic estrogen. Bind to estrogen receptors at a fraction of the strength. Evidence for treating hot flashes is mixed at best - multiple large reviews find no significant difference from placebo.

The gap

A Cochrane systematic review of phytoestrogen trials found no significant reduction in hot flash frequency compared to placebo. Actual estrogen therapy reduces hot flashes.

A woman in perimenopause with significant vasomotor symptoms - hot flashes, night sweats, disrupted sleep - is experiencing a real, physiological hormone deficit. She may have real reasons to avoid prescription HRT, or she may simply not have had a conversation with a provider yet. Either way, she is a target. And the product targeting her is named to sound like a solution it biologically cannot be.

“Bioidentical” is doing a lot of work in that product name. It implies clinical precision. What it actually describes is marketing language applied to an herbal cream.

Why this is legal

Because of the Dietary Supplement Health and Education Act of 1994, supplement manufacturers don’t have to prove their products do what their labels imply — they just can’t explicitly claim to treat a disease. So you can’t say “treats menopause.” But you can call your product “Bioidentical Estrogen Cream,” list plant extracts as ingredients, and let the consumer fill in the rest.

The word “estrogen” in the name is not a guarantee of estrogen in the product. It is a marketing decision. Under current law, no one is required to stop it.

What to actually look for

If you are looking for actual estrogen therapy, it requires a prescription. Period. Over-the-counter products cannot legally contain pharmaceutical estrogen. Any cream, patch, or capsule you can buy on Amazon without a prescription does not contain it, regardless of what the name implies.

If a clinician has told you that you’re a candidate for hormone therapy and you want to understand your options, that conversation belongs in a clinical setting - not on a product page. Phytoestrogens may have a modest role for some people with mild symptoms, but they are not a substitute for estrogen, and they should not be sold under a name that implies otherwise.

If it’s sold over the counter, it is not estrogen. The supplement industry doesn’t have to lie to mislead you. It just has to name things carefully and let you assume the rest.

References

The North American Menopause Society. The 2022 hormone therapy position statement of The North American Menopause Society. Menopause. 2022;29(7):767-794. doi:10.1097/GME.0000000000002028

Lethaby A, Marjoribanks J, Kronenberg F, Roberts H, Eden J, Brown J. Phytoestrogens for menopausal vasomotor symptoms. Cochrane Database Syst Rev. 2013;(12):CD001395. doi:10.1002/14651858.CD001395.pub4

National Institutes of Health Office of Dietary Supplements. Phytoestrogens. Updated 2023. Accessed March 2026. https://ods.od.nih.gov

U.S. Food and Drug Administration. Dietary Supplement Health and Education Act of 1994 (DSHEA). Updated 2020. Accessed March 2026. https://www.fda.gov

Stuenkel CA, Davis SR, Gompel A, et al. Treatment of symptoms of the menopause: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015;100(11):3975-4011. doi:10.1210/jc.2015-2236

For a long time, a positive genetic test result was delivered with very little context - a result, a set of risk numbers, and a referral. The conversation was often technically accurate but clinically incomplete, leaving patients to process complex, high-stakes information without a clear sense of what to do next. Not to mention that 15 minute visits make meaningful conversations impossible.

The good news is that we have the NCCN Guidelines, which offer a detailed, gene-specific framework for managing hereditary cancer risk. The challenge is that while these guidelines are comprehensive, they are not always easy to translate in real time during a clinical visit. I found myself wanting something that could distill the key points - something visual, structured, and easier to walk through with a patient sitting in front of me.

Hereditary cancers account for roughly 5–10% of all cancer diagnoses, but they carry a disproportionate clinical burden. These patients often present earlier, with more aggressive disease, and have the greatest potential to benefit from early identification and intervention. We now have strong data, effective tools, and growing clinical consensus around management. The remaining challenge is translating that information into a clear, actionable plan.

In practice, we organize hereditary cancer management around three core strategies: enhanced surveillance, preventive medication, and risk-reducing surgery. These can be used individually or in combination depending on the gene, penetrance, age, and patient preference. Earlier and more sensitive screening - particularly MRI-based protocols - allows for detection at more treatable stages. Preventive medications can meaningfully reduce risk in selected patients. And for some, risk-reducing surgery offers the most significant reduction in cancer incidence and mortality. These are evidence-based interventions that can substantially change outcomes when applied appropriately.

A key concept in all of this is penetrance - the likelihood that a pathogenic variant will manifest as disease over a patient’s lifetime. This distinction has direct implications for management. High-penetrance genes such as BRCA1, BRCA2, PALB2, and TP53 are associated with markedly elevated lifetime risks and often warrant more proactive strategies, including consideration of surgery. Moderate-penetrance genes such as CHEK2, ATM, and RAD51 variants confer lower absolute risks, but still significantly above baseline. These patients require structured surveillance and thoughtful counseling; the management is more nuanced, but no less important.

I started putting this cheat sheet together after seeing a 25-year-old patient who tested positive for a BRCA1 mutation after her father was diagnosed. She came in with her parents so we could talk through what this meant and what her next steps might look like. The conversation covered risk estimates, screening, possible surgery, and implications for other family members. Even with a careful, thorough discussion, it was a large amount of information to absorb in a single visit.

This tool grew out of that experience. It’s a simple, practical reference that I now use regularly in clinic to frame risk discussions in real time, compare gene-specific risks, and highlight associated cancers beyond breast and ovarian - including pancreatic, prostate, and syndrome-specific malignancies that are easy to overlook.

The broader point is that a “positive” genetic result is not a uniform category. Risk varies widely depending on the gene, and management should reflect that. High-risk variants often lead to more proactive intervention strategies, while moderate-risk variants require a more individualized approach - but still a clear, structured plan.

Hereditary cancer risk management is now grounded in a strong and evolving evidence base. We have increasingly precise risk estimates, interventions with demonstrated benefit, and guidelines that are updated regularly. What remains essential is the ability to translate that information into a meaningful, patient-centered conversation.

This guide is intended to support that process - helping move from risk identification to informed, practical decision-making.

Make an appointment here

Click here: www.washgyn.com for more info

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Based on NCCN Guidelines v3.2026. These are updated frequently, and it is important to confirm current recommendations when making clinical decisions. This content is for educational purposes and not a substitute for individualized medical care.
For education only - genetics referral as appropriate