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Why Housing Costs Are So High - Spacing Vancouver | Spacing Vancouver

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[Editor’s Note: Patrick Condon is a well-respected voice on local planning issues and a contributor to Spacing Vancouver. Recently, he sat down with The Tyee’s David Beers to discuss affordability and his most recent book Broken City: Land Speculation, Inequality and Urban Crisis. We are posting the interview in full below, with permission from the author.]

Here on The Tyee, University of British Columbia professor of landscape architecture Patrick Condon has often argued that merely rezoning for density and fast-tracking mainly market-rate developments won’t fix affordability crises in cities like Vancouver. His opposition to some developments and policies for not delivering enough low-income housing has drawn attacks from people who argue the time for such quibbling is past and we need the sweeping, denser zoning imposed from above by the BC NDP government.

Condon’s response over the past two years has been to go largely quiet on these pages while writing Broken City: Land Speculation, Inequality and Urban Crisis, the academic, peer-reviewed book published this spring by UBC Press. Its basic thesis is that unfettered speculation, fuelled by global wealth looking for asset investments, drives Vancouver land costs up so high they erase savings that can be delivered by building many units on a parcel instead of a few.

That’s why, Condon says, new towers keep rising but their units cost the same as surrounding housing rather than pressuring price drops. If we don’t get a handle on land price super-inflation, he argues, we can’t deliver affordability. And he has some ideas about how to do that.

Settle in for a conversation that runs longish in service of the respectful probing for clarity and nuance needed in this charged moment for housing policy discussions.

David Beers: Hi Patrick, congratulations on Broken City. Truly a useful and provocative challenge to what a lot of us take for granted about housing affordability these days. I suggest we have a back-and-forth by email to craft an interview-like result. So, first question: Why did you write this book?

Patrick Condon: I wrote this book, originally, in a state of emotional cold fury. I was and am furious about how all the efforts made by me and others over the course of three decades of adding well-planned new density to this city failed to make housing as affordable as we had hoped.

You see, what brought me to Vancouver originally was its reputation for “city building done right.” The urban life opportunities created at False Creek South and Yaletown were already famous in the 1990s when I arrived — famous for providing new medium- and high-density housing, with rich amenities at your doorstep, for average wage earners and their families.

I enthusiastically embraced the idea that if you got the density right, and got the amenities right, the home prices would be affordable as a result. That strategy became known as “Vancouverism” and is the visible legacy of hundreds of citizens, staff members, and elected officials working to what was, in retrospect, a shared vision of a sustainable 21st-century city.

But as time passed and home prices spiraled more and more out of reach for average wage earners in defiance of simple notions of “supply and demand,” I felt betrayed. I know others my age and background in this city who feel the same sense of loss.

It’s not widely known but Vancouver has added more housing than any other centre city in North America. Since the 1970s, Vancouver has tripled its total number of housing units. If adding housing supply and new density to a city leads to affordable housing as many now contend, Vancouver should have the lowest housing prices in North America. It has the highest!

So this book is my attempt to understand why this didn’t work out, and what can be done about it.

Beers: And the thesis of your book is that land prices in Vancouver, which is a rather geographically confined global city, are unhooked from local income levels. Rather, at a moment when wealth is increasingly concentrated among a global elite, land has become the place to stash their wealth, and as they turn land into wealth-storing assets, they bid each other up. So, land prices now have increased fivefold in Vancouver over the past 15 years, while income levels have stayed fairly flat.

Still, people will say, that no matter how expensive land gets, building 25 storeys of units on top of it instead of a single-family home is bound to yield more homes at more affordable prices. No?

Condon: You are correct that the common expectation is that this problem is solved if you just add new density onto expensive land in the hope of diluting the land price component. But if you just rezone for more density, you find that the main beneficiary of the upzoning is not the renter or owner, but the land speculator. And that the final rental or ownership cost of the new units is no lower, and most often even higher, than the housing units nearby.

That’s not true just for Vancouver; it’s global. Particularly throughout the so-called English-speaking world. Sydney, Australia, just edges out Vancouver on the very top of the Demographia list of the world’s most unaffordable cities when measured against median household income, which is the lowest of any North American centre city by the way.

Simply stated, urban land has the tendency to absorb every nickel of value created by the people living and working above it into its price.

Urban land is a monopoly product and like any monopoly, there is little limit on its asset value, a price based on its location in the centre of commerce. “Buy land, they are not making any more of it,” Mark Twain famously said.

Twain said this at a time when it was more obvious to all, the height of the American Gilded Age when the fabulously wealthy were making most of their money on urbanized or urbanizing land. That historically repeating cycle of urban land wealth was interrupted in the early 20th century when sequential economic shocks — the First World War, the Great Depression, and the Second World War — in relatively short order collapsed the relative value of urban land worldwide. So we got used to the idea of urban land price not being a serious impediment to affordable housing.

We are now in the habit of thinking if housing prices are too high it must be a problem of restrictive zoning, or construction costs, or taxes. It’s not. It’s a problem of our gradual return to the norm where land absorbs too much value uselessly, and unrelentingly, into the value of urban land. It’s the return of “landlordism,” really, a problem that the first real economist, Adam Smith, identified 250 years ago.

Beers: What you’ve just said would seem to be not at all “anti-progressive.” Instead, you seem to be naming ever-widening wealth inequality and late capitalism as the culprit.

Yet I’ve noted when you’ve floated similar ideas when writing in The Tyee, you attract on social media all kinds of name-calling. People who say more and denser development is inherently a solution, and a progressive one, call you a NIMBY and all kinds of other names. It feels weirdly visceral to me as if these “abundant housing” advocates don’t want to entertain your basic thesis.

And yet I have known you for 30 years and I know you to be squarely in the camp of those trying to make housing more affordable. You’ve never argued for keeping things the same. You’re no defender of single-family zoning. For example, you’ve argued in The Tyee for sweeping zoning that would lock in far more co-ops. You’ve argued market mortgage and rental developments should include more sub-market or not be built. You’ve argued for lots of forms of infill that have very much a densifying effect.

Why do you think you’ve received such backlash?

Condon: I am exactly identifying wealth inequality and late capitalism as the culprit. Or more precisely, a global economy that has moved markedly away from one based on earned wages to one based primarily on the value of assets — a global economy based on your assets making money, not your wages. Urban land now represents, by far, the largest single asset category on Earth, exceeding other categories by many trillions of dollars.

The housing problem, both here and elsewhere, is part of a larger global shift (as economist Thomas Piketty points out) from an economy based on wages to an economy based on assets. Currently, the world’s growth comes from assets making money rather than wage earners making money. Of these assets, the lion’s share is in the single category of urban land, worldwide.

So, anyway, this shift has pushed the values of urban land up and out of sync with regional wages. Housing prices end up escaping their traditionally assumed “real estate fundamental” ratio of four to one, home price to annual wages. That ratio in Vancouver is now 12 to one.

My assertion is this: the only way regions can get control of this out-of-control phenomenon is by exerting control over the land base and asking for a degree of social benefit to accrue from these global investments. This puts me in a different camp from those who argue that more market-driven density alone will bring down the cost of housing by itself. Sometimes, yes, I have spoken against denser development but not because I’m opposed to density, per se, but because if it can’t deliver affordability, then we must ask whether this particular proposed building is a good precedent to approve.

As for attacks on social media, I must say that the ability to block is a wonderful thing. But beyond that, it’s true that this turn of events is a peculiar twist for me to experience at the end of my professional career, after decades of writing and working with communities on making mixed-use, affordable, and walkable communities come to life.

I guess to anyone that calls me a NIMBY I’d have to politely respond that this is laughable. And in this, I am not alone. There are scores of now aging architects, planners, urban designers, and elected officials who helped create this amazing city, who are similarly reviled for arguing, as I do, that just throwing proper planning away, with all its associated social benefits, the benefits that made Vancouverism famous, is not a path to affordability. The opposite is true. The ordinary tools of planning and zoning policy can and have been used to gain amazing levels of social benefits in this remarkable city.

To throw all of that away in blind allegiance to the libertarian conceit that an unfettered market will eventually lead to affordability is simply not credible. And it’s certainly not “progressive.” This attitude really represents a “trickle-down housing” revival of the 1980s “trickle-down economics.” Trickle-down housing is no more likely to work now than did the trickle-down economics of the 1980s.

Beers: Yes, there has been, to me, a surprisingly sharp turn in popular notions of how to design a livable city, what was hailed in the late 20th century as the New Urbanism. As an adherent, you championed mixed-use, walkable, mixed-income neighbourhoods with three-to-six-storey buildings along a broad web of light rail lines as a way to densify a city while maintaining its human scale and reducing dependence on polluting cars.

There was also the feeling in your cohort that local citizens could be involved democratically in shifting their neighbourhoods towards such approaches, if the benefits were explained in a respectful way. Granted, in the richest parts of Vancouver the blowback to pretty much any changes has long been fierce. But residents in poorer neighbourhoods also enjoyed the right to speak out against what was planned for their communities.

Now local democracy has been swept aside by provincial fiat in ways that deprive all neighbourhood residents of much if any input.

What would you say to people who greet this change by saying the old approach gave residents too much power to protect single-family lots, and anything new, particularly lower-income housing, was nigh impossible to push through? Do we need to sacrifice local democracy for that reason?

Condon: That’s a contention that is wildly at variance with reality. First off, the complaint that housing is unaffordable because NIMBYs block new development is demonstrably false. For example, the previous council, charged with adjudicating all zone change requests in the context of public hearings, had 250 zone change requests that came before them. Despite many citizens raising objections at public hearings, all but one were approved, and that single instance was ultimately approved after design variations. So, if NIMBYs are the problem, they are a profoundly ineffective one.

Second, a lot of research shows that planning decisions do not restrict housing growth. At best, they direct the market into mutually beneficial locations, enhanced by the negotiated public benefits consequent to the urban plan.

For example, Yaletown is a very well-planned area where market value was enhanced by amenity demands made on development, where proceeds from “land lift” ended up being used for things like the seawall, which in turn increased the value of nearby homes. A true “both and” solution. I am a strong believer that working with communities is the best way to arrive at these kinds of “both-and” solutions. Former Vancouver city planning manager Larry Beasley often says the same thing.

Exemplary high-density projects like the Arbutus Lands result from this deep civic collaboration. My own work and publications draw from the strain of planning belief, manifested especially in my East Clayton project and described in my Design Charrettes for Sustainable Communities book.

So, to blame local democracy for our affordability problems is a tragic mistake, especially here where highly collaborative, neighbourhood-focused urban design became world famous. We have sadly lost that plot.

The Broadway plan is based on the flawed notion that development need not pay for itself in the form of civic amenities and affordable housing because this will impede the magic of the “free market.” Vancouver is the built proof that this is false.

Beers: I’d like to return to an assertion you made quickly earlier in our conversation, one you elaborate on well in your book. You say:

“Simply stated, urban land has the tendency to absorb every nickel of value created by the people living and working above it into its price.”

Can you explain in a bit more detail how this works?

Condon: I first heard that phrase from Richard Wozny, a well-known Vancouver real estate consultant, now deceased. For me, it took time to fully understand the significance of his aphorism.

It is this: when the public improves a part of a city with private investment, like a job centre, or a public investment, like a subway, the effect of this improvement is to elevate land values within the impact zone of these improvements, up to and even over the aggregate value of all these improvements. The main influence of this land price inflation goes to the landowner, and in particular to the land speculator who is smart enough to anticipate this effect — “getting in on the ground floor,” so to speak.

We see this influence now along the Broadway subway corridor, where land values have more than doubled in just a few years and for many strategic parcels increased by 1,000 percent.

Nobel Prize-winning economist Joseph Stiglitz made his reputation for proving that the value of these changes, embodied in land price, met or exceeded the aggregate value of these improvements, leading to the conclusion that this added value tied up in land price should be taxed at levels equivalent to these area-wide, or citywide, improvements. He proved that this could pay the full cost of the social and physical infrastructure needed by the city.

We don’t do that. We tax land value at about one percent of its true value through property taxes. That leaves most of this gain on the table as capital gains, which are not taxed at anything like its full value and not until sold.

Anyway, all this sheds light on a problem: the financial benefits of our collective efforts go largely to the land speculator, and this land price inflation is by far the biggest reason why developers, who would love to provide affordable housing if they would not go broke trying, can’t do so.

The market, influenced by all these improvements, pushes land prices too high for affordable housing to “pencil out,” and sadly, when cities allow new density without any form of social benefit required, this too generally inflates land prices, eliminating the hoped for affordability gains assumed to be the result of new density allowances.

Beers: What you are saying can feel a bit like we’re up against unalterable laws of physics. Land, the dark star that sucks up all matter, er, money. But in your book, you say recognizing this phenomenon actually is the first step to making policy to counter it. I’m sure Tyee readers are all ears. What are your prescriptions then for making housing in a city like Vancouver more affordable if it’s not just adding more and more supply and hoping market prices come down?

Condon: Yes, it does sound a bit daunting when you realize that the very structure of urban real estate economics is working against your social ambitions — ambitions such as broad access to affordable housing.

When you look to the past for solutions there are places where you see we took a wrong turn on the land problem. Political economists like Adam Smith in the 1700s and Henry George in the late 1800s had real solutions to the land problem. They said if you are going to tax anything in a free market economy, tax not productive labour or entrepreneurs, but tax the land it all sits on — the landlord. If you don’t, the landlord will take more and more of the pie (or “products of production”) in the form of monthly rent or land purchase price.

Taxing the land at its “full rent value” shifts collective gains away from land price and into productive labour and capital. Both Smith and George claimed that this would allow taxes on incomes and capital gains to maybe be zero, taking the tax burden off of the two productive factors of production: workers and entrepreneurs.

Sadly their views did not win out. At the turn of the 20th century, when national land taxes were considered, Gilded Age barons, whose wealth was largely from the asset value of various lands, were strongly opposed. There is more on this history in my book.

Beers: So, what was the “wrong turn” we took back then?

Condon: The U.S. put its new national tax on income, not on land. Even Milton Friedman, famous conservative financial guru, wistfully said a land tax would have been best, but alas.

My own view is that a major shift of the tax structure away from income and capital gains onto land is today politically unlikely in the extreme. But happily, there are models for regional-scale actions that can mitigate the damage.

In fact, Vancouver is sort of famous for one of these: the community amenity contributions or CAC tax on “land lift.” This tax specifically targeted the moment of upzoning, in recognition that this was also the moment where land prices could increase by a factor of 10 or even more, to insist that 80 percent of this new value would go to social benefit — benefits including affordable housing, parks, community centres, and a first-class public realm.

The point here is that the CAC tax strategically targets the assessed change in land value consequent to the public policy change (upzoning in this case) being deliberated. In this way, a locality can capture land value for local area social benefit.

This is a modern version of the general land tax economists have long recommended. It is modern because it captures this value locally, not nationally, and it is acquired at the incremental moments of city change using the ordinary rules of zoning policy. Less disruptive. Less revolutionary. More possible within our current framework of laws.

Vancouver has, sadly, over the years lost the plot on this one, where now in the Broadway plan this land lift model has been replaced entirely. To incentivize market-rate rental construction over condo projects we are streaming what would have been land lift to the city to private developers so they will agree to finance market-rate rental construction.

A more direct model is flat-out “density bonusing” for affordable housing. Municipalities can simply institute a requirement that a certain, hopefully, large percentage of new units are perpetually affordable for households making average regional income and below.

This requirement puts downward pressure on land prices. If developers know they can’t build market-priced units for global buyers on a certain parcel of land, they won’t bid up its price. The price of the zoned-for-affordable land will adjust to the lower profits that can be made.

I suggest that 50 percent permanently affordable is a reasonable benchmark for large, zoned parts of Vancouver going forward.

In my view the very best model for density bonusing comes from Cambridge, Massachusetts, where they allowed double density anywhere in the city — but only in return for 100 percent permanently affordable housing.

The point again is this: in Cambridge, if you want to sell your land into the land market, you can sell at present market value under current zoning. If you want to double the density, fine, but the rents have to be at permanently affordable levels. To make the second case “pencil out,” the land price residual (i.e., your offer to the landowner) should not end up much higher than the market price under current zoning.

In short, the Cambridge model incentivizes affordable housing and at the same time suppresses land speculation by placing a ceiling on what the development land can sell for.

Beers: Hmm. How long has Cambridge had those zoning rules in place, and have significant amounts of below-market housing resulted? Did the investors respond, activating the private equity market to fund below-market housing, which seems the elusive dream?

Condon: Let’s see. Since the Cambridge bylaw was passed a few years ago, the number of housing units in the pipeline is pushing 1,000, which is a big chunk for a small urban city of just over 100,000 residents. I also think this number represents the majority of higher-density units built citywide during that same period. In that sense, its success certainly proves the method — that is of shifting the market towards the non-market mentioned earlier.

As for financing, the money came mostly from the financial markets at prevailing rates, but with the government assuming financial risk. This is basically the financial model used here from the 1970s to the 1990s to get places like False Creek South and Champlain Heights up and running. Again, we are not talking about taxpayer-subsidized housing but managing the land markets to stream zoning-related increases in land value away from the already overstuffed pockets of speculators into social benefit instead.

Beers: OK, but what about massive government investment in below-market housing that I hear some left-wing affordability advocates calling for? Some real estate economists argue that’s not effective because we are at a point where you can never really build enough and it creates a lottery for the lucky few who get the housing. They tend to say the government should increase welfare payments and other cash subsidies for low-income people to help pay market rents.

Another option you haven’t mentioned yet, but I’ve heard you suggest in the past, is using a lot of publicly owned land to build below-market housing — like public golf courses — because that gets around the land speculation issue.

Condon: I am for an all-hands-on-deck strategy to find ways to use our land base for social good.

The provocative proposal for the golf course restructuring makes sense because it too is a way to leverage global investment for local social benefit.

There are other ways, such as predetermining a land tax on development, as passed by the Vancouver City Council in 2018, for lands along the upzoned Broadway corridor. The tax was $340 for each additional interior square foot over current zoning. Sadly, this lost its effect thanks to a later council decision to shift to largely market rental units, not condos, along the corridor. Rentals were, and are, exempted from this tax.

Beers: Right, so to boil it down, let’s presume B.C. Premier David Eby and Vancouver Mayor Ken Sim are in a book club, and they read yours. Naturally, each decides to appoint you their special adviser on housing policy. Right off, what key things would you advise them to do?

Condon: An extremely unlikely scenario, I must say. But I would offer the following.

In the shorter term I would ask them to extend rent control beyond the tenant to the unit itself — so called “vacancy control.” This also has the benefit of making rental district lands less attractive to the global real estate investment trusts, or REITs, by reducing the speculative value of these city lands.

Second, starting no later than Monday, do it like Vienna did — by renting city lands for NGOs or co-op corporations to build on at prices that match what affordable rents can amortize. There are many parcels available.

Over the longer term, do not allow new density unless 50 percent or more of the new units are permanently affordable. Increasing this from its current policy of 20 percent below market to 50 percent “permanently affordable to median wage earners” may slow development in the short term, but in time the land markets will adjust to this new requirement.

You see, within the next 30 years, the large majority of all private parcels in the city will be sold to someone. And when that happens, if my advice is followed, those parcels will be sold at land prices that are “market” prices at that time — prices that you will have not yourself inflated with the kind of unconditional upzoning we are allowing today unfortunately.

This is a process of what you might call “disciplining the land market.” Currently, the land market is very undisciplined in Vancouver. In fact, built into how our city land markets are working is an assumed large annual increase in urban land value inflamed by allowing new market density citywide — as we have done.

Unless this trend can be slowed, the market will likely never be able to deliver affordable housing. We are currently just feeding the land price inflationary beast.

Disciplining the land markets via a suggested 50 percent permanently affordable requirement is, I would argue, a locally practical way to hold down urban land prices. Vienna and Singapore, two very good precedents, did something similar. They both shunted more and more of their urban land beyond the reach of the global market, all by managing land value.

Vienna did it by taxing residential land at a high rate to drive down its speculative value while producing the revenue needed to purchase city land for affordable housing.

Singapore had an easier time of it in one key respect. Much of their urban land belonged to the city, and still does. In Singapore, the city rents out the land that housing sits on to new residents at affordable rates. Residents thus own the apartment unit itself, sans land value. That lets homeowners build equity on their unit but not the land.

But of course, having Premier Eby and Mayor Sim embrace and advance these policies is an impossible dream, because both of them are touting the exact opposite approach—a kind of “trickle-down housing” solution that assumes government impediments, not land speculation itself, stand in the way of cheaper housing. They both support releasing development from most of the social betterment requirements, in the faith that this will lower prices.

It won’t. It will just make landowners richer.

The recent raft of housing bills passed by the B.C. legislature last November are illustrative of what is now an international trend. All three bills (44, 46 and 47) remove local policy control over city building. They justify this approach, remarking that “getting out of the way of the private sector,” (or words to that effect) will make housing cheaper.

But hold on! Vancouver is literally world famous for adding, over the entire post-Second World War era, proportionately more new market-rate housing units than any other North American centre city. It flowed from Vancouverism.

If adding density to an already built-out city automatically led to a more affordable city, Vancouver should have North America’s cheapest housing. It has North America’s most expensive.

*This piece was originally published on The Tyee

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Endometriosis in a Man as a Rare Source of Abdominal Pain: A Case Report and Review of the Literature - PMC

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Endometriosis occurs when a tissue resembling endometrial glands and stroma grows in ectopic sites, commonly causing infertility and pain. This condition is most often seen in women of reproductive age, involving pelvic sites such as the ovaries, broad ligaments, uterosacral ligaments, and posterior cul-de-sac. Very rarely, endometriosis has also been found in the lower genitourinary tract of men. A 40-year-old man presented to his primary care physician with abdominal pain. Further imaging discovered a midline mass. Surgical removal of the mass and histological investigations led to the diagnosis of endometriosis. There are multiple theories on the etiology of both female and male endometriosis. The prevailing risk factor proposed in previous cases of male endometriosis is prolonged exposure to estrogen therapy. Should endometriosis become symptomatic, cessation of estrogen therapy and careful surgical intervention may successfully relieve the associated symptoms.

Endometriosis has largely been studied in women, yet the precise etiology is unknown. In extremely rare cases, endometriosis is also found in men with a total of 16 cases previously reported in the literature [115]. In these cases, endometriosis was most commonly found attached to the bladder, lower abdominal wall, and inguinal region. It was previously hypothesized that either prolonged estrogen therapy [1, 3, 5, 79, 11, 13, 15], liver cirrhosis [2, 6], or chronic surgical inflammation [2, 6, 12] was a prerequisite for the development of endometriosis in males. We report a case of endometriosis in a 40-year-old man that was confirmed through immunohistochemical analysis. None of the commonly reported clinical risk factors for male endometriosis were evident in this patient; thus, we postulate hormonal alterations secondary to obesity as the main contributing factor to this patient's pathology.

A 40-year-old man with no significant past medical history presented to his primary care physician with worsening intermittent right lower quadrant abdominal pain radiating to his right flank. This pain was described as a constant dull ache with intermittent sharp pains. For the last three days, he had feelings of being bloated with progressive abdominal discomfort. His medical history was unremarkable aside from asthma, hypertension, and obesity with BMI of 35.7, while family history was significant for ovarian cancer in his mother. Of note, within the past week, he was treated with a course of high dose steroids for asthma exacerbation. His social history consisted of being a father to four biological children. Upon presentation, the patient denied dysuria, diarrhea, and blood or pain with bowel movements. On physical exam, he had a distended abdomen with right lower quadrant tenderness but no costovertebral angle tenderness, rebound tenderness, or guarding. A CT scan of the abdomen and pelvis revealed a large midline pelvic complex cystic lesion that appeared to arise from the right vas deferens (Figures 1(a) and 1(b)). Radiology recommended an MRI for clearer visualization and location of the mass based on results of the CT scan (Figures 1(c) and 1(d)). The MRI displayed intensity of the mass on T2-weighted imaging (Figure 1(c)). The distal portion of the right vas deferens was also dilated near the ejaculatory duct junction. The patient had followup appointments with general surgery and urology for surgical evaluation. A joint procedure between general surgery and urology was planned for cystourethroscopy, diagnostic laparoscopy, and excision of the pelvic mass.

Figure 1

Computed tomography scan with contrast [(a) sagittal and (b) axial] displaying a complex midline cystic pelvic mass with thick walls found between the bladder and the rectum. Sagittal MRI of the pelvic mass with (c) T1-weighted imaging and (d) intensity on T2-weighted imaging.

A cystourethroscopy was performed to visualize the urethra and prostate. Diagnostic laparoscopy confirmed the presence of a mass anterior to the rectum and under the parietal peritoneum covering the dome of the bladder. The remainder of the procedure was converted to exploratory laparotomy for safer removal of the mass. The mass was palpated and found to be separate from the bladder and prostate and attached to the right vas deferens near the junction of the bladder and prostate. The right vas deferens was surgically divided proximal to the mass. A 9.0 × 5.6 × 5.3 cm, 125 g mass was successfully excised without evidence of invasion into surrounding structures or vasculature.

Gross exam of the mass in the operating room revealed a central cystic cavity with cloudy brown fluid. Further, the results from immunological stains performed by pathology revealed a highly unexpected diagnosis with an immunoprofile consistent with endometriosis. The H&E stain (Figure 2) displayed a layer of endometrial epithelium with underlying stroma. The cells lining the cystic mass stained strongly positive for CK7 (Figure 3(c)) and estrogen receptors (Figure 3(a)). CD10 stains were positive (Figure 3(e)) and CD15 staining was focally positive (Figure 3(d)) in the underlying stromal-like tissue. GATA-3 stain was negative. The patient was discharged on postoperative day two. In a two-week followup appointment, he had complete resolution of abdominal pain.

Figure 2

Immunohistochemical analysis staining with H&E at 100x, 200x, and 400x displaying epithelial cells and underlying stromal cells.

Figure 3

Immunohistochemical analysis stained (100x) (a) strongly positive for estrogen in epithelial and stromal cells, (b) strongly positive for progesterone receptor in epithelial and stromal cells, (c) strongly positive for CK7 in epithelial cells, (d) focally positive for CD15, and (e) positive for CD10 in the cytoplasm of stromal cells.

Identifying the causative factors of endometriosis in men may shed light on the existing theories of endometriosis in women, which include retrograde transport, immunologic, induction, and coelomic metaplasia [16]. Further, this may provide evidence against the prevailing theory of retrograde transport as studied in female endometriosis. In the transport model, viable endometrial tissue is refluxed in a retrograde manner through the fallopian tubes during menstruation and grows on surrounding structures including the pelvis and peritoneum [16]. This theory would not explain the incidence of endometriosis in males who lack menstruation material. Thus, a more likely theory of induction of embryological remnants causing development of endometriosis should remain at the forefront.

A comprehensive review of risk factors, location, immunohistochemistry, and outcome of prior documented cases of endometriosis in males has been accomplished for comparison (Table 1). Most of the cases involve increased estrogen in men with liver cirrhosis [2, 6] or prostate cancer treated with long-term estrogen therapy [1, 3, 5, 79, 11, 13, 15]. Although this patient did not have the aforementioned risk factors, it is possible that his obesity with a BMI of 35.7 caused increased systemic estrogen levels. In the case reported by Zamecnik and Hostakova, the only identifiable risk factor was obesity as well [14]. Several studies have identified a clear, positive association between increased obesity in men and increased estrogen production [17]. This phenomenon is likely associated with increased aromatization activity of adipose tissue, overexpression of proinflammatory cytokines, insulin resistance, and hyperactivation of insulin-like growth factor pathways [17]. In relation to male endometriosis, it could be theorized that this increase in aromatization could provide pathologically elevated estrogen levels to drive the growth of endometriosis from remnant embryological cells in a male.

Reported cases of endometriosis in males.

Source Age Risk factors Clinical presentation Immunohistochemistry Location, size Treatment Followup
Beckman et al. [1] 78 Prolonged estrogen therapy Not reported Not reported Prostatic urethral crest Not reported Not reported
González et al. [2] 52 Cirrhosis, spironolactone use, 2x inguinal hernia repair Stabbing pelvic pain Epithelium: ER+, PR+ 
Stroma: CD10+
R. inguinal area, attached to bladder serosa, 2.5 cm Surgical resection Not reported
Fukunaga [3] 69 9 years of hormonal therapy for prostatic adenocarcinoma, 1 year of radiotherapy and chemotherapy Swelling of the left testis on a routine examination Vimentin+, CD10+, ER+, PR+ L. paratestis, 5.2 × 3.1 × 3.0 cm Bilateral orchiectomy Not reported
Giannarini et al. [4] 27 Not reported 2 weeks of postcoital left scrotal pain ER+, PR+, CK7, 8, 18, 19+, vimentin, CEA, CD10− Head of the L. epididymis, 1.7 cm Surgical resection Asymptomatic at 5 years
Young and Scully [5] 82 3 years of DES for prostatic adenocarcinoma Palpable firm mass on the tail of the epididymis on routine examination Not reported Between vas deferens and testis, close to the tail of the epididymis, 5 cm Bilateral orchiectomy Died 9 months later due to metastatic prostatic adenocarcinoma
Jabr and Mani [6] 52 Cirrhosis secondary to Hep. C; inguinal hernia repair with mesh Right lower quadrant pain ER+, PR+, CD10+ Cystic mass attached to urinary bladder and right inguinal area, 4.5 × 2.5 cm Surgical resection Asymptomatic
Martin and Hauck [7] 83 TACE therapy for prostatic adenocarcinoma Not reported Not reported Lower abdominal wall Not reported Not reported
Oliker and Harris [8] 80 Prolonged hormonal therapy Not reported Not reported Bladder Not reported Not reported
Pinkert et al. [9] 50 TACE therapy for prostatic adenocarcinoma Hematuria, hydroureter H&E Ulceration surrounding trigonal area, bladder muscular wall Surgical resection, discontinued hormonal therapy Asymptomatic at 4 years
Tulunay et al. [10] 43 Within clear cell carcinoma of tunica vaginalis Hemoptysis, abdominal pain, weight loss H&E Left paratestis Left orchiectomy Died 2 weeks later due to tumor progression
Schrodt et al. [11] 73 5-year hormonal therapy for prostate adenocarcinoma Right hydronephrosis Not reported Right ureterovesical junction Not reported Not reported
Simsek et al. [12] 49 Inguinal hernia repair ×3 Intraoperative hernia repair, mass discovered along the spermatic cord H&E Left ductus deferens, 8 × 7 × 6 cm Surgical resection Not reported
Taguchi et al. [13] 74 Radical prostatectomy for prostatic adenocarcinoma; leuprorelin and ethinylestradiol for 5 years Painless macrohematuria ER+, PR+, CD10+, PSA− Left ureteral orifice, 3 cm Surgical resection, discontinued hormonal therapy Tumor shrank on imaging; no PSA elevation at 6 months
Zamecnik and Hostakova [14] 46 Obesity, BMI of 31 Cyst found adjacent to seminoma Epithelium: ER+, PR+, CK5,6,7+, calretinin+, EMA+ 
Stroma: PR+, calretinin+, CD10+
Within mesothelial cyst of tunica vaginalis; 4 mm focus of endometriosis found in 7 mm cyst Right-sided orchiectomy Not reported
Scully [15] Not reported Hormonal therapy for prostate adenocarcinoma Not reported Not reported Scrotum Not reported Not reported
Scully [15] Not reported Hormonal therapy for prostate adenocarcinoma Not reported Not reported Scrotum Not reported Not reported
Present case 40 Obesity, BMI of 35.7 Right lower quadrant abdominal pain radiating to the right flank CK7+, ER+, CD10+, CD15+, GATA-3− Right vas deferens, 9.0 × 5.6 × 5.3 cm Surgical resection Asymptomatic at 2 weeks

The induction theory of endometriosis hypothesizes that embryonic cell rests may persist in males and be induced into endometrial tissue. Divergence between male and female urogenital systems occurs from a common primordium, allowing for homologous structures to exist between the two genders [16]. The Müllerian ducts, which form the majority of the female genitourinary tract, normally disintegrate in males under the influence of anti-Müllerian hormone [9]. Thus, the cranially located appendix testes and caudally located prostatic utricle are typically the only vestigial structures derived from paramesonephric ducts [14]. The prostatic utricle serves as a homologue of the uterus and vagina [18]. It could therefore be theorized that while in the majority of males the Müllerian tissue atrophies completely, Müllerian cells may rarely persist between the ejaculatory duct and vas deferens when imperfect dissolution occurs [9]. These cell rests can further differentiate into endometrial tissue and lead to the development of endometriosis in males, likely under the influence of prolonged estrogen therapy or inflammation due to repeat surgeries [2, 6, 12]. The embryonic cell rest theory is the most congruent with the majority of cases of male endometriosis including the present case, as many of these lesions have occurred along the route of the Müllerian duct.

A third theory of endometriosis involves inadequate immune function. Various studies have cited alterations in both cell-mediated and humoral immunity [16] that coincide with the development of endometriosis. While this data shows promise, the exact mechanism needs to be further elucidated, especially in male patients, to show clear causation between the two.

Lastly, the coelomic epithelium metaplasia theory hypothesizes that, under the influence of certain signaling mechanisms, likely inflammatory cytokines, the peritoneal mesothelium undergoes metaplasia into tissue that resembles endometrial-like tissue and stroma. This theory could explain how women with Müllerian agenesis, who completely lack a uterus or have only a hypoplastic uterus, still show incidences of endometriosis [16]; however, it is less supportive than the induction theory. One case report of male endometriosis is in support of the coelomic epithelium metaplasia theory as the discovered endometriosis retained residual mesothelial phenotype, thus suggesting continuity and origin with a mesothelial cell layer [14].

The present and previously published cases of endometriosis in males may provide insight into the true origin of endometriosis. This presiding clinical evidence discredits the leading theory of retrograde menstruation as the dominant origin of endometriosis and points more towards an embryologic origin as the mechanism of this disease process.

The authors declare that there are no conflicts of interest regarding the publication of this paper.

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Articles from Case Reports in Obstetrics and Gynecology are provided here courtesy of Wiley

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This should put the nail in the coffin for the retrograde menstruation hypothesis
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Until this connection was discovered - thanks to the chemo drug - people with this condition were told there was nothing wrong with them or they were just anxious or imagining things.

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Dichloroacetate for the treatment of endometriosis-associated pain (EPiC1): a single-arm feasibility study - The Lancet Obstetrics, Gynaecology,

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Introduction

Endometriosis is a chronic incurable condition affecting an estimated 190 million women worldwide.

1

It is defined by the presence of endometrial-like tissue outside the uterus (lesions), commonly on the peritoneum. Hallmarks of the disease include debilitating pelvic pain and infertility. Management options for endometriosis-associated pain are often unsatisfactory; painful symptoms recur within 5 years following surgical treatment in 40–50% of women,

2

and drug treatments are often ineffective or have unacceptable side-effects.

3

Furthermore, as the mainstay of medical treatments are hormone-based and usually contraceptive, they are inappropriate for women desiring pregnancy, and the hypo-oestrogenic state induced by gonadotropin-releasing hormone agonists can preclude long-term use.

4

Therefore, there is an urgent unmet need for new non-hormonal treatments for endometriosis.

5

Research in context

Evidence before this study

We searched PubMed for articles published from database inception to June 1, 2025. We used the search terms “endometriosis” AND “treatments” AND “dichloroacetate” OR “sodium dichloroacetate” OR “dichloroacetic acid”. Three studies were found, which included our published study protocol. The second paper was a summary of our preclinical studies, in which dichloroacetate appeared a promising non-hormonal treatment for endometriosis. The third paper replicated our preclinical findings of elevated pyruvate dehydrogenase kinase 1 and lactate concentrations in endometriosis stromal cells, and that treatment with dichloroacetate inhibited lactate levels. There were no published in vivo studies assessing dichloroacetate in patients with endometriosis. In previous clinical trials, in both paediatric and adult populations with other conditions such as congenital and acquired lactic acidosis, diabetes, and liver cirrhosis, dichloroacetate was effective at reducing systemic lactate levels. In trials of dichloroacetate in glioblastoma, pulmonary hypertension, and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes syndrome, higher doses of dichloroacetate, or more prolonged treatment regimens resulted in a reversible peripheral neuropathy.

Added value of this study

This study represents the first reported use of dichloroacetate in individuals with endometriosis. The study assessed the feasibility of conducting a trial, using the outcomes of recruitment and retention. The study generates novel insights into dichloroacetate-related adverse effects in this population. Genotyping was also done to assess any association between GSTZ1 haplotypes, drug concentrations, and susceptibility to adverse effects. This study was the first time that genotyping had been performed specifically for this enzyme in patients with endometriosis.

Implications of all the available evidence

Although this trial was not designed to evaluate the efficacy of dichloroacetate or to determine whether it exerts disease-modifying effects in endometriosis—as previously suggested by preclinical models—we have shown the feasibility of recruiting individuals with endometriosis into dichloroacetate-focused clinical research. Although not all retention metrics were achieved, these shortfalls were attributable to necessary adaptations in study delivery imposed by the COVID-19 pandemic, rather than deficiencies in the design of the trial. On this basis, we believe advancing to a randomised placebo-controlled trial assessing dichloroacetate for the treatment of endometriosis with the use of genotyping as a means to mitigate side-effects and optimise treatment tolerability, is appropriate. A further larger, definitive, adequately powered, placebo-controlled trial will ultimately be required to determine whether dichloroacetate is an effective treatment for endometriosis-associated pain. Should efficacy be established, the off-patent status of dichloroacetate could make it a cost-effective therapeutic option, addressing the crucial need for a non-hormonal medical treatment in endometriosis care.

We have previously shown that pelvic peritoneal mesothelial cells recovered from women with endometriosis exhibit substantially higher glycolysis and increased production of lactate compared with pelvic peritoneal mesothelial cells from women without endometriosis.

6,7

Single-cell sequencing of paired eutopic and ectopic endometriosis lesions has confirmed the latter have an altered metabolic signature.

8

In tumours, lactate is a key factor driving cell invasion and angiogenesis,

9

processes also implicated in the establishment and survival of endometriosis lesions. These data prompted us to investigate whether dichloroacetate, a pyruvate dehydrogenase kinase inhibitor, could be a novel non-hormonal therapy for endometriosis. We showed that dichloroacetate normalises pelvic peritoneal mesothelial cell metabolism, reduces lactate secretion, and abrogates endometrial stromal cell proliferation in a co-culture model. In mice with induced endometriosis, dichloroacetate reduced peritoneal fluid lactate production and lesion size.

10

Others have confirmed that dichloroacetate reduces lactate levels and pyruvate dehydrogenase kinase 1 activity in cultured stromal cells from endometriosis lesions.

11

Dichloroacetate is already used as a treatment for pyruvate dehydrogenase deficiency in neonates and children

12

and has been assessed in phase 2 and 3 trials for multiple conditions including other mitochondrial disorders,

13

pulmonary hypertension,

14

and malignancy.

15,16

Results from these trials informed our choice of dose of 25 mg/kg or less, because some individuals reported a dose-related reversible peripheral neuropathy with higher doses.

17

Notably, response to dichloroacetate can be influenced by the haplotype of the gene that encodes the enzyme

GSTZ1

.

17

Carriers of the genetic variant

GSTZ1C

are reported to metabolise dichloroacetate faster than non-carriers, which could have implications for the risk of developing side-effects.

18

We aimed to perform a single-arm feasibility study of dichloroacetate for the treatment of endometriosis-associated pain. The key questions were whether a subsequent randomised controlled trial could be feasibly conducted, and whether the uncertainties surrounding recruitment and retention could be effectively addressed before proceeding.

Methods

Study design

We conducted a single-centre, single-arm, open-label feasibility study at the Royal Infirmary of Edinburgh, NHS Lothian, UK (EPiC1). Ethics approval for EPiC1 was obtained from Scotland A Research Ethics Committee (19/SS/0063). Following completion of the study, participants were invited to consent to provide an additional blood sample for genotyping of the dichloroacetate metabolising enzyme,

GSTZ1

. Ethics approval for genotyping was obtained from West Midlands–Solihull Research Ethics Committee (22/WM/0158). The trial protocol has been published.

19

A patient panel informed the study design and development of patient-facing materials. The trial was registered with

ClinicalTrials.gov

(

NCT04046081

).

Participants

Participants were recruited from gynaecology outpatient clinics in NHS Lothian, UK. Recruitment was temporarily suspended during 2020 due to the COVID-19 pandemic, forcing some participants to be withdrawn. An anonymised screening log was maintained of potential participants, including reasons for non-eligibility and reasons for not participating if eligible.

The inclusion criteria were premenopausal women aged 18 and older; bodyweight of 50–100 kg; American Society for Reproductive Medicine stage I or II endometriosis surgically confirmed within the past 5 years; and pelvic pain for more than 6 months with an average pain score over the preceding 4 weeks of 4 or more on a numerical rating scale of 0–10. Patients were excluded if they were pregnant, actively trying to conceive, or breastfeeding, or if they had a history of pre-existing peripheral neuropathy, malabsorption, diabetes, or kidney or liver disease. A full list of inclusion and exclusion criteria is given in the protocol.

19

Participants were advised to use effective contraception throughout the trial if they were sexually active. Ethnicity was self-reported. Participants were permitted to use hormonal medication if they had started treatment more than 3 months previously.

All participants provided written informed consent. For women recruited after Aug, 20, 2020, consent was initially obtained by telephone, with written consent obtained at the first study visit.

Procedures

Dichloroacetate was provided in capsules containing 333 mg or 500 mg dichloroacetate powder (Curaltus, Vilnius, Lithuania). The total duration of treatment was 12 weeks.

19

Participants were prescribed dichloroacetate at a dose approximate to 6·25 mg/kg total bodyweight twice daily for 6 weeks. After 6 weeks, if good control of painful symptoms had been achieved, the participant continued the dose without escalation. However, if participants had ongoing painful symptoms and tolerable side-effects, they were asked to increase the dose to an equivalent of 12·5 mg/kg total bodyweight twice daily. If side-effects were experienced at the higher dose, the participant could opt to return to the 6·25 mg/kg total bodyweight dose twice daily. Throughout the study, if a participant had side-effects and no improvement in pain symptoms, they could discontinue treatment. Participants were permitted to take oral analgesics and alternative treatments for pain.

Average pain scores over the preceding 4 weeks were recorded on a 0–10 numerical rating scale for assessment of eligibility. At baseline, after informed consent had been received, we obtained demographics, past medical history, and information about current treatments, and we asked participants to do a urine pregnancy test. We asked participants to complete the Endometriosis Health Profile-30,

20

PainDETECT,

21

Brief Fatigue Inventory,

22

and Pain Catastrophizing Questionnaire,

23

as well as provide recalled average pain scores over the preceding four weeks on a numerical rating scale of 0–10, at baseline and after 6 weeks and 12 weeks of dichloroacetate use. At the end of the 12-week study, and 4 weeks after cessation of dichloroacetate, participants were asked to complete an acceptability questionnaire (11 questions using a 5-point Likert scale) and a perception in change of overall health as rated using a 7-point Likert scale).

Before the COVID-19 pandemic, blood pressure, pulse, respiratory rate, and oxygen saturation were checked at baseline (visit 1) and weeks 2 (visit 2), 6 (visit 3), 8 (visit 4), and 12 (visit 5). Venous blood samples were also obtained at these timepoints, for measurement of dichloroacetate levels. Following the pandemic (March 17–Aug 20, 2020), all these assessments were performed at baseline and weeks 6 and 12 only. Adherence was assessed by the study nurse at each study visit by questioning patients and reviewing dichloroacetate levels.

Dichloroacetate levels were assessed by liquid-chromatography with tandem mass spectrometry. Serum was obtained from venous blood collected in 9 mL Sarstedt Monovette Serum gel tubes (Sarstedt, Leicester, UK); the tubes were centrifuged at 2500 g at 4°C for 10 min and stored at –80°C until liquid-chromatography with tandem mass spectrometry was carried out for analysis of dichloroacetate levels. This method was validated following European Medical Agency guidelines

24

for bioanalytical methods.

All participants were offered genotyping, which enabled exploration of the effect of the

GZTZ1

haplotype on dichloroacetate levels. Sanger sequencing was performed on venous blood samples obtained from the subset of participants who consented. DNA was extracted from venous blood collected in 9 mL EDTA tubes (Sarstedt) using the QIAamp blood mini kit (Qiagen, Manchester, UK) following the manufacturer's instructions. DNA was quantified using the Nanodrop 1000 (Thermo Fisher Scientific, Loughborough, UK) and adjusted to 10 ng/μl. Primers specific to

GSTZ1

single-nucleotide polymorphisms (Thermo Fisher Scientific;

appendix p 1

) were analysed using

SNPcheck

. Sanger sequencing was performed on Applied Biosystems 3500XL (Thermo Fisher Scientific) in the accredited NHS Lothian Molecular Pathology Department (Edinburgh, UK) under ISO 15189:2012.

Adverse events were assessed at each study visit by the study team in addition to ad hoc reporting by participants. All adverse events were reviewed by the Principal Investigator or delegated to clinicians within the study team who were also responsible for determining the likelihood of association with dichloroacetate use. Known side-effects, including reversible peripheral neuropathy, were not reported as adverse events but were collected in the case report form at each study visit. Persistent peripheral neuropathy was graded according to Common Terminology Criteria for Adverse Events (version 4.0). Grade 3 neuropathy and below was not considered as a serious adverse event.

Outcomes

Our primary outcomes were recruitment and retention. Retention was assessed based on the proportion of recruited participants ever receiving dichloroacetate who at week 6 (visit 3) and week 12 (visit 5) completed the six retention metrics including submitting their average numerical rating scale scores, completing the assessment tools (ie, the Endometriosis Health Profile-30, PainDETECT, Brief Fatigue Inventory, and Pain Catastrophizing Questionnaire), and attending per-protocol blood testing. Recruitment of 50% or more of the eligible patients approached, and retention of 80% or more of the participants who commenced treatment and completed all per-protocol metrics of retention, was deemed acceptable for progression to a subsequent randomised controlled trial based on our previous feasibility studies.

25,26

Secondary outcomes included measures of adherence (ie, self-reported compliance and presence of dichloroacetate in serum), self-reported side-effects, and study acceptability (as per the questionnaire at study end).

Statistical analysis

The emphasis in this study was to establish feasibility, not statistical significance. We aimed to recruit 30 participants. Assuming the target of 50% eligible individuals recruited was achieved, this would allow us a precision of less than 15%. Summary data were used to describe baseline characteristics: for continuous variables mean and SD or median and IQR, and minimum and maximum were reported, and for categorical variables the number (percentage) of individuals was reported. The recruitment and retention rates were reported with exact binomial 95% CIs, due to the small sample size. Questionnaires were scored according to the manuals or author guidelines supplied. A statistical analysis plan was created before any analysis was done (

appendix p 31

).

Role of the funding source

The funders had no role in study design, data collection, data analysis, data interpretation, writing of the report, or the decision to submit the results for publication.

Results

Screening of patients began on Nov 19, 2019, and the last participant started dichloroacetate on April 23, 2021. The study ended on Aug 13, 2021. Recruitment was paused during the COVID-19 pandemic from March 17 to Aug 20, 2020. As advised by the funder, participants who were in the first 6 weeks of treatment were withdrawn from the study (ie, two participants). Participants who were in week 7 or later were allowed to continue treatment, but subsequent visits were conducted remotely (five participants).

Of 93 women who were identified by screening, 77 patients could be contacted and were approached to participate (

figure

), of whom 54 (70%, 95% CI 59–80) were eligible. Of the eligible women, 30 (56%, 95% CI 41–69) were recruited. One participant was withdrawn immediately after consent as their bodyweight was greater than the 100 kg limit for the inclusion criteria. The remaining 29 (97%) participants were prescribed dichloroacetate and were used to calculate subsequent retention metrics. Two (7%) people were lost to follow-up and a further nine (30%) stopped their treatment early (three due to side-effects, two due to unexpected pregnancy, two due to restrictions following the onset of the pandemic, and two due to anxiety). 18 (60%) participants completed all 12 weeks of treatment.

Figure Trial profile

*Other reasons for non-eligibility: laparoscopy date outwith protocol criteria (n=2), no endometriosis at laparoscopy (n=1), weight obtained following consent outwith protocol criteria (n=1), abnormal liver function test (n=1), Gilbert syndrome (n=1), breastfeeding (n=1), and evidence of pre-existing peripheral neuropathy (n=1).

Participant characteristics are reported in

table 1

. All participants were female. The initial dose of dichloroacetate was determined by the bodyweight of the participant. At 6 weeks, 19 (83%) of 23 participants still receiving dichloroacetate had had their dose escalated (

appendix p 2

).

  n=29*
Age at time of informed consent, years25 (23–30)
Height, cm164 (163–168)
Bodyweight, kg67·0 (57·4–74·5)
BMI, kg/m224·3 (21·1–27·5)
Education
 Primary0
 Secondary1 (3%)
 Tertiary28 (97%)
Ethnicity
 White28 (97%)
 Mixed or multiple1 (3%)
 Asian or Asian British0
 Black, African, Caribbean, or Black British0
Stage of endometriosis
 I22 (76%)
 II7 (24%)
Average pain score (scale 0–10)
 41 (3%)
 54 (14%)
 66 (21%)
 78 (28%)
 86 (21%)
 91 (3%)
 10 (worst)3 (10%)
Average pain score7 (6–8)
Number menstruating20 (69%)
Number reporting period pain8 (8–9)
Number using hormonal treatment20 (69%)
Contraception used (not mutually exclusive)
 Combined oral contraceptive pill3 (10%)
 Progesterone only pill3 (10%)
 Contraceptive patch1 (3%)
 Progesterone implant2 (7%)
 Injectable progesterone1 (3%)
 Levonorgestrel-releasing intrauterine system11 (38%)
 Condoms6 (21%)
 Tubal ligation0
 Vasectomy2 (7%)
 Copper intrauterine device0
 Other1 (3%)
 None (not sexually active)2 (7%)
Baseline analgesic use
 Paracetamol13 (45%)
 Non-steroidal anti-inflammatory drug19 (66%)§
Opiate
 Any22 (76%)
 Weak opioid20 (69%)
 Strong opioid**6 (21%)
Neuromodulator††7 (24%)‡‡
Table 1

Baseline participant characteristics

Data are n (%) or median (IQR).

*

30 participants consented but one was excluded immediately after consenting due to weight being outside the study criteria. Data for the 29 participants who were eligible to proceed to treatment are reported here.

A further seven participants took paracetamol as part of co-codamol.

Ibuprofen, naproxen, mefenamic acid, or diclofenac.

§

Four participants reported the use of more than one type of non-steroidal anti-inflammatory drug.

Seven participants reported the use of more than one type of opiate.

Codeine, co-codamol, dihydrocodeine, or tramadol.

††

Pregabalin, amitriptyline, nortriptyline, or duloxetine.

‡‡

One participant reported the use of two neuromodulators.

Of 145 possible study visits that could be completed by the 29 participants who commenced treatment, 128 (88%, 95% CI 82–93) were completed. However, only 19 (66%, 56–89) participants completed all retention metrics, which was predominantly due to missing numerical rating scale scores for pain at week 12, which were returned by 21 participants (72%, 56–89;

table 2

;

appendix p 7

). The eight people who did not return scores were the two individuals who had been lost to follow-up and six participants who stopped treatment. All other individual metrics for retention had rates of more than 80% (

table 2

). Numerical rating scale scores for pain were returned in week 6 by 24 (83%, 69–97) participants, and 27 (93%, 73–98) participants completed some (ie, one to two or three) questionnaires at the final study visit in week 12 (

table 2

). Pain scores and questionnaires at baseline, week 6, and week 12 are reported in the

appendix (pp 7–8)

. Perceived change in analgesic use was reported at weeks 2, 6, 8, and 12 (

appendix p 9

).

 Number of participants on treatmentStopped treatment since last visitNumerical rating scale score returned (%)Questionnaires returned (%)
Visit 1 (consent day and proceeding to treatment; week 0)29*N/A29 (100%)29 (100%)
Visit 2 (week 2)281N/A28 (97%)
Visit 3 (week 6)24424 (83%)26 (90%)
Visit 4 (week 8)222N/A23 (79%)
Visit 5 (week 12)18421 (72%)27 (93%)

Retention was assessed based on the proportion of recruited participants proceeding to treatment (n=29) who submitted their average numerical rating scale scores for pain at visits 3 (6 weeks) and 5 (12 weeks) and completed the Endometriosis Health Profile-30, PainDETECT, Brief Fatigue Inventory, and Pain Catastrophizing Questionnaire at these timepoints. The additional retention metric was attendance for per-protocol designated blood testing at visits 3 and 5 (n=24 and n=14 respectively;

appendix p 3

). N/A=not applicable.

*

30 participants consented but one was excluded immediately after consenting due to their bodyweight being outside of the study criteria and so did not commence treatment and was not replaced.

Acceptability questionnaires were returned by 17 (94%) of the 18 participants who completed 12 weeks of treatment and by five (45%) of the 11 who stopped treatment early (

table 3

). Most participants described their experience positively (

table 3

).

  Stopped treatment earlyCompleted treatment
Number who completed a questionnaire5/11 (45%)17/18 (94%)
Overall experience of EPiC1 participation
 1 (positive)1 (20%)14 (82%)
 22 (40%)2 (12%)
 32 (40%)0
 401 (6%)
 5 (negative)00
Acceptability of paperwork
 1 (positive)2 (40%)11 (65%)
 21 (20%)4 (24%)
 31 (20%)1 (6%)
 41 (20%)1 (6%)
 5 (negative)00
Acceptability of side-effects
 1 (positive)06 (35%)
 21 (20%)5 (29%)
 32 (40%)4 (24%)
 402 (12%)
 5 (negative)2 (40%)0
Table 3

Acceptability

At week 2, 28 (97%) participants were still taking dichloroacetate; at week 6, 23 (79%); week 8, 22 (76%); and 18 (62%) participants completed all 12 weeks of treatment. Self-reported adherence in those continuing to take dichloroacetate was good with at least 95% of participants, across all weeks, reporting taking all or almost all of their medication (

table 4

). For those participants who stopped between visits they could still return their diaries, which would include the dichloroacetate that they had taken before stopping.

 Week 2 (n=28)Week 6 (n=24)Week 8 (n=23)Week 12 (n=21)
None (0%)0000
Hardly any (1–24%)0000
Some (25–49%)01 (4%)01 (5%)
Most (50–74%)001 (4%)0
Almost all (75–99%)14 (50%)17 (71%)12 (52%)15 (71%)
All of it (100%)14 (50%)6 (25%)10 (43%)5 (24%)
Table 4

Compliance with dichloroacetate treatment

N denotes the number who returned compliance data (ie, patient-reported self-assessment of the proportion of how much dichloroacetate had been taken). This includes participants who had stopped taking dichloroacetate since the preceding study visit but still returned study diaries.

At week 6, 24 women were still in the study (one had stopped taking dichloroacetate but had not been withdrawn). Of the per-protocol visits for blood testing (encompassing protocol changes that required some participants not to attend for testing due to COVID-19 restrictions or if they had stopped treatment), 24 (100%; 95% CI 86–100) attended for blood sampling at week 6 and 12 (86%; 57–98) of 14 participants at week 12 attended (

appendix p 3

). Testing of venous blood samples confirmed that dichloroacetate had been used in all participants who were tested, except for four blood samples from three participants (

appendix p 3

). Two of these participants had low levels of dichloroacetate in the first stage of treatment before undetectable levels later in the study. Both participants reported completion of treatment, although both returned only some of the end of study assessments. A third participant had undetectable levels at week 6 and discontinued treatment before week 12.

No serious adverse events or changes in blood pressure were reported. 12 (41%) of 29 participants reported a total of 21 adverse events (

appendix p 4

), of which 12 (57%) were unrelated to dichloroacetate treatment, as determined by the study team. Known side-effects of dichloroacetate were frequently reported (

table 5

). The most common side-effect was nausea, reported by 17 (61%) of 28 participants at any time during the trial. 15 (54%) participants reported a tingling sensation, consistent with paraesthesia, or numbness. Most occurrences of these known side-effects were intermittent and mild, but six participants developed persistent symptoms consistent with peripheral neuropathy (

appendix p 5

). Four had grade 1 neuropathy and one each had grade 2 and grade 3; in these latter two cases, treatment was stopped by the trial team after dose reduction did not substantially improve symptoms. A further two participants with grade 1 neuropathy stopped treatment early for unrelated reasons: one because of the onset of the COVID-19 pandemic and one from anxiety. All occurrences of peripheral neuropathy fully reversed with the cessation of treatment. One participant who developed neuropathy had a PainDETECT score in keeping with neuropathic pain at baseline, but no other participants who developed neuropathy returned scores in keeping with neuropathic pain at any timepoint. Of the two women who became pregnant during the study and discontinued, one opted for medical termination of the pregnancy in the first trimester (maternal choice, unrelated to study participation). The second continued with her pregnancy: fetal anomaly, cardiac scans, and growth scans were all normal and a healthy baby was born at term.

 Week 2 (n=28)Week 6 (n=24)Week 8 (n=23)Week 12 (n=21)At any time (n=28)
Tingling or numbness6 (21%)6 (25%)6 (26%)10 (48%)15 (54%)
Sleepy6 (21%)5 (21%)3 (13%)3 (14%)10 (36%)
Confused002 (9%)1 (5%)2 (7%)
Heartburn5 (18%)5 (21%)5/22* (23%)5 (24%)11 (39%)
Mental fogginess3 (11%)4 (17%)3 (13%)5 (24%)8 (29%)
Nausea11 (39%)4 (17%)8 (35%)2 (10%)17 (61%)
Other (see adverse events)01 (4%)2 (9%)1/20* (5%)4 (14%)
Any of the above20 (71%)17 (71%)16 (70%)13 (62%)26 (93%)
Table 5

Known side-effects associated with dichloroacetate use

Data are n (%) of those reporting the presence of these side-effects.

*

One participant did not answer this question.

Ten participants consented to genotyping, of whom five had developed peripheral neuropathy during treatment (

appendix p 6

). One participant's sequencing results did not pass quality control and was not repeated. The two participants who had grade 2 or 3 neuropathy were homozygous for polymorphisms associated with slow metabolism (

GSTZ1B/GSTZ1B

and

GSTZ1D/GSTZ1D

); the two participants reporting grade 1 neuropathy were heterozygous (both

GSTZ1C/GSTZ1B

). Of the other five individuals who underwent genotyping but who did not report neuropathy, one was homozygous for the fast metabolism polymorphism (

GSTZ1C

/

GSTZ1C

) and four were heterozygous for fast and slow polymorphisms. Of the four participants who were heterozygous, two had not increased their dose and one had dose reduction after escalation for intermittent side-effects. None of the three participants who had undetectable dichloroacetate levels at blood testing underwent genotyping.

Discussion

The EPiC1 study is the first trial reporting the use of dichloroacetate in women with endometriosis. The primary objective was to determine whether women with endometriosis would wish to take part in a study using dichloroacetate. EPiC1 successfully met its prespecified threshold for acceptable recruitment and achieved all but one retention metric. Retention challenges were largely attributable to the COVID-19 pandemic due to the nationwide restrictions on in-person hospital visits. Despite this, participants reported favourably on the acceptability of the study and no serious adverse events were reported. Side-effects such as gastrointestinal upset and paraesthesia were common but consistent with the known safety profile of dichloroacetate, and only three participants stopped treatment because of these side-effects. These findings support further investigation of dichloroacetate as a potential treatment for endometriosis.

The COVID-19 pandemic affected trial delivery, with a halt in recruitment and loss of some follow-up data for seven participants who had already commenced treatment. As follow-up visits for any participant who stopped treatment early were rationalised on resumption of the trial, this could have affected the collection of numerical rating scale scores, which were collected in person at study visits. The collection of numerical rating scale scores was the only retention-related metric not to reach 80%. By contrast, end-of-study questionnaires (which were completed online) were completed by all participants, including those who had stopped treatment, except the two who were lost to follow-up. Recruitment and retention outcomes were broadly comparable with those in a pre-pandemic feasibility study investigating another non-hormonal therapy for endometriosis.

26

The shift to remote delivery for study aspects, including telephone consent and online completion of questionnaires, could improve recruitment and retention in a future randomised controlled trial of dichloroacetate. These strategies might also enhance accessibility for historically under-represented groups, such as those from lower socioeconomic backgrounds, for whom more frequent hospital visits pose logistical and financial barriers to participation.

All participants were advised to use effective contraception if they could become pregnant during study participation. In animal studies, dichloroacetate exposure in utero is associated with an increased rate of miscarriage, cardiac and renal congenital abnormalities, and decreased birthweight.

27,28

Although our study reports the first pregnancy outcomes in women receiving dichloroacetate, and no adverse outcomes occurred in the completed pregnancy, substantially more robust safety data would be needed before dichloroacetate use could be considered in those actively trying to conceive.

Reversible peripheral neuropathy was reported by some participants, despite a lower initial dose of dichloroacetate than the 25–50 mg/kg per day used in previous studies for other indications.

17

However, most occurrences of neuropathy developed after dose escalation, and only two affected participants stopped treatment specifically because of neuropathy, at the instigation of the trial team. For all participants reporting neuropathy, symptoms resolved after treatment cessation, although the time to resolution was typically associated with neuropathy grade. Although previous studies have suggested dichloroacetate-associated neuropathy is broadly dose-dependent,

15,18

no clear plasma concentration threshold has been identified.

17

In our study, the two participants with the highest dichloroacetate serum levels experienced a higher grade of peripheral neuropathy. However, some of those with grade 1 neuropathy had similar dichloroacetate levels to those without a persistent neuropathy, which suggests additional factors could influence susceptibility. Other studies have postulated that age and comorbidities such as diabetes, or chemotherapy-induced peripheral neuropathy, could increase vulnerability to dichloroacetate-related neuropathy.

13

Notably, the two participants with higher-grade neuropathy were homozygous for

GSTZ1

haplotypes associated with slow dichloroacetate metabolism (

GSTZ1B

and

GSTZ1D

). Conversely, the participant who was homozygous for

GSTZ1C

had one of the lowest serum levels at week 6, but the other two participants with low dichloroacetate levels were not genotyped, preventing further speculation. Another participant had an early onset of grade 1 peripheral neuropathy, but due to the COVID-19 pandemic stopped treatment in week 3. It is uncertain whether they would have developed more severe symptoms if they had continued with treatment. Of the remaining participants with grade 1 neuropathy, one stopped treatment early due to anxiety unrelated to neuropathy, and two completed the 12-week course, reflecting that these symptoms did not affect adherence. Without including systematic genotyping in our study design, we cannot be certain whether the variations in dichloroacetate levels reflect the underlying

GSTZ1

genotype. However, the potential association between dichloroacetate dose, plasma concentrations, and neuropathy severity suggests a putative role for pharmacogenetics to facilitate dichloroacetate dose adjustment. This strategy is now advocated in other areas for which dichloroacetate could have an application (eg, oncology).

15

EPiC1 was not an efficacy study, nor did it incorporate qualitative components, so we were unable to further assess the relationship between reported side-effects, the effect on endometriosis symptoms, and adherence. Hormonal treatments remain the mainstay of medical treatment for endometriosis, but they often cause adverse events such as unscheduled bleeding, effects on mood, and skin disorders.

29

Despite this, patient use and adherence to these treatments continues.

30

A medication with a different side-effect and safety profile might be acceptable to patients, especially if associated with high efficacy.

There was very little ethnic diversity in EPiC1, although participant ethnicity was reflective of Scotland (92·9% White according to the 2022 Scottish census).

31

Greater diversity in the next phase of study (EPiC2) will be important to ascertain more generalisable estimates of acceptability and efficacy, particularly given the potential link between the

GSTZ1

polymorphism and ethnicity.

32

Social deprivation, gender identity, and sexual orientation were not captured, precluding analysis of these factors and their effect on the acceptability of the study. Additionally, the open-label single-arm design could have influenced recruitment and retention. Although we did not specifically assess efficacy, perceived benefit as reflected by the Endometriosis Health Profile-30 scores, analgesia use, and quality of life, could have contributed to retention. Our next planned trial (EPiC2) will address many of these limitations. EPiC2 is a multicentre study with a double-blind, placebo-controlled design, which will incorporate dose modification based on baseline genotyping and bodyweight and will include recruitment from a study site with a more ethnically diverse patient population. Patient-reported outcome measures will be collected digitally, minimising the need for in-person hospital visits. We will assess the effect of a placebo group and blinding on recruitment and retention, of genotyping to minimise side-effects, and generate a signal of efficacy data.

EPiC1 is the first reported use of dichloroacetate in women with endometriosis in whom treatment for 12 weeks with oral dichloroacetate appears acceptable. Side-effects in this population could be influenced by polymorphisms of the GSTZ1 enzyme response for dichloroacetate metabolism. These data support further exploration of dichloroacetate to treat endometriosis-associated pain in this common and debilitating condition, and the EPiC2 study is planned (funding code RG2415).

Contributors

All authors contributed to the conception, design, and delivery of the study. AWH, PTKS, and JPD secured funding. MK, AMD, FC, LCS, and PF were responsible for the day-to-day management of the trial. AWH, JPD, AMD, FC, M-CJ, LHRW, and LJW were the trial management group. LJW performed the statistical analyses, AMD conducted the data cleaning before analysis, and LHRW, LJW, and AMD directly accessed and verified the data with additional clarification from PF. All authors had full access to the data. LHRW, LJW, M-CJ, JPD, and AWH drafted the report, and all authors provided input into editing the manuscript for publication. All authors accept responsibility for the decision to submit for publication. The corresponding author had full access to all of the data and the final responsibility to submit for publication.

Data sharing

The datasets used and/or analysed during this study, including de-identified individual patient data and data dictionaries are available from the corresponding author upon reasonable request. Requests will be assessed for scientific rigour before being granted. Data will be anonymised and securely transferred. A data sharing agreement might be required. The study protocol and statistical analysis plan are included in the

appendix (pp 10, 31)

.

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Epstein-Barr virus appears to be trigger of lupus disease, say scientists | Immunology | The Guardian

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A common childhood virus appears to be the trigger for the autoimmune disease lupus, according to groundbreaking research.

The study suggests that Epstein-Barr virus (EBV), which for most people is harmless, can cause immune cells to “go rogue” and mistakenly attack the body’s own tissues. The team behind the work said that uncovering the cause of lupus could revolutionise treatments.

“We think it applies to 100% of lupus cases,” said Prof William Robinson, a professor of immunology and rheumatology at Stanford University and the study’s senior author. “I think it really sets the stage for a new generation of therapies that could fundamentally treat and thereby provide benefit to lupus patients.”

Lupus, which affects about 69,000 people in the UK, is a chronic autoimmune condition in which the immune system creates antibodies that attack the body’s own tissues. The causes have not been well understood and there is no known cure for the condition, which can cause joint and muscle pain, extreme tiredness and skin rashes.

Epidemiological surveys have previously hinted at a link between EBV and lupus, an idea that has gained traction after a recent breakthrough proving the link between EBV and multiple sclerosis, another autoimmune disorder. The latest work helps uncover, at a cellular level, how EBV appears to cause lupus by sending the immune system into a tailspin.

“This study resolves a decades-old mystery,” said Shady Younis, an immunologist at Stanford and first author of the paper.

EBV is typically a mild illness which causes a sore throat, fever and tonsillitis. By adulthood, about 19 out of 20 people become infected and – since the virus deposits its genetic material into DNA – carry the dormant virus in their cells.

“The reason why this is so surprising is because this is a common virus that most of us get from our brother or sister at the kitchen table when we’re growing up, or if we haven’t, then when we kiss somebody else as a teenager,” said Robinson. “Practically the only way to not get EBV is to live in a bubble.”

Among the cell types in which EBV takes up permanent residence are B cells, part of the immune system. These cells are specialised at binding to proteins on the surface of viruses, known as antigens. About 20% of B cells also have the potential to bind to parts of the body’s own cells, but in healthy individuals these “autoreactive” B cells remain largely inactive.

The scientists first used high-precision genetic sequencing to uncover differences in the number and type of B cells that are infected in 11 lupus patients compared with 10 healthy controls.

In the control group, fewer than 1 in 10,000 B cells hosted EBV, compared with about 1 in 400 cells for the lupus group – a 25-fold difference. EBV was also more likely to be found in autoreactive B cells.

The presence of the dormant virus appeared to flip these cells into a hyperactive state in which they not only targeted antigens inside the body, but recruited other immune cells, including killer T-cells, to join the attack.

“We think this is the critical discovery: that EBV … then activates those B cells to drive the autoimmune response that mediates lupus,” said Robinson.

There are other well-known risk factors that feed into a person’s susceptibility, beyond EBV. For instance, lupus disproportionately affects women, which could be due to hormones such as oestrogen amplifying B-cell activity, Robinson said. People with an African, Caribbean or Asian background are also at a higher risk

Prof Guy Gorochov, a professor of medicine at the Sorbonne University said the work was “impressive”.

“It’s not the final paper about lupus, but they’ve done a lot and developed an interesting concept,” he said.

If confirmed, the findings would add impetus to clinical trials for an EBV vaccine, which are already under way. There are also several teams exploring repurposing cancer treatments designed to wipe out B cells for severe cases of lupus.

The findings are published in the journal Science Translational Medicine.

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Epstein-Barr virus reprograms autoreactive B cells as antigen-presenting cells in systemic lupus erythematosus | Science Translational Medicine

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By Guy Gorochov, Alexis MathianScience Translational Medicine12 Nov 2025

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