New diagnostic and treatment modalities could drastically cut the time to endometriosis diagnosis, help prevent complex pelvic pain and preserve fertility, experts say.

Laparoscopy won’t be needed to make a diagnosis

Under new endometriosis guidelines, slated for release in the next couple of months, diagnosis will no longer rely on surgery. Instead, it can be made provisionally via history, physical examination and investigations (usually an ultrasound scan), says Associate Professor Anusch Yazdani, a subspecialist in reproductive endocrinology and infertility, reproductive endosurgeon and medical director for Endometriosis Australia.

The ultrasound should ideally be transvaginal, he says. “And preferably it’s done in a specialist service where they have the capacity to perform an endometriosis type of ultrasound scan. But those services are not available everywhere in Australia, so that’s not mandated.”

“And if a woman has extensive endometriosis, even a non-endometriosis-specific scan is very likely to demonstrate that—it has a sensitivity of over 90% for demonstrating deep and particularly extensive disease.”

While definitive diagnosis will still be by histology, the need for a laparoscopy “should no longer now be the bottleneck to instituting appropriate treatment,” Associate Professor Yazdani says.

AI imaging tools could accelerate diagnosis and reduce need for laparoscopies

Definitive non-surgical diagnosis may be a step closer with the development of AI-enabled imaging tools.

Gynaecologist and CREI accredited fertility specialist, Professor Louise Hull from the Robinson Research Institute, University of Adelaide, who has a PhD in endometriosis from Cambridge University, is leading a team developing IMAGENDO®––a technology that uses AI algorythims to combine diagnostic markers seen in specialised transvaginal ultrasound and MRI scans to look for endometriosis markers.

“Very experienced sonographers, sonologists and MRI experts provide high quality images which we annotate manually initially, but after learning from enough data, AI can automate that process,” Professor Hull says.

“Imaging is now able to detect small nodules on the uterosacral ligaments but also sometimes we can pick up superficial markers now, so scanning techniques are getting much better, and AI is improving it.”

Ultrasound results are used to pre-train the MRI AI model and vice versa, improving the accuracy of both, she adds.

If all goes well, GPs would be able to order these scans, and AI could help automate the rebate process by confirming that an endometriosis assessment had been correctly completed.

Professor Hull hopes this will mean women need fewer imaging tests.

“I see patients with eight scans, none of which have looked for the ultrasound signs of endometriosis,” she says. “And then we get a genuine endometriosis scan, and there were clearly nodules that should have been detected.”

Imaging-based diagnosis could not only reduce the need for laparoscopies, it could also lead to the discovery of evidence-based treatment pathways in primary care.

“We have no evidence to base treatment decisions on in general practice because we’ve never done any trials with participants who have not already had surgery” Professor Hull says. “So the next step is going to be how can we start running trials in general practice recruiting people with endometriosis who have not had surgery to show which are the best treatments in a non-surgical setting.”

Blood tests may support endometriosis identification

Associate Professor Yazdani says several companies are developing blood tests that look for different endometriosis markers—including enzymes, vesicular changes and proteins—and which vary in terms of their sensitivity and specificity.

“Some of them are better for more extensive disease; some of them are better for less extensive disease, but then also pick up a whole lot of things that are not endometriosis,” he says.

Some companies are using artificial intelligence to develop their tests, enabling them to “better distinguish the noise from the actual signal” to improve diagnostic accuracy, he says.

These tests are still under investigation, but one thing we do know is that tumour markers like CA-125 don’t work particularly well, Associate Professor Yazdani says.

New drugs to manage symptoms

Although privately available for a number of years, dienogest (Visanne) was PBS-listed for endometriosis treatment last December.

Professor Hull says it “can be quite effective,” but it is important to know it does not provide contraceptive cover. “Visanne is a synthetic progestin,” she explains, “which suppresses the oestrogen driven growth of endometriotic lesions. It can cause mild to moderate bone density loss.

Drospirenone (Slinda) is a progesterone-only oral contraceptive pill,“so the usefulness is that compared to other progesterone only delivery systems such as depo provera, the Mirena coil and Implanon, it is easy to stop if you have side effects. Sinda suppresses ovulation so can be used as a contraception with little loss of bone mineral density loss,” she says. It will be PBS-listed from 1 May.

Likewise, Yas and Yasmin were PBS-listed earlier this year, providing more cost-effective options.

“First line management of endometriosis is hormonal, and that’s the oral contraceptive pill and progestins,” Associate Professor Yazdani explains. “There is actually no evidence that one particular hormonal treatment is better than another. It’s just a matter of tailoring the side effect profile of all of those if the patient is happy to do that.”

Second and third line management

This month the Government announced that Ryeqo would also be PBS-listed beginning in May. It was approved for endometriosis last year and can be initiated by any specialist medical practitioner with experience in the diagnosis and management of endometriosis – including GPs.

“It is a daily oral tablet that some people with endometriosis just find it really helpful to manage pain,” Professor Hull says.

It contains GnRH receptor antagonist relugolix, which blocks GnRH receptors in the pituitary gland, inhibiting the release of follicle-stimulating hormone and oocyte maturation, inducing a low oestrogen, menopause-like state.

“Ryeqo suppresses ovulation, so it has a contraceptive effect. Essentially, you take it daily without a break and don’t have periods,” Professor Hull explains.

It also contains low doses of oestradiol and norethisterone acetate to help prevent or reduce the side effects of GnRH receptor blockade (called ‘add-back’ therapy).

Associate Professor Yazdani says Ryeqo “is very very good at reducing pain,” and while the GnRH analogues goserelin (Zoladex) and nafarelin acetate (Synarel) are also PBS-listed and effective, they can only be used for six months or less.

“Zoladex and Synarel have been used for a very long time in Australia. They are as effective as Ryeqo, but the difference is they’re more likely to lead to bone mineral density loss and therefore they are limited to six months,” he explains, whereas Ryeqo can be used for up to two years.

Professor Hull says while Ryeqo already contains oestradiol, you need to test bone density before commencing it. “And then every year you check it again.”
If there are mild bone density changes, it may be possible to continue Ryeqo, she explains, but you may need to implement other bone-preserving strategies—such as additional oestrogen or weight training.

Other treatments

Other researchers are looking into potential endometriosis therapies, including non-hormonal treatments and immunobiologicals, Professor Hull says.

She explains research has proven the immune system and inflammation (largely linked to the prostaglandin response) are involved in endometriosis, “which is why people with endometriosis experience bloating, pain and systemic effects like fatigue.”

While the exact aetiology remains elusive, the underlying mechanisms show that cyclic inflammation and healing and repair of endometriotic lesions which offers scope for treatment and even prevention, she says.

“Although we might not be able to prevent the lesions developing, it may be possible to prevent the complex pain syndrome that occurs if repeated monthly pain triggers upregulate neural pathways.”

For example, the EndoChill trial is looking at cold water immersion, mindfulness and breathing exercises to manage pain, she says. The Alyra trial is looking at an an intrauterine device with a pain management system for both pain relief and period suppression.

“And we might be able to prevent infertility because we’ve frozen your eggs when you were young, or you’ve thought of freezing embryos,” she adds.

Key takeaways:

• Under new guidelines to be released soon, doctors will be able to make a provisional endometriosis diagnosis via history, examination and ultrasound scan.
• AI-enabled imaging tools could help diagnose endometriosis earlier, with less surgery.
• Earlier diagnosis means earlier treatment and less chronic pain and fertility issues.
• Various blood tests are under development and may be helpful for diagnosis.
• Visanne is now PBS listed but it does not provide contraceptive cover.
• Ryeqo contains small doses of oestrogen and progesterone add back, allowing for longer GnRH suppression than isolated GnRH analogues with less likelihood of bone sequelae, although bone density must still be monitored.

Note: This article has been updated to correct some inaccuracies. A previous version implied that GPs could not initiate Ryeqo; this is not true. GPs with experience in the diagnosis and treatment of endometriosis can prescribe Ryeqo.