Ryeqo for Endometriosis: How is it different to the combined contraceptive pill?
Also known as relugolix-estradiol-norethisterone, or relugolix combination therapy (RCT), Ryeqo is a daily pill that has been approved for use on the NHS as of March 2025 to help manage endometriosis, or endo for short. Ryeqo was originally approved in 2021 as a pill for fibroids, but being the first major ‘treatment’ option introduced in 6 years for endometriosis, it’s unsurprising that the headlines are filled with phrases like “ground-breaking”, “game-changing”, and “transformational”. But is it really that transformational when compared to the options already available? Let’s explore.
The first thing to unpack here is the use of the word ‘treatment’. Ryeqo is being marketed as a treatment option for endometriosis, however, as this medication does not actually treat the disease but instead helps to manage the symptoms by creating a temporary, reversible state of menopause, I would switch this terminology for managing endometriosis instead. There is no known cure for endometriosis and we do not know the exact cause(s) of the disease either, despite there being multiple theories.
What is endometriosis?
Endo is a disease where tissue similar to - but not the same as - the inside lining of the womb grows in places outside the womb, and it affects around 1 in 10 women. The growth of the lesions is fuelled by a number of things including estrogen, inflammation, immune system dysfunction, endocrine-disrupting chemicals, and more. It is a multi-factorial disease that cannot just be treated in one single way. The location of endometrial lesions can be wide-ranging; they have been found on the fallopian tubes, ovaries, the lungs, the diaphragm, intestines, the brain (albeit in rare cases), and more. Symptoms include period pain, fatigue, IBS or IBS-like symptoms, pain during sex, painful urination, and infertility.
How does Ryeqo differ from contraceptive pills?
In very simple terms, Ryeqo is essentially a stronger type of contraceptive pill, although it does not primarily act as a contraceptive. For more on this, read the NICE guidelines on contraception with Ryeqo. Both the combined contraceptive pill and Ryeqo contain something called a progestin (albeit different types), and synthetic estrogen. But Ryeqo contains one extra ingredient - Relugolix.
How do these three ingredients work?
Progestins: in both contraceptive pills and Ryeqo
These are commonly referred to as a type of synthetic progesterone, although I disagree with this terminology - more on progesterone below. Ryeqo uses the progestin norethisterone acetate, but the type of progestin found in contraceptive pills (both the progestin-only pill and the combined pill) differs depending on the brand.
Relugolix: in Ryeqo only
This is a GnRH antagonist. I’ll explain what this means in a second.
Synthetic estrogen: in the combined pill and Ryeqo
Both Ryeqo and the combined pill contain synthetic estrogen, but different types. Ryeqo contains hemihydrate, and for the CP it differs again depending on the brand.
Now let’s look at what these ingredients do.
#1: Progestins
Despite progestins frequently being described as synthetic progesterone, I personally don’t tend to refer to them in this way because progesterone is an entirely different molecule, and it has a different range of effects in the body. Progesterone is a hormone that you make as a result of ovulation, and this hormone is known for its calming and anti-inflammatory effects. In fact, if you have low progesterone or if your progesterone drops too quickly in the run-up to your period, you’ll likely feel this in the form of PMS symptoms. For more on progesterone, have a read of this Instagram post - shared as part of my series Meet Your Hormones - or check out this post for the symptoms of low progesterone.
One of the main things that progestins do is reduce the production of GnRH (gonadotropin-releasing hormone). GnRH is a hormone that is made in the brain - let’s call this Phase 1 - and it triggers the release of two other hormones in your pituitary gland, FSH (follicle stimulating hormone) and LH (luteinising hormone) - let’s call this Phase 2.
Phase 1: GnRH is made in the brain, in the hypothalmus
Phase 2: GnRH is sent to the pituitary gland in the brain, where it triggers the release of FSH and LH
FSH and LH then make their way to your ovaries to drive your menstrual cycle and the production of other hormones like estrogen and testosterone. Without FSH and LH, you don’t have a menstrual cycle.
So, what happens if you take a medication that includes a progestin? You reduce the production of GnRH and suppress natural hormone production in the ovaries as a result. Remember: Ryeqo, the combined contraceptive pill, and the progestin-only contraceptive pill all contain progestins, so they all have this effect. The amount of progestin in the medication affects the strength of this suppression. This is why you have to get the hormonal coil replaced every few years - because the amount of progestin that it releases each day will gradually decrease over time.
#2: Relugolix
Relugolix is a GnRH antagonist, meaning it stops GnRH from being able to trigger the release of FSH and LH in the pituitary gland. In other words, it interferes with Phase 2, whereas progestins interfere with Phase 1.
As the new pill Ryeqo contains both progestins and Relugolix, it interferes with both Phase 1 and 2, and subsequently has a stronger effect in terms of suppressing the natural production of your reproductive hormones.
This essentially causes a temporary, reversible state of menopause. Natural menopause is the time in a woman’s life where her ovaries have shut down and she no longer has a period. Natural menopause is irreversible, but is a normal part of life, with most women reaching menopause between the ages of 45 and 55. In menopause, you do not ovulate (no eggs are released from your ovaries) and therefore you cannot have a period or become pregnant.
Now let’s look at why estrogen is added to Ryeqo.
#3: Synthetic estrogen
The lead-up to menopause - called perimenopause - is known for the commonly accompanying symptoms like hot flushes and night sweats. But where do these symptoms come from exactly? They come as a result of decreasing estrogen levels due to your ovaries winding down for menopause!
Now, if you take a medication that causes a temporary state of menopause, then you’re likely to experience these associated low-estrogen symptoms (among others). Synthetic estrogen is therefore added to both the combined contraceptive pill and Ryeqo, to not only combat these symptoms but also to reduce the long-term risks of having low estrogen, which includes things like osteoporosis or low bone density. This is commonly referred to as add-back therapy, or hormone replacement therapy (HRT).
Manufacturers add enough estrogen into these medications to reduce these long-term risks, but not so much that it supports the growth of endometrial lesions. For more on the role of estrogen in endometriosis, read this blog post by Katie Edmonds.
P.S., did you know that no matter your age, estrogen plays a crucial role in your ability to absorb calcium from your diet? Watch this video to learn more.
“Ally, the headlines are all describing Ryeqo as a pill that will eliminate the need for injections... what injections are they referring to?”
One current option for managing endometriosis is to get a regular injection that includes a GnRH agonist, which is something that desensitises your pituitary gland to the effects of GnRH over time - this leads to lowered FSH and LH production and subsequently lower reproductive hormone levels. This injection has to be administered once every 1-3 months by a healthcare professional, whereas Ryeqo is a pill that can be taken at home. In this regard, it makes sense that Ryeqo is being described as “game-changing”, as overused as that term may be!
However, there’s a catch - as you may have seen already, Ryeqo is predicted to only be able to help 1000 women per year. This is an extremely small number when you compare it to the estimated 1.5 million women who have endometriosis in the UK.
That’s only 0.07% of the women with endometriosis who are estimated to be able to benefit from Ryeqo.
Why? Because in order to try Ryeqo, you have you have tried every other option first - including pain killers, the contraceptive pill(s), hormonal coil, surgery, and the injections. If the goal is to truly help women with this often debilitating disease, I’d say we’re moving rather slowly and failing to address the hurdles that exist from getting a diagnosis in the first place through to being able to access help post-diagnosis.
So. What do I think about Ryeqo for endometriosis?
Having a new option for the management of endometriosis symptoms is a good thing, especially when it gives women a more accessible option compared to the injections, and it sounds like it will offer symptom relief for those who try it. But…
With Ryeqo only being made available for women who have tried every other option already, I disagree with the statements saying that Ryeqo is “game-changing”.
In my opinion, women still deserve better, especially for a disease that can be so debilitating for so many.
I’d much prefer it if the funding went towards research into the exact cause(s) of endometriosis, and the role of the immune system in this disease.
As far as we currently know, there is no one, singular ‘miracle’ option for endometriosis. It is a multi-factorial disease that needs to be managed or treated in multiple ways. If you only focus on the hormonal aspect, then you’re letting the immune aspect run wild. If you only focus on the immune aspect, then you still have the hormones to address. Add the topics of chronic inflammation to that as well as gut health and endocrine-disrupting chemicals, and you can see how women with endo deserve - and need - a multi-factorial health support network around them.
It annoys me that endometriosis is still thought of as a reproductive disease, when in reality, endo is a full-body disease driven by chronic inflammation and immune system dysfunction. Branding it as a women’s reproductive disease also adds fuel to the “women’s hormones are what makes them crazy” fire, and it drives home the incorrect idea that hormones do nothing other than cause problems.
If the only options we have are medications that suppress the production of brain-supportive hormones like progesterone, then of course we are going to feel like trash and our mood is going to be unstable.
The options available for women with endo are still far too limited. Yes, Ryeqo may help manage endometriosis for a small number of women, but at what cost? Why are we focused solely on suppressing reproductive hormones instead of also looking at the role of the immune system when developing treatment options?
In the words of Emma Collier from BBC Sounds Women’s Hour this week: “any step forward is a good one, but I’m not celebrating.”
I’d love to hear your thoughts on Ryeqo, especially if you’re one of the few who have tried it for managing your endometriosis (or fibroids!). Join in the conversation here.
