Endometriosis is a complex and often debilitating condition affecting millions worldwide. Characterised by the growth of endometrial-like tissue outside the uterus, it can lead to chronic pelvic pain, dysmenorrhoea, and infertility. Hormonal therapies are a cornerstone of endometriosis management, aiming to reduce oestrogen levels and alleviate symptoms. There remains an important clinical need for safe, highly effective, convenient medical treatments that can be used long term for endometriosis related pain, which may reduce the need for opioids and repeated surgery.
Advance Laparoscopic Surgeons, Nedlands and Subiaco
Advance Laparoscopic Surgeons, Nedlands and Subiaco
Ryeqo® is an orally administered, gonadotropin-releasing hormone (GnRH) analogue that combines three active ingredients: relugolix 40mg, oestradiol hemihydrate 1mg, and norethisterone acetate 0.5mg. Although these ingredients have been used for many years, Ryeqo® is the first treatment approved for endometriosis in 13 years.
Relugolix is an oral non-peptide selective gonadotrophin-releasing hormone (GnRH) receptor antagonist. It inhibits the pituitary release of luteinising hormone (LH) and follicle-stimulating hormone (FSH), leading to suppression of ovarian follicular growth and development which reduces oestrogen production. Prevention of an LH surge inhibits ovulation and development of the corpus luteum, which precludes progesterone production. Monotherapy relugolix is unsuitable for long-term use, hence oestradiol is included to minimise hypo-oestrogenic symptoms, and loss of bone mineral density (BMD). Norethisterone acetate is included as a progesterone for endometrial protection in non-hysterectomised women.
Efficacy
The SPIRIT 1 and 2 trials demonstrated efficacy in reducing endometriosis-associated pain compared with placebo. More patients reported reduction in dysmenorrhoea (75% versus 27-30%) and reduced non-menstrual pelvic pain (58-66% versus 40-43%) at six months of follow-up. Some 62.5% reported amenorrhoea at 24 weeks of use.
LIBERTY 1 and 2 studied fibroid-associated heavy menstrual bleeding. More patients in the treatment arms achieved the primary endpoint (menstrual blood loss of less than 80 mL during the final month of treatment and at least a 50 percent reduction in menstrual blood loss from baseline to the final month) compared with placebo (71-80% versus 15-19%). An improvement in a number of other secondary endpoints was also seen, including anaemia, bulk-related symptoms, and uterine volume [reduction of approximately 12-15%; range -3.2 to -23%]) with preservation of BMD.
In the LIBERTY trials, women with a fibroid uterus receiving active medication, were more likely to experience amenorrhoea (51.6%) or cyclic bleeding (15.4%), with the remainder (31.9%) reporting an irregular bleeding pattern at 24 weeks of use. At 52 weeks of use, 70.6% were likely to experience amenorrhoea. In the SPIRIT trials, a majority of patients with endometriosis (65.2%) reported amenorrhoea at 24 weeks of use.
Anovulation can be observed 4 weeks following initiation leading to effective contraception after this time. A rapid return to ovulation occurs on discontinuation. Concomitant use of hormonal contraceptives is contra-indicated.
Common side effects include vasomotor symptoms, headache, fatigue, nausea, nasopharyngitis, dizziness, abnormal uterine bleeding, loss of libido, hair loss, irritability, sweating and breast cyst formation.
There has been an association with a potential decrease in bone mineral density. However, this loss was less than 1% in the SPIRIT trials and not considered clinically significant. An observational study of untreated age-matched women with endometriosis was subsequently conducted to characterise longitudinal BMD of premenopausal women aged 18-50 years. Through 52 weeks of observation, there was minimal change in BMD compared with those in an age-matched cohort of premenopausal women with endometriosis.
Regular monitoring of BMD is therefore recommended for patients receiving long-term therapy. Assessment of BMD by DEXA scan is recommended at baseline, after one year of treatment, and annually thereafter. Use is recommended to be limited to 24 months, with extension of therapy conditional on stability of DEXA and reassessment of risk/benefit in the individual patient by the treating physician.
Data comparing to established treatments for endometriosis-related pain are lacking. For endometriosis and fibroids, indirect comparisons with other GnRH agonists such as Goserelin show similar efficacy.
Indications
This new medication is indicated for the management of endometriosis-associated pain. The effect is usually noted within the first four weeks of use. It is recommended for patients who have not responded to, or who are intolerant of, other treatments. Before initiating treatment, other medical treatments should be considered.
Ryeqo® is not currently PBS listed, however an application is underway. Currently in Australia, Ryeqo® is indicated in adult women of reproductive age for:
- treatment of moderate to severe symptoms of uterine fibroids,
- symptomatic treatment of endometriosis in women with a history of previous medical or surgical treatment for their endometriosis.
Key messages
- A significant advancement in the hormonal management of endometriosis, has been approved for use
- It can provide comprehensive hormonal suppression, leading to significant reductions in endometriosis-associated pain.
- Careful consideration of its risks, side effects, and long-term implications is essential in ensuring its safe and effective use in clinical practice.
– References available on request
Author competing interests