O-174 Con

Abstract GnRH antagonists (GnRHant) promptly suppress gonadal activity, induce hypo-oestrogenism, inhibit metabolism of endometriotic lesions, and are very effective in relieving associated pain symptoms. However, whether GnRHant can revolutionise the current management of endometriosis and improve clinical outcomes is controversial. First, because nociceptive pain relief is generally related to the degree of hypoestrogenism achieved, GnRH-ant, even at full doses, are not superior to GnRH agonists (GnRHa). Second, the avoidance of initial pituitary hyperstimulation may be a marginal benefit of GnRHant if the first depot GnRHa preparation is injected in the mid-luteal phase or at the start of a 10-day course of an oral progestogen. Third, the convenience and acceptability of a daily oral intake compared with a monthly or quarterly intramuscular injection appears to be a personal preference rather than a proven advantage of GnRHant over GnRHa. Fourth, to avoid the typical adverse effects of hypo-oestrogenism, full-dose GnRHant can be combined in a single tablet with a low-dose oestrogen-progestogen combination. Although there is no need to take two separate tablets, this hampers the customisation of “add-back” therapies. The most physiological and safest way to limit hypo-oestrogenic symptoms would be to combine GnRHa and GnRHant with transdermal oestradiol and vaginal progesterone. Moreover, pre-packaged combinations of a GnRHant with an “add-back” formulation impede the temporary discontinuation of oestrogen-progestogens in the event of unexpected bleeding. The inability to adopt tailored cycling may be a disadvantage of GnRH combination therapy. Fifth, GnRHant can be used at different doses, allowing modulation of the degree of ovarian suppression. Reduced doses of GnRHant do not induce profound hypo-oestrogenism and can keep serum oestradiol levels within the range of the so-called threshold hypothesis (approximately 30-50 pg/mL). In theory, this should make it possible to maintain unvaried efficacy while avoiding hypo-oestrogenic side effects and the need for add-back therapies. Unfortunately, reduced doses of GnRHant are associated with irregular bleeding and reduced pain relief. Notably, as ovarian function is inconsistently inhibited, the use of low doses of GnRHant is associated with a risk of unwanted conception. The use of serial pregnancy tests is therefore highly recommended to timely differentiate between drug-induced amenorrhoea and unrecognised ongoing gestation. Sixth, oral GnRHant can be discontinued immediately if intolerable adverse effects develop. This is not possible with depot GnRHa formulations. However, the occurrence of serious safety problems or severe intolerance when starting GnRHa is rare. Seventh, GnRHant are very expensive and offer no economic advantage over GnRHa. Indeed, a large body of data shows that the monthly 3.75 mg triptorelin preparation can be injected every six instead of four weeks without resumption of gonadal function or detrimental effect on pain relief. Reducing the cost of GnRHa therapy by a third may allow more patients to be treated for longer or to have access to this second-line treatment, thereby reducing health inequalities. Eighth, while progestogens have been used as the standard comparator in several trials of GnRHa for endometriosis, such comparative effectiveness research is not available for GnRHant, and the magnitude of their additional net benefit over standard progestogens is currently unknown. Ninth, the focus of GnRHant use should be on difficult-to-treat symptoms, typically severe dyspareunia. Assessing changes in menstrual pain when using a drug that induces amenorrhoea is potentially confounding. Tenth, in future trials of GnRHant, outcomes should be chosen that are important to patients, and measures should be used that reflect the overall benefit/harm balance, such as the patient’s global impression of change scale and level of satisfaction with treatment. Finally, like GnRHa, GnRHant should also be used only when first-line treatments cause prolonged and heavy bleeding, intolerable adverse effects, or inadequate pain relief.