Table II.

Potential approaches for patients who have failed initial therapy for endometriosis and the currently available evidence.

Cause of progestin failure	Potential approaches	Evidence
Hormone type	To change the type of progestin	Observational study: NETA and dienogest may have similar effects (Vercellini et al., 2016a). In-vitro studies: different progestins may have different mechanisms of action (Grandi et al., 2016; Nirgianakis et al., 2016; Roth et al., 2019).
	To avoid estrogen association	RCTs did not show meaningful differences between isolated progestins and progestin-estrogen associations (Cheewadhanaraks et al., 2012; Razzi et al., 2007b; Vercellini et al., 2002; Vercellini et al., 2005). Prospective self-control study: for patients who do not respond to COC, changing to NETA may be beneficial (Vercellini et al., 2018c).
	To inhibit estrogen synthesis	Non-randomised open-label trials: for patients who fail to respond to progestins, letrozole can be tried as a second line therapy (Ferrero et al., 2009; Ferrero et al., 2014).
Therapeutic regimen	To change therapeutic regimen	Systematic review: continuous administration may be better than cyclic regimens (Seracchioli et al., 2009).
Route of administration	To change the route of administration	RCT: systemic and local progestins may be similar (Carvalho et al., 2018).
Progesterone resistance	To associate NSAIDs to progestin therapy	No high-quality evidence for NSAIDs effectiveness on endometriosis symptoms, but the association with hormonal treatments might diminish the inflammatory response that boosts progesterone resistance (Brown et al., 2017).
	To associate antioxidants	Multi-centre open-label non comparative clinical trial: antioxidant preparations containing N-acetyl-cysteine may mitigate symptoms (Lete et al., 2018).

NETA: norethisterone acetate; RCTs: randomised controlled trials; COC: combined oral contraceptive; NSAIDs: non-steroidal anti-inflammatory drugs