A new concept for ‘starting menopause hormone therapy’ using an oral GnRH antagonist with an estrogen and a progestin (or an estrogen and a selective estrogen receptor modulator): why must we wait to treat women in perimenopause?

The target population for menopause hormone therapy (MHT) comprises women who have not menstruated for 12 months or more. However, vasomotor symptoms (VMS) can affect perimenopausal women for some years before their final menstrual period. In this case, hormonal replacement with combined hormonal contraceptives (CHCs) or sequential estro-progestin combinations may be proposed in appropriate cases with some drawbacks in terms of safety, tolerability and adherence. Abnormal uterine bleeding (AUB) is a very common challenge across the menopause transition. Unfortunately, the hormonal management of women with VMS and bleeding problems may be difficult until the final shutdown of ovarian function and the absence of endometrial stimulation. In this proof of concept, we propose the use of oral gonadotropin-releasing hormone (GnRH) antagonists under a new indication as 'starting MHT' (sMHT), initiated as soon as the first VMS appear in early or late perimenopause in combination with an estrogen and a progestin (or with an estrogen plus a selective estrogen receptor modulator [SERM]). sMHT could then be transitioned to conventional MHT some years later, when no risk of AUB is still present and ovarian function has definitively ceased. Indeed, the use of CHCs to achieve contraception and bleeding control in this life stage has some cardiometabolic and vascular contraindications that do not seem to absolutely apply to the use of sMHT regimens. Is the availability of oral GnRH antagonists therefore an opportunity for treating symptomatic women in the perimenopause earlier with sMHT.