Tolerability considerations for gonadotropin-releasing hormone analogues for endometriosis

ABSTRACT

Introduction

The second-line treatment of endometriosis-related pain symptoms includes injectable depot formulations of gonadotropin-releasing hormone analogs (GnRH-as). These drugs improve the symptomatology by inducing a hypoestrogenic status and a consequent regression of endometriotic implants. However, GnRH-a may cause a not negligible rate of adverse events, in particular vasomotor symptoms and bone mineral density loss, that may limit patients’ adherence and safety on long-term treatment. Several strategies have been suggested to improve the compliance to treatment.

Areas covered

This narrative review aims to give an overview of the safety and tolerability of GnRH-a therapy and to present the different options of steroidal and non-steroidal add-back therapies in order to reduce the hypoestrogenic side effects.

Expert opinion

Side effects of long term GnRH-a treatment are particularly relevant. Although it has been known the efficacy of GnRH-as for treating endometriosis-associated pain, the best schedules of therapy in terms of duration and dosages are still to be defined. The ideal treatment schedule of GnRH-a is still a matter of debate as to the optimal add-back combination.

KEYWORDS:

• Endometriosis
• hormonal therapy
• gonadotropin-releasing hormone analogs
• add-back therapy
• norethisterone acetate
• combined oral contraceptives
• bone mineral density
• vasomotor symptoms

Article highlights

• Currently, the use of gonadotropin releasing hormone analogs (GnRH-a) is adopted in patients with endometriosis refractory first-line hormonal options such as combined oral contraceptives or progestins.

• All GnRH-a demonstrated efficacy in the treatment of endometriosis independent of their chemical structure and route of administration.

• The onset of hypoestrogenism-related adverse events such as vasomotor symptoms and bone mineral density loss tends to limit the long-term use of GnRH-a. The common agreement is that a treatment longer than 6 months with GnRH-a need to be combined with add-back therapy.

• Several GnRH-a schedules have been proposed to limit the sides effect of the induced hypoestrogenic state and to provide at the same time hormonal suppression within endometriotic lesions.

• A variety of add-back regimens based on steroids (progestins and/or estroprogestins) have been proposed. The add-back therapy based on estrogen plus progestins (in primis norethindrone acetate) is considered a suitable option as it maintains the benefits of GnRH-a treatment nevertheless improving their tolerability profile.

This box summarizes key points contained in the article.

Reviewer disclosures

A reviewer of this manuscript discloses serving as a scientific advisory board member for Theramex Gedeon Richter and providing counseling for Exeltis.

Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.