Current approaches to overcome the side effects of GnRH analogs in the treatment of patients with uterine fibroids

ABSTRACT

Introduction:

Uterine fibroids (UFs) are the most prevalent benign neoplastic threat originating from myometria of reproductive age women, with a profound financial load valued in hundreds of billions of dollars. Unfortunately, there is no curative treatment so far except surgery and available pharmacological treatments are restricted for short-term treatment options. Thus, there is a large unmet need in the UF space for noninvasive therapeutics.

Areas covered:

The authors reviewed the literature available for the utility of gonadotropin-releasing hormone (GnRH) analogs in women with UFs. We also focused on clinical studies exploring the therapeutic benefits of novel oral non-peptide GnRH antagonists that were recently approved by the U.S. Food and Drug Administration (FDA) in combination with estradiol/norethindrone acetate for the management of heavy menstrual bleeding associated with UFs in premenopausal women.

Expert opinion:

The results regarding the efficacy of new-generation oral GnRH-antagonists, such as elagolix, relugolix and linzagolix, are promising and offer potential prospect for the future therapy of UFs. However, these antagonists must be combined with hormonal add-back therapy to minimize the resultant hypoestrogenic side effects such as bone loss.

KEYWORDS:

• GnRH analogs
• add-back therapy
• hypoestrogenic side effects
• leiomyoma
• uterine fibroids
• safety

Article highlights

• Uterine fibroids have a significant impact on patients’ quality of life and health-care costs worldwide.

• The mechanisms triggering uterine fibroid pathogenesis remain unclear, which in turn limits its effective treatment. Currently available therapeutic opportunities aim to interfere with tumor growth hormonal dependence, mainly gonadotropin releasing hormone (GnRH) analogs (agonists and antagonists).

• If feasible, many UFs patients would prefer a non-invasive pharmacological alternative over a surgical intervention to maintain their future fertility.

• Elagolix and relugolix are orally bioavailable, second-generation, non-peptide GnRH antagonists recently approved by the US Food and Drug Administration (FDA) in combination with estradiol/norethindrone acetate for the management of heavy menstrual bleeding associated with uterine fibroids in premenopausal women up to 24 months.

• These GnRH antagonists must be combined with hormonal add-back therapy to minimize the resultant hypoestrogenic side effects such as bone loss.

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Declaration of interests

One author is a consultant for Allergan, Bayer, Repros and Myovant Sciences, as well as AbbVie. The authors have no other 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 study was supported in part by the National Institutes of Health grants: R01 HD094378-04, R01 ES 028615-02, R01 HD100367-01, U54 MD007602 and R01 HD094380-02