Investigational and experimental GnRH analogs and associated neurotransmitters

ABSTRACT

Introduction: The GnRH agonistic analogs enable for desensitizing the hypothalamo-pituitary-gonadal axis in malignant and benign conditions where minimizing the production of sex hormones, or blocking ovulation is necessary. The possible indications are prostate cancer, benign prostate hyperplasia, breast cancer, endometriosis, precocious puberty, uterine leiomyomata, assisted reproduction (ART)/in vitro fertilization (IVF), PCOS, minimizing the gonadotoxic effect of chemotherapy in young women, and possibly ovarian cancer.

Areas covered: The aim of the current review is to summarize, giving a critical overview, of the investigational GnRH agonists, and shortly discuss the difference between the GnRH agonists, antagonists, Kisspeptin, and Neurokinin B analogs.

Expert opinion: The broad armamentarium of agonists may make it possible, in the future, to expand the indications and uses of these analogs, choosing and specifically tailoring the analog to the required effect, while minimizing side effects.

KEYWORDS:

• Gonadotropin releasing hormone
• GnRH
• agonistic analogs
• GnRHa

Article highlights

• Orally active analogs may prove beneficial and increase compliance in children with precocious puberty, where injections are problematic in some cases.

• Bi-functional GnRH analog-steroid conjugates, may prove beneficial in cases where profound estrogen and/or testosterone suppression is unnecessary. Furthermore, the amount and quantity of the secreted estrogen (or other sex steroid), can be possibly tailored for every specific patient and clinically adapted, according to the measured and desired serum concentrations.

• In prostate cancer, using future long-acting GnRH antagonist preparations may prevent the flare-up effect of the long acting GnRHa used in the past, and prevent the frequent injections necessary with the clinically available antagonists, at present. Oral preparations of the GnRH antagonist may be even more patient friendly.

• Young women, exposed to gonadotoxic chemotherapy, face possible gonadal toxicity and future ovarian failure due to the use of cytotoxic therapy for malignancy, or autoimmune diseases (such as SLE). Future using of long-acting GnRH antagonist preparations may prevent the flare-up effect of the long acting GnRHa used today, thus eliminating the 7-14 days waiting, due to flare-up effect, before starting chemotherapy.

• Since Kisspeptin can induce a gonadotropin surge, future use of Kisspeptin and its agonistic analogs, may replace the GnRHa trigger, used today for preventing OHSS. The Kisspeptin replacement of the GnRHa trigger may be more physiologic, preventing the luteolysis, induced by the GnRHa trigger, thus eliminating the need for aggressive luteal support with pharmacologic doses of estrogen and progesterone. Such a physiologic trigger (Kisspeptin or its agonist); will also eliminate the need of hCG administration, as ‘luteal rescue’, a few days after the GnRHa trigger, possibly associated with OHSS.

• Future validation of Neurokinin B as a possible inducer of Kisspeptin and GnRH secretion may also bring about a ‘soft’ gonadotropin surge, for IVF/ART. Future experience will prove if such attitude is clinically efficient and safe. In addition, it remains for future comparative studies to compare the efficiency and safety of Neurokinin B, Kisspeptin, GnRHa, and hCG as different optional ‘triggers’ for final oocyte maturation before follicular aspiration and egg retrieval for ART/IVF.

• Future antagonistic and agonistic analogs of Kisspeptin and Neurokinin B, and their efficiency and safety will be tested for the many indications, such as precocious puberty, endometriosis, uterine leiomyomata, and other diseases where profound suppression of sex steroids is not necessary, for minimizing the side effects associated with such GnRHa induced profound suppression.

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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.