Gonadotropin‑Releasing Hormone Analogs: Understanding Advantages and Limitations

Review Article Gonadotropin‑releasing hormone analogs: Understanding advantages and limitations ABSTRACT Pratap Kumar, Alok Sharma1 Pituitary stimulation with pulsatile gonadotropin‑releasing hormone (GnRH) analogs Department of Obstetrics and induces both follicle‑stimulating hormone (FSH) and luteinizing hormone (LH). Pituitary Gynecology, Kasturba Medical College, Manipal University, gonadotropin secretions are blocked upon desensitization when a continuous GnRH Manipal, Karnataka, stimulus is provided by means of an agonist or when the pituitary receptors are occupied 1Department of Obstetrician with a competitive antagonist. GnRH antagonists were not available originally; therefore, and Gynecologist, Deen Dayal prolonged daily injections of agonist with its desensitizing effect were used. Today, Upadhyaya Hospital, Shimla, Himachal Pradesh, India single‑ and multiple‑dose injectable antagonists are also available to block the LH surge and thus to cause desensitization. This review provides an overview of the use of GnRH analogs Address for correspondence: which is potent therapeutic agents that are considerably useful in a variety of clinical Dr. Pratap Kumar, indications from the past to the future with some limitations. These indications include Department of Obstetrics and Gynecology, Kasturba Medical management of endometriosis, uterine leiomyomas, hirsutism, dysfunctional uterine College, Manipal University, bleeding, premenstrual syndrome, assisted reproduction, and some hormone‑dependent Manipal ‑ 576 104, tumours, other than ovulation induction. Karnataka, India. E‑mail: pratap.kumar@ manipal.edu Received: 18.09.2014 Review completed: 23.09.2014 Accepted: 19.09.2014 KEY WORDS: Advantages, gonadotropin‑releasing hormone analog, limitations INTRODUCTION by GnRH‑receptor competition, thereby avoiding the initial stimulatory phase Gonadotropin‑releasing hormone (GnRH) of the agonists. Discontinuation of and its analogs have been extensively GnRH antagonist treatment leads to a used in clinical medicine since they rapid and predictable recovery of the were identified and synthesized in 1971. pituitary‑gonadal axis. Agonists would This was a logical consequence of the be used as strong sustained stimulators of discovery of the amino acid sequence of gonadotropin secretion and the antagonists GnRH, which led to the development of promised to be a potential tool for chemical agonistic and antagonistic analogs with hypophysectomy. It was relatively simple many scientific clinical perspectives. to develop safe agonist by just changing Native GnRH stimulates gonadotrophs of one or two amino acids but it required the anterior pituitary and has been used almost 30 years of trial and error with Access this article online for induction of ovulation. The GnRH replacement of three or more amino acids Quick Response Code: agonists are more potent and have got a to obtain an antagonist with an acceptable longer half‑life than native GnRH. They pharmacokinetic, safety, and commercial produce an initial stimulation of pituitary profile. gonadotrophs that results in secretion of follicle‑stimulating hormone (FSH) and Half‑life of GnRH is 2‑4 min as it is degraded luteinizing hormone (LH) and the expected by peptidase and cleared by glomerular gonadal response. This response is followed filtration. This was the sole reason that of Website: by down‑regulation and inhibition of the GnRH, analogs with agonistic or antagonistic www.jhrsonline.org pituitary‑gonadal axis. As compared properties have been synthesized to increase DOI: to GnRH agonists, GnRH antagonists their potency and duration. These properties 10.4103/0974-1208.142476 promptly suppress pituitary gonadotropin were developed by deleting, substituting 170 Journal of Human Reproductive Sciences / Volume 7 / Issue 3 / Jul - Sep 2014 Kumar and Sharma: GnRH analog, advantages, limitations or modifying amino acid sequence at different positions Among many advantages one of the major advantages of of GnRH. the long protocol of GnRH agonist administration is that the initiation of exogenous gonadotropins after pituitary Gonadotropin‑releasing hormone and its analogs are being desensitization can be delayed to prevent ovum pickup used therapeutically in many clinical conditions. (OPU) in the weekends (the so‑called “programming”), without any detrimental effect on IVF outcome.[6] OVARIAN STIMULATION Furthermore, delay in hCG administration for 24‑48 h seemed to improve fecundity and contributes to planning As discussed earlier pulsatile administration of GnRH in of the OPU.[7,8] Ideally the GnRH agonist should be started physiologic amounts at a frequency that is similar to the one week before the expected menses. There is an initial endogenous release stimulates the ovaries which will induce flare up of the FSH and LH but this seems to lasting for ovulation in anovulatory conditions, such as hypothalamic a short time. Later the receptors are downloaded in the amenorrhea and polycystic ovarian disease.[1] pituitary to a very low level. Except PCOS , all other women the dose can be halved when the menses starts Gonadotropin‑releasing hormone agonists in combination and Gonadotropins can be stated for stimulation of the with gonadotropins for ovarian stimulation in assisted follicles. This kind of half the dose continuation along reproductive technology (ART) have been extensively with gonadotropins keeps the LH at a low levels rather investigated. The above combination also termed as than getting the surges.[9] The agonist is given on the day “Superovulation therapy” is very effective in women of hCG also.The agonist depletes the receptor, which who respond poorly to gonadotropin stimulation or regenerates only long after the agonist administration who have premature ovulation. Benefits of this therapy is stopped. However, sometimes the dose used may be seem to be suppression of endogenous gonadotropin excessive, causing too much of suppression of the ovaries. release, prevention of premature ovulation, recovery of All this kind of suppression will cause luteal phase defect, a larger number of oocytes, a decrease in the number of which, therefore, needs supplementation.[10] Ovarian canceled cycles, and an increase in pregnancy rate. Now, hyper stimulation syndrome has to be thought of when GnRH antagonists also have been used during the late high dose is used for ovarian stimulation. Some of the follicular phase of normal menstrual cycles as well as women have a cyst on the second day of menses and this gonadotropin‑stimulated cycles.[2] is one of the side effect of starting the GnRH analogue in the luteal phase, which leads to cancellation of the cycle. TREATMENT REGIMENS Short protocol There are many treatment schedules in which GnRH Instead of starting the GnRH analogue in the luteal phase agonists in ART. Their duration and initiation particularly of the cycle it can be started at the beginning of the cycle. in ovarian hyperstimulation in vitro fertilization (IVF)/ This leads to the flare effect of FSH and LH and augments intracytoplasmic sperm injection treatments varies. One the folliculogenesis already in progress. Though follicles can start the treatment either in the early follicular or are recruited with this method, the excess of LH in the midluteal phase of the preceding cycle. This cycle may be early part may be deleterious to the growing follicle. With spontaneous or may be under the influence of progestagens this method the dosage of gonadotropins can be reduced and/or estrogens. for an initial period of 2‑3 days at least, wherein the cost would come down. The dose of agonist it is stopped when Long or desensitization protocol the follicular maturity is attained and ovulation triggering The idea is to suppress LH hormone so that there is planned with hCG. This is one of the methods chosen for no sudden rise of the same. In this type of protocol the a poor responder. agonist starts in the early, mid‑, or late luteal phase in the preceding cycle or the follicular phase until human Microdose flare protocol chorionic gonadotropin (hCG) administration. However, This is not very popular and is very similar to the short starting in the early luteal phase showed lesser number protocol except that the dose of agonist is reduced.[11] of eggs retrieved compared to the follicular phase start.[3] More of the dosages of Gonadotropin were needed in Stoping gonadotropin‑releasing hormone agonist protocol the long protocol compared to the other regeems like In this protocol though the GnRH analogue is started in the ultrashort, short and higher number of eggs were obtained luteal phase one week before the expected start of menses, as shown in a meta analysis[4] when compared to the long is it stopped at the initiation of gonadotropin therapy since follicular phase protocol more profound and prompt the suppression is less to start the gonadotropins. However suppression was found after midluteal administration.[5] this is not popular due to the irratic response.[10,12] Journal of Human Reproductive Sciences / Volume 7 / Issue 3 / Jul - Sep 2014 171 Kumar and Sharma: GnRH analog, advantages, limitations Ultrashort protocol Idiopathic precocious puberty is the disorder characterized Gonadotropins are started on the day of the menses by premature GnRH activity. The aim of various and the agonist is also started but stopped in 2‑3 days, therapeutic methods was to suppress the pituitary as the suppression will outlast the stimulation.[13] In gonadal function, in precocious puberty also

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