GnRH Agonists, Antagonists, and Assisted Conception

André C.D. van Loenen, MD, Judith A.F. Huirne, MD, Roel Schats, MD, PhD, Peter G.A. Hompes, MD, PhD, Cornelis B. Lambalk, MD, PhD

Disclosures

Semin Reprod Med. 2002;20(4) 

In This Article

GnRH Agonist in Art

Types of GnRH Agonists

There are seven agonistic analogues that are approved and clinically used: leuprorelin, buserelin, goserelin, histrelin, deslorelin, nafarelin, and triptorelin ( Table 1 ). These agonists may be delivered by intranasal, subcutaneous, or controlled release (intramuscular or subcutaneous) depot/implant preparations. Nasal sprays require two to four administrations per day to maintain an effective drug concentration, and subcutaneous injections can be given once daily. With the intranasal route, the absorption of the agonist inter-and intraindividually is unpredictable. Considerable losses of the peptide occur by proteolysis and swallowing, giving a fluctuating desensitization level. But in most cases it is sufficient to prevent premature LH surges.[33,34] Because of their more stable effect, daily subcutaneous injections deserve preference. After subcutaneous injection, the agonist is rapidly absorbed and blood concentrations remain elevated for many hours. Four agonists (buserelin, leuprorelin, nafarelin, and triptorelin) are routinely used in ART. Because of their long duration of action, depot preparations (like goserelin) are not used as first choice of treatment in ART. A hypogonadotrophic and hypogonadal state was sustained for 8 weeks after a single depot of triptorelin in regularly cycling women. The suppression lasts longer than actually needed and the effect can endure into the first weeks of pregnancy.[35] In two different studies, a depot and daily administration of a GnRH agonist were compared. No differences in terms of stimulation and IVF outcome were reported.[36,37] Devreker et al found obvious negative effects of depot preparations in IVF treatment: a prolonged stimulation phase and consequently more ampoules needed, but more importantly, lower implantation- and delivery rates. Their conclusion was that a long-acting GnRH agonist might interfere with the luteal phase and embryonal development, and therefore short-acting GnRH agonists should be preferred in ART.[38] In contrast, a comparative prospective randomized study showed significantly higher implantation rates and live birth rates when the agonist was continued after human chorionic gonadotropin (hCG) for 14 days versus no continuation after hCG.[39] It was concluded that a continuous administration of a GnRH agonist during the luteal phase might facilitate implantation and prevent the paradoxical drop of serum gonadotropins, which occurs after cessation of the GnRH agonist.[40,41,42,43] There is not enough evidence to advocate the use of an agonist for a long time, as it may affect an emerging pregnancy. The agonists deslorelin and histrelin have not been used in ART but for indications that require sustained gonadotropin suppression, such as endometriosis, prostate cancer, and precocious puberty.[44,45,46,47,48,49] In prospective comparative studies of different GnRH agonists for the use in IVF cycles,[50,51,52,53,54,55,56,57,58,59,60,61] no specific GnRH agonist seems to be superior as a pituitary-suppressive drug during COH for IVF. A recent meta-analysis in which nafarelin was compared with intranasal (i.n.) nafarelin, subcutaneous leuprolide, and subcutaneous triptorelin in IVF showed equivalent efficacy of LH suppression in all groups but shorter stimulation period and lower gonadotropins requirements in the nafarelin group.[62] Regarding the type of GnRH agonist used in ART we can only conclude that a daily subcutaneous injection with a short-acting agonist is preferred. Solid conclusions cannot be drawn concerning the best GnRH agonist to be used in ART, because the minimally effective dosage in IVF is determined only for triptorelin ( Table 2 ), and no comparative studies performed so far are using the minimal effective dose for each individual agonist.

Treatment Regimens

Prevention of the premature LH surge results in lower cancellation rates, improved follicular recruitment with a larger number of oocytes recovered, and improvement in routine organization of assisted reproduction.[63] Many treatment schedules with the use of GnRH agonists in ART, particularly in ovarian hyperstimulation IVF/intracytoplasmic sperm injection (ICSI) treatments, have been designed (Fig. 1). The duration and initiation of agonist administration before the start of the actual ovarian stimulation varies widely. Initiation of the agonist treatment may either be in the early follicular or midluteal phase of the preceding cycle. This cycle may be a spontaneous cycle or an artificial one under the influence of the administration of progestagens and/ or estrogens.

Figure 1.

The different kind of GnRH agonist and antagonist protocols. *This cycle day time schedule applies also for the other protocols below;Zigzag, variable; M, menstruation; hCG, hCG administration.

In the long or desensitization protocol, the agonist starts in the early, mid-, or late luteal phase in the preceding cycle or in the follicular phase until hCG administration. Stimulation with gonadotropins is started when pituitary and ovarian suppression has been achieved. Comparing different initiation moments of GnRH agonists, it was found that the initiation of GnRH agonist administration in the early luteal phase resulted in the development of fewer follicles than in the follicular or mid- to late luteal phases.[64] A meta-analysis comparing ultrashort, short, and long IVF protocols showed higher number of oocytes retrieved and higher pregnancy rates in the long protocol, although more ampoules of gonadotropins were needed.[65] When the long follicular phase protocol was compared with the long midluteal phase protocol, more profound and prompt suppression was found after midluteal administration.[66,67,68] A major advantage of the long protocol of GnRH agonist administration is that the initiation of exogenous gonadotropins after pituitary desensitization can be delayed to prevent ovum pickup (OPU) in the weekends (the so-called "programming"), without any detrimental effect on IVF outcome.[69] Also, delay in hCG administration for 24 to 48 hours seemed to improve fecundity and contributes to planning of the OPU.[70,71,72,73]

With oral contraceptive (OC) (pre)treatment in combination with a long protocol, the agonist can be started during the use of OC. The precycle estrogen-progestin pretreatment may augment the patient's subsequent response to gonadotropins and prevent premature LH surges.[74] The main advantage of a long agonist protocol with OC is the fact that the treatment does not need matching with the patient's cycle. This allows the time of oocyte recovery to be planned several weeks in advance.[75,76,77] An unwanted side effect of the long protocol is the induction of the formation of functional ovarian cysts. The incidence of functional cysts is higher if the GnRH agonist in the preceding cycle is commenced in the follicular phase compared with the luteal phase.[66,78] In cycles with ovarian cyst formation, poor stimulation outcome and reduced pregnancy rates were found.[79] However, Feldberg et al could not confirm this finding.[80] Ovarian cyst formation was reduced in combination with an OC.[81] A possible hazard with luteal phase initiation of the GnRH agonist is the unsuspected presence of an early pregnancy with the risk of inadvertent exposure of the conceptus to the GnRH agonist.[66,82] With OC pretreatment this exposure to the conceptus will be prevented. Pretreatment with OC before gonadotropin stimulation has also improved the outcome in poor responders (see below, "Special Applications"). In a retrospective study subcutaneous GnRH agonist was started in a long protocol on the 20th day of 25-day OC administration and gonadotropins were started during withdrawal bleeding. This dual suppression showed an effective and improved IVF outcome in patients with a tendency for high response on gonadotropins (some normal patients, with polycystic ovary syndrome [PCOS]). The explanation for these results may be through an improved LH/FSH ratio following dual suppression.[83]

In conclusion, a long GnRH agonist protocol in combination with OCs seems to be of advantageous in (1) prevention of functional cysts and spontaneous pregnancy, (2) prevention of LH surges, (3) improved response to gonadotropins, and (4) allowing programming of the IVF cycle and the prevention of unwanted administration of agonists during a spontaneous pregnancy.

The short or flare-up protocol combines GnRH agonist therapy, started at cycle day 2, with gonadotropins initiated 1 day later. The immediate stimulatory action of the GnRH agonist serves as the initial stimulus for follicular recruitment. Adequate follicular maturation is on average reached in 12 days, which should allow enough time for sufficient pituitary desensitization to prevent any premature LH surges.[84,85]

In the ultrashort protocol, the agonist is given during a period of 3 days in the early follicular phase. At the second day of agonist administration stimulation with gonadotropin is started.[86,87,88,89,90]

In the long short, early cessation, or discontinuation long protocol, several investigators have tried to shorten the duration of GnRH agonist administration by early cessation. The agonist is started midluteal in the preceding cycle and discontinued during or even before the FSH treatment is started.[91,92,93,94,95] The results on IVF outcome were comparable to the long protocol with sustained LH suppression despite early cessation of the agonist.[93] In a prospective study in poor responders, a beneficial effect of this strategy in combination with high-dose FSH was found. In comparison with a depot preparation of triptorelin, the early cessation protocol required less FSH.[96,97] These results are not surprising as we know that GnRH agonist depot protocols require higher amounts of FSH in comparison with daily administration regimens. In contrast, in comparison with the long protocol, adverse effects on follicular development were found with longer stimulation phase and higher FSH requirements, although pregnancy rates were not different. The paradoxical drop of serum LH after early cessation, leading to significantly lower estradiol levels on the day of hCG, may have a deleterious effect on oocyte quality and thereby on pregnancy rates.[42,43,98] In conclusion, the available data are not in favor of an early cessation protocol.

Dose-Finding Studies for Agonists

GnRH agonist doses used in IVF are derived from treatment schedules used in disseminated prostate cancer,[99] in which complete gonadal suppression is necessary. In ART, GnRH analogues are used to prevent a premature LH surge, for which it may be enough to suppress gonadotropin secretion only partially. Using lower dosages could have some advantages, such as avoidance of a direct effect of agonists on the ovary, oocyte, embryo, and endometrium.[100] During COH, pituitary desensitization has proven to be agonist dose-dependent.[101] There are some comparative studies that indicate that the daily dose of agonist used in IVF may be decreased without compromising the results.[102,103,104] There is only one prospective, randomized, double-blind, placebo-controlled dose-finding study performed in IVF for a GnRH agonist (triptorelin). The dosage necessary for suppressing the spontaneous LH surge is only 15 to 50% (15 to 50 mcg) of the dosage needed for the treatment of prostate cancer (100 mcg), which is usually used in IVF.[2] It has also been demonstrated that once the pituitary is suppressed, the dose of GnRH agonist needed to prevent a LH surge decreases with the length of treatment.[105] Halving the dose of a daily administered GnRH agonist at the beginning of the stimulation has been successfully performed in normal[106,107] and poor responders,[108,109] without adverse effect on the quality of ovarian response to stimulation. In conclusion, it is very likely that the dosage of the commonly used GnRH agonists is far too high. Dose-finding studies must be performed first, before proper comparative studies between the commonly used daily administered GnRH agonists can be designed.

Special Applications

PCOS. The first studies using GnRH agonist in combination with human menopausal gonadotropin (hMG) for anovulatory PCOS patients showed optimistic results[110]; seven of eight PCOS patients conceived. These promising pregnancy rates were confirmed by others.[111,112,113] Nevertheless, subsequent prospective randomized studies indicated that GnRH agonists provide no benefit over hMG therapy alone and did not reduce the tendency of the polycystic ovary to multifollicular development, cyst formation, or ovarian hyperstimulation syndrome (OHSS).[112,114,115] Also, 3-month pretreatment with a GnRH agonist in ovulation induction with low-dose pure FSH did not improve ovulation and pregnancy rates.[116] GnRH agonists have also been employed to enhance responsitivity of patients with PCOS to other ovulation-induction drugs such as pulsatile GnRH. Rates of ovulation were disappointing, however, and miscarriage rates were as high as 45%.[117,118,119] In a recent systematic review it was assessed that in an ovulation induction protocol with GnRH agonist pretreatment and FSH/hMG, in comparison with FSH/ hMG only, no significant differences were noted between the groups in pregnancy rates and rates of OHSS. In the absence of evidence suggesting a benefit of GnRH agonist augmentation for PCOS, it should not be recommended as a standard treatment for this patient group.[120]

In COH protocols for IVF treatment the diagnosis of PCOS is important because these patients are more likely to develop OHSS.[121,122,123] Suppression of endogenous LH by GnRH agonists may have a particular advantage for women with PCOS. In the sensitive polycystic ovary, free from the adverse environment of high tonic LH concentrations, oocyte-containing follicles can develop.[124] In cycles with pituitary desensitization oocytes appear to fertilize better. This suggests that it is indeed the abnormal hormonal milieu rather than the polycystic ovary itself.[125] With both long and short protocols, significantly more eggs are collected from woman with polycystic ovaries and the total dose of exogenous gonadotropins is the same for either regimen.[126]

Poor Responders. The various therapeutic strategies that have been used to improve the success rate in ART in poor responders cannot easily be compared, because a uniform definition of a poor responder is lacking.[82,126,127,128,129] Poor responders represent a heterogeneous group of patients. Strategies for the treatment of poor responders that have been studied are: (1) high dosages of gonadotropins, (2) reduced GnRH agonist dose, (3) short and ultrashort protocols, (4) cotreatment with growth hormone, and (5) precycle estrogen and/or progestogen pretreatment. The use of a long protocol in poor responders has been found to result in reduced ovarian responses to hormonal stimulation.[130] The short GnRH agonist protocol has been proposed as a better stimulation protocol for poor responders. The initial stimulatory effect of GnRH agonist on pituitary hormone levels may improve the ovarian response.[109,131,132,133] On the other hand, this short protocol might increase gonadotropins in the early phase, which induces enhanced ovarian androgen release, which in turn is associated with declined oocyte quality and reduced ongoing pregnancy rates compared with the long protocol.[134,135] Nevertheless, experience to date shows that the short protocol has an important role in the treatment of poor responders.[136] Scott and Navot have introduced a microdose GnRH flare protocol after OC treatment. They pretreated poor responders with OC before applying their microdose GnRH agonist flare-up protocol and reported significantly improved outcomes.[137] In a prospective study the results of 42 poor responders using OC for 28 to 42 days, followed immediately by stimulation with gonadotropins, were compared with the results obtained in previous stimulation cycles of the same women with CC/hMG regimen. Higher estrogen levels, more mature follicles, lower cancellation rates, and higher number of oocytes and pregnancy rates were noticed in the OC group.[138] In conclusion, pretreatment with OC may represent an alternative protocol for poor responders and may be worth attempting.

Ovarian Hyperstimulation Syndrome. OHSS is an important complication of COH.[139] The risk of OHSS in agonist COH cycles ranges from 6.6 to 8.4%.[140,141,142] The use of GnRH agonist in COH protocols allows continuous stimulation by gonadotropins, which will drive more follicles to maturation, increasing the risk of OHSS.[143] Besides multiple follicular development, hCG is an additional promoting factor of OHSS. This may be explained by the longer half-life time of hCG in comparison with LH. However, hCG as a substitute for the midcycle LH surge is often used in ovulation induction and ART. Alternative ways for triggering ovulation are: recombinant LH, native GnRH, or a GnRH agonist. GnRH agonist have been successfully used for the induction of the final meiotic division of oocytes in IVF cycles, as well as ovulation in non-ART cycles.[74,144,145,146] Most reports show low incidence of OHSS. However, in spite of these results, GnRH agonist cannot be given in cycles in which GnRH agonist induced pituitary desensitization, in contrast to cycles in which GnRH antagonists are given.

Intrauterine Insemination. Different treatment protocols have been used for controlled ovarian hyperstimulation in intrauterine insemination (IUI) treatment, including CC and gonadotropin alone or in combination with CC. COH in IUI treatment showed increased pregnancy rates in comparison with IUI alone, ranging from 3 to 40% versus 0 to 21%.[147,148,149,150,151,152] GnRH agonists are not frequently used during IUI as longer pretreatment period is required and the risk on multiple pregnancies is increased due to increased follicular growth. In a prospective randomized study on this subject, no significant differences were observed in subsequent cycle fecundity or live-birth rates between patients treated with hMG alone or in conjunction with GnRH agonists (midluteal phase initiation).[153] In a prospective study, the clinical efficacy of hMG alone in comparison with a short protocol of GnRH agonist/ hMG in IUI revealed no significant beneficial effect in terms of pregnancy rate, although hMG requirement was increased and estradiol levels were elevated in the agonist group.[154] Kim et al[155] described in a prospective randomized clinical trial the use of GnRH agonist in a stimulated IUI protocol in patients with various stages of endometriosis. In patients with stage III or IV endometriosis, the clinical pregnancy rate per cycle was significantly higher in an ultralong group compared with a long protocol group (50% versus 19%, respectively). They suggested that a simplified ultralong protocol of GnRH agonist may give better chances of achieving pregnancy in endometriosis patients undergoing IUI per cycle. In conclusion, although GnRH agonists may have some beneficial effects on IUI results in endometriosis, it does not seem to have major advantages in other patient groups.

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