As usual, the journal Fertility and Sterility has tons of interesting research.  This particular article grabbed my attention, since every year one of my clients will have problems with hyperstimulation.  The article discusses the use of a GnRH agonist (encourages the pituitary to secret higher levels of FSH/LH) as the trigger before retrieval.  Most IVF cycles use HCG (identical to FSH/LH) as the trigger, which has a long half life (it lingers for a long time in the blood stream before the body can eliminate it) and it can encourage the continual growth of follicles.


OHSS is serious consequence of IVF, mostly for PCOS women, but I notice a trend with women who have a history of cyst formation (naturally occurring or produced with fertility drugs in IUIs) struggling with OHSS.  These women have ovaries that are easily stimulated to produce cysts, resulting in poor quality follicles or OHSS.  Reactive LH receptors cause excess androgen production and OHSS can be viewed from a Chinese perspective, as phlegm and dampness settling in the uterus and ovaries.  Actually, phlegm and dampness can destory/suffoicate a healthy oocyte.  This is why OHSS is more likely to produce poor quality follicles.   Imagine, pond scum all over your clean bed….it wouldn’t be very nice to sleep in.  You would get covered in green slimy stuff.  It sticks to you body and when your head is on the pillow you breath in the scum.  That’s how excess androgens produced by theca cells (stimulated by the HCG trigger shot) react with the follicles.  I believe cystic women have highly sensitive follicular receptors to androgens and LH, which allows this problem to arise.  This is another reason why it is important to work with an acupuncturist before an IVF cycle.  Acupuncture and herbs can improve the environment of the ovaries, so they do not over react with HCG to produce cysts.        


Hopefully, if you are an OHSS that this article will provide a treatment option for you in the next IVF.



The use of gonadotropin-releasing hormone (GnRH) agonist to induce oocyte maturation after cotreatment with GnRH antagonist in high-risk patients undergoing in vitro fertilization prevents the risk of ovarian hyperstimulation syndrome:  a prospective randomized controlled study.
Fertility and Sterility, Vol. 89 pg 84.
Author:  Lawrence Engmann


Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication of controlled ovarian hyperstimulation (COH) It may be associated with massive ovarian enlargement, ovarian torsion, ascites, hydrothorax, liver dysfunction, thromboembolism, electrolyte imbalance, and renal failure. In addition, cancellation of an IVF cycle for risk of OHSS as well as prolonged bed rest or hospitalization.


Despite significant advances in assisted reproductive technology over the years, there are currently no effective strategies to eliminate this disorder. High-risk patients include young women with polycystic ovary syndrome (PCOS) or polycystic ovarian morphology (PCOM) on ultrasound without the clinical or biochemical evidence of the syndrome and patients with a history of previous high response to gonadotropins.


Currently, one of the standard COH protocols used for high-risk patients undergoing IVF is the dual pituitary suppression with oral contraceptive pills (OCPs) and GnRH agonist overlap  followed by hCG to induce oocyte maturation. Despite its benefits, the administration of hCG results in a prolonged luteotropic effect, which may result in a potential risk of OHSS in high-risk patients.


It has been proposed that the administration of a GnRH agonist to induce the final oocyte maturation may result in a reduced risk of OHSS. This is due to the shorter half-life of the endogenous LH surge and subsequent pituitary suppression leading to early luteolysis and reduced luteal phase steroidal concentration. However, previous studies have suggested that GnRH agonist trigger may impair implantation rates in normal responders.
There are no randomized studies assessing specifically the effect of GnRH agonist to induce oocyte maturation after GnRH antagonist cotreatment followed by adequate luteal phase and early pregnancy supplementation with both E2 and P on the occurrence of OHSS and implantation rates in high-risk patients.We therefore sought to test the above hypothesis.


Sample Size  – 30 subjects in each group


Participants – Patients were enrolled in the study if they fulfilled the following criteria: age 20–39 years at the time of screening, normal early follicular phase serum FSH concentration, and undergoing their first cycle of IVF with either PCOS or PCOM or undergoing a subsequent cycle with a history of high response in a previous IVF cycle. Women with hypogonadotropic hypogonadism were excluded from the study, because they may have an abnormal endogenous LH surge after GnRH agonist trigger.


Treatment Protocol  – All the women in the control group underwent a dual pituitary suppression protocol, which consisted of pretreatment with OCP for 25 days overlapping with 1 mg leuprolide acetate (Lupron) commenced on day 21 of the OCP. Once pituitary suppression was achieved, the dose of leuprolide was reduced to 0.5 mg daily and COH was commenced as described below. Leuprolide was continued until the day of trigger.
All of the women in the study group underwent pretreatment with OCPs for 21 days. COH was commenced on day 2 of withdrawal bleeding. Ganirelix acetate (Organon) was commenced once the leading follicle was ≥14 mm and continued every morning until and including the day of trigger.
In both groups, COH was achieved using a step-down protocol of recombinant FSH (Follistim) in a starting dose of 112–225 IU. Monitoring of follicular growth was achieved with serial ultrasound and serum E2 measurements and the dose of gonadotropins adjusted, if necessary, according to follicular response. When two or three leading follicles were ≥18 mm in diameter, patients in the control group received SC hCG (Profasi) in a dose ranging from 3,300 to 10,000 IU depending on follicular response and serum E2 levels.  Patients in the study group received SC leuprolide in a dose of 1 mg approximately 12 hours after the last dose of ganirelix. The leuprolide used for the trigger in the study group.
Luteal Phase Supplementation – All patients received 50 mg IM P in oil daily for luteal support starting the evening after oocyte retrieval and continuing until a negative pregnancy test. Patients in the study group received three 0.1 mg transdermal E2 patches (Vivelle-Dot) every other day starting the day after oocyte retrieval until a negative pregnancy test.


None of the patients in the study group developed any form of OHSS compared with 31% of patients in the control group. Five of these patients developed mild OHSS, four developed moderate OHSS, and one developed severe OHSS.  The control group was at least 3.79 times more likely to develop OHSS and at least 1.35 times more likely to develop moderate or severe OHSS than the study group.
The implantation (36% vs. 31%) and clinical (56.7% vs. 51.7%) and ongoing (53.3% vs. 48.3%) pregnancy rates were similar between the study and control groups, respectively. There were two biochemical pregnancies in the control group and one in the study group. There was one anembryonic pregnancy and one spontaneous miscarriage in each group. The twin pregnancy rate was comparable between the study and control groups.


The findings of this study also suggest that its use may not impair implantation rate if a strategy of adequate steroidal monitoring and supplementation is adopted during the luteal phase and early pregnancy.


Several strategies have been proposed for the prevention of OHSS in high-risk patients, but none of them have been shown to completely eliminate the risk of OHSS. The dual pituitary desensitization protocol is widely used for patients with PCOS, PCOM, or previous high response, even though it does not prevent the development of OHSS. Although it has been suggested that use of GnRH antagonist during IVF treatment may reduce the incidence of OHSS recent studies have shown that it does not completely eliminate the risk. The use of hCG trigger in these protocols accounts for the development of OHSS. One of the advantages of the use of the GnRH antagonist protocol in high-risk patients is the potential use of GnRH agonist trigger to prevent OHSS.
To the best of our knowledge, the present study is the first randomized trial with an adequate sample size to clearly demonstrate that the use of GnRH agonist to trigger oocyte maturation reduces the risk of OHSS without affecting implantation rates. Even though all forms of ovarian stimulation may result in some degree of ovarian hyperstimulation, none of the patients in the present study who received GnRH agonist trigger developed any form of OHSS, and they were all totally asymptomatic 7 days after oocyte retrieval.


The mechanism of OHSS prevention after GnRH agonist trigger has not been previously fully explored. Administration of a single dose of GnRH agonist, after cotreatment with GnRH antagonist, induces an endogenous rise of both FSH and LH which results in the induction of the final stages of oocyte maturation. The shorter half-life of the endogenous LH surge and the subsequent pituitary suppression and withdrawal of LH support for the corpora lutea may lead to early luteolysis. The significantly lower luteal phase steroidal concentration after GnRH agonist trigger is further evidence of the defective corpora lutea function and secretion of peptides responsible for causing OHSS. Moreover, the significantly smaller midluteal MOV after GnRH agonist trigger, which is a surrogate marker of OHSS and corpora lutea function, is additional evidence of luteolysis. A direct local effect on the granulosa/luteal cells is also possible, because studies in primates have demonstrated the presence of GnRH receptors in the ovary as well as a local effect on the induction of oocyte maturation.


GnRH agonist to trigger oocyte maturation and ovulation has been advocated since 1989). Nevertheless, it has not gained popular acceptance and widespread use for several reasons. First, it fell out of favor during the 1990s because of the widespread use of GnRH agonist desensitization protocols, because the pituitary becomes unresponsive for inducing an endogenous LH surge with a GnRH agonist. Second, one of the major drawbacks of GnRH agonist trigger is the induction of an inadequate luteal phase and impaired steroid circulation.


In fact, recent publications have suggested that GnRH agonist trigger may lead to impaired implantation and ongoing pregnancy rates in normal responders. However, we did not notice any differences in implantation rates and we obtained excellent clinical and ongoing pregnancy rates using our modified luteal phase and early pregnancy supplementation protocol.


Adequate luteal phase steroidal supplementation after GnRH agonist is essential in view of the overwhelming evidence of abnormal luteal phase steroid profile after GnRH agonist trigger. The optimal route of P administration after COH is debatable, although one may hypothesize that after GnRH agonist trigger the IM route is preferable because of the abnormal luteal phase and the need for adequate supplementation. The route of E2 administration may also be important in correcting the abnormal luteal phase, and it is likely that the use of transdermal E2 patches may be preferable because it avoids the first-pass effect of oral E2. Moreover, early discontinuation of steroid supplementation may be detrimental for patients triggered with GnRH agonist, because the endogenous rise of hCG during early pregnancy may not rescue the early luteolysis that occurs after GnRH agonist trigger.