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Mild Ovarian Stimulation for IVF

Joe B Massey, MD


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Dr Massey has long had an interest in low cost IVF. He is currently working  in a center where optimal drug stimulation is used, and fees are low for full IVF.

CNY Fertility Center is a national leader in this approach. Offices are in Lathan, Rochester and Syracuse New York.

Since the early days of in vitro fertilization (IVF), stimulation of the ovaries has proven to be beneficial. Production of multiple eggs makes up in part for the natural inefficiency of human reproduction. In the earliest days, laboratory conditions were problematic, but now we seem to get the best out of the eggs available. Still one egg just is not enough.


There is a re-evaluation now of the optimal use of drugs and stimulation. In some countries this is driven by an emphasis on the birth of a single baby. In the US, the emphasis is on the economics of a successful IVF outcome as much as any other factor. In our country, the risk of twins, which are five times riskier for mother and baby does not deter the transfer of two embryos very often. Everyone involved wants the optimal pregnancy rate. This includes the most cost effective method. Cost effective translates to dollars per baby. There are few studies which address this issue directly, so some common sense has to be applied to the available evidence. The lowest cost treatment might be more costly in the long run. At the same time we don’t want to use drugs doses that are higher than they need to be, especially if this might be harmful.


Let us examine some of the options which are now gaining attention.


Natural Cycle IVF uses no drugs, allows one follicle to develop and egg retrieval is done based on clinical measures mostly ultrasound. This can work, but the take home baby rates are around 9% per cycle. It has little application in the US currently.


Drug free IVM or in vitro maturation seems like a new promising technology. I traveled to Korea in 2009 to learn from the master, Dr  Jin-ho  Lim. I also visited an experienced center at Brown University.  In New York City with Dr Joel Batzofin, we attempted to attract patients to a study based on the idea that no drugs were needed, thus costs would be saved. Little monitoring was needed as eggs were aspirated from medium sized follicles. We had difficulty recruiting patients as we knew the results would be less than IVF, though we thought perhaps more cost effective. We had only early pregnancies, none making it to term among 9 young patients. We found that the effort by the physician was much higher to retrieve the eggs from small follicles, and the laboratory effort was at least triple normal. Thus logically the fee for the in vitro fertilization service should actually be higher than usual.  Since the results in other centers seem not to exceed 25% success, at this point its utility seems is limited. It may find a role in certain patients with polycystic ovaries.


Current mainstream IVF involves multiple medications which comprise about a third of the cost of the treatment cycle. In order to monitor the effects of the drugs frequent ultrasound and blood testing for response is needed.


There have been minimal regimens used which revolve around oral medication only or as an initial drug. Clomiphene is the number one choice, with no real evidence showing an advantage for letrazole.

The published results to our knowledge are in the range of 15% success per cycle. Cheap it is, but it is not likely to be a trend in the US.  Now it is improving though the use of freezing of embryos and later replacement. The results in one study show doubling of success which would approach age matched results for standard IVF. The costs in terms of lab time will be a factor in the application of this scheme.


There are options for simplifying IVF compared to treatment with the time honored long luteal Lupron protocol. This method can involve up to 2 months of management and requires more drug than any other protocol. Before getting to the popular antagonist method,


One study has shown the benefit of use of the Lupron flare method in normally responding women. The use of Lupron at the beginning of the cycle causes a boost of FSH hormone form the pituitary. It is like free gonadotropin, about 300 r more units per day. Then the remainder of the cycle continues on Lupron and injectable gonadotropins. Even before this publication, Dr Rob Kiltz has found this to be a very patient friendly choice here at CNY Fertility Center in Syracuse.


The use of antagonists which can be added only in the last few days of stimulation have made life simpler for the IVF patients for at least 10 years now.


The big question in this discussion revolves around the ideal dose of gonadotropins to use. Until recently, it was generally felt that the more eggs retrieved the better. Doses were adjusted for patient age and response in previous cycles to avoid hyperstimulation, but beyond that, no dose was too large.


Now let’s look at two groups of patients and considerations of doses used.  First, the low responders are  patients who are frustrated and have challenged us as providers.  Now we know that the abundance of treatment protocols suggests that no protocol can really solve the basic problem of low ovarian reserve. Giving over 300 IUI of drug per day is not really improving results and arguably the maximum effective dose is lower for many women.


In the normal responders, mild stimulation protocols used mostly in Europe will begin FSH 150 IU starting on day 5. The method passes up the extra egg recruitment that can occur with an earlier start date. Fewer days of drugs and monitoring all add up to reduced complexity, patient discomfort and risk. A major argument is that the high customary doses are producing eggs which are abnormally driven and incompetent.

Thus the new benefit in the lower dose regimens is an apparent improvement in egg quality, and thus embryo quality. The number of eggs is lower, but the pregnancy rates are the same as in higher dose regimens.


Three studies have shown that low number of eggs in mild stimulation is not a concern. Modest number of eggs in a conventional stimulation of course is associated with low outcomes.


The only real disadvantage is a real one. Lower number of embryos frozen reduces the cumulative chance for success from one egg retrieval. No one knows exactly how to tailor the low doses for the individual patient. As yet the ultimate cost effectiveness has not been shown.

Still the new methods are appealing as they lower the initial cost of an IVF cycle.





Fauser BCJM et al Mild stimulation for IVF: 10 years later. Hum Reprod advanced on line access




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