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Overcoming Poor Response to IVF Stimulation

Don't be discouraged if you show signs of poor response to IVF stimulation. At CHR, we work with you to understand why you aren't producing enough follicles and ultimately find a solution that can work for you.

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When a patient produces very few eggs in response to ovulation induction, we call that, "poor response." People have defined it in different ways, but most often it means that you produce fewer than four eggs in a fully-stimulated cycle. An average person, of average reproductive age, using the normal amount of medication we have used for ovulation induction in an IVF cycle, would probably produce around six, eight, ten eggs, or something like that. So, poor response (fewer than four eggs) is a pretty good standard definition. In general, we understand that the more eggs that you can produce, the more opportunity you have to select among those eggs, or the embryos that come from those eggs, to have the best chance of pregnancy. And it's been shown time and time again, in many studies, that the more eggs that you produce in a cycle, the better chance you have at achieving your goal of having a pregnancy. And, so, our goal is to try to help you achieve yours by producing enough eggs to do that. One might ask, "Why are you producing so few eggs?" and the bottom line is, the most common reason for that is, that you've aged out, or you're aging out of average reproductive potential. So, as women get older, their ability to produce eggs decreases, and I guess it wouldn't be surprising to know that somebody who's 55 or 60 would be very unlikely to produce any eggs. But, you can go back on that on a steady basis every five years, going backward, and the farther you move along the scale of either going younger or older, will depend on how many eggs you are able to produce. I'd say the average forty-year-old going through an average ovulation induction would probably produce only about (at most) five or six eggs. The average forty four-year-old will be lucky if she's able to produce three or four eggs. The average for women older than 44 probably would be lucky to produce one or two eggs. There are unusual people who are able to produce much more than that, but what we're talking about would be the median or the expected for somebody of a particular age group. Now, you can have women who have premature ovarian insufficiency and that, by definition, is a woman who is under the age of 40 and is unable to produce the numbers of eggs that would normally be expected of her age. For instance, somebody who's 35, but is only producing one or two eggs under, you know, the maximal effort to try to produce eggs would have premature ovarian insufficiency. We've called it in the past, "premature ovarian aging." And, some women who become menopausal (meaning they haven't had a period in six months to a year), would be considered "premature ovarian failure" under similar circumstances. The reasons for premature ovarian sufficiency, premature ovarian failure. There are many different kinds of reasons. The most common would be a genetic reason-- either you're lacking a gene, which is necessary to produce eggs, or to maintain your eggs, or your chromosomal makeup is such that you weren't able to produce eggs or maintain your eggs. So, it requires a careful workup. Now, there can also be metabolic reasons why somebody who appears to have premature ovarian insufficiency is not able to produce eggs. And, sometimes, that can be fixed by just correcting the hormonal problem that led to this. Some examples might be a woman who's, for one reason or another, not able to produce adrenal steroids. In which case, replacement of adrenal androgens (like DHEA) can almost fully restore you to normal function. Those cases are unusual, but we look carefully and try to see if they're present. Other endocrine problems: hypothyroidism, certain immune problems. There are a variety of other metabolic issues that can impact on the ovarian function. So, the obvious next question would be, "What can we do about this?" Well, let me explain to you a little bit about how the ovaries work and then say how we can try to work with that to make it work better. A woman in her normal reproductive life will only have about 400 to 600 cycles (meaning she's only ovulating 400 to 600 eggs in all of her lifetime), but in fact, when she reaches puberty, she has about 400,000 eggs. So, on the average, she's going through about a thousand eggs in each cycle. In fact, when she's younger, she's probably going into three or four thousand eggs in each cycle and that diminishes as you get older. It averages out to about a thousand per cycle, but it goes from thousands when you're young to hundreds when you're older. [There are] a couple of consequences there, and a couple of things to think about. You can kind of think about these thousands of eggs like kids trying out to be on an Olympic gymnastics team. So, there's probably thousands of children doing gymnastics class, and then a few of them make it to the States, and then a few would them make it to the Olympic team. At the beginning of your menstrual cycle, it's kind of like the Olympic team of eggs. So, those 20 or so that have been selected from the thousands that began the process. And when we do ovulation induction, on average women, we can sometimes get all 20 of those promoted to ovulate. Whereas, under normal circumstances, only one would have ovulated (like one kid gets the Olympic gold medal). So, we promote everybody to get gold medals-- all those last ones. Now, that math continues to be true, even people who have evidence of some ovarian insufficiency. So, although you're fighting to produce that one egg, or two or three eggs, the process began with hundreds, or maybe thousands, of eggs trying to get to that point. And, so, one of the ways we at CHR have been working to try to improve that process is to try to salvage those eggs that are trying to get promoted to that Olympic team by using medications that help protect that early follicle development. And, one of the ways we've used for years is to use a hormone known as DHEA. And, DHEA is a weak androgen. Androgens help promote the survival of these early antral follicles, and instead of your body sort of weeding them out or letting them go, which it does on normal circumstances when it's trying to just get down to a few eggs. They only ovulate one at a time. If we exposed you to androgens, more of those early antral follicles will survive to make it to that team of follicles that are going to be able to be affected by fertility medications. So, the one example of this might be women who naturally produce more and androgens than average, and they have lots of these little follicles. And that's called, "polycystic ovary syndrome." When a woman with polycystic ovary syndrome uses fertility medication, she makes 30-40 eggs because she has all these little follicles sitting around. Those little follicles are sitting around because her body produced excess androgen hormones, like DHEA, and promoted the survival of those early follicles. When we give a woman DHEA, we're not going to turn her into somebody with polycystic ovary syndrome, but we are going to help to salvage some of those early follicles that she would have otherwise lost. And, in general, we're able to increase the numbers of follicles that survive, and eggs that are produced, and improve the quality of the eggs that end of being produced. We've also used human growth hormone in a similar way. To some extent, human growth hormone can be complementary to these other medications. Not everybody responds to human growth hormone. Problems with human growth hormone are that it's expensive, it requires an injection, and not everybody has a good response to it, but it's one of the other adjuvant treatments that we've tried to use. In some women who don't respond to DHEA, we can use transdermal testosterone, which has the same effect of increasing your level of androgens and promoting the survival of these early antral follicles. Now, you hear that I keep saying early antral follicles, and what that means is, you don't start these medications at the very beginning of your ovulation induction. In fact, you have to start it several weeks ahead of time. And, whenever we're trying to improve ovarian function, we ask women to start DHEA or whatever adjuvant we're using at least six to eight weeks before their planned ovulation induction. So, all of this takes a little bit of planning. Another intervention that we found can be helpful, and that others use as well, is the use of estrogen. So, we give estrogen for about 10 days before our planned beginning of an ovulation induction. And, the idea there is to, first of all, suppress your own gonadotrophins a bit. That helps sensitize the follicles to be able to respond better when they're exposed to gonadotrophins at the beginning of your cycle. So, there are lots of things to talk about here. We can talk about them together if you come in to see us. But, there are several things that we've been lucky enough to use to help people to still stay in the game, even when they've been told they have some evidence of premature ovarian insufficiency.

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