Premature Ovarian Aging
Treatment for Women with POA
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Summary of POA Treatment at CHR, a "Fertility Center of Last Resort"
Premature ovarian aging is one of the major causes of female infertility. As women get older, their ovarian reserve (OR, the ability of the ovaries to produce good-quality eggs) naturally declines. Approximately 10 percent of women, however, experience this decline of ovarian function much earlier than others. This means that, if their OR is evaluated, it is found to be lower than what is expected for their age. These women are considered to suffer from premature ovarian aging (POA), a clinical term coined by the CHR researchers. Women with POA have a hard time conceiving on their own, or even with fertility treatments, if the treatment is not appropriate for their ovarian status; with appropriate treatment, however, women with POA can conceive, as many of our POA patients can testify.
Dr. Norbert Gleicher explains what premature ovarian aging is, how it is linked to diminished ovarian reserve and the use of DHEA supplementation for improving ovarian reserve.
Treatment of premature ovarian aging starts with timely diagnosis. At CHR, patients are evaluated based on age-specific hormone values, instead of universal cut-off values, to promptly diagnose POA. Timely diagnosis is crucial, because once the OR starts declining, it continues to decline with time. (Read more about POA diagnosis below.)
After a POA diagnosis, patients at CHR receive individualized treatment based on their OR status and any other factors involved in their infertility condition, such as autoimmune abnormalities (which are often found in conjunction with POA). This individualized and proactive approach, born as a result of CHR's years of clinical research on POA and diminished ovarian reserve (DOR), and our excellent pregnancy rates even in patients with severe DOR, are what separate CHR from most other IVF centers, and why we came to be known internationally as "the fertility center of last resort." (Read more about POA treatments below.)
Get the FACTS about Premature Ovarian AgingCHR's Prematurely Aging Ovaries Program
A woman's fertility potential is defined by her ovarian reserve (OR). OR, in turn, is defined by how many follicles/eggs she has left in her ovaries. As women age, their OR declines, and it becomes increasingly difficult to conceive. Menopause represents the last step in this gradual loss of fertility.
Most fertility centers routinely refuse treatment to women with significantly diminished ovarian reserve (DOR), unless they are willing to utilize donor eggs. DOR can be a consequence of advanced female age or due to a premature ovarian aging (POA) process, which affects approximately 10 percent of women in reproductive ages. Some people also call POA "occult primary insufficiency (OPOI)." POA patients are disproportionately represented in fertility centers, because women with premature ovarian aging experience infertility issues. Unfortunately, they are often diagnosed with premature ovarian aging only much too late!
Both forms of DOR represent major, but often ignored, causes of female infertility. CHR's Medical Director, Dr. Gleicher, recognized this fact many years ago. For over ten years, CHR, therefore, in contrast to other fertility centers, has been consciously developing special expertise in treating "older ovaries," whether ovarian aging was due to a woman's age or a consequence of POA. Physicians and investigators at CHR, therefore, gained clinical experience by treating patients affected by the "old ovaries" or "aging ovaries," but also by focusing the center's infertility research efforts to a large degree on diagnosis and treatment of DOR, including, of course, DOR due to premature ovarian aging.
This research has led to major breakthroughs, not only beneficially affecting CHR's patients but women worldwide, as fertility specialists all over the world have started to incorporate CHR's often revolutionary treatment approaches into their clinical practices. Nothing exemplifies this better than CHR's introduction of dehydroepiandrosterone (DHEA) into infertility treatment. DHEA is now used worldwide, benefitting thousands of women every year who, otherwise, would have had no choice but to resort to egg donation.
As CHR's clinical experience with "aging ovaries" increased, our clinical IVF pregnancy outcomes continued to improve. Since we did accept women into fertility treatment for severe DOR due to advanced age or premature ovarian aging, this differentiated CHR from practically all other fertility centers. This separation grew wider as CHR produced progressively improving IVF pregnancy rates in patients of continuously increasing severity in terms of their "ovarian age."
As word started getting around, CHR became New York City's "fertility center of last resort." With increasing popularity of the Web, CHR's reputation very quickly spread to the whole country and into Canada. Over the last two years, we've also witnessed explosive growth in overseas patients, seeking out treatments that they simply cannot obtain in their countries of residence. In many ways, CHR has, thus, become the "world's fertility center of last resort," a designation we are very proud of! Today, over half of the center's new patients are long-distance patients, and over a third comes from overseas for our special expertise in treating women with severe DOR, whether it is due to advanced age or premature ovarian aging (POA).
What is Premature Ovarian Aging?
As women get older, their OR declines. This means that the number of follicles/eggs in their ovaries declines in a predictable way. Approximately 10 percent of women, however, demonstrate decline of ovarian function ahead of time. This means that, if their OR is evaluated, it is found to be lower than what is expected for their age. These women are considered to suffer from premature ovarian aging (POA), a clinical term coined by the CHR researchers.
Unfortunately, quality of eggs declines in parallel to decline in quantity. Women with DOR, if left untreated, therefore, experience the highest miscarriage rates of any infertility diagnosis because approximately 95 percent of embryo quality comes from the egg, and poor quality embryos are more likely to result in miscarriages.
Diagnosis of Premature Ovarian Aging
POA is one of many causes of female infertility but, likely, the most frequently overlooked one. The reason why POA is frequently overlooked, even by good infertility centers, is the fact that most centers still use universal OR parameters, independent of patient age. For example, most centers still consider a follicle stimulating hormone (FSH) level under 10.0 mIU/mL as normal at all ages. This, of course, makes absolutely no sense since everybody knows that FSH levels increase as women age. An FSH of 9.5 at age 20, therefore, means something very different from the same FSH level at age 45!
And the same, of course, also applies to other OR parameters, and especially anti-Müllerian hormone (AMH), which in recent years has become increasingly popular in assessing OR. CHR's team, indeed, were the first to propagate use of age-specific FSH and AMH levels in a number of publications, a routine slowly accepted by colleagues around the world. Figure 1 demonstrates age-specific FSH and AMH levels, as established at CHR [See figure below, modified from Gleicher et al, Reprod Biol Endocrinol 2010;8:64].
A diagnosis of POA is reached when age-specific FSH levels are too high and/or age-specific AMH levels are too low. This fact will explain why, without age-specific levels, a diagnosis of POA will be difficult, and why POA is still so frequently overlooked, leading to critical delays in treatment.
In recent years, AMH, especially in younger women, has been proven a better predictor of OR than FSH. CHR investigators were amongst the first to report this fact [Barad et al, Fertil Steril 2009;91(4):1553-5]. Above age 42, AMH, however, loses its predictability, as also reported first by CHR investigators [Gleicher et al, Reprod Biol Endocrinol 2010;8:64].
While very low AMH has been associated with low pregnancy chances, the latest CHR research suggests that even women with undetectably low AMH levels can still conceive and successfully carry pregnancies to term [Weghofer et al, Hum Reprod 2011;26(7):1905-9.]. For detail, please refer to our scientific publications page.
Some colleagues use antral follicle counts (AFCs) to assess OR. At CHR, we do not consider this method to be as reproducible as AMH and FSH levels. However, if AFCs are used to diagnose POA, they, also, should be age-specific.
Premature Ovarian Aging and Infertility
POA negatively affects female fertility primarily through suboptimal numbers and poor quality of egg (Table1 below).
| Table 1: POA's Effects on Female Infertility |
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POA and Premature Ovarian Failure (POF): What's the Difference?
The distinction between POA and premature ovarian failure (POF) is of crucial importance: POF, now often also called primary ovarian insufficiency (POI), is defined by FSH level above 40 mIU/mL (post-menopausal range). Women with elevated FSH levels below 40 mIU/mL are considered to suffer from POA, also called OPOI. "Early menopause" or "premature menopause" are also terms used to refer to this condition.
Even in best hands, pregnancy in women with POF is a rare event, unless donor eggs are utilized. CHR does offer experimental treatments to POF patients, but we usually recommend donor eggs as the treatment of choice. However, at CHR, it is always the patient who decides which treatment she wants to pursue.
POA patients, in contrast, will at CHR still have an excellent IVF pregnancy chance with use of their own eggs. As a result, an ever-increasing number of POA patients from all over the world has been seeking treatment at CHR. Today, indeed, no other diagnosis brings as many patients to CHR.
To learn more about getting pregnant with POA or POF, please contact us.
Treatment for Premature Ovarian Aging
CHR's success in treating POA patients is partially based on the introduction of DHEA supplementation by CHR investigators. Today, seven years later, DHEA is used worldwide! According to one survey, as of late 2010, more than one third of the world's IVF centers reported to use DHEA. But DHEA, by itself, is only a significant but small part of CHR's comprehensive treatment approach to POA. There are various additional factors that need to be considered when determining the best treatment approach for individual patients with POA. Those factors include:
- Patients should receive the right DHEA, in terms of potency, micronization, etc.
- Patients should be on DHEA supplementation long enough to see its full benefits
- Patients should be monitored closely while on DHEA
- Ovarian stimulation protocols for IVF cycles have to be appropriate for "ovarian age"
- Some POA patients may require additional medications to control contributing factors, such as autoimmune abnormalities, which sometimes present in association with POA
In other words, although the introduction of DHEA in fertility treatment for women with DOR has revolutionized infertility treatment, especially for women with premature ovarian aging, DHEA, alone, has only limited beneficial effects. A successful, comprehensive fertility treatment paradigm for women with POA has at least three components:
- An ovarian stimulation protocol that is adjusted for individual patients' OR;
- Pre-stimulation supplementation with DHEA; and
- Highly individualized management other associated medical conditions (Figure 2 below).
Likely no other center in the world has experience and expertise in diagnosis and management of POA comparable to CHR's. This is one very important reason why CHR has earned a reputation as the "world's center of last resort" for infertility patients.
DHEA Supplementation in Premature Ovarian Aging
Let us explain a little more about DHEA (for a more detailed explanation, and a list of CHR's scientific publications on DHEA, please refer to our DHEA page.
DHEA is a mild male hormone converted in the body to testosterone and estradiol. For a number of years, CHR physicians have been using DHEA in women with DOR, whether ovarian impairment is due to advanced age or premature ovarian aging. In doing so, we have been able to demonstrate that in such women, DHEA supplementation has quite remarkable beneficial effects, best summarized as rejuvenating ovarian function:
| Table 2: DHEA's Beneficial Effects on Female Fertility |
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In recognition of these claims, CHR was awarded two DHEA-related U.S. patents (#7,615,544 and #8,067,400). For more details, please refer to our DHEA page.
DHEA Clinical Trial
Our prospectively double-blinded, randomized clinical trial on the effect of DHEA on pregnancy chances in women with suspected POA (NCT00650754) is recruiting volunteers. More details are available here. If you are interested in participating, please fill out the screening form.
Predicting POA through Genetics
Significant evidence from animal studies suggests that ovarian reserve is genetically controlled. How this genetic control works in humans has, however, so far not been determined. Over the last few years, CHR investigators have extensively researched and published on effects of the FMR1 (fragile X mental retardation 1) gene on ovarian reserve. CHR's research has revealed that this gene, which is well known for its neuro-psychiatric consequences, also plays a crucial role in ovarian aging. CHR research has identified that, for ovarian function, separate from the neuro-psychiatric risks, the normal range of CGG repeats on the FMR1 gene is 26 to 34 repeats, with the median at 30, as shown in the Figure 3 below [modified from Gleicher et al. Reprod Biomed Online 2010;20(6):768-75.]
The figure on the right (Figure 3) shows the distribution of the CGG repeat counts on the FMR1 gene, with the 26-34 counts being the normal range. As previously reported, the median count was 30.
Probably most importantly, CHR investigators defined new FMR1 genotypes and sub-genotypes, each associated with specific ovarian aging patterns. Because each woman has two alleles (copies) of the FMR1 gene, there are various genotypes and sub-genotypes, based on whether neither, one or both of the alleles are in the normal range, and if abnormal, high abnormal or low abnormal. For example, a CHR publication in the prestigious online medical journal PLoS One identified the FMR1 sub-genotype "het-norm/low" to be associated with almost 50% lower pregnancy rates after IVF.[Gleicher et al, PLoS One 2010:16;5(12):e15303]. Implications of these findings go beyond fertility treatment and IVF because, based on a young girl's FMR1 genotype, one can now reasonably well predict how she, likely, will age her ovaries.
We are only at the beginning of a better understanding of the ovarian aging process. One can foresee that this new knowledge about genetic regulation of ovarian aging via the FMR1 gene will lead to better diagnostic tools and, therefore, chances for early intervention. For example, if a young woman knows that her ovarian function may prematurely decline, exposing her to the risk of early menopause, she can take proactive steps to preserve her fertility.
To read more about CHR's latest research on the FMR1 gene's influence on IVF outcomes, ovarian reserve, premature ovarian aging, and not fertility-related areas of medicine, please refer to our scientific publications page.
Next Step
The first step is easy, simply complete the prematurely aging ovaries contact form to determine if you may benefit from our POA/DHEA Treatment Program.
CHR's premature ovarian aging program draws many patients from outside the New York tri-state area, because we offer the innovative and aggressive fertility treatment options that other IVF centers do not, to women with even severely diminished ovarian reserve. Through our experience with these "long-distance" patients, both international and domestic, we have developed a number of ways to minimize travel needs while maintaining the absolute same level of clinical care. You can read the basic treatment logistics for long-distance patients here.
Last Updated: February 28, 2012
