Premature Ovarian Aging
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Dr. Gleicher explains early and premature menopause, how it is linked to diminished ovarian reserve and the use of DHEA supplementation for improving ovarian reserve.
What is Premature Ovarian Aging (POA)?
POA is defined as having a low ovarian reserve or poor ovarian reserve relative to what is expected at any given age. POA is one of the major, often overlooked, causes of female infertility.
The ability of a woman's ovaries to produce high-quality eggs is known as ovarian reserve (OR). As women get older, their OR naturally declines. Women attempting pregnancy after age 40 often have difficulty getting pregnant for this reason.
However, in approximately 10 percent of women, this decline of ovarian function occurs 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 reserve status. However, with appropriate treatment, women with POA can conceive - as many of our POA patients can testify.
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 high FSH levels but still 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 the 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.
In contrast, POA patients at CHR still have an excellent IVF pregnancy chance with use of their own eggs. As a result of CHR's ongoing research on diminished ovarian reserve and its clinical application, 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, which is now considered the "center of last resort" for patients with POA and diminished ovarian reserve.
Premature Ovarian Aging and Infertility
POA negatively affects female fertility primarily through sub-optimal quantity of eggs and poor quality of eggs. Unfortunately, quality of eggs declines in parallel to decline in quantity of eggs. Therefore, women with untreated diminished ovarian reserve 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.
POA's Effects on Female Infertility
- Leads to diminished ovarian reserve
- Poor ovarian response to ovarian stimulation ("poor responder")
- Poor quality eggs
- Poor quality embryos
- Embryos with disproportionately high rate of chromosomal abnormalities (aneuploidy)
- Reduced number of euploid embryos (balanced set of chromosomes)
- Low pregnancy rates
- High miscarriage rates
Diagnosis of POA
Effective treatment of low ovarian reserve starts with timely diagnosis. Timely diagnosis is crucial because once the OR begins declining, it continues to decline with time. At CHR, patients are evaluated based on age-specific hormone values, instead of universal cut-off values, to promptly diagnose POA.
CHR's age-specific hormone values prevent missed diagnosis
POA is likely the most frequently overlooked diagnosis of female infertility. Even good infertility centers fail to identify POA as a cause of infertility because most centers still use universal ovarian reserve 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!
The same principle also applies to another ovarian reserve parameter, specifically, anti-Müllerian hormone (AMH), which in recent years has become increasingly popular in assessing ovarian reserve. CHR's team was 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].
How POA is diagnosed
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 details, 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.
Treatment of Premature Ovarian Aging
After receiving a diagnosis of POA, or poor ovarian reserve,diagnosis, patients at CHR are given individualized treatment based on their ovarian reserve 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 IVF 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."
CHR's success in treating POA patients is partially based on the introduction of DHEA supplementation by CHR investigators. Today, eight years later, DHEA is used worldwide! According to one survey, as of late 2010, more than one third of the world's IVF centers have started using DHEA. However, DHEA is only a small part of CHR's comprehensive treatment approach to POA.
Comprehensive Treatment Approach to POA
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:
- 1. An ovarian stimulation protocol that is adjusted for individual patients' OR;
- 2. Pre-stimulation supplementation with DHEA; and
- 3. Highly individualized management other associated medical conditions
How DHEA Supplementation Treats POA
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 maternal 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:
Benefits of DHEA on Female Fertility
- Increased IVF pregnancy rates
- Increased egg and embryo numbers
- Improved egg and embryo quality
- Reduced aneuploidy (chromosomal abnormalities) in embryos
- Reduced risks of miscarriages
- Shortened time to pregnancy
- Increased spontaneous conceptions
- Improved cumulative pregnancy rates in patients under fertility treatment
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.
Experts in POA: About our Program
DOR as a result of POA or as a result of advanced female age (attempts of pregnancy after 40) represent a major, but often ignored, causes of female infertility. In fact, most fertility centers routinely refuse treatment to women with significantly diminished ovarian reserve (DOR), unless they are willing to utilize donor eggs.
We feel very fortunate to be pregnant after treatment at CHR, especially after so many failed attempts at IVF at two other centers. We really owe it to CHR's professionalism and special expertise. The staff was very supportive and Dr. Gleicher never gave up hope for us, even when we almost did.
CHR's Medical Director, Dr. Gleicher, recognized this fact many years ago and since then has been consciously developing special expertise in treating "older ovaries." Physicians and investigators at CHR have gained specialized clinical experience by treating patients affected by the "old ovaries" or "aging ovaries," but also from focusing the center's infertility research efforts to a large degree on diagnosis and treatment of DOR. This includes,of course, DOR due to premature ovarian aging.
This research has led to major breakthroughs that not only benefit CHR's patients, but women worldwide, as fertility specialists all over the world have started to incorporate CHR's 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, benefiting thousands of women every year who otherwise would have had no choice but to resort to egg donation.
Our research, experience and success transformed CHR into "The Center of Last Resort"
At CHR, we not only accepted women into fertility treatment for severe DOR, but as our experience with "older ovaries" increased we also progressively improved IVF pregnancy rates in patients of continuously increasing severity in terms of their "ovarian age." This differentiated CHR from practically all other fertility centers in the world.
As word of our success started getting around, CHR became New York City's "fertility center of last resort." Not long after, with the help of the Internet, CHR's reputation very quickly spread to the whole country and into Canada. Over the last few years, we've also witnessed explosive growth in overseas patients who are 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 POA.
Research: Predicting POA with Genetics
CHR Publications on POA
- Human Reproduction Aiming to understand the mechanism of DHEA's positive effects on ovarian reserve, this study compared the various androgen levels in women with diminished ovarian reserve. The study found that women with DOR in general has significantly lower testosterone levels, and with women with premature ovarian aging (POA) having even lower testosterone levels, suggesting that DOR is an androgen-deficient condition.
The role of androgens in follicle maturation and ovulation induction: friend or foe of infertility treatment?Reproductive Biology and Endocrinology A comprehensive review of both animal and human studies, this article pointed out the essential contribution of androgens to normal follicle maturation and female fertility. Despite widely held opinion that androgens are detrimental to female fertility, this study suggested that some androgens, such as testosterone and DHEA, may be effective in improving functional ovarian reserve in women with diminished ovarian reserve.
Towards a better understanding of functional ovarian reserve: AMH (AMHo) and FHS (FHSo) hormone ratios per retrieved oocyte.Journal of Clinical Endocrinology & Metabolism FSH and AMH reflect distinct stages of folliculogenesis, and how they reflect ovarian reserve is not well understood. Investigating the ratios of FSH and AMH to oocyte yields in IVF, this study proposed a novel outcome predictor for IVF cycles. FSH per oocyte, but not AMH per oocyte, was statistically associated with pregnancy chances with IVF.
CHR investigators have been conducting extensive genetic research on ovarian reserve in order to better understand how ovarian aging occurs and develop a method of both early diagnosis and prediction of POA development.
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 below (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 predict reasonably well 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.
Key Facts about Premature Ovarian Aging
Contact Our POA Experts
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Because we offer (even to women with severely diminished ovarian reserve) innovative and aggressive fertility options not offered by other IVF centers, CHR's premature ovarian aging program draws many patients from outside the New York Tri-state area. Throughout 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 same level of clinical care. You can read the basic treatment logistics for long-distance patients here.
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Written by Norbert Gleicher, MD
Last Updated: December 31, 2013