CHR Update April 2011

As briefly mentioned in last month’s UDPATE, April is probably the busiest month of the year at CHR, because by the beginning of May, ASRM abstracts become due. So, forgive us for a relatively brief UPDATE this month; everybody is really busy generating the research data.

Based on what we hear from CHR patients and from the large number of outside e-mails we receive daily, it appears that a number of important topics are of primary interest, and, from amongst those, here are the ones we have chosen to cover in this month’s issue:

Polycystic Ovaries or Polycystic Ovary Syndrome (PCOS)

CHR now daily receives between 40 and 60 e-mails from women (and men) from all over the world, usually addressing specific questions or clinical circumstances they face. One of the most frequently addressed clinical issues is Polycystic Ovary Syndrome (PCOS). This is a very common clinical problem, often associated with female infertility. Before going into detail about the clinical presentation of PCOS, it is important to get a few terms right: PCOS is a syndrome and not a disease. Indeed, PCOS was once called PCOD (Polycystic Ovarian Disease), and this term was discarded on purpose. A syndrome in medical lingo represents a “waste basket” term, i.e., many different conditions, with different etiologies, can all be called PCOS.

Another way of looking at this is that polycystic ovaries, quite obviously a very typical characteristic of PCOS, can occur for many different reasons. And this is probably one of most important messages we can leave you with, because PCOS, erroneously, is widely considered one, uniform condition, and it is not!

It would exceed the space we have to go into too much detail, but here are a number of additional important points about PCOS: The condition is widely assumed associated with trunkal obesity, signs of hyperandrogenism (too much male hormone), insulin resistance, risk of diabetes, and hypertension and cardiovascular diseases later in life. The truth is, however, that only approximately 40% of women affected by PCOS present with an obese physical presentation (i.e., phenotype). And this percentage is pretty much applicable to almost all phenotypical presentations of PCOS. They can all be found in only about 40% of all PCOS patients.

So, just like there are roughly 40% of PCOS patients who are obese, there are many who are really skinny; and just like ca. 40% demonstrate signs of high androgens, many do not. We are, thus, really dealing with a waste basket of conditions, which clinically present differently, carry different long-term relevance for future medical risks, and most importantly for fertility treatments, require different clinical approaches.

Readers of the CHR UPDATE will recall that CHR investigators recently reported a new phenotype of PCOS (Gleicher et al., FMR1 genotype with autoimmune-associated polycystic ovary-like phenotype and decreased pregnancy chance. PLoS ONE 5:e15303). It is of course defined by polycystic ovaries, but otherwise with unique characteristics: Affected patients appear genetically predisposed, because their FMR1 gene reflects a very specific sub-genotype (het-norm/low). This genotype (i.e., gene characteristics) at younger age gives them polycystic ovaries. These women, however, very quickly deplete their ovarian reserve, and at mid- and late-ages often demonstrate prematurely depleted ovarian reserve (i.e, premature ovarian aging, POA).

Phenotypically, these women are usually anything but obese, do not demonstrate signs of excessive androgens, and usually lack most of the other clinical characteristics that are often automatically associated with PCOS.

Most relevant to infertility treatment, however, is the fact that women with this genotype demonstrate significantly decreased pregnancy chances with IVF in comparison to women with other FMR1 genotypes. In trying to elucidate why that may be, CHR investigators also discovered that this FMR1 sub-genotype is statistically highly associated with risk towards autoimmunity, an observation which opens very intriguing new research avenues.

The long arm of the X chromosome, where the FMR1 gene is located, has recently been strongly associated with autoimmune risk. Indeed, some investigators have come to believe that this is a principal reason why women have so much higher risk of developing autoimmune diseases than men.

Autoimmunity and the FMR1 gene are the two main reasons for developing POA and premature ovarian failure (POF), often also called primary ovarian insufficiency (POI). The long arm of the X chromosome, where FMR1 maps to, therefore, appears to represent the physiological cross roads of ovarian function and autoimmunity, strongly suggesting that (i) autoimmunity may be much more important to female fertility/infertility than is generally appreciated; (ii) At least one form of PCOS may be autoimmune in nature in etiology; and (iii) at least one form of PCOS may be associated with reduced pregnancy chances in IVF.

CHR investigators are actively investigating many issues related to this newly reported PCOS phenotype and genotype. Stay tuned for further news on the subject in the near future!

Ovulatory Dysfunctions

A major reason why PCOS is associated with infertility is the fact that the condition often (though not always) leads to anovulation (failure to ovulate spontaneously). PCOS is one of the principal causes of anovulation. There are, however, many other reasons why women may stop having regular spontaneous ovulations. Some may be hormonal abnormalities (elevated prolactin, so-called hyperprolactinemia, for example), others may be behavioral (travel, lack of minimal body fat, drug abuse, etc.).

When a woman fails to ovulate, she does not release an egg. If she does not release an egg, she, of course, cannot conceive in that cycle. Intermittent anovulation, especially with excessive stress, like air travel, is common, and by no means abnormal. Women usually recover their regular ovulatory pattern quickly once things settle down. Excessive weight loss and/or absence of minimal body fat, as often seen in runners or other female athletes, can, however, become semi-permanent, until affected females either receive medical help or decide to increase their body fat.

Nowadays, the diagnosis of anovulation is relatively easy to make, and represents a very basic step in initial infertility work ups. Once the diagnosis is made, the question arises: what causes the problem? If a treatable underlying problem is diagnosed, then successful anovulation treatment usually quickly reestablishes spontaneous ovulation, allowing patients to conceive on their own. A good example is the treatment of hyperprolactinemia, which, if successful, reestablishes spontaneous ovulation in most cases.

Often, however, no underlying problem for anovulation can be found, and in such cases, patient requires treatment to “induce” follicle growth and ovulation. This is where the so-called fertility drugs come into play, but that is a story on its own, to be reviewed in future issues of the UPDATE.

Pregnancy with Premature Ovarian Failure (POF)?

We are always surprised by the sheer number of patients with POF, often also called primary ovarian insufficiency (POI). However, we are even more surprised how many of the patients who contact us with a presumed diagnosis of POF/POI actually do not really suffer from POF but have premature ovarian aging (POA), now also called occult primary ovarian insufficiency (OPOI).

Correct distinction between POF and POA is of crucial importance, because with even severe POA, CHR has still remarkably good pregnancy results, while for women with true POF, chances of pregnancy with use of their own eggs are rather small, and always involve experimental treatments (CHR is currently running a clinical trial in POF patients to investigate the efficacy of DHEA).

The distinction between POA and POF is not difficult. It is based on maximum follicle stimulating hormone (FSH) levels. FSH levels of POA patients, in principle, should never exceed 40.0mIU/mL. This automatically defines POF patients as those having demonstrated FSH levels above 40.0mIU/mL.

Even though we now consider anti-Mullerian hormone (AMH) to be a more specific assessment tool of ovarian reserve than FSH, to differentiate between POA and POF, we do not make use of AMH. Even with extremely low AMH levels (even at undetectable levels) CHR has successfully established quite a large number of pregnancies that reached delivery. Therefore, even very low levels of AMH do not allow for a conclusion that a patient should no longer be treated with use of her own eggs.

Age Discrimination and Treatment Refusals

Age discrimination and outright treatment refusals are becoming very prevalent, especially in some European countries. Patients from Norway recently told us that they could not receive treatment in their country after age 40, while patients from The Netherlands told us the same above age 41 years.

CHR, of course, does not agree with such arbitrary cut offs. Indeed, we consider them discriminatory against women (would anybody withhold treatment to men at ages 40 and 41?). Can anybody imagine the uproar in this country if anybody (state or insurance company) established age cut-offs at such young ages?

Who, then, can be surprised that more and more European patients come to the U.S. for treatment (see also March 2011 UPDATE)? CHR, of course, very gladly welcomes patients from all over the world who feel discriminated against because of age. As we have pointed out over and over again, what really matters in fertility is not a patients’ chronological age but her “ovarian age.”