Polycystic Ovary Syndrome (PCOS) and Fertility
PCOS and Fertility Treatment Options
Affecting about 6-12% of women in reproductive age, polycystic ovary syndrome (PCOS) is a "basket" of different medical conditions, with one finding in common: polycystic ovaries (PCO). In polycystic ovaries, multiple small cysts appear along the outer capsule of the ovaries on ultrasound imaging. PCOS is often associated with infertility, because of anovulation (lack of ovulation) and amenorrhea (lack of menstruation). However, with proper fertility treatments for PCOS, patients can usually get pregnant with their own eggs. This page explains:
Polycystic Ovarian Syndrome and Fertility Treatment Video
How PCOS causes infertility: polycystic ovaries
PCOS has many variations and represents more of a "basket diagnosis" with wide-ranging phenotypes (clinical presentation) and associated problems. However, PCOS does have one common characteristic: multiple small cysts aligned along the outer capsule of the ovaries, with an appearance of a chain of pearls on ultrasound (see Figure on the left; Creative Commons credit: Je Hyuk Lee). These small cysts on the ovaries are the major cause of PCOS infertility.
Most PCOS patients do not ovulate, due to arrested follicle development
Those little "pearls" are the so-called preantral follicles. Antral follicles are at a very early stage of follicle (egg) maturation. In PCOS patients, follicles and eggs stop developing at the preantral follicle stage. As a consequence, women with PCOS rarely reach ovulation, in which a mature egg would be released from the ovary for potential conception. Women with PCOS also often (though not always) do not have regular menstrual cycles. Affected women often experience prolonged periods between menstruations, a condition called oligo-amenorrhea. Anovulation and oligo-amenorrhea are frequent characteristics of PCOS. Since a woman cannot conceive without ovulation, PCOS infertility is one of the most common types of female infertility.
PCOS varies greatly in clinical characteristics
Other clinical characteristics of PCOS can differ greatly. For example, a widely held misconception of PCOS, even amongst physicians, is that every woman with PCOS is relatively short and obese with signs of overexpression of male hormones (hyperandrogenism) and virilization, such as oily skin, acne, excessive facial hair, etc. In reality, only approximately 40% of women with PCOS demonstrate this kind of peripheral phenotype (appearance). Women with PCOS can also be six feet tall, model-skinny, with absolutely no sign of high levels of androgens (male hormones).
One of the most common endocrinologic problems in women, PCOS is now recognized not only as a hormonal problem resulting in PCOS-related infertility. Especially (though not exclusively) its hyperandrogenic form is also associated with the so-called metabolic syndrome, a combination of risk factors for arteriosclerotic heart disease and diabetes mellitus. Timely and correct diagnosis of PCOS, and its specific phenotypes, therefore, has importance not only for fertility but also for the overall health of patients.
Diagnosing PCOS: High AMH as diagnostic tool for PCOS
Given the wide variety of PCOS symptoms, professional organizations have attempted to unify diagnosing criteria for PCOS in recent years. Currently, the most widely utilized criteria are the so-called Revised Rotterdam Criteria, agreed to in coordination between ASRM and ESHRE: a PCOS patient has to demonstrate at least two out of the following three criteria: (1) Oligo- or amenorrhea; (2) hyperandrogenism (either by clinical signs or by laboratory testing): and (3) evidence of an ovarian PCO phenotype by imaging (ultrasound).
These criteria have, however, remained somewhat controversial, not the least because, theoretically, a woman can be diagnosed with PCOS without ultrasound evidence that she has PCO.
Increasingly, PCOS diagnosis is made by anti-Müllerian hormone (AMH) levels. Excessively high AMH levels characterize PCOS, though absolute cut off levels have not been established. The likely reason is that AMH levels decline with advancing female age, and what represents excessively high levels varies with age (for further information on age-specific hormone levels, please refer to our high FSH page). As noted, clinical manifestations of PCOS also decline with advancing age.
PCOS patients can develop diminished ovarian reserve later in life
Another major misconception about PCOS is that this condition remains static over time. It most definitely is not: Various authors recently reported that the clinical expression and severity of PCOS decline with advancing age. It is not uncommon that we see patients presenting with a dated diagnosis of alleged PCOS, and after some testing, they turn out to suffer from diminished ovarian reserve (DOR). At younger ages, they may have indeed suffered from PCOS, but by the time they present for infertility treatment at our NYC fertility center, they have gone on to develop diminished ovarian reserve. From a state of excessive follicle recruitment, they have transitioned into a state of abnormally low follicle recruitment.
In conducting research on the FMR1 gene, CHR described a sub-genotype of the gene, which does exactly that: women with the so-called het-norm/low sub-genotypes presents with a PCO-like ovarian phenotype at young ages, when they recruit a large number of follicles and, at relatively young ages. Then they are left with DOR because of excessive early recruitment of eggs. The het-norm/high FMR1 genotype, in turn, does exactly the opposite. Women with this sub-genotype recruit unusually slowly at young ages and, therefore, at very advanced ages (above age 42) still have unusually good ovarian reserve.
Fertility medications for PCOS patients and avoiding complications
If the primary goal of treatment is pregnancy with PCOS, then the primary effort is to induce ovulation. Because PCOS is characterized by arrest of follicle maturation at preantral follicle stages, treatment has to overcome this block. Two classes of oral fertility medications can induce ovulation: so-called clomiphene citrate (Clomid), and so-called aromatase inhibitors (Letrozole, with trade name Femara being the most widely used). Whether either of these drugs is preferable as first-line medication has remained controversial, and is currently under investigation in a number of multicenter clinical trials.
Otherwise, ovulation needs to be induced with a class of fertility drugs called gonadotropins. Gonadotropins are more potent, produce larger numbers of follicles and, therefore, pose higher risk of ovarian hyperstimulation syndrome (OHSS) and high-order multiple births.
OHSS is the most feared maternal complication of ovarian stimulation, and the risk is especially high in PCOS patients. OHSS must be avoided at all cost! High-order multiples is the most feared complication in offspring due to the associated risk of severe prematurity, which, in turn, is associated with severe neurological and other defects in newborns. High-order multiples should also be avoided in fertility treatments, not only for PCOS patients but for fertility patients in general!
CHR, therefore, rarely uses gonadotropins in PCOS patients unless they are stimulated for in vitro fertilization (IVF). In IVF, both complications can be greatly reduced by stimulating carefully, puncturing all follicles, even very small ones, aspirating their fluid, and controlling the number of embryos transferred. We have cautioned against using gonadotropins in established PCOS patients, and reported over 10 years ago in the prestigious New England Journal of Medicine that even with most careful medical supervision, high-order multiples are almost impossible to avoid in association with spontaneous intercourse and/or intrauterine inseminations (Gleicher et al., N Engl J Med 2000;343:2-7).
Success of fertility treatments in PCOS patients
Practically speaking, significant hyperstimulation is a rare risk after age 40. Under age 40, CHR defines normal AMH levels in an age-specific way, and considers women with AMH levels over the 95% confidence interval for their age as "at risk" for hyperstimulation. CHR, however, also considers follicle-stimulating hormone (FSH) levels in the diagnosis. FSH and AMH levels usually move in opposite directions: as AMH declines with advancing female age, FSH rises. In most cases, both hormones statistically relate quite well, as CHR investigators reported in a number of recent research publications on reproduction.
A small group of women, however, do not follow this pattern. Especially, women with high FSH and AMH levels recently have come to the attention of CHR investigators because high FSH levels would usually come with low AMH levels. In a study recently submitted for publication, CHR investigators studied a sizable group of such women, and noted that the combination of high FSH and AMH denotes superior outcomes in IVF cycles. It appears that this combination of high FSH and high AMH results in significantly better oocyte yields and IVF pregnancy rates than all other FSH/AMH combinations.
This finding may explain why the published literature is divided on whether or not PCOS negatively affects IVF pregnancy rates. These recent observations by CHR investigators further support the "basket" nature of PCOS as a diagnostic entity. They, however, also suggest a first potential tool to differentiate which type of PCOS patients have better pregnancy chances with IVF.
The good news is that a large majority of PCOS patients will conceive with use of their own eggs. To shorten time to conception and increase pregnancy chances with IVF for PCOS patients, fertility treatments in PCOS patients must be appropriately individualized to the specific phenotype of PCOS a patient represents. CHR's pioneering discovery of the role of FMR1 sub-genotypes in determining oocyte yields and IVF pregnancy chances in PCOS patients, as discussed above, is one of the ways to improve success rates of fertility treatments for PCOS patients through individualization.
Next step for fertility treatments for PCOS: Contact us!
Please contact us to learn more about effective fertility solutions for PCOS. Our fertility experts are ready to guide you through the sometimes tricky process of assisted conception for women with PCOS.
Written by Norbert Gleicher, MD
Last Updated: January 28, 2013