Much has changed in the fertility world since 1935, when two Chicago gynecologists — Dr. Irving Stein and Dr. Michael Leventhal — first described an unusual cluster of symptoms in seven of their patients1,2. To the doctors, it seemed more than coincidental that these women manifested absent menstrual periods, hirsutism (excess hair growth on the face, chest, abdomen, and thighs), and enlarged ovaries. As astute surgeons of that era, Drs. Stein and Leventhal performed abdominal surgery on these women. Fortunately, no cancer cells were found but under the microscope, portions of the enlarged ovaries contained multiple simple cysts. One unexpected benefit of surgery was the resumption of menstrual cycles, and even some pregnancies!
Gynecology textbooks have classically viewed Stein-Leventhal syndrome, (also called polycystic ovary syndrome, or PCOS), as a curiosity, with no apparent cause or cure. What is most interesting, however, is how common this problem has become, and how dramatic an impact it has created for women's health and reproductive function. Even more significantly, we now know that it is shortsighted for healthcare providers to view Stein-Leventhal/PCOS as simply an ovarian disease or disorder.
Defining Syndrome O
The evidence has become clearer to many endocrinologists that fertility and ovarian function are profoundly impacted by metabolism, nutrition, activity, and stress. While the ovaries are genetically programmed to house and protect thousands of healthy eggs, many other organs in a woman's body are responsible for initiating, and potentially interfering with, regular ovulation. Organs and tissues such as the brain, pituitary, liver, pancreas, muscle, adipose, and adrenal glands are part of an interconnected fertility hormone system we call the glandular internet. For women, these seemingly diverse parts of the body can have dramatic effects upon ovarian function and regular, healthy ovulation.
Ovulation disruption (or anovulation) has become the #1 worldwide cause of infertility3. For the majority of women who manifest ovulation disruption, an understanding of the other aspects of Syndrome O — Ovarian confusion and Overnourishment — may help explain the roots of their fertility problem. Ovarian confusion implies that improper production of key hormones — androgens ('male' hormones) and estrogens ('female' hormones) — disrupts many of the tiny follicles, or egg incubators within the ovaries. Polycystic or 'poly-follicle' ovaries can result even when small imbalances in ovarian androgens occur. Depending on other metabolic factors, many women have accompanying undesired problems associated with slight androgen excess — acne and/or hair growth on the face, chest, abdomen, and thighs4.
Why are the ovaries confused? For years, gynecologists and endocrinologists have pondered this question. However, as far back as the days of Drs. Stein and Leventhal, some astute physicians hypothesized that metabolism hormones such as insulin could be involved. In more recent years, both clinical and basic researchers have unequivocally established the link between ovarian function, ovulation, and the insulin family of hormones. Along this line of thinking, it has also become clearer that metabolic states associated with insulin overproduction have a direct impact on female fertility3,4.
Overnourishment is the simplest and most direct way to explain how 20th century societal changes have driven the rising current epidemic of insulin overproduction states — obesity, type II diabetes, and insulin resistance. In the 1970s, Dr. Gerald Reaven described the widespread heart, vascular, and general health detriments of insulin overproduction, calling the problem Syndrome X. As a keynote speaker at the recent 2001 PCOS Association Conference, Dr. Reaven, an emeritus Stanford University professor, spoke about insulin overproduction in women. However, recent books about Syndrome X don't truly delve into female reproductive and fertility concerns5. For this reason, Dr. Feinberg conceived of Syndrome O as a tool for teaching his patients about the modern phenomena linking insulin, metabolism, and fertility.
Eighty to ninety percent of women with Syndrome O are above their ideal body weight when they first seek fertility care. Most women with Syndrome O take in more calories than their bodies require (our definition of overnourishment), and very few have a regular exercise routine. Excessive carbohydrate intake, along with foods containing partially hydrogenated oils (i.e. trans fats) probably exacerbate insulin overproduction6. Other aggravating factors appear to be modern 20th/21st century societal conveniences — motorized transportation, telecommunications, and computerization (including the Internet) — most of which necessitate inactivity for long periods of time7. In 1935, Drs Stein and Leventhal described merely seven cases of their new Syndrome, identified after many years in medical practice. In 2001, the Polycystic Ovary Syndrome Association (www.pcosupport.org) estimates that a staggering 5 to 10 million women in the United States are now affected.
Syndrome O and Your Fertility Options
Most readers of AIA newsletters, and this article in particular, have likely been prescribed one or more medications to promote ovulation. Clomiphene citrate, an oral compound, has been the mainstay of ovulation induction therapy for many years8. It works by tricking the brain and pituitary gland into producing higher levels of follicle stimulating hormone (FSH), thus promoting follicle growth. Both gynecologists and fertility specialists prescribe clomiphene, but there are many different nuances to cycle monitoring which can help achieve a pregnancy. It is beyond the scope of this article to review all the "tricks of the trade" associated with clomiphene usage. However, combining clomiphene with hCG injection, and/or intrauterine inseminations may improve the cycle outcome. With repeated ovulatory cycles not resulting in conception, a close assessment of other potential problems (i.e. fallopian tube disease, pelvic adhesions, male factors, and female metabolic factors) is strongly suggested. Gonadotropin injections are commonly prescribed when clomiphene has failed to induce ovulation. Conservative "step-up" gonadotropin protocols should be utilized (only by experienced fertility specialists), to minimize the risks of multiple pregnancy and ovarian hyperstimulation syndrome3.
With clinical studies demonstrating the impressive impact of insulin-lowering agents upon ovarian function and ovulation, Reproductive Associates of Delaware was one of the first fertility centers in the U.S. to prescribe troglitazone (Rezulin, Parke-Davis) to women with clomiphene-resistance and a strong desire to avoid gonadotropin injections. The initial results were impressive. Troglitazone, with or without clomiphene, restored ovulation in 13 of 14 women, and 10 successful pregnancies resulted within 4 months of therapy. Troglitazone is no longer on the market, due to very rare but lethal liver abnormalities. Two chemically-related medications, rosiglitazone (Avandia, GlaxoSmithKline) and pioglitazone (Actos, Takeda and Lilly) are FDA-approved for type II diabetes, but have not been tested for Syndrome O-related anovulation. Another insulin-lowering agent, metformin (Glucophage, Bristol-Myers Squibb), is now widely prescribed for both type II diabetes and insulin resistance, although it is only FDA-approved for type II diabetes.
As a short term adjunct to help promote ovulation induction, published studies incorporating metformin are very encouraging9,10. For long term usage related to insulin resistance and Syndrome O, the potential benefits and risks are not clearly established. Furthermore, the impact of consistent and diligent insulin-lowering lifestyle strategies appears quite favorable in halting the progression of Syndrome O 11.
Helping Your Doctor Help You
There is no magic cure or miracle pill for Syndrome O. Each woman’s treatment plan will vary with her symptoms and specific concerns – metabolic, cosmetic and/or reproductive. Therefore, it is essential to seek medical care from a physician who understands the whole-body complexities of Syndrome O, and who is willing to individualize care and treatment options. Finding a physician who is both knowledgeable and interested in providing quality Syndrome O care can be challenging, but rewarding. Fortunately, in today’s environment of accessible support networks and increased awareness, the likelihood of finding top-flight Syndrome O fertility care is better than ever.
Here are some tips for organizing your approach to Syndrome O fertility care:
- Develop and prioritize a personal Syndrome O symptom inventory
- Determine what types of specialists you may need
- Seek referrals for care from reliable sources — primary care health providers, trustworthy websites, community physician directories, other Syndrome O patients
- Fellowship trained Board-certified and Board-eligible reproductive endocrinologists tend to be the most updated about fertility care as it relates to insulin overproduction.
- Stay positive and do your part to optimize your health
We believe that while many physicians do offer high quality options and services to women with Syndrome O, your success with fertility treatment will greatly depend on YOU! In Part II of this article, we will delve into more details regarding insulin-ovary-fertility connections, and how specific insulin-busting strategies can be incorporated into your life. We will also explain the dramatic impacts of nutrition and exercise upon Syndrome O symptoms, and encourage you to find your own personal approaches.
There is no one diet, no one exercise plan, and no one book or article that holds all the answers. Finding what works for you may take some trial and error. Educate yourself, don’t be afraid to experiment and, most importantly, keep a positive attitude!
Coming in Part II of Getting Pregnant When Syndrome O Gets In The Way:
Calming the Insulin Storm. . . For Your Fertility's Sake
Get Real. . . And Get Strategic!
Networks of Support
About The Authors
-Dr. Feinberg is a Board-certified reproductive endocrinologist, and the IVF Medical Director for Reproductive Associates of Delaware, located in Newark, DE on the campus of Christiana Care Health System. He is also an Associate Professor (adjunct) in the Department of Obstetrics and Gynecology at Yale University School of Medicine. Dr. Feinberg is currently writing a book entitled "Giving Your Fertility A Fighting Chance When Syndrome O Challenges You", to be published and released by Penguin Putnam in 2003.
-Ms. Childers is CEO of PCOStrategies, Inc., a non-profit 501c corporation committed to Education, Motivation, and Stimulation for women with Syndrome O and 'polycystic' ovaries. She is a recognized national leader in the PCOS advocacy and support movement, serving as the Mid-Atlantic United States and International Chapter Development Coordinator for the PCOS Association. She has been responsible for initiating 14 PCOSupport Chapters in 7 states. She was recently appointed by the AIA to assist with PCOS Division Development. Ms. Childers works as the Regional Coordinator of Child and Family Case Management for the Smoky Mountain Center, a mental health agency serving the area west of Asheville, NC.
This article originally appeared in the American Infertility Association Newsletter.
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2. Stein IF and Leventhal ML (1935). Amenorrhea associated with bilateral polycystic ovaries. Am. J. Obstet. Gynecol. 29: 181-91.
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