Polycystic Ovarian Syndrome – PCOS
PCOS
Ultrasound demonstrating a polycystic appearing ovary
This ultrasound appearance alone does not mean the patient has polycystic ovarian syndrome. Other clinical findings which comprise the syndrome include:
- Polycystic appearing ovaries
- Hyperandrogenism . Increased:
- Testosterone
- DHEAS – dehydroepiandrosterone sulfate (adrenal gland)
- Hirsutism (male pattern hair growth such as facial hair)
- Hyperinsulinemia (increased insulin secretion) and Insulin Resistance
- Abnormal uterine bleeding oligo-ovulation (irregular ovulation)
- Amenorrhea (absence of uterine bleeding)
- Infertility Obesity. Not all patients with PCOS are overweight.
- Laboratory findings
- Elevated LH and reversal of the LH/FSH ratio as LH becomes higher than FSH throughout the menstrual cycle
- Estrogen and testosterone elevation
- 17-OHP – 17 hydroxyprogesterone
- Skin abnormalities
- Acanthosis Nigricans (darkened scaly like rash commonly on patients neck)
- Skin tags – small outgrowths of skin
- Possible long term effects Increased risk of cardiovascular disease from increased lipids
- Increased risk of endometrial cancer
- Increased risk of breast abnormalities
- Increased risk of developing type II diabetes
- Increased risk of heart disease
Many of these findings are inter-related in a complex system of cause and effect. The exact etiology of the syndrome is commonly considered “unknown”. There are several theories as to the underlying cause or causes.
Obesity
Obesity alone cannot account for all of the findings of PCOS, however, it does worsen the degree of insulin resistance. Weight loss can often lead to a reversal of the clinical manifestations. Patients have been able to reduce the effects of the elevated androgens as well as resume normal ovulation with weight loss alone.
Insulin Resistance
Resistance to the effects of insulin produces an increase in insulin production and circulating levels of insulin (hyperinsulinemia) and can lead to skin disorders and elevated androgens (hyperandogenism). The elevated androgens like DHEAS and testosterone can lead to male pattern hair growth and acne. The androgens cause an increase in free estrogen (by reducing sex hormone binding globulin which binds both estrogens and androgens) which results in a decrease in FSH. The follicles are initially stimulated to grow but do not have enough FSH to continue to grow and are also affected by the elevated LH. The disturbance in follicular growth results in the polycystic appearance of the ovaries. Because follicles are not developing normally women will not ovulate normally and will not have normal menses.
Other names which have been used to refer to this syndrome include Insulin Resistance Syndrome and Hyperestrogenic Anovulation. It is most likely this syndrome does not represent one disease process but several physiologic abnormalities which result in a similar clinical presentation. Recently there has been growing acceptance that insulin resistance is the primary abnormality associated with PCOS. PCOS seems to worsen with weight gain, high carbohydrate diets, age, and genetic influences. The medical literature has not been able to agree on a common etiology, however, there is a lack of consensus in insulin assays, methods of testing, and interpretation of studies of varying quality. Overall methods to reduce insulin resistance such as weight loss, diet modification, and metformin have been shown to improve insulin resistance and the clinical effects of PCOS. California IVF physicians use dietary modification as a primary means to improve pregnancy and reduce the risk of miscarriage.
Infertility
PCOS is associated with infertility. The most likely cause of infertility is anovulation or lack of ovulation. Ovulation can be induced by oral medications such as clomid, letrozole (Femara), or gonadotropins. Ovulation can also be restored for many women with PCOS by correcting of insulin resistance through diet, exercise and Metformin. Some investigators have reported a lower than normal fertilization rate during IVF in women with PCOS and is likely do to a reduction in egg quality. There may also be a higher miscarriage rate in women with PCOS also, but this has been debated.
Women with PCOS are at increased risk of ovarian hyperstimulation when taking gonadotropins. A history of PCOS and/or irregular menses should be reported to your physician before taking any fertility medications. Fortunately, recent advances in how injectable fertility medications are used with patients at risk for ovarian hyperstimulation have led to a minimal risk of ovarian hyperstimulation and improved rates of pregnancy.
While the appearance of multiple small follicles on ultrasound can be suggestive of PCOS, it is insufficient evidence that someone has PCOS. The same is true for anovulation. Multiple findings taken together can be used to classify someone as having polycystic ovarian syndrome, but this is NOT a diagnosis of a disease. PCOS is a set of clinical findings associated with an underlying abnormality, so it is technically incorrect to say someone is diagnosed with PCOS.
There has been much attention given to the documentation of insulin resistance in patients with PCOS. Newer findings are demonstrating insulin resistance can be detected before the appearance of other clinical findings of PCOS. Patients with PCOS findings, and in some cases patients with only anovulation, are being tested for insulin resistance, however, due to a lack of consensus and standardized testing, there isn’t a single test that is used clinically to determine if a patient is insulin resistant. In research settings, it is likely that giving fixed doses of glucose and monitoring insulin responses over time is a useful method for documenting a person’s insulin status.
Glucose values over 200 at any point may indicate diabetes and further testing may be needed to confirm the diagnosis of diabetes. Hemoglobin A1C levels are also used frequently to determine if there is an elevated risk of fetal malformations due to chronically elevated glucose levels. Often times patients with diabetes will have elevated fasting glucose levels which again is evidence for diabetes. Diabetes can occur when the pancreas does not make sufficient levels of insulin to regulate blood sugar. Diabetes may be successfully managed in a similar manner to insulin resistance described above.
Treatment of polycystic ovarian syndrome has two distinct directions. Patients not desiring pregnancy at the time of treatment will be managed differently than patients actively seeking pregnancy.
For patients desiring pregnancy there are several approaches. The more modern approach in younger patients involves the use of dietary modification, exercise, and occasionally insulin sensitizing agents. These medications allow for a better response to the insulin in the circulation. Very frequently, the manifestations of PCOS will improve or resolve. Many women begin to ovulate and have a return of normal menses as insulin resistance improves. Many patients have been successful at achieving pregnancy by using diet alone. When insulin sensitizing medications are used, they are usually discontinued after achieving pregnancy. In some patients, ovulation induction using Clomid, and occasionally gonadotropins, may be required. Because of the risk of ovarian hyperstimulation and multiple gestation associated with ovarian stimulation; this approach is used as a secondary treatment.
Patients not seeking pregnancy are generally treated with oral contraceptive pills which allow the endometrium to cycle normally (reducing the risks of endometrial cancer and hyperplasia), reduce acne, and reduce hair growth. Additional therapy may be required to decrease the androgenic effects of PCOS. Medications that can be used to treat androgen excess of PCOS include finasteride (Proscar, Propecia), reglan, and spironolactone. Current trends to treat these patients with insulin sensitizing agents are gaining more popularity. Diet and exercise are usually the most effective approach for all aspects of PCOS.
Insulin sensitizing agents include metformin (Glucophage) and Avandia (rosiglitazone). Metformin is known to cause gastrointestinal upset in a large percentage of patients and should be started slowly and tapered to a therapeutic dose. Avandia seemed to be better tolerated though after several warnings, Avandia is not commonly used any longer.
See more information on hyperinsulinemia and insulin resistance here.
Dietary modification and exercise can be a very effective treatment for PCOS and insulin resistance. Click Here.
Prior to the use of embryo cryopreservation, any remaining embryos following an embryo transfer or a canceled cycle (as in the case with hyperstimulation syndrome prior to embryo transfer) were discarded. With the development of improved cryopreservation techniques, these additional embryos can be frozen for use at a later time. Cryopreservation allows for subsequent “frozen embryo transfers” (FET) and additional attempts at conception. This helps to avoid additional stimulation of the ovaries with expensive fertility medications while saving the embryos for use in the future. This improves the overall safety and cost of infertility treatment. Oocyte recipients and IVF patients almost always choose cryopreservation as a means of extending their attempts at achieving pregnancy. The consent process for freezing eggs, sperm, and embryos must take into account several possibilities that could occur in the future before additional attempts at pregnancy are made. Examples of these events could include divorce or the death of one or both partners. Parent(s) must indicate their desires for disposition of the embryos in the event of a divorce or death of one of the partners. There are several options for extra embryos created during IVF.
Embryo freezing techniques have continued to evolve. The biggest challenge in freezing embryos is to protect them from damage during the freezing and thawing process. Ice crystals may form inside the embryo which can damage delicate structures inside of the embryo. The older technique of freezing embryos is referred to “slow freezing”. During this procedure, a computerized device is used to control the slow decrease in temperature until the embryos reach the transition point between liquids and solids. A technique called seeding is used by touching the vial containing the embryos at the time when ice is forming within the liquid containing the embryos. This causes ice crystals to form in the container away from the embryos. To further prepare for this procedure, embryos are dehydrated and placed in cryoprotectants, or chemicals to protect the embryos from ice crystal formation. Embryos are usually frozen in groups of 1 to 2 per vial. This allows us to limit the number of embryos thawed at any given time in the future. When possible, we only thaw the number of embryos that are needed at the time of the frozen embryo transfer.
The newest technique of freezing embryos is called vitrification. During this process, embryos are suspended in a thin membrane of liquid. Imagine a child’s bubble wand with a thin layer of soap within the loop. Embryos are suspended in the cryo loop and plunged into liquid nitrogen. The thin layer of liquid and rapid nature of freezing will minimize the formation of ice crystals that can damage embryos. This technique has opened the doors to egg freezing and fertility preservation. As the success of vitrification continued to improve, the way IVF cycles are performed have changed. By freezing embryos and allowing the uterus to recover from the hormones associated with ovarian stimulation, success rates have climbed by 15 to 20%. Over the last 1-2 years, our success rates have remained around 70% without genetic testing and approximately 80% with genetic testing. Many clinics are still struggling to perfect vitrification and have not made the transition to the next generation of IVF treatments.
Another important concern is the safety of the techniques to the embryo and the potential future child. There have been many studies on the safety and long term effects of cryopreservation. Currently there is not any known risk associated with cryopreservation. Such studies are very difficult to conduct due to demographics of different countries, occurrence of abnormalities in the general population, and the number of years needed to make such assessments.
Our lab uses very strict techniques and labeling procedures to insure proper identification of embryos. The lab also uses a witness system and redundant paperwork to maintain strict protocols regarding identity and safety. [More Information]
The diagnosis of insulin resistance implies a patient has a disorder in tissues related to an impaired ability to respond to the action of insulin. This leads to a situation where the pancreas produces extra insulin in an effort to overcome the resistance to insulin. This elevation in insulin is known as hyperinsulinemia, or high blood insulin. Insulin resistance is not the same as diabetes although it is considered an early form of diabetes. The main difference in the two disorders is that the person with insulin resistance is capable of producing excessive amounts of insulin to maintain blood glucose, whereas the diabetic patient can no longer produce adequate levels of insulin to control blood sugar. Insulin resistance can come about through more than one mechanism. Receptor defects and obesity appear to be independent risk factors that may appear alone or in combination. There appears to be a genetic link so a family history of adult onset diabetes is a risk factor. Hyperinsulinemia can also occur in situations where the body is overproducing insulin but the tissues aren’t technically resistant to the effects of insulin. This occurs most commonly in the setting of excessive sugar intake. Insulin is a hormone which causes changes in different cells throughout the body. Excessive hormones can cause changes in the appearance of individuals. Polycystic Ovary Syndrome and Syndrome X are labels to describe a common appearance among patients with high insulin levels and insulin resistance. Insulin resistance is the most likely the underlying metabolic abnormality in PCOS and metabolic syndrome X. There is a lack of unanimous consensus about appropriate testing and diagnosis which often confuses patients and doctors. Many tests focus on tissue resistance to insulin rather than the absolute level of circulating hormone. We have specialized tests designed to find these elevations in hormones, however the actual tests are generally not needed as most everyone can benefit from the lifestyle modifications that can effectively reverse the effects of excess insulin. Treatment results can be quite impressive and can lead to pregnancy without fertility medications in many cases.
Insulin is secreted by the pancreas in response to glucose. Glucose transport into cells requires insulin. Insulin binds to a receptor on the cell surface and causes a signaling cascade that leads to uptake of sugar. When receptors do not process the signal appropriately, the blood sugar will remain elevated unless the pancreas makes more insulin. The elevation in serum insulin can have far reaching effects in the body.
Insulin can cross into another hormone pathway known as Insulin-Like Growth Factor 1 (IGF-1). Insulin and IGF-1 are responsible for interrupting ovulation, stimulating the uterine lining, and initiating the development of heart disease. Insulin and IGF can alter the metabolism and actions of androgens which lead to excess hair growth, alopecia, and acne. Insulin and IGF can directly and indirectly increase cholesterol and lipids as well as increase plaque formation seen in cardiovascular disease. Insulin and IGF-1 play a key role in fat storage. Hyperinsulinemia leads to a predisposition towards central obesity. Obesity in turn increases insulin resistance. This leads to a cycle of disease progression that can be resistant to diet and exercise alone.
Treatment sometimes involves a three-fold approach. A diet designed to reduce the demand for insulin will lead to lower insulin levels. This can be combined with exercise for a treatment method that is successful in most patients. We have an easy to understand diet plan that can lower the demand for insulin. Exercise helps to alter proteins that reduce the effects of insulin on the body as well as help decrease weight. These effects together improve insulin resistance. Occasionally these to treatments are not sufficient and medications may be required. Insulin sensitizing drugs improve the signaling mechanism of insulin at the level of the cell and receptor. Our treatment approach will combine the medication with diet and exercise if necessary. Metformin in the proper dose can be an effective treatment by correcting the underlying abnormality associated with polycystic ovarian syndrome. Proper treatment allows many women to ovulate and become pregnant. The associated weight loss can be impressive and many patients are able to adapt a new way of life for long term health.
The most commonly used medication is metformin (Glucophage). 30% of patients may experience nausea, diarrhea, and abdominal bloating. Starting low and building up to the desired dose over several weeks may alleviate these problems. A metallic taste during initial therapy is reported in 3% of patients. 1 in 33,000 people taking metformin develop a build up of lactic acid (lactic acidosis). While this is fatal in 50% of cases, it is not likely to occur in someone without impaired liver or kidney function. Symptoms include: weakness, unusual muscle pain, trouble breathing, stomach discomfort, feeling cold, dizzy or lightheaded, and suddenly developing a slow or irregular heart beat. All patients on metformin should follow up regularly with a physician familiar with metformin. Metformin may be continued during the first trimester of pregnancy or longer, however patients must consult a physician regarding their individual case and risks.
For more information on polycystic ovarian syndrome (PCOS – PCO) click here.
Metformin is also known as Glucophage. It is a medication commonly used to treat diabetes that works by improving the body’s sensitivity to insulin. This allows the pancreas to produce a lower amount of insulin to keep the blood sugar regulated. Metformin has been used for many years to treat diabetics, but only became popular for the treatment of infertility in the late 1990’s and early 2000’s. Metformin has also established itself as relatively safe in pregnancy and is considered a category B drug (a better rating than many other medications commonly used in pregnancy).
Metformin is used most frequently in the setting of polycystic ovarian syndrome or PCOS. In this setting, metformin helps to reduce the insulin that can interfere with the production of follicles. There are complex hormones that control the normal growth and maturation of follicles. When insulin is high as in the setting of insulin resistance or hyperinsulinemia, the follicles may not grow properly. This can lead to poor quality eggs and even interfere with ovulation.
Metformin alone has been show to improve fertility and increase a woman’s chances of getting pregnant and having a baby. This treatment is much more effective when combined with dietary changes that lower circulating insulin levels. Our doctors specialize in helping women overcome the challenges of insulin problems and polycystic ovarian syndrome (PCOS) using diet and metformin when necessary.
Metformin is a prescription medication that should be used only as prescribed. 30% of patients may experience nausea, diarrhea, and abdominal bloating. Starting low and building up to the desired dose over several weeks may alleviate these problems. A metallic taste during initial therapy is reported in 3% of patients. 1 in 33,000 people taking metformin develop a build up of lactic acid (lactic acidosis). While this is fatal in 50% of cases, it is not likely to occur in someone without impaired liver or kidney function. The risk of lactic acidosis in a young and healthy population has been estimated to occur in less than 1 in 250,000 patients. Symptoms include: weakness, unusual muscle pain, trouble breathing, stomach discomfort, feeling cold, dizzy or lightheaded, and suddenly developing a slow or irregular heart beat. All patients on metformin should follow up regularly with a physician familiar with metformin.