POLYCYSTIC OVARIAN SYNDROME
Presented at Medical Grand Rounds
The Christ Hospital
January 19, 2001
Polycystic Ovarian Syndrome (PCOS) is an extremely common clinical disorder. Its prevalence is estimated to be between 5-10%. It was initially described in the 1930’s by two gynecologists, Dr. Stein and Dr. Leventhal. The initial constellation of findings included amenorrhea, hirsutism, and enlarged polycystic ovaries. The management of polycystic ovaries has evolved over the years. Initially surgical management was utilized to simply reduce the size of ovaries. This is described as a wedge resection of the ovary. Reduction of the size of the ovary reduced the amount of circulating androgens and did improve symptomology and also resulted in conception in some cases. Advances in pharmacological therapy have now resulted in the management of this disorder primarily by medical means.
The full clinical presentation of PCOS includes android obesity, hirsutism, acne, oligo or amenorrhea, infertility, and insulin resistance. Symptoms typically first present in the peripubertal years. As teenagers, typically affected individuals will have irregular menstrual periods and then begin to note weight gain. Acanthosis nigricans is a hyperpigmentation of intertrigenous skin areas. It is commonly associated with insulin resistance. Additionally, the ovaries may appear polycystic by ultrasound. This appearance is a subcortical ring of small atretic follicles. It is also important to note that obesity is not a required feature of this condition. It occurs in approximately 70% of cases.
Endocrine findings include an elevation of the LH to FSH ratio. LH/FSH is greater than 2. This is particularly common if BMI is less than 30. As BMI increases this ratio is less consistent. There is slight elevation of testosterone. Total testosterone should be less than 200ng/dl. There is also an increase in free testosterone. There is a slight increase in DHEAS. This is typically less than 250mcgm/dl. There may also be an increase in androstenedione. The 17 hydroxy progesterone if tested should be normal. It is important to recognize that extensive endocrinological testing is not generally necessary. Because these patients present with irregular periods, they should have a screening study of a TSH and prolactin level. If androgen levels are tested, this is primarily to rule out ovarian or adrenal tumors. Androgen testing is not performed to verify that these patients have elevated androgens. One can typically use the patient herself as a bioassay.
Pathophysiology
A great deal of research has gone into clarifying the pathophysiology of PCOS. It is generally agreed that LH secretion is increased and FSH secretion is decreased. It is believed that GnRH pulsitility is increased in patients with PCOS. This results in a pituitary response where the LH secretion is increased and the FSH secretion is decreased. Increased LH secretion results in theca cell hyperplasia, which leads to increased androgen production. Decreased FSH secretion is associated with granulosa cell hypo function and decreased aromatization of androgens to estrogens. This contributes to the circulating levels of androgens. PCOS is also associated with insulin resistance and elevated serum insulin levels. Insulin appears to act on the theca cells by increasing androgen production as well. Also, there is evidence that adrenal hyperandrogenism is associated with PCOS. This is probably related to increased cP450 activity. One other factor in the pathophysiology of PCOS is that increased androgens and insulin result in decreased sex hormone binding globulin levels. This results in increased free androgens. This generally will manifest itself in the form of hirsutism or acne.
Obesity is a factor in 70% of cases of PCOS seen regionally. Adipose tissue is an active endocrine compartment. Androgens are aromatized to estrogens in fat cells. This causes tonic feedback and increased LH release. PCOS is thought to be transmitted by an autosomal dominant mechanism. This appears to have variable penetration. It is known that 40% of first degree relatives are effected with PCOS.
Hyperinsulinemia
A great deal of interest has been focused on the hyperinsulinemia associated with PCOS. Insulin effects three major target cells. These include the liver, muscle, and fat cells. Insulin causes decreased glucose output and decreased gluconeogenesis by the liver. It causes increased uptake of glucose by muscle cells as well as fat cells. It also decreases lipolysis in the fat cells. Insulin resistance in PCOS is related to a defect in post receptor phosphorylation. There is a strong correlation between hyperinsulinemia and hyperandrogenism. A strong case can be made for the fact that the high insulin levels cause an increase production of androgens. Reduction in insulin levels is associated with a decrease in serum testosterone. Also, obesity in and of itself appears to be associated with insulin resistance and amplifies this resistance in patients with PCOS. 20-40% of patients with PCOS are known to have impaired glucose tolerance. Also, there is an increased incidence of type II diabetes. The diagnosis of hyperinsulinemia is made based on a fasting insulin level of greater than 20U/ml. Also, it can be made if the ratio of fasting glucose to insulin is less than 4.5. In the past few years several insulin sensitizers have become available on the market. The first two that were studied were Rezulin and Metformin (Glucophage). Rezulin has been withdrawn from the market due to hepatictoxicity. There are two new drugs Avandia and Actose. These are in the same class of drugs as Rezulin. These are not as widely utilized for PCOS. This is primarily due to the fact that they require monitoring of LFT’s. Also, Glucophage appears to have more weight loss associated with its use. The mechanism action of Glucophage is increased glucose transport in hepatic and muscle cells. Also, there is decreased hepatic gluconeogenesis. Glucophage is a class B drug. There is no evidence of teratogenicity of this agent based on animal studies. The side effects of Glucophage include diarrhea, which is common. Rarely lactic acidosis can be seen. Glucophage is contraindicated in renal, hepatic, or major cardiovascular disease.
Glucophage is usually given in a dosage of 500mgs p.o. t.i.d. It is helpful to initiate dosage on a once daily basis then increase gradually to three times daily to reduce side effects. Glucophage is frequently associated with a decrease in weight. Also, it results in resumption of ovulation in approximately 35% of cases. The pregnancy rates seen with Glucophage are approximately 30%. If Glucophage alone is not sufficient then addition of clomiphene citrate 50 mgs will usually result in improved ovulation rates. While pregnancy rates of 30% may not be seen as impressive, it is important to note that many of these individuals are extremely heavy and would generally respond poorly to clomiphene citrate as a single agents or to gonadotropins. In clinical practice, for the patient with increased body weight, we may attempt Glucophage therapy for 3-6 months. If she does not spontaneously conceive then either clomiphene or gonadotropins can be added. In normal weight individuals with PCOS insulin levels are generally not elevated and response to Glucophage is poor. In these cases ovulation inducing agents are preferable. Although Glucophage is a class B drug, we recommend discontinuation of use when pregnancy is diagnosed.
Management of PCOS
Since there is not one medication that completely reverses the abnormalities of polycystic ovarian disease, we generally focus on the goals of the patient. In treatment of PCOS we may wish to manage any of the following manifestations: (1) obesity (2) hirsutism (3) menstrual irregularity (4) infertility and (5) hyperinsulinemia.
Our goals of management are to reduce long term sequelae. These include type II diabetes, endometrial carcinoma (which is related to chronic oligo-ovulation or hypersecretion of estrogens) and cardiovascular disease.
Treatment of obesity is always clinically challenging. The main approach has been one of diet and exercise. However, many patients will respond to Glucophage in addition to diet and exercise. In 30% of cases we can obtain weight loss of 10-20 lbs. We have seen patients in the practice that have lost 30-80 lbs. It is important to understand that a modest reduction of weight in the range of 10% will reduce risk factors for coronary artery disease.
Before initiating a management scheme for hirsutism it is important to assess the degree of hirsutism. Take into consideration in addition to the patient’s physical appearance, any ancillary cosmetic measures that she is utilizing including electrolysis and use of facial creams or shaving. This will help the clinician to understand how much of a problem hirsutism is. Oral contraceptives agents are an excellent therapeutic option. They decrease the LH and therefore androgen production. Additionally, the estrogen component of the OCP’s will result in increases in SHBG resulting in a decrease of total free androgens. Also, OCP’s will reduce the incidence of endometrial hyperplasia. There are several agents available as androgen receptor blockers. These include Spironolactone, Cyproterone acetate, and Flutamide. Cyperterone acetate is not available in the United States. Flutamide is a potent anti-androgen used for cases of prostate cancer and generally its use requires monitoring of LFT’s. Spironolactone is the most common clinically utilized agent can be used in combination with OCP’s or as a single agent. Also, there are five alpha reductase inhibitors such as Finasteride. This is commonly used as a treatment for alopecia. It is not commonly used as a treatment for hirsutism.
If the patient’s major complaint is menstrual irregularity, then this can be managed by the use of progestins. Provera can be given is a dose of 5-10mgs for ten days every month. This will result in cyclic shedding of the endometrium and a reduction in the incidences of endometrial hyperplasia and adenocarcinoma. If the patient is young and taking Provera she would require another contraceptive agents such as a barrier method. Oral contraceptives are also an excellent choice. Finally, Glucophage may result in cycle regularity. If the patient does not wish to conceive and is taking Glucophage, she would require barrier contraception.
PCOS is associated with an increase in serum triglycerides, LDL, and VLDL cholesterol. It is associated with a decrease of HDL. Because of obesity, dyslipidemia and insulin resistance, patients with PCOS have increased risk factors for hypertension, coronary artery disease and diabetes mellitus. Clearly there is an observed increased incidence of hypertension and diabetes. As far as cardiovascular disease, there is some controversy. Some studies have shown subclinical atherosclerosis by carotid ultrasound. Also, patients with PCOS have been noted to have more extensive atherosclerosis at the time of coronary artery disease. However, a recent large thirty-two year follow up study of 900 women diagnosed with PCOS at the mean age of twenty-five has been conducted. It has shown that when compared with a geographically age matched control, there is an increase in risk factors for coronary artery disease. However, there was no increase in the incidence of coronary artery disease. There was no increase in the incidence of all cause mortality. It is suspected that there may be a cardioprotective factor associated with these cases possibly the hyperestrogenism.
As far as the treatment of infertility in patients with PCOS, weight loss is ideal but difficult to achieve. Therapy with Glucophage as discussed above is associated with a pregnancy rate of roughly 30%. For those patients that are resistant to Glucophage then Serophene can be administered with a conception rate of 35%. If therapy is ineffective then gonadotropin therapy with either an FSH/LH agent such as Pergonal or one of the new recombinant FSH only agents such as Gonal F is very effective. Ultimately, if ovulation induction is not effective, then in vitro fertilization can be utilized to treat this condition. Ovulation induction in patients with PCOS is typically difficult. Usually one struggles between a hyperresponse or hyporesponse. It is not uncommon for these patients to have a relatively narrow therapeutic window with gonadotropins.
Tremendous progress has occurred in our understanding of the pathophysiology of PCOS. Also, the new insulin sensitizing drugs such as Glucophage have been a very valuable recent addendum. PCOS remains a common chemical entity with multiorgan manifestations. It remains a clinical challenge to manage the disease during the reproductive life span of affected individuals.
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