Weight loss and medication in polycystic ovary syndrome therapy. (Nutrition and Disease).
Nutrition Today, March-April, 2002, by Linda G. Tolstoi, John B. Josimovich
In 1935, Stein and Leventhal described a gynecologic disorder that was characterized by amenorrhea, hirsutism, and bilaterally enlarged polycystic ovaries. (1) Today, healthcare professionals recognize polycystic ovary syndrome (PCOS) as a heterogeneous syndrome with both short- and long-term consequences. (2) PCOS affects approximately 6% of reproductive-age women. (3)
In the past, pharmacologic treatment for PCOS involved correcting anovulation and the adverse effects of hyperandrogenism. (4) Today, treatment for PCOS also includes minimizing insulin resistance and hyperinsulinemia. This focus change results from new insights into the pathogenesis of PCOS. Insulin-sensitizing agents have beneficial effects by reducing both hyperinsulinemia and excess androgen production. (4)
This article discusses the role of hyperinsulinemia in the pathogenesis of PCOS and both the nonpharmacologic and pharmacologic management of hyperinsulinemia in women with PCOS.
Clinical and Biochemical Features
PCOS is not a disease, but rather a syndrome. (5) The variable clinical features of PCOS include menstrual dysfunction, hyperandrogenism, infertility, obesity and glucose intolerance, and a possible predisposition to coronary heart disease.
The most common complaint of women with PCOS is menstrual irregularity with or without periods of amenorrhea. (6) Clinical signs of excess androgens range from mild to pronounced acne and hirsutism. Women with PCOS who are obese have a characteristic android “apple” shape because of the tendency to accumulate fat in the upper region of the body and abdominal areas. The presence of acanthosis nigricans (hyperpigmentation on the nape of neck, axillae, and inguinal areas) also suggests excess secretion of insulin (6) (Figure 1). (7)
[FIGURE 1 OMITTED]
The biochemical features of PCOS include hyperandrogenemia, hyperestrogenemia, abnormalities of the hypothalamic-pituitary axis associated with reproduction, hyperinsulinemia and insulin resistance, and polycystic ovaries on ultrasonography. (5)
In women with PCOS, the ovary’s outer layer (cortex) is like a thickened and hardened capsule that prevents ovulation. (5) The cortex contains many 2- to 6-mm cystic follicles with thecal hyperplasia, which accounts for the polycystic appearance of the ovary. Excessive levels of circulating androgens from any source, such as the adrenal glands, may disrupt the development of follicles and cause the small cystic follicles to accumulate in the ovary’s cortex. (6)
Diagnosis of PCOS is based upon the presence of the common clinical features (eg, menstrual irregularities, hirsutism, central obesity). (8) Also, endocrinologic abnormalities are confirmed with biochemical tests (eg, increased testosterone activity and insulin resistance with compensatory hyperinsulinemia) and the exclusion of other etiologies.
The most important disorders to exclude include androgen-secreting tumors (eg, ovarian, adrenal) and an adrenocorticotropin-producing tumor (eg, Cushing syndrome) that causes oligomenorrhea or amenorrhea. (5) Anovulatory disorders may be caused by pituitary prolactinomas (9) and systemic illnesses, such as hypothyroidism, malnutrition, and anorexia nervosa. (5) Certain drugs (eg, danazol) may cause hyperandrogenism and irregularities of the menstrual cycle (5); therefore, many diagnostic tests are necessary.
Three interlinked but not necessary mutually exclusive hypotheses are proposed to explain the pathophysiology of PCOS. (5) The LH hypothesis proposes that the primary neuroendocrine defect is in hypothalamic–pituitary function, resulting in hyperandrogenism and anovulation. The insulin hypothesis suggests a defect in insulin action, resulting in excess secretion of androgens and anovulation. Finally, the ovarian hypothesis proposes a defect in the synthesis or metabolism of sex steroids, resulting in ovarian hyperandrogenism and anovulation. Each hypothesis attempts to explain the multiple abnormalities associated with PCOS, but confusion still exists because of the complexity of the syndrome. (10)
THE INSULIN HYPOTHESIS
In 1921, the association of diabetes mellitus with hyperandrogenism was described and named the “diabetes of bearded women” or Achard-Thiers syndrome, but the researchers did not propose a cause for it (as cited by Burghen). (11) In 1980, new clinical evidence emerged that suggested a relationship between hyperandrogenism and insulin resistance in patients with PCOS who are obese. (11) Dr John E. Nestler of the Medical College of Virginia states “PCOS is an excellent example of the importance of clinical research and of how a simple clinical observation can sometimes pave the way for new scientific discoveries.” (12)(p119)
Researchers hypothesized that hyperinsulinemia stimulates an ovarian enzyme complex that in turn causes excessive production of ovarian androgens. (13) In the ovarian theca cells, insulin may directly stimulate cytochrome P450c17[alpha], a key enzyme in the biosynthesis of the ovarian androgens. Cytochrome P450c17[alpha] converts progesterone to androstenedione, which is then converted to testosterone by the enzyme 17B-reductase. Figure 2 provides an explanation of the interrelated hormonal mechanisms that contribute to the pathophysiology of PCOS. (8)
[FIGURE 2 OMITTED]
Insulin indirectly influences the clinical androgenic state by regulating circulating levels of the steroid hormone-binding globulin (SHBG). (12) It is assumed that the fraction of testosterone not bound to SHBG is bioavailable to tissues. Insulin directly inhibits the hepatic synthesis and/or secretion of SHBG. (14) Women with PCOS who are obese have significantly lower serum levels of SHBG and higher serum levels of free testosterone compared with women with PCOS who are lean. Also, the levels of SHBG are inversely related to the levels of insulin. (14)
Insulin may indirectly increase ovarian androgen production by enhancing the secretion of the luteinizing hormone (LH) from the pituitary gland. (13) The gonadotropin may stimulate the activity of the ovarian cytochrome P450c17[alpha].
The best way to test the insulin hypothesis is to reduce serum insulin levels and to monitor the patient’s response to the intervention. (15) When women with PCOS who are obese were treated with metformin, an oral antihyperglycemic drug, their serum insulin concentrations decreased. (13) At the same time, there was a decrease in the activity of the ovarian cytochrome P450c17[alpha] and a decrease in the unbound serum testosterone concentration. Therefore, the researchers concluded that the hyperandrogenism associated with PCOS could be improved by reducing serum insulin levels. (13)
Insulin Resistance and Hyperinsulinemia
Insulin plays an important role in cellular processes involving glucose metabolism. (16) Glucose uptake by muscle and fat cells is dependent upon insulin. The hormone also converts glucose to glycogen in muscle and the liver and suppresses hepatic gluconeogenesis and secretion of glucose in the liver. However, the pancreas must secrete additional insulin to maintain serum glucose levels in the presence of insulin resistance. (16) When the pancreas can no longer secrete sufficient insulin to overcome insulin resistance in peripheral tissues (eg, muscle: and fat cells), postprandial serum glucose levels increase. Eventually, fasting glucose levels increase because of inadequate suppression of hepatic production of glucose. (16)
Many clinical studies have proven that most women have a form of insulin resistance that is unique and intrinsic to the syndrome. (3) However, women with PCOS who are obese compared with normal weight and thin women with PCOS have the additional burden of excess adiposity that further contributes to their insulin resistance.
In women with PCOS, the uptake of glucose into muscle and fat cells by insulin is decreased. (16) The woman with PCOS who is obese will have impaired glucose tolerance if her pancreas cannot secrete excess insulin to overcome peripheral insulin resistance. Women with PCOS compared with their age-matched control subjects have greater rates of gestational diabetes, impaired glucose tolerance, and diabetes mellitus. (16)
The metabolic consequences of hyperinsulinemia include altered lipoprotein and cholesterol metabolism, increased lipid storage (eg, upper abdomen obesity), and altered steroid hormone metabolism that leads to PCOS (eg, hyperandrogenism, infertility). (17) Hyperandrogenism also contributes to the increase in insulin resistance (Figure 3). (8)
[FIGURE 3 OMITTED]
Polycystic Ovary Syndrome vs Syndrome X
In 1988, the term “syndrome X” was coined to describe a group of abnormal metabolic changes that have a tendency to occur in the same individual. (18) Abnormal metabolic changes that are believed to be secondary to insulin resistance increase the risk of coronary artery disease. They include glucose intolerance, hyperinsulinemia, increased very-low-density lipoprotein triglyceride, decreased high-density lipoprotein cholesterol, and hypertension. (18)
A study was conducted to assess the frequency of gynecologic disorders associated with PCOS at a population level in women with metabolic syndrome (eg, syndrome X). (19) The researchers concluded that the pathophysiology of PCOS and the metabolic syndrome are closely interwoven. However, at the population level PCOS is a distinct subgroup of the larger group of people suffering from the metabolic syndrome, which is a much broader problem. (19)
One approach to treating PCOS is to reduce circulating insulin levels. (12) Decreases in serum insulin levels by means of weight loss (20) or insulin-sensitizing drugs (eg, metformin) improve endocrine and ovarian function in women with PCOS. (12)
Diet should be the first line of treatment for women with PCOS who are obese. (12) However, insulin-sensitizing agents may offer an alternative when compliance with diet is poor, especially in those women with glucose intolerance. Also, these agents may prove to be useful in preventing or treating the potential complications (eg, glucose intolerance, dyslipidemia) of PCOS that result from the hyperinsulinemic insulin resistance to PCOS. (12)
Clomiphene citrate is a drug that helps to induce ovulation by means of its anti-estrogen action. Metformin increases the rates of ovulation and pregnancy from clomiphene citrate in women with PCOS who are unresponsive to clomiphene citrate alone. (21) However, because only 55% of the participants who received both metformin and clomiphene citrate became pregnant, (21) metformin is not the drug of choice of most reproductive gynecologists. For patients who fail to respond to clomiphene citrate, reproductive gynecologists may employ pituitary gonadotropins to induce ovulation.
Weight loss is recommended for women with PCOS who are obese because of its beneficial effects on the patients’ clinical status. Diet-induced weight loss causes a decrease in fasting and glucose-stimulated serum insulin levels and an increase in serum SHBG and a decrease in unbound serum testosterone levels. (14) In women with PCOS who are obese, intensive dietary intervention, along with adequate weight loss, improves their metabolic cardiovascular risk profile by increasing insulin sensitivity and fibrinolytic capacity. (22)
Weight loss is important in reducing insulin resistance in women with PCOS. Approximately 55% to 70% of the women with PCOS are obese. (23) Obesity reinforces the genetic tendency toward the hormonal and ovulatory disorders in patients with PCOS. However, insulin resistance has also been observed in women with PCOS who are lean, suggesting that insulin resistance is not entirely due to obesity. (24) Because the cause of obesity in women with PCOS is unknown, there is no specific method or treatment to achieve weight loss among them. Thus, an insulin-sensitizing drug, such as metformin, may help to break the link between hyperinsulinemia and the characteristic hormonal and metabolic features of PCOS. (24)
The specific clinical and laboratory (eg, hormonal) characteristics that differentiate women who are obese, amenorrheic, and hyperandrogenic (with and without polycystic ovaries) who responded with significantly improved menstrual cyclicity to diet therapy and weight loss from those who did not are unknown. (25) Women with PCOS have a more difficult time losing weight than the general population, and they also do poorly with fad diets. (26) Weight loss programs that focus on modification of diet, decreased caloric intake, sensible exercise, and stress management have been helpful in controlling the signs and symptoms of PCOS.
The glycemic index is a ranking of foods based upon their effect on postprandial blood glucose levels compared with a reference food. (27) A low glycemic index diet, which emphasizes dietary fiber-rich vegetables and legumes, compared with a higher glycemic index diet composed of simple sugars and starches made from refined flour has been proposed to help women with PCOS to lose weight. (28) However, this type of diet has not been clinically evaluated in such women.
In the past, physicians prescribed oral contraceptives with or without androgen-blocking drugs such as spironolactone. (29) Today, there are sufficient data suggesting that lowering insulin resistance by means of insulin-sensitizing drugs (eg, metformin, rosiglitazone, and pioglitazone) can improve menstrual cyclicity, increase ovulation, lower circulating levels of androgens, and ameliorate the clinical features of syndrome X. (29)
Metformin, an oral antihyperglycemic drug, improves glucose tolerance in patients with type 2 diabetes mellitus. (30) It is effective in treating insulin resistance by decreasing both glucose production by the liver and intestinal glucose absorption and by increasing the uptake and use of peripheral glucose. The drug does not cause hypoglycemia in patients with insulin-dependent or type 2 diabetes mellitus, and it does not cause hyperinsulinemia. (30)
Gastrointestinal distress, such as nausea and diarrhea, is the most common side effect of metformin. (31) The side effects can be minimized by taking the drug with meals and by starting therapy with a low dose of the drug and gradually increasing the dose.
Because metformin is excreted by the kidneys, it is contraindicated in patients, with renal disease because the risk of lactic acidosis increases with the degree of impaired renal function. (30) Only patients who have normal renal function (creatinine < 125 [micro]mol/L) and normal hepatic function should be prescribed the drug. (31) When metformin interacts with specific drugs (eg, diuretics, corticosteroids, oral contraceptives) that have the potential to produce hyperglycemia, control over blood sugar may be disrupted. (30) Also, metformin decreases the absorption of vitamin [B.sub.12] and folic acid. A small percentage of the patients experience hematologic side effects (eg, aplastic anemia, hemolytic anemia). So far, most of the clinical studies with metformin to treat hyperinsulinemia and insulin resistance in women with PCOS have been short-term and uncontrolled. (30) The drug improves insulin metabolism in some studies, but other studies show no change. (32) A decrease in serum insulin levels by metformin is accompanied by a decrease in serum testosterone levels. (33) Conversely, when the drug does not reduce serum insulin levels, there is no change in serum testosterone levels. Metformin is not yet approved by the US Food and Drug Administration (FDA) for the treatment of PCOS. (34) It is believed that the drug improves hyperinsulinemia in women with PCOS primarily by suppressing hepatic glucose output. (33) However, metformin may not be tolerated in women with PCOS who are lean and not absolutely insulin resistant or hyperinsulinemic. (35) Large-scale randomized placebo-controlled studies are necessary to determine both the benefits and the risks of metformin before it can be recommended as the frontline therapy in women with PCOS. (35) Thiazolidinediones Troglitazone belongs to a class of insulin-sensitizing agents known as thiazolidinediones. (33) The drug is effective in treating women with PCOS who are obese. However, troglitazone was withdrawn from the market by the FDA because of reports of fatal hepatotoxcity. Recently, two new thiazolidinediones known as rosiglitazone and pioglitazone were approved to treat type 2 diabetes mellitus in the United States. (33) The risk of hepatotoxicity associated with these drugs is less than that with troglitazone. (36) However, no published reports are available that discuss either drug in treating PCOS. (33) Summary The complex interrelationships between obesity, insulin resistance, and endocrinologic abnormalities in PCOS are poorly understood. (37) Evaluation of obesity, body fat distribution, and the patient's dietary habits help to screen for metabolic abnormalities and manage women with PCOS. It is possible that the discovery of the molecular mechanism of insulin resistance in PCOS may improve pharmacologic management. (35) Three theories are suggested to explain the PCOS syndrome: * LH hypothesis * Insulin hypothesis * Ovarian hypothesis REFERENCES (1.) Stein IF, Leventhal ML. Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol. 1935;29:181-191. (2.) Bachmann GA. Polycystic ovary syndrome: metabolic challenges and new treatment option. Am J Obstet Gynecol. 1998;179(6 part 2):S87-S88. (3.) Nestler JE. Polycystic ovary syndrome: a disorder for the generalist. Fertil Steril. 1998;70:811-812. (4.) Patel SR, Korytkowski MT. Treating polycystic ovary syndrome: today's approach. Women's Health Primary Care. 2000;3(2): 109-113. (5.) Taylor AE. Polycystic ovary syndrome. Endocrinol Metab Clin North Am. 1998;27(4):877-902. (6.) Patel SR, Korytkowski MT. Polycystic ovary syndrome: how best to establish the diagnosis. Women's Health Primary Care. 2000;3(1):55-58, 63-64, 66, 69. (7.) Rebar RW. Disorders of metabolism, ovulation, and sexual response. In: Becker KL, ed. Principles and Practice of Endocrinology and Metabolism. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2001:947-967. (8.) Hopkinson ZEC, Sattar N, Fleming R, et al. Polycystic ovarian syndrome: the metabolic syndrome comes to gynaecology. BMJ. 1998;317:329-332. (9.) Tolstoi LG. Hyperprolactinemia in nonpregnant women due to pituitary tumors. Life Sci. 1986;38:1981-1989. (10.) Strauss JF III, Dunaif A. Molecular mysteries of polycystic ovary syndrome. Mol Endocrinol. 1999;13:800-805. (11.) Burghen GA, Givens JR, Kitabchi AE. Correlation of hyperandrogenism with hyperinsulinism in polycystic ovarian disease. J Clin Endocrinol Metab. 1980;50:113-116. (12.) Nestler JE. Role of hyperinsulineumia in the pathogenesis of the polycystic ovary syndrome, and its clinical implications. Sem Reprod Endocrinol. 1997; 15:111-122. (13.) Nestler JE, Jakubowicz DJ. 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Relationship of the metabolic syndrome and obesity to polycystic ovary syndrome: a controlled, population-based study Am J Obstet Gynecol. 2001; 184:289-296. (20.) Kiddy DS, Hamilton-Fairley D, Bush A, et al. Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin Endocrinol (Oxf). 1992;36:105-111. (21.) Vandermolen DT, Ratts VS, Evans WS, et al. Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone. Fertil Steril. 2001;75:310-315. (22.) Andersen P, Seljeflot I, Abdelnoor M, et al. Increased insulin sensitivity and fibrinolytic capacity after dietary intervention in obese women with polycystic ovary syndrome. Metabolism. 1995;44:611-616. (23.) Futterweit W. Polycystic ovary syndrome: clinical perspectives and management. Obstet Gynecol Surv. 1999;54:403-413. (24.) Ehrmann DA. Attentuation of hyperinsulinemia in polycystic ovary syndrome: what are the options? J Endocrinol Invest. 1998;21:632-635. (25.) Pasquali R, Antenucci D, Casimirri F, et al. Clinical and hormonal characteristics of obese amenorrheic hyperandrogenic women before and after weight loss. J Clin Endocrinol Metab. 1989;68:173-179. (26.) Marantides D. Management of polycystic ovary syndrome. Nurse Pract. 1997;22(12):34, 36-38, 40-41. (27.) Powell-Foster K, Miller JB. International tables of glycemic index. Am J Clin Nutr. 1995;62:871S-893S. (28.) Case problem: dietary recommendations to combat obesity, insulin resistance, and other concerns related to polycystic ovary syndrome. J Amer Diet Assoc. 2000;100:955-960. (29.) Iuorno MJ, Nestler JE. Insulin-lowering drugs in polycystic ovary syndrome. Obstet Gynecol Clin North Am. 2001;28(1):153-163. (30.) Kutteh WH. Treating PCOS-related infertility with insulin sensitizing agents. OBG Manage. 2000:12(5):106-108, 110, 113-114, 116. (31.) Iuorno MJ, Nestler JE. The polycystic ovary syndrome: treatment with insulin sensitizing agents. Diabetes Obes Metab. 1999;1:127-136. (32.) Sattar N, Hopkinson ZEC, Greer IA. Insulin-sensitizing agents in polycystic ovary syndrome. Lancet. 1998;351:305-307. (33.) Taylor AE. Insulin-lowering medications in polycystic ovary syndrome. Obstet Gynecol Clin North Am. 2000;27(3):583-595. (34.) Wright LJ. Polycystic ovary syndrome. US Pharm. 2000;25 (9):HS35-HS41. (35.) Legro RS. Polycystic ovary syndrome: current and future treatment paradigms. Am J Obstet Gynecol. 1998(6 part 2);179:S101-S108. (36.) Kim LH, Taylor AE, Barbieri RL. Insulin sensitizers and polycystic ovary syndrome: can a diabetes medication, treat infertility? Fertil Steril. 2000;73:1097-1098. (37.) Lefebvre P, Bringer J, Renard E, et al. Influences of weight, body fat patterning and nutrition on the management of PCOS. Human Reprod. 1997;12(suppl 1):72-81. Linda G. Tolstoi received a Bachelor of Arts degree in biology from West Virginia University, a Bachelor of Science degree in pharmacy from Duquesne University, a Master of Science degree in biology from the University of Pittsburgh, and a Master of Education degree in human nutrition from the Pennsylvania State University. She is visiting scholar in the Center for Advanced Biotechnology, Department of Biomedical Engineering, Boston University. She has published several articles in medical, pharmacy, nursing, and nutrition journals. John B. Josimovich received his AB degree at Harvard College and MD from Harvard Medical School. After post-graduate training in reproductive physiology at Harvard Medical School and residency training in surgery at the Boston City Hospital and obstetrics/gynecology at the Boston Lying-In Hospital and Free Hospital for Women (now Brigham-Women's Hospital, Boston, Mass), he spent a career in clinical practice, teaching basic and clinical research in obstetrics/gynecology reproductive endocrinology full-time from 1964 to 1996 and part-time, subsequently. Currently, he is Clinical Professor of Obstetrics/Gynecology Women's Health at New Jersey Medical School in Newark. He is author of more than 50 refereed journal articles and editor of 6 books. He was codiscoverer of the placental growth factor, human placental lactogen. From Boston University, Mass (Ms Tolstoi), and New Jersey Medical School, Newark (Dr Josimovich). Corresponding author: Linda G. Tolstoi, RPh, MS, MEd, 30 Montview St, Uniontown, PA 15401 (e-mail: firstname.lastname@example.org).
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