PCOS: A Common Endocrine Disorder

by Pamela W. Smith, MD, MPH, MS

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age worldwide. It affects 10% of women in the US and accounts for 75% of the women with amenorrhea. PCOS also accounts for 85% of women with androgen excess and hirsutism.^1–12

For a diagnosis of PCOS, two of the following three criteria must be met: oligoovulation and/or anovulation, clinical or biochemical signs of excess androgen activity, polycystic ovaries on ultrasound (greater than or equal to 12 follicles 2–9 mm in size or the volume is greater than 10 mL).^13,14

Symptoms of PCOS commonly begin in the teen years. The following are signs and symptoms of PCOS^15–27:

• obesity or the inability to lose weight
  • Weight gain is usually around the waist as opposed to overall weight gain.
• irregular or absent menstrual cycles
• infertility and/or recurrent miscarriages
  • Infertility affects 75% of women who are obese.
• hirsutism
  • 40% of hirsute women who have normal cycles are anovulatory.
  • Hirsutism is present in 70% of women in the US and is much less common in women in Japan who have PCOS.
• oily skin and/or acne
  • Acne is seen in 1/3 of patients.
  • Hirsutism and acne are present in 70% of women with PCOS and 10% of women without PCOS.
• acrochordons (skin tags)
• acanthosis nigricans
• depression/irritability/tension
• gray-white breast discharge
• sleep apnea
• pelvic pain
• thinning scalp hair
• hypertension
• possible epilepsy connection
  • Women with epilepsy have a 10% to 26% higher risk for PCOS than other women.

There are numerous lab abnormalities commonly associated with PCOS:

• high testosterone and other androgens such as androstenedione
• elevated insulin level/insulin resistance
• elevated LH:FSH ratio (elevated LH and decreased FSH)
• decreased sex hormone binding globulin (SHBG)
• abnormal lipid profile
• elevated DHEA levels
• high estrone

All of the etiologies of PCOS are not yet known. Scientists believe that PCOS has a hereditary component.^28–30 In fact, 40% of women with PCOS have a sister with PCOS and 35% of women with PCOS have a mother with the disease.^31,32 There is some suggestion in the medical literature that women with PCOS are born with a gene that triggers higher than normal levels of androgens and/or insulin.^33,34 Furthermore, studies have shown that the high levels of testosterone and insulin in patients with PCOS are linked through a gene called follistatin.³⁵ Follistatin in the body plays a role in the development of the ovaries and is also needed to make insulin. Likewise, women, overweight or not, who have this disease process have both a higher rate of insulin resistance and hyperinsulinemia than controls.³⁶ High insulin levels are correlated with a decrease in SHBG, which increases the level of circulating testosterone.^37,38 Insulin also works with luteinizing hormone (LH) to increase androgen production in the ovarian theca cells.³⁹ Looking further at a possible hereditary component to PCOS, women with the disease tend to have a hyperactive production of CYP17 enzyme that is responsible for forming androgens from DHEA-S at those sites. This mechanism is further exacerbated when the patient is obese.

When considering other causes, about half of the women with PCOS have elevated DHEA levels.^40,41 High DHEA is due to stimulation of ACTH produced by the pituitary gland, mainly due to stress. The excessive DHEA is then converted into androgens via adrenal metabolism. This contributes to high androgen levels in PCOS. High testosterone levels correlate to the high LH levels. Subsequently, high androgen levels in the ovary inhibit follicle stimulating hormone (FSH) which then inhibits the development and maturation of the follicle.

In addition, the metabolism of estrogens changes by way of the 2-hydroxylation and 17-alpha-oxidation pathways which are decreased. Estrogen levels elevate due to the peripheral aromatization of androstenedione. This process then results in estrogen dominance due to the over production of estrogens.^42,43

Skin and adipose tissue are also postulated to contribute to the etiology of PCOS. Women who have hirsutism have an elevated sensitivity to androgen activity in the skin, so they may develop abnormal patterns of hair growth. Aromatase and 17-beta-hydroxysteroid activities are increased in the fat cells, and peripheral aromatization increases with the increase in weight.

Toxicities also play a role in the causation of PCOS. Phthalates, bisphenol-A, cadmium, and mercury toxicities have all been shown to be related to PCOS. These substances are associated with being possible endocrine disrupters which alter hormones and cause anovulation, increase the risk of developing insulin resistance, and hyperandrogenemia.⁴⁴

The imbalance in the hypothalamic-pituitary-ovarian axis that occurs in PCOS is part of the etiology of the disease. Twenty-five percent of women with PCOS have hyperprolactinemia. ⁴⁵ The high prolactin levels are due to the abnormal estrogen negative feedback from the pituitary. Furthermore, elevated prolactin can contribute to high estrogen levels.

Stress may be a major contributing factor to PCOS.⁴⁶ Studies have shown that many women with the condition cannot process cortisol effectively, which leads to elevated cortisol levels in the body.⁴⁷ When women are under stress, too much prolactin may be released. This may affect the ability of the ovaries to product the right balance of hormones.^48,49

Hypothyroidism may also be a cause of PCOS. One study of teenage girls with PCOS showed that on ultrasound, the ovarian cysts resolved when their hypothyroidism was treated. LH levels also decreased.⁵⁰ Another trial showed that when women with hypothyroidism were given levothyroxine alone or with clomiphene citrate and/or dexamethasone, ovulation was normalized.⁵¹ Furthermore, a study of women with PCOS found that 27% of them had elevated thyroid antibodies and 42% had a hypoechoic pattern on thyroid ultrasound which was consistent with autoimmune thyroiditis. Women with PCOS were found to have a prevalence of autoimmune thyroiditis that was more than three times higher than controls who did not have PCOS.⁵²

It is important when evaluating a patient for PCOS to consider the following differential diagnosis^53,54:

• hypothyroidism
• hypothalamic amenorrhea
• Cushing’s syndrome
• congenital adrenal hyperplasia
• ovarian/adrenal tumors
• hyperprolactinemia
• premature ovarian failure

PCOS is a risk factor for the development of other major diseases such as diabetes, heart disease, hypertension, infertility, hormone-related cancers, and obesity.^55–60

If the patient has PCOS, this is a risk factor for the development of diabetes; in fact, she is seven times more likely to become diabetic.^61,62 Likewise, about half of all women with PCOS have insulin resistance.⁶³ Some studies suggest that women with PCOS who have irregular cycles or no cycles may have double the risk of developing diabetes.⁶⁴ The risk of developing diabetes in patients with irregular cycles increases even more if they are obese.⁶⁵ Furthermore, the risk of getting diabetes is also increased in patients with PCOS who are not overweight or insulin resistant. ⁶⁶

Women with PCOS have an increased risk of developing heart disease when compared with women without PCOS.^67–69 Up to 70% of women in the US with PCOS have dyslipidemia.⁷⁰ Women with PCOS frequently have elevated total cholesterol, LDL, and triglycerides. They also tend to have low HDL and apoprotein A-1 levels.^71–76 Furthermore, patients with PCOS also tend to have impaired fibrinolysis as evidenced by elevated circulating levels of plasminogen activator inhibitor. This is associated with hypertension and atherosclerosis. Moreover, women with PCOS have a 7-fold risk of having an acute myocardial infarction.⁷⁷ Also, homocysteine levels may be increased in patients when they have PCOS;as well, women with this disease process tend to have higher than usual C-reactive protein (CRP) levels.^78,79 Just as interestingly, women with PCOS frequently have decreased total antioxidant status and increased oxidative stress.⁸⁰ These patterns may be some of the contributing causes of heart disease in women with PCOS.

Women with PCOS have 4 times the rate of hypertension as those who do not have the condition.⁸¹ Insulin resistance and hyperinsulinemia raise blood pressure.⁸² High levels of insulin correlate with low sodium in the urine. This leads to an increase in water retention, which makes it harder for blood to flow through the circulatory system, consequently leading to an increase in blood pressure. High insulin levels also elevate blood pressure by negatively affecting the elasticity of the arterial walls. Insulin likewise alters the mechanical action of the blood vessel walls by acting on smooth muscle cells, which stimulate them and make them enlarged. As smooth muscle cells grow, they make the arterial walls thicker and less supple. This forces the heart to work harder and exert more pressure to force the blood through the narrowed vessels.

In women with PCOS, the ovarian follicles start to mature but fail to ripen or to be released. They stay in the ovaries and continue to produce estrogen, but no progesterone. This increases the risk of developing infertility. Also elevated levels of LH and estrogen have been found in some women with PCOS.⁸³ This may block ovulation. Likewise, high levels of testosterone inhibit ovulation.⁸⁴ Moreover, women with PCOS may miscarry at a higher rate than women without the condition.^85,86 In addition, insulin itself plays a role in ovulation. The ovaries have insulin receptors. Insulin stimulates an increase in LH and androgen levels, decreasing SHBG. In the presence of elevated androgen, LH levels increase and lead to poor follicle development and failure to ovulate.

Importantly, women with PCOS have an increased risk of developing hormone-related cancers. For example, women with a history of PCOS and irregular periods have a 5-fold increase in the risk of developing endometrial cancer.⁸⁷ Likewise, one study showed that women with PCOS may have an increased risk of developing ovarian cancer.⁸⁸ In addition, women with this endocrine disorder may be at risk for the development of breast cancer, since they tend to be overweight and have hormonal changes that can lead to unopposed estrogen in the body.⁸⁹

Lastly, studies have shown that women with PCOS store fat better and burn calories more slowly than women who do not have PCOS, so they have an increased risk of being overweight or obese.^90–92 Therefore, there are several disease processes that women with PCOS are at risk in developing.

There are many treatments for PCOS. Medications such as antiandrogen medications, testosterone metabolism blockers, oral hypoglycemic agents, gonadotropin-releasing hormone antagonists, 5-alpha reductase inhibitors, hair metabolism inhibitors, ovulation inducers, and oral contraceptive are used commonly. Surgery is also suggested in some cases.^93–101

From a metabolic/anti-aging/functional medicine perspective, there is also a lot to offer. Natural progesterone has been found to be very helpful. It is imperative to measure hormone levels before beginning therapy.

Also, there is no disease process that cannot be made better by eating a healthful diet. Studies have shown that high-fiber, low-glycemic-index eating programs, weight loss, and exercise are very beneficial for women with PCOS. To be specific, high-fiber diets lower blood sugar, blood pressure, and cholesterol.^102–104 Furthermore, in a 6-month trial, 18 women with PCOS were placed on a low-glycemic-index eating program along with moderate exercise. The study found an 11% reduction in central fat, 71% improvement in insulin sensitivity index, 33% decrease in fasting insulin levels, and 39% decrease in LH levels; and 50% of the women started ovulating.¹⁰⁵ Another medical trial showed that in women with PCOS, weight loss alone helped 60% of them get pregnant without other medical intervention.¹⁰⁶

In addition, weight loss alone has been shown to improve the following^107–114:

• signs of hyperandrogenism
• menstrual irregularity
• hyperinsulinemia
• restoring ovulation and fertility
• improve gonadotropin pulsatile secretion
• may prevent non-insulin-dependent diabetes and heart disease
• decrease ovarian P450c17 alpha activity

Furthermore, when it comes to exercise, several studies showed that women with PCOS who exercised improved ovulation, reduced insulin resistance, and promoted weight loss.¹¹⁵ Interestingly, one medical trial compared the effects of exercise versus a low-calorie diet in women with PCOS. The women who exercised had a higher ovulatory rate, better insulin sensitivity, and a larger reduction in waist circumference than women who did not exercise.¹¹⁶

Reducing stress has been found to be very beneficial for patients with PCOS. Cortisol stimulates the release of glucose, fats, and amino acids for the production of energy in the body. During times of stress, cortisol and insulin levels rise in the body. Cholesterol levels may rise as well. If cortisol is elevated, it decreases the making of progesterone and its activity. Cortisol competes with progesterone for common receptors. Consequently, if cortisol levels are elevated, the symptoms of PCOS can be exacerbated.¹¹⁷

Essential fatty acids supplementation may be helpful. They slow down the absorption of carbohydrates in the blood stream. They also decrease inflammation. PCOS has been shown to have an inflammatory component.¹¹⁸

Drinking enough water is also very important. It has been estimated that the amount of water that the patient needs to drink daily is one-half her body weight in ounces, if she has normal renal and heart function. Furthermore, a study showed that people who drink 5 to 8 glasses of water a day have fewer heart attacks. Dehydration increases the tendency for the blood to clot.¹¹⁹

Being nutritionally sound also helps with the symptoms as well as aiding in the prevention of other disease processes that are associated with PCOS. Vitamin D deficiency is common in women with PCOS. A medical trial found that supplementation with 1500 mg of calcium a day along with 50,000 IU of vitamin D2 on a weekly basis normalized menstrual cycles and/or fertility in all women studied with PCOS-related menstrual irregularities within 3 months of treatment.¹²⁰ This was a small medical trial but certainly suggests that more research needs to be done in this area, particularly using D3 as the form of vitamin D supplemented.

D-chiro-inositol is a stereoisomer of inositol. A placebo-controlled trial with 44 women was done where one-half of the women received D-chiro-inositol for 6 to 8 weeks versus controls.¹²¹ Insulin and testosterone levels were lowered in all of the women, and 18 who received D-chiro-inositol ovulated. Furthermore, evidence suggests that the insulin resistance seen in women with PCOS may be partially due to a deficiency of D-chiro-inositol containing phosphoglycan or a defect in its tissue availability or utilization.¹²² This nutrient is currently not available in every country. D-pinitol (3-0-methyl-D-chiro-inositol) has similar chemical structure and biochemical actions as D-chiro-inositol and is available in most countries. D-chiro-inositol is also found in high concentrations in buckwheat. D-pinitol is found in legumes, citrus fruits, and soy meal.^123,124 Caution may be advisable in patients with bipolar disorder; some practitioners have expressed concern that a high consumption of inositol may exacerbate it.¹²⁵

Short-term use of N-acetylcysteine (NAC) may be helpful as well for PCOS. Studies have shown that using NAC in conjunction with clomiphene citrate increased ovulation, and pregnancy rates in women with infertility who had PCOS that could not conceive with the use of clomiphene citrate alone.^126,127

Herbal therapies for PCOS have medical trials that support their use such as adaptogens for stress or herbal therapies to aid in hormonal regulation.

Adaptogens have been shown to improve the stress response and HPA function such as American ginseng, ashwagandha, eleuthero, rhaporticum, rhodiola, and schizandra.¹²⁸ Of course, stress-reduction techniques are also important to help to normalize cortisol.

Some of herbal therapies affect hormonal function such as Cimicifuga racemosa (black cohosh), which binds to estrogen receptors and lowers LH.^129,130Vitex agnus-castus (chasteberry) has several therapeutic effects. It reduces prolactin secretion, since it has dopamine-agonist activity at the hypothalamic-pituitary level, and it also lowers the estrogen-progesterone ratio. Chasteberry also indirectly increases progesterone levels.^131–133 In addition, Serenoa repens (saw palmetto) inhibits 5-alpha reductase, which inhibits the conversion of testosterone to dihydrotestosterone (DHT). It also reduces androgen effects at the hair follicle and the pilosebaceous unit, which decreases hirsutism and acne.^134–136Urtica dioica (nettle) root binds to and increases SHBG, which then decreases the amount of testosterone available for the body to use. Nettle leaf does not work for this purpose.^137–139Camellia sinensis (green tea) increases SHBG, which decreases testosterone;and it also has been shown to help promote weight loss.^140,141 A placebo-controlled trial of women with PCOS revealed that the body weight of the group that used green-tea decreased by 2.4%, whereas the weight and BMI of the control group was higher at the end of the study.¹⁴²Glycyrrhiza glabra (licorice root) can decrease testosterone synthesis, according to research and a medical study.^143–145 Spearmint tea, as with several of the other herbal therapies, has been show to lower testosterone levels. It also may raise FSH and LH and can improve hirsutism.¹⁴⁶ Maitake mushroom extract (Grifola frondosa) in a medical trial was given to patients with PCOS versus clomiphene. After three cycles, the rate of ovulation in the maitake group was 76.9% and the rate of ovulation in the clomiphene group was 93.5%.^147,148 White peony (Paeonia lateriflora) has several effects upon hormonal regulation. It increases progesterone, reduces testosterone, and modulates estrogen and prolactin. It also affects the ovarian follicle by its action on aromatase. It has been used in the treatment of PCOS and also for hyperprolactinemia, endometriosis, and ovarian failure.^149,150 Combination therapies are also efficacious. The traditional Chinese formula Shakuyaku-kanzo-to, or TJ-68, a decoction of Glycyrrhiza glabra and Paeonia lateriflora, has clinical trials showing that it is a very effective treatment for PCOS.¹⁵¹

Other treatments shown to be effective for PCOS include detoxification, acupuncture and weight-loss surgery. Acupuncture can have a positive effect on PCOS patients, since it influences the sympathetic nervous system, endocrine system, and neuroendocrine system.^152,153 A study on women with PCOS who had bariatric surgery showed resolution of menstrual irregularity in 100% of the patients, improvement in hirsutism in 75% of the patients, resolution of type 2 diabetes and ability to stop drugs for hypertension in 78%, and the ability to stop medication for hyperlipidemia in 92% of the patients. ¹⁵⁴

Medicine has changed a great deal in the last 20 years. Through a metabolic/anti-aging/functional medicine approach, we can now look at the cause of the patient’s problem and not just treat the symptoms. Likewise, we can customize and individualize the treatment program. This provides patients the best of both worlds, where for disease processes such as PCOS they can have the advantage of conventional approaches along with metabolic medicine therapies.

Notes

1. Marchese M. Polycystic ovarian syndrome: a natural treatment approach. Townsend Lett. Feb/March 2012:66–68.
2. Guzick D. Polycystic ovarian syndrome. Obstet Gynecol. 2004;103(1):181–193.
3. Romm A. Botanical Medicine for Women’s Health. St. Louis: Churchill Livingstone/Elsevier; 2010:175–185.
4. Wei A et al. Therapy for polycystic ovarian syndrome. Curr Opin Pharmacol. 2003;3:678–682.
5. Ring M. Polycystic ovarian syndrome. In: Rakel D. Integrative Medicine. 3rd ed. Philadelphia: Elsevier;2012:345–352.
6. Azziz R. Androgen excess is the key element in polycystic ovary syndrome. Fertil Steril. 2003;80:252–254.
7. Azziz R et al. The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab. 2004;89:2745–2782.
8. Balen A et al. Polycystic ovary syndrome: the spectrum of this disorder in 1741 patients. Hum Reprod. 1995;10:2107–2111.
9. Book C et al. Selective insulin resistance in the polycystic ovary syndrome. J Clin Endocrinol Metab. 199;84(9):3110–3116.
10. Dunaif A. Hyperandrogenic anovulation (PCOS): a unique disorder of insulin action associated with an increased risk of non-insulin dependent diabetes mellitus. Am J Med. 1995;98:33S–39S.
11. Tsilchorozidou T et al. The pathophysiology of polycystic ovary syndrome.
    Clin Endocrinol (Oxf). 2002;60:1–17.
12. Richardson M. Current perspective in polycystic ovary syndrome. Am Fam Physician. 2003;68(4):697–704.
13. Alexander, C., Polycystic ovary syndrome: a major unrecognized cardiovascular risk factor in women. Rev Obstet Gynecol 2009;2(4):232–39.
14. Ibid., Marchese.
15. Ibid., Speroff.
16. Solomon, C., The epidemiology of polycystic ovary syndrome: prevalence and associated disease risks. Endocrinol Metab Clin North Amer 1999;28(2):247–63.
17. Fraser, I et al. Current recommendations for the diagnostic evaluation and follow-up of patients presenting with symptomatic polycystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol 2004;18(5):813–23.
18. Ahene, S et al. Polycystic ovary syndrome. Nurs Stand 2004;18(26):40–4.
19. Futterweit, W., A Patient’s Guide to PCOS. New York: Henry Holt and Company, 2006.
20. Ibid., Marchese.
21. Carmina, E., Diagnosing PCOS in women who menstruate regularly. Contemp Obstet Gynecol 2003;53–64.
22. Ibid., Marchese.
23. Hill, K., Update: the pathogenesis and treatment of PCOS. Nurse Pract 2003;28:8–25.
24. Ibid., Romm.
25. Ibid., Marchese.
26. Pritts, E., Treatment of the infertile woman with polycystic ovarian syndrome. Obstet Gynecol Surv 2002;57:587–97.
27. Ibid., Futterweit.
28. Atimo, W et al. Familial ssociations in women with polycystic ovary syndrome. Fert Steril 2003;80(1):143–45.
29. Gonzalez, C et al. Polycystic ovaries in childhood: a common finding in daughters of PCOS patients of PCOS patients. A pilot study. Hum Repro 2002;17(3):771–76.
30. Govind, A et al. Polycystic ovaries are inherited as an autosomal dominant trait: an analysis of 29 polycystic ovary and 10 control families. Jour Clin Endocrinol Metab 1999;84:38043.
31. Ibid., Futterweit.
32. Azziz, R et al. Family history as a risk factor for the polycystic ovary syndrome. Jour Pediatric Endocrinol Metab 2000;13:1303–06.
33. Strauss, J et al. Some new thoughts on the pathophysiology and genetics of polycystic ovary syndrome. Ann NY Acd Sci 2003;997:42–8.
34. Carey, A et al. Evidence for a single gene effect causing polycystic ovaries and male pattern baldness. Clin Endocrinol 38(6):653–8.
35. Urbanek, M et al. Thirty seven candidate genes for PCOS: Strongest evidence of linkage is follistatin. Proc Nat Acd Sci 1999;38(6):653–58.
36. King, J., Polycystic ovarian syndrome. Jour Midwifery Women’s Health 2006;51(6):415–22.
37. Ibid., King.
38. Ibid., Tsilchorozidou.
39. Ibid., Marchese.
40. Ibid., Speroff.
41. Ibid., Romm.
42. Ibid., Speroff.
43. Hopkinson, Z et al. Polycystic ovarian syndrome: the metabolic syndrome comes to gynecology. BMJ 1998;317:329–32.
44. Ibid., Marchese.
45. Ibid., Romm.
46. Marantides, D et al. Management of polycystic ovary syndrome. Nurse Pract 1997;22(12):34–8, 40–1.
47. Tsilchorozidou, T et al. Altered cortisol metabolism in polycystic ovary syndrome: insulin enhances 5 alpha-reduction but not the elevated adrenal steroid production rates. Jour Clin Endocrino Metab 2003;88(12):5907–13.
48. Barnea, E et al. Stress-related reproductive failure. Jour IVF Embryo Transfer 1991;8:15–23.
49. Tsilchorozidou, T et al. The pathophysiology of polycystic ovarian syndrome. Clin Endocrinol (Oxf) 2004;60:1–17.
50. Lindsay, A et al. Multicystic ovaries in primary hypothyroidism. Obstet Gynecol 1983;61:433–37.
51. Ghosh, S et al. Subclinical hypothyroidism: a determinant of polycystic ovary syndrome. Horm Res 1993;39:61–66.
52. McNamara, D., Thyroiditis rate three-fold higher with PCOS. Fam Pract News 2004;Mar 1: 75.
53. Ibid., Marchese.
54. Chang, R et al. Normal ovulatory women with polycystic ovaries have hypoandrogenic pituitary-ovarian responses to gonadotropin-releasing hormone-agonist testing. Jour Clin Endocrinol Metab 2000;85(3):995–1000.
55. Pelusi, B et al. Type 2 diabetes and the polycystic ovary syndrome. Minerva Ginecol 2004;56(1):41–51.
56. Talbott, E et al. Cardiovascular risk in women with polycystic ovary syndrome. Obstet Gynedol Clin North Amer 2001;28(1):111–33.
57. Rajkhowa, M et al. Polycystic ovary syndrome: a risk for cardiovascular disease. BJOG: Int Jour Obstet Bynecol 2000;107(1):11–8.
58. Trent, M., et al. Fertility concerns and sexual behavior in adolescent girls with polycystic ovary syndrome: implications for quality of life. Jour Pedatr Sdolesc Gynecol 2003;16(1):33–7.
59. Radulovic, A et al. Obesity and hormone function changes in female patients with polycystic ovaries. Med Pregl 2003;56(9–10):476–80.
60. Gonzalez, C et al. Polycystic ovarian disease: clinical and biochemical expression. Ginecol Obstet Mex 2003;71:253–58.
61. Pelusi, B et al. Type 2 diabetes and the polycystic ovary syndrome. Minerva Ginecol 2004;56(1):41–51.
62. Legro, R et al. Prevalence and predictors of risk for Type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. Jour Clin Endocrinol Metabol 1999;84(1):165–69.
63. De Leo, V et al. Polycystic ovary syndrome and type 2 diabetes mellitus. Minera Ginecol 2004;56(1):53–62.
64. Solomon, C et al. Long or irregular menstrual cycle as a marker for the risk of type 2 diabetes mellitus. JAMA 2001;286(19):2421–26.
65. Ibid., Solomon.
66. Danaif, A et al. Beta cell dysfunction independent of obesity and glucose intolerance in the polycystic ovary syndrome. Jour Clin Endocrinol Metab 1996;81:942–47.
67. Christian, R et al. Prevalence and predictors of coronary artery calcification in women with polycystic ovary syndrome. Jour Clin Endocrinol Metab 2003;88(6):2562–68.
68. Wild, S et al. Cardiovascular disease in women with PCOS: A long-term follow up: A retrospective cohort study. Clin Endocrinol (Oxf) 2000;52(5):595–600.
69. Talbot, E et al. Cardiovascular risk in women with polycystic ovary syndrome. Obstet Gynecol Clin North Amer 2001;28(1):111–33.
70. Ibid., Marchese.
71. Orio, F et al. The cardiovascular risk of young women wit polycystic ovary syndrome: an observational, analytical, prospective case-control study. Jour Clin Endocrinol Metab 2004;89(8):3696–701.
72. Ibid., Marchese.
73. Chang, R., A practical approach to the diagnosis of polycystic ovary syndrome. Amer Jour Obstet Gynecol 2004;191:713–17.
74. Phelan, N et al. Lipoprotein subclass patterns in women with polycystic ovary syndrome (PCOS) compared with equally insulin-resistant women without PCOS;Jour Clin Endocrinol Metab 2010;95(8):3933-39.
75. Wild, R et al. Assessment of cardiovascular risk and prevention of cardiovascular disease in women with the polycystic syndrome: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) society. Fertil Steril 20011;95(3):1073-79.
76. Ehrmann, D., Polycystic ovarian syndrome. NEJM 2005;353:1223-36.
77. Ibid., Romm.
78. Loverro, G et al. The plasma homocysteine levels are increased in polycystic ovary syndrome. Gynecol Obstet Invest 2002;53(3):157-62.
79. Boulman, N et al. Increased C-reactive protein levels in the polycystic ovary syndrome: a marker of cardiovascular disease. Jour Clin Endocrinol Metabol 2004;89(5):2160-65.
80. Fenkev, I et al. Decreased total antioxidant status and increased oxidative stress in women with polycystic ovary syndrome may contribute to the risk of cardiovascular disease. Fertil Steril 2003;8091):123-27.
81. Lefebvre, P et al. Long-term risks of polycystic ovaries syndrome. Gynecol Obstet Fertil 2004;32(3):193-98.
82. Landsberg, M., Insulin sensitivity in the pathogenesis of hypertension and hypertensive complications. Clin and Experimental Hyper 1996;18(3-4):337-46.
83. Milsom, S et al. LH levels in women with polycystic ovarian syndrome: have modern assays made them irrelevant? British Journ of Obstec and Gynecol 2003;110(8):760-4.
84. Franks, S., The ubiquituous polycystic ovary. Jour Endocrinol 1991;129:317-19.
85. Diejomaoh, M et al. The relationship of recurrent spontaneous miscarriage with reporductive failure. Med Princ Pract 2003;12(2):107-11.
86. Rai, R et al. Polycystic ovaries and recurrent miscarriage—a reappraisal. Hum Repro 2000;15:612-15.
87. Hardiman, P et al. Polycystic ovary syndrome and endometrial carcinoma, Lancet 2003;361(9371):1810-12.
88. Spremovi, R et al. The polycystic ovary syndrome associated with ovarian tumor. Srp Arh Celok Lek 1997;125 (11-12):375-77.
89. Wild, S et al. Long-term consequences of polycystic ovary syndrome: results of a 31-year study. Hum Fertil (Camb) 2000;3(2):101-05.
90. Robinson, S et al. Postprandial thermogenesis is reduced in polycystic ovary syndrome and is associated with increased insulin resistance. Clin Endocrinol (Oxf) 1992;36(6):537-43.
91. Faloia, E et al. Body composition, fat distribution and metabolic characteristics in lean and obese women with polycystic ovary syndrome. Jour Endocrinol Invest 2004;27(5):424-29.
92. Gambineri, A et al. Obesity and the polycystic ovary syndrome. Int Jour Obes Relat Metab Disord 2002;26(7):883-96.
93. Ibid., Romm.
94. Ibid., Wei.
95. Ibid., Richardson.
96. Ibid., Speroff.
97. Guzick, D., Polycystic ovary syndrome: symptomatology, pathophysiology, and epidemiology. Amer Jour Obstet Gynecol 1998;196(6 Pt. 2):S89-93.
98. D’Hooghe, T et al. Infertility. In Novak’s Gynecology. Philadelphia: Lippincott Williams & Wilkins, 2002.
99. Fleming, R et al. Ovarian function and metabolic factors in women with oligomenorrhea treated with metformin in a randomized double-blind placebo controlled trial. Jour Clin Endocrinol Metabol 2003;87(2):557-69.
100. Lord, J et al. Insulin-sensitizing drugs (metformin, troglitazone, rosiglitazone, pioglitazone, D-chiro-inositol) for polycystic ovarian syndrome. Cochrane Database Syst Rev 3(CD003053), 2003.
101. McCarthy, E et al. Metformin in obstetric and gynecologic practice: a review. Obstetrical and Gynecologic Survey CME review Article, 2004. Huber-Buchholz, M et al. Restoration of reproductive potential by lifestyle modification in obese polycystic ovary syndrome: role of insulin sensitivity and luteinizing hormone. Jour Clin Endocrinol Metab 1999;84(4):1470-74.
102. Anderson, J et al. Dietary fiber: diabetes and obesity. Amer Jour Gasteroenterol 1986;81:898-906.
103. Burke, V., Dietary protein and soluble fiber reduce ambulatory blood pressure in treatment of hypertensives. Hypertension 2001;38(4):821-26.
104. Sprecher, d et al. efficacy of psyllium in reducing serum cholesterol levels in hypercholesterolemic patietns on high-or low-fat diets. Ann Inter Med 1993;119:545-54.
105. Huber-Buchholz, M et al. Restoration of reproductive potential by lifestyle modification in obese polycystic ovary syndrome: role of insulin sensitivity and luteinizing hormone. Jour Clin Endocrinol Metab 1999;84(4):1470-74.
106. Ibid., Richardson.
107. Ibid., Romm.
108. Ibid., Solomon.
109. Ibid., D’Hooghe.
110. Crosignani, P et al. Overweight and obese anovulatory patients with polycystic ovaries: parallel improvements in anthropometric indices, ovarphysiology and fertility rate by diet. Human Repro 1932;18(9):1928-32.
111. Jakubowicz, D et al. 17-alpha-hydroxyprogesterone responses to leuprolide and serum androgens in obese women with and without polycystic ovary syndrome offer dietary weight loss. Jour Clin Endocr Metabol 1997;82(2):556-60.
112. Kahn, J et al. Polycystic ovary syndrome. Adolesc Med 1999;10(2):231-36.
113. Pasquali, R et al. Weight control and its benefits on fertility in women with obesity and polycystic ovary syndrome. Hum Repro 1997;12 (Suppl 1):82-7.
114. Van Dam, E et al. Increase in daily LH secretion in response to short-term caloric restriction in obese women. Amer Jour Physiol Endocrinol Metab 2001;282:865-72.
115. Ibid., Ring.
116. Palomba, S et al. Structured exercise training programme versus hypocaloric hypperproteinemic diet in obese polycystic ovary syndrome patients with anovulatory infertility: a 24-233k pilot study. Hum Reprod 2008;23:642-50.
117. Bland, J., Introduction to neuroendocrine disorders. Functional Medicine Approaches to Endocrine Disturbances of Aging. Gig Harbor, Washington: The Functional medicine Institute, 2001;p. 121.
118. Kasim Karakas, M et al. Metabolic and endocrine effects of a polyunsaturated fatty acid-rich diet in polycystic ovary syndrome. Jour Clin Endocrinol Metabol 2004;89(2):615-20.
119. Chan, J et al. Water, other fluids, and fatal coronary heart disease. Amer Jour Epidemiol 2002;155(9):827-33.
120. Thys-Jacobs, S et al. Vitamin D and calcium dysregulation in the polycystic ovarian syndrome. Steroids 1999;64(6):430-5.
121. Nestler, J et al. Ovulatory and metabolic effects of d-chiro-inositol in the polycystic ovary syndrome. NEJM 1999;340:1314-20.
122. Baillargeon, J et al. Altered D-chiro-inositol urinary clearance in women with polycystic ovary syndrome. Diabetes Care 2006;29:300-05.
123. Gaby, A., Nutritional Medicine. Concord, NH: Fritz Perlberg Publishing, 2011, pages 829-31.
124. Davis, A et al. Effect of pinitol treatment on insulin action in subjects with insulin resistance. Diabetes Care 2000;23:1000-05.
125. Ibid., Ring.
126. Badawy, A et al. N-acetyl cysteine and clomiphene citrate for induction of ovulation in polycystic ovary syndrome: a cross-over trial. Acta Obstet Gynecol Scand 2007;86:218-22.
127. Rizk, S et al. N-acetyl-cysteine is a novel adjuvant to clomiphene citrate in clomiphene citrate-resistant patients with polycystic ovary syndrome. Fertil Steril 2005;83:367-70.
128. Low Dog, T., The Endocrine System. In Foundations in Herbal Medicine. Albuquerque: Foundations in Herbal Medicine, 2000.
129. Ibid., Mills.
130. McKenna, D et al. Botanical Medicines: The Desk Reference for Major Herbal Supplements. New York: Haworth Press, 2002.
131. Wuttke, W et al. Chaste tree (Vitex agnus castus): pharmacology and clinical indications. Phytomedicine 2003;10:348-57.
132. Westphal, L et al. A nutritional supplement for improving fertility in women: a pilot study. Jour Reprod Med 2004;49:289-93.
133. Westphal, L et al. Double-blind, placebo-controlled study of Fertilityblend: a nutritional supplement for improving fertility in women. Clin Exp Obstet Gynecol 2006;33:205-08.
134. Ibid., Marchese.
135. Pais, P., Potency of a novel saw palmetto ethanol extract, SPET-O85, for inhibition of 5alpha-reductase II. Adv Ther 2010;27(8):555-63.
136. Vassiliandi, D et al. Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome. Jour Clin Endocrinol Metab 2009;94:3558-66.
137. Chrubasik, J et al. A comprehensive review on the stinging nettle effect and efficacy profiles. Part II: urticae radix. Phytomedicine 2007;14(7-8):568-79.
138. Anon. Urtica dioica;Urtica urens (nettle). Monograph Altern Med Rev 2007;12(3):280.
139. Ibid., Marchese.
140. Nagata, C et al. Association of coffee, green tea, and caffeine intakes with serum concentrations of estradiol and sex hormone-binding globulin in premenopausal Japanese women. Nutr Cancer 1998;30(1):21-4.
141. Chan, C et al. Effect of Chinese green tea on weight, and hormonal and biochemical profiles in obese patients with polycystic ovary syndrome: a randomized placebo controlled trial. Jour Soc Gynecol Invdestig 2006;13:63-68.
142. Chan, C et al. Polycystic ovary syndrome—a randomized placebo-controlled trial. Effects of Chinese green tea on weight and hormonal and biochemical profiles in obese patients with PCOS. Jour Soc Gynecol Investig 2006;13(1):63-8.
143. Ibid., Marchese.
144. Amanini, D et al. History of the endocrine effects of licorice. Exp Clin Endo Diabetes 2002;110(6):257-61.
145. Amanini, D et al. Licorice reduces serum testosterone in healthy women. Steroids 2005;69:763-66.
146. Grant, P., t al., Spearmint herbal tea has significant anti-androgen effects in polycystic ovarian syndrome. A randomized controlled trial. Phytother Res 2010;24:186-88.
147. Chen, J et al. Maitake mushroom (Grifola frondosa) extract induces ovulation in patients with polycystic ovary syndrome: a possible monotherapy and a combination therapy after failure with first-line clomiphene citrate. Jour Altern Complement Med 2010;16(12):1295-99.
148. Ibid., Marchese.
149. Yang, H et al. Paeoniflorin: an antihyperlipidemic agent from Paeonia lactiflora. Fitoterapia 2004;7591):45-9.
150. Hsu, F et al. Antihyperglycemic effects of paeoniflorin and S-debenzoylpaeoniflorin, glucosides from the root of Paeonia lactiflora. Planta Medica 1997;63(4):323-25.
151. Takahashi, K et al. Effects of TJ-68 (shakuyaku-kanzo-to) on polycystic ovarian disease. Int Jour Fertil Menopausal Stud 1994;39(2):69-76.
152. Lim, C et al. Current evidence of acupuncture on polycystic ovarian syndrome. Gynecol Endocrinol 2010;26:473-78.
153. Stener-Victorin, E et al. Low-frequency electroacupuncture and physical exercise decrease high muscle sympathetic nerve activity in polycystic ovary syndrome. Amer Jour Physiol 2009;297:R387-R395.
154. Eid, G et al. Effective treatment of polycystic ovarian syndrome with Roux-en Y gastric bypass. Surg Obes Relat Dis 2005;1:77-80.