NEW YORK—A particular form of hyperinsulinemia underlies the hyperandrogenism that drives polycystic ovary syndrome (PCOS). Nutritional strategies that normalize insulin levels can greatly benefit women with this disorder, said Alan Gaby, MD, at the annual meeting of the New York Association of Naturopathic Physicians.
Diet and exercise aimed at weight loss may help some women with PCOS if they’re obese. In some cases, weight loss leads to lower androgen levels and restored ovulation. But many PCOS patients are not obese, and even among those who are, weight loss does not always normalize insulin–glucose metabolism. “The insulin resistance seen in women with PCOS is unique … in that it occurs largely independently of body weight and is not always corrected by weight loss,” said Dr. Gaby.
Targeted use of specific nutrients including vitamin D, chromium, D-chiro-inositol, pinitol and n-acetyl cysteine (NAC) can help many women with PCOS, often obviating the need for metformin or other drug therapies.
Vitamin D
Vitamin D deficiency is common in PCOS patients, as it is in people with type 2 diabetes (see related article from the current issue on our website, www.holisticprimarycare.net: Can Vitamin D & Calcium Reduce Diabetes Risk?), and contributes to the biochemical abnormalities associated with PCOS, said Dr. Gaby. In one small sample of 13 women with PCOS, 5 were frankly deficient, with serum 25-hydroxy vitamin D levels below 9 ng/ml. Three others had borderline levels.
In this study, all 13 were treated with vitamin D2 at a dose of 50,000 IU once or twice weekly, until they reached serum levels of 40–40 ng/ml. They also took 1,500 mg of supplemental calcium. Of the 9 who were amenorrheic or oligomenorrheic prior to the study, 7 had normalized menstrual cycling within 2 months; the other two were pregnant within several months. Two patients who’d had dysfunctional uterine bleeding at the outset experienced complete resolution while taking the vitamin (Thys-Jacobs S, et al. Steroids. 1999; 64: 430–435).
Dr. Gaby noted that vitamin D3, the more common form of vitamin D used supplement products and also the form produced endogenously by the skin following sun exposure, is nine times more potent than D2, which was used in the Thys-Jacobs study. Consequently, when using D3 to treat a woman with PCOS, one can usually obtain good response at doses of 800–1,200 IU per day, though up to 2,000 IU per day is generally considered safe for long term use. He also recommended giving vitamin D in relatively small daily doses rather than in mega-doses given once or twice weekly.
Vitamin D deficiency is strongly associated with higher cardiovascular risk, as shown in a new study by Thomas Wang, MD, and colleagues of Massachusetts General Hospital (see related article from the current issue on our website, www.holisticprimarycare.net: D, C and CVD: New Studies Correlate Deficiencies With Cardiovascular Risk). So increasing vitamin D intake may mitigate heart disease risk associated with insulin resistance.
Chromium
This trace mineral potentiates insulin action, and there are several trials showing that it improves glycemic control in people with type 2 diabetes, gestational diabetes, and diabetes associated with glucocorticoid therapies.
In the PCOS context, there are three published studies. In the first, a small pilot trial, researchers at Stony Brook University Hospital, New York, treated three women with PCOS with 1,000 mcg per day of chromium picolinate for two months. It improved insulin sensitivity by 30%, as measured by euglycemic–hyperinsulinemic clamp. One of the three patients resumed normal menstruation (Lydic ML, et al. Fertil Steril. 2003; 80(Suppl. 3): S45–S46).
The Stony Brook team then studied a second series of five patients, also treated with 1,000 mcg per day of chromium picolinate, and found a mean 38% increase in glucose disposal rate (Lydic ML, et al. Fertil Steril. 2006; 86: 243–246).
Researchers at the University of Texas Health Science Center, San Antonio tested a daily dose of chromium picolinate, 200 mcg/d, in a small group of PCOS patients and found that while it significantly decreased 1- and 2-hour plasma glucose levels following glucose tolerance testing, it had no overall effect on insulin resistance, ovulation or hormone levels (Lucidi RS, et al. Fertil Steril. 2005; 84: 1755–1757). While chromium is certainly not a cure-all for PCOS, it is worth a try, as it has no significant adverse effects, said Dr. Gaby.
N-Acetyl Cysteine
This nutrient, a form of the amino acid cysteine, seems to increase ovulation and pregnancy rates in women with PCOS who do not respond to clomiphene citrate alone. Investigators at the University of Benha, Egypt, randomized 150 overweight or obese infertile women with PCOS and unable to ovulate despite clomiphene therapy, to treatment with either 600 mg NAC twice daily, or placebo. All patients continued on clomiphene, at a standard dose of 100 mg per day.
The group taking NAC had an ovulation rate of 49% versus 1% in those getting placebos; the pregnancy rates were 21% versus 0%, a very clear benefit in terms of improving fertility. The investigators saw nothing suggestive of ovarian hyperstimulation in the women taking NAC, though there were two miscarriages among those who got pregnant (Rizk AY, et al. Fertil Steril. 2005; 83: 367–370).
NAC also improves insulin sensitivity in women with PCOS who also have impaired insulin sensitivity, but not in those who have more or less normal insulin sensitivity. This was shown in a study involving 39 women at the department of obstetrics and gynecology, Universita Cattolica del Sacro Cuore, Rome.
Researchers tested NAC at a dose of 1.8 grams per day for those with body mass indices of 30 kg/m2 or less and 3 grams per day for those over 30 kg/m2. Those with impaired sensitivity at baseline were clearly more responsive to insulin after 5–6 weeks of supplementation; those with normal baseline sensitivity showed no change (Fulghesu AM, et al. Fertil Steril. 2002; 77: 1128–1135).
“Additional research is needed to determine the long-term safety and efficacy of NAC for women with PCOS,” said Dr. Gaby. “But it seems clear that short term adminstration of NAC as an adjunct to clomiphene citrate is promising for treatment of resistant infertility.”
D-chiro-Inositol & Pinitol
One of the strongest androgen-lowering effects ever documented in women with PCOS comes from a relatively unknown nutrient called D-chiro-inositol, a stereoisomer of myo-inositol normally produced in the body, and found in some legumes and other foods. Dr. Gaby noted that the insulin resistance seen in PCOS women might be due, in part, to a deficiency of an endogenous insulin-mediating phosphoglycan that contains D-chiro-inositol.
Researchers at Virginia Commonwealth University randomized 44 obese women with PCOS to receive either placebo or 1,200 mg of D-chiro-inositol daily for eight weeks. Those taking D-chiro-inositol had a marked increase in insulin sensitivity, as well as a 55% reduction in mean serum free testosterone. This translated directly into functional improvements; 86% of the inositol-treated women were ovulating at the end of the study, compared with only 27% of those on placebo (Nestler JE, et al. N Engl J Med. 1999; 340: 1314–1320).
Unfortunately, there are no commercially available preparations of D-chiro-inositol in the US. But it is possible to obtain D-pinitol, which is 3-O-methyl-D-chiro-inositol, a compound with similar chemical structure and behavior, said Dr. Gaby. Legumes and citrus fruits contain pinitol.
“Pinitol is probably converted to D-chiro-inositol in vivo, as demonstrated by a 14-fold increase in the mean serum concentration of D-chiro-inositol after administration of pinitol to diabetic patients,” he added, citing a study by Davis and colleagues in Diabetes Care, several years ago. At a dose of 600 mg, twice daily, pinitol produced significant improvements in insulin sensitivity after 3 months of treatment (Kim JI, et al. Eur J Clin Nutr. 2005; 59: 456–458).
“While pinitol has not been studied in women with PCOS, it would presumably be beneficial if it exerted the same effect on the insulin resistance of PCOS as it does on the insulin resistance of type 2 diabetes,” Dr. Gaby said. Pinitol is available from a number of practitioner-level nutraceutical companies, including Vital Nutrients (www.vitalnutrients.net).
Thyroid Dysfunction & PCOS
Given the interconnections between endocrine organs, it is not surprising that thyroid issues often play a role in PCOS. There seems to be an overlap between hypothyroidism and PCOS; this was discovered many years ago, but it often goes unrecognized clinically. In a 1983 study of 12 pre- and early-adolescent girls with severe hypothyroidism, 9 of 12 showed polycystic ovaries on pelvic ultrasound. Thyroid replacement therapy resulted in a rapid disappearance of the cysts, and this correlated with reduced plasma levels of leutinizing hormone (Lindsay AN, et al. Obstet Gynecol. 1983; 61: 433–437).
More recently, McNamara and colleagues found a three-fold increased prevalence of thyroiditis in women with PCOS. They studied 175 women with PCOS, 27% of whom had elevated thyroid peroxidase or thyroglobulin antibodies, strongly suggesting autoimmune thyroiditis; 42% had hypoechoic findings on thyroid ultrasonography.
Dr. Gaby stressed the importance of considering thyroid function in all patients with PCOS, and of looking at thyroid antibody status, “when considering empirical treatment with thyroid hormone.”
Dr. Gaby is leading the comprehensive Nutritional Therapy in Medical Practice seminar from March 28–30, at the Ramada Hotel & Conference Centre, Toronto–Don Valley. For more information, visit www.integrativehealthseminars.com or email Dr. Gaby directly at drgaby@earthlink.net.
