Edward Lichten, M.D.,PC
POLYCYSTIC OVARIAN DISEASE is a constellation of symptoms first described by Stein and Leventhal in 1935. They noted amenorrhea (no menstruation), hirsuitism (increased facial and body hair), and obesity associated with enlarged ovaries. The ovary, with multiple cysts just below the surface, is described as "polycystic." Although this is a common condition occurring in approximately 7% of women of reproductive age, the present concept is that this represents a number of different medical conditions: some genetic, some induced by natural production of androgens from the ovaries and/ or the adrenals, some with a defect in testosterone to estrogen conversion and some with an excess of testosterone to dihydrotestosterone metabolism. The use of testosterone in women will, over time, produce a picture identical to polycystic ovarian disease (PCO).
Hyperandrogenism (elevated testosterone) and a lack of ovulation (no menses) are necessary for the diagnosis of PCO. These two biological events occur with other endocrine dysfunction include: Cushing's syndrome, thyroid disease, simple obesity, ovarian or adrenal tumors and significant hyperprolatinemia (high prolactin). However, these conditions, for the most part lack an elevated LH (luteinizing hormone) assay. Endocrinologist may measure the bioavailable LH to make this diagnosis.
POLYCYSTIC OVARIAN DISEASE is a frequent cause of infertility. The original treatment by Stein and Leventhal was the wedge resection of the ovaries. This involved cutting out a triangular piece of the surface of the ovaries and closing the defect with absorbable suture. This was the standard of care for almost 50 years. However, the last 20 years has seen a shift to the use of clomiphene to trigger ovulation chemically. When clomiphene is not successful (50- 70% of the time), infertility experts will add GnRH agonists (Synarel, Lupron) to suppress the elevated LH. As most of these women produce normal estrogen and testosterone levels, it is the failure to produce normal levels of sex hormone binding globulin that may be a consistent finding in PCO. These women show the signs of both excessive estrogen (no ovulation) and excessive testosterone (facial and body hair) because the bioavailable estrogen and testosterone levels are elevated (not bound to SHBG). Lobo (1982) pointed out that although the total serum estradiol levels were normal the low SHBG resulted in increased estradiol and estrone free in the serum. Mishell concludes in his textbook, Infertilty, Contraception and Reproductive Biology, 1991, that "ovarian changes may influence hypothalamic-pituitary hormonal secretion and that "normalization" of LH secretion may occur after ovulatory ovarian function." In other words, getting pregnant and ovulating corrects PCO.
HYPERANDROGENISM: Increased signs of testosterone; i.e. body and facial hair.
Testosterone primarily serves as a marker of ovarian production while DHEA-sulfate marks elevated adrenal production. The origin of the androgen is not as significant as the combination response with elevated insulin and obesity.
What then is the 'problem' with the polycystic ovary? GF Erikson showed that the ovaries are exactly the same but are missing the normal FSH response. What is therefore apparent is that the increase in DHEA under adrenal stress, the drop in FSH, the increase in LH, the decrease in sex hormone binding globulin and the resultant increase in bio-available testosterone form a perpetuating circle of disease that is only broken by ovulation and pregnancy.
What other measures might be helpful for these individuals? Lemieux in 1999 described his findings after laparoscopic ovarian drilling. History tells us that Stein and Leventhal resected one-third of the ovary in these individuals with subsequent successful pregnancy and reversal of the hirsuitism and obesity. Lemieux used the technique of Dan Martin, M.D., to drill holes into the ovary, thereby, destroying some of the cortex surface. Lemieux reported afterwards a significant decrease in the woman's androgens: androstenedione, testosterone and free testosterone. However, there was no change in the insulin resistance now recognized as part of the PCO syndrome.
Many patients with polycystic ovaries are moderately obese. It has been suggested by some authors that treatment with Metformin (Glucophage) should be started to reduce the insulin levels. As I agree that weight loss is a primary factor in PCO, I agree with this therapy. However, I believe that the treatment of obesity with weight loss is primary. Should the individual lose weight, the polycystic ovarian syndrome- insulin resistance should disappear.
Acien in 1999 confirmed this idea. He stated that there was no difference in insulin resistance between PCO patients and obese patient at comparible weights. Patients were clearly with or without insulin resistance and with and without obesity. For example,he went further to state that "slim women with PCOS had insulin and metabolic variables similar to those without PCOS". Obese patients with PCOS were both insulin resistant and hyperandrogenic.
The primary treatment for increased androgenicity is first, aldosterone (Spirolactone). This mild diuretic can block the conversion of testosterone to potent di-hydrotestosterone. For many of my patients, this alone has been helpful. Secondly, treatment with a progesterone dominant oral contraceptive, or Depo-provera or Megace, suppresses both the ovarian and adrenal androgen production. Micronor may be initially preferred because it causes little or no weight gain.
Lastly, weight loss is extremely important. A carbohydrate restricted diet, exercise program and a supportive weight-loss program and physician are most helpful. Diet medication may be used for a short period of time to encourage compliance. Rarely have we used Metformin because the above treatments and ovarian drilling are usually successful.
Newer discoveries such as DeLeo's report this month show the close interreaction of growth hormone, insulin like growth factor-1 with the testosterone production of the ovary. He reported that Metformin caused a drop in insulin resistance which improved the sexc hormone binding globulin and thereafter lowered the testosterone by 20%.
Polycystic ovarian disease is a multi-faceted disorder with a multitude of contributing hormonal factors. The comprehensive understanding of DHEA, DHEA-S, testosterone, sex hormone binding globulin, FSH, LH, estradiol and the bio-available state free hormones with insulin makes this a most challenging gynecological, surgical and medical disorder.
1. Lemieux S, Lewis GF, Ben-Chetrit A, Steiner G, Greenblat EM. Department of Medicine and Physiology, University of Toronto, Ontario, Canada. Correction of hyperandrogenemia by laparoscopic ovarian cauterization in women with polycystic ovarian syndrome is not accompanied by improved insulin sensitivity or lipid- lipoprotein levels. Journal of Clinical Endocrinology and Metabolism. 1999; 84(11): 4278-82
2. Acien P, Quereda F, Malattin P, Villarroya E, et al. Insulin, androgens, and obesity in women with and without polycystic ovary syndrome: a heterogeneous group of disorders. Fertility and Sterility. 1999;72(1):32-40
3. De Leo V, la Marca A, Orvieto R, Morgante G. Effect of Metformin on Insulin-like Growth Factor (IGF-1) and IGF-binding Protein I in Polycystic Ovary Snydrome. Journal of clinical Endocrinology and Metabolism. 2000; 85(4): 1598-1600
multiple, cystic ovaries