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Insulin resistance in non-obese women with PCOS is much less dramatic than that seen in obese women. Metformin is still, however, a very important component of the treatment. This was first demonstrated by Dr. Jean-Patrice Baillargeon5, who found that up to 90% of thin women with PCOS ovulated in the six month after initiating metformin treatment. The direct effect of metformin on steroidogenesis by ovarian tissue seems to account for this effect. It has been shown in in-vitro culture that metformin has a significant inhibitory effect on androgen production by ovarian cells.6 Thin women usually do best with regular metformin 500 mg up to three times per day.
Weight loss is obviously not advised for this group of women, and they must in fact be cautioned about the weight loss often associated with the use of metformin.
While many women with PCOS will respond to metformin, a significant subset will not. These women present a particular challenge. Clomiphene, which is the treatment of choice for normalization of ovulation in obese PCOS women, is difficult to use in thin women. Clomiphene is an anti-estrogen, and the anti-estrogenic properties of clomiphene often result in inadequate endometrial development as documented by mid-cycle ultrasound. We have observed that the use of clomiphene in this particular group of women in associated with an extremely low probability of conception. The use of gonadotropins is also difficult in this group – ovarian hyper-responsivity is typical with the attendant risks of multiple pregnancy and ovarian hyperstimulation.
In 1998 we treated the first of this group of women with ovarian diathermy. Ovarian diathermy, a procedure first described by Gjönnaess7, involves the cauterization of ovarian stromal tissue using unipolar cautery. This procedure differs significantly from other laparoscopic procedures such as ovarian drilling in that diathermy does not involve destruction of any of the cortical part of the ovary. It is rather, the stromal part of the ovary that produces the excess testosterone and androstenedione that result in PCOS and diathermy results in dramatic reductions in levels of both of these hormones8 and normalization of cycles in a significant percentage of patients.
Between 8/98 and 7/03 we have performed 108 ovarian diathermy procedures. (Data under preparation for submission for publication.) Diathermy was performed at the time of laparoscopy. The pelvis was filled with an irrigation solution of lactated Ringer’s with 5,000 units of heparin per liter. The ovary was immobilized using an atraumatic grasping forceps and the Corson needle (Karl Storz Endoscopy- America, Inc. Culver City, CA. cat # 30677CN ) introduced into the ovary at a right angle to the ovarian cortex. The Corson needle has a diameter of only 1mm. The tip of the needle protrudes 10mm beyond the insulation that covers the remainder of the needle. Cautery is performed to a depth of 15mm with a monopolar coagulating current set at 40-W for five seconds at each of three to as many as eight sites. This cauterizes the stroma without affecting the ovarian cortex. Any other pathology encountered such as endometriosis or adhesions was treated and chromotubation was performed.
Of these, 74 women had a Body Mass Index of 25 or less (thereby meeting the definition of thin woman PCOS) and were 38 years of age or younger at the time of the procedure. This if the first reported series of this nature. Of these, 59 patients desired conception and were available for follow-up. They had a mean duration of infertility of 3.7 years and a mean body mass index of 23.9. 49 (83%) of these patients have conceived with a mean time to conception of 4.2 months. Most of these conceptions have occurred without further intervention, although 11 of these women conceived with the subsequent use of clomiphene/FSH for IUI and three conceived through IVF because of male factor issues. None of these women experienced hyperstimulation. There have been no post-operative complications and there have been no cases of ovarian failure.
One of the serious concerns about surgical treatment of PCOS is the risk of adhesion development. This is much more of a concern with procedures that destroy cortical tissue such as ovarian drilling than it is with ovarian diathermy. We have performed 10 repeat procedures, all of these in individuals who conceived following the initial procedure and then had recurrence of their oligo-/anovulatory pattern.
There have been no adhesions in any patient. In another study of 20 repeat procedures8 no adhesions were noted. Many thin women with PCOS do not have elevated androgen levels as usually defined. It has been estimated that as many as 20% of patients with PCOS have normal androgen levels.9 We found this to be true in our patient population and have in fact observed that many of these women were, at one point, very thin and frequently athletic. It has, in fact, been hypothesized that the relative hyperandrogenicity of these young women may account for some of their athletic ability10.
We believe they experience relative hyperandrogenicity at this point. Their androgen levels are not really increased but their estrogen levels may actually be lower than normal owing to the low percent body fat (an important source of estrogen production). The ovaries continue to function, demonstrated by persistent menstrual cycles, in all but a very small percentage of these women. But in the absence of estrogen production from peripheral fat cells, the environment is actually relatively hyperandrogenic.
And it has been demonstrated that even brief exposure to elevated androgen levels can set up a “self-propagating cycle of abnormal follicular growth and function”11. We hypothesize that this relative hyperandrogenism sets the stage – that the pattern of PCOS is set up in these thin women at a young age and this pattern persists into adulthood even in the absence of demonstrably elevated androgen levels at that time.
It has been demonstrated that ovaries from women with PCOS have fewer healthy primordial follicles than do normal ovaries with their growth arrested when they are between 5 and 8 mm in diameter10. This abnormal development is due to the relative excess of the ovarian androgens. And fewer healthy follicles develop in spite of a significantly greater density of follicles per mm3 in PCOS than is seen in normal ovaries.10
These two facts explain why women with PCOS have a much greater risk of ovarian hyperstimulation and lower success rates when undergoing, for example, IVF (In Vitro Fertilization). Correction of insulin status, with medical treatment and/or surgical intervention, is crucial prior to the use of gonadotropins in these women to ensuring safe, successful, and cost-effective procedures, be it simple ovulation induction and insemination or IVF. Ovarian diathermy has been shown to significantly improve pregnancy rates in POCS women undergoing IVF13.
Reduction of ovarian androgen production not only improves ovulation and pregnancy rates, but also reduces spontaneous abortion rates. The high loss rate experienced by women with PCOS is partly due to compromised oocyte quality, but may also be due to the compromised uterine perfusion that occurs as a result of elevated androgen levels12. Correction of androgen status clearly results in a decrease in the spontaneous abortion rate in these individuals.
In conclusion, PCOS is tremendously more treatable than ever before, owing to medical treatment with metformin and surgical treatment with ovarian diathermy. Correction of the underlying insulin abnormalities, particularly in the obese individuals with PCOS is of paramount importance whether or not conception is desired. Decreasing ovarian androgen production allows many women to conceive without further intervention. If further intervention is required, these women will experience a better chance of success with less risk than ever before.
A note about the algorithms: Our experience suggests that, if individuals who have undergone the full gamut of treatment for PCOS still require ovulation induction, the combination of clomiphene and FSH is the most efficacious approach. The anti-estrogenic properties of clomiphene are offset by the estrogenic properties of FSH. Adequate endometrial development can be anticipated without risking the potentially excessive response encountered when using FSH alone.
Click here for an additional (free) PDF Handout on PCOS:
http://www.jarrettfertility.com/PCOS...%20handout.pdf
1. Nestler JE, Stovall D, Akhter N, Iuomo MJ, Jakubowic DJ. Strategies for the use of insulin-sensitizing drugs to treat infertility in women with polycystic ovary syndrome. Fertil Steril 2002;77:209-215.
2. The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2005;81:19-25.
3. Dunaif A, Segal KR, Futterwait W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 1989;38:1165-74.
4. Azzizz R. Androgen excess if the key element in polycystic ovary syndrome. Fertil Steril 2002;80:252-254.
5. Barbieri, RL. Metformin for the Treatment of Polycystic Ovary Syndrome. Obstet Gynecol 2003;101:785-93.
5. Baillargeon J-P. Oral presentation. The Endocrine Society. San Francisco, 2002.
6. Mansfield R, Galea R, Brincat M, Hole D, Mason H. Metformin has direct effects on human ovarian steroidogenesis. Fertil Steril 2003;79, 956-62.
7. Gjonnaess H. Polycystic ovarian syndrome treated by ovarian electrocautery through the laparoscope. Fertil Steril 1984;41:20.
8. Amer SAK, Li T-C, Coole ID. Repeated laparoscopic ovarian diathermy is effective in women with anovulatory infertility due to polycystic ovary syndrome. Fertil Steril 2003;79:1211-5.
9. Knochenhauer ES, Sanchez LA, Azziz R. The different phenotypes of the polycystic ovary syndrome (PCOS) [abstract]. Fertil Steril 2001;76:S208.
10. Rickenlund A, Carlström K, Ekblom B, Brismar TB, von Schoultz B, Hirschberg AL. Hyperandrogenicity is an alternative mechanism underlying oligomenorrhea or amenorrhea in female athletes and may improve physical performance. Fertil Steril 2003;79:947-55.
11. Webber LJ, Stubbs S, Stark J, Trew GH, Margara R, Hardy K, Franks S. Formation and early development of follicles in the polycystic ovary. The Lancet 2003;362:1017-21.
12. Ajoss S, Guerriero S, Paoletti AM, Orrừ M, Melis, GB. The antiandrogenic effect of flutamide improves uterine perfusion in women with polycystic ovary syndrome. Fertil Steril 2002;77:1136-40.
13. Colacurci N, Zullo F, De Franciscis P, Mollo A, De Placido G. In vitro fertilization following laparoscopic ovarian diathermy in patients with polycystic ovarian syndrome. Acta Obstet Gynecol Scand 1997;76:555-558.
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Pcos Treatment - Non-obese Women 
