Ovulation induction in PCOS
PCOS Patient Handout on Paper
This PDF file which can be downloaded is the same information given in the office to all patients diagnosed with PCOS. It discusses both the classic type of PCOS and the thin woman type. PCOS is one of JFGs particular focuses, and JFG is recognized as a leader in the treatment of PCOS. Thin women with PCOS were once one of the most difficult groups of patients to treat. Now, with a better understanding of PCOS, and new treatment options, some of which were intiated by Dr. Jarrett, most women with this ovulatory issue can anticipate successful conception and pregnancy.
Polycystic ovary syndrome (PCOS) affects about 5% of all American women. PCOS is the most common endocrine abnormality in women of reproductive age, and is the most common cause of female infertility in the United States1. It is the primary cause of ovulatory abnormalities and associated infertility. While many women with PCOS who desire pregnancy will respond to clomiphene or gonadotropin induction of ovulation, a better understanding of the underlying causes of this disorder had opened many new treatment alternatives. Furthermore, because of some of the associated metabolic abnormalities in women with PCOS, treatment of the underlying pathophysiology has become of paramount importance.
There are many ways to define and diagnose PCOS. A recent consensus workshop defined PCOS as:
1. the presence of oligo or anovulation (irregular periods),
2. clinical or biochemical signs of hyperandrogenism (excess male hormone),
3. polycystic ovaries and exclusion of other etiologies.
The ultrasound appearance of PCOS is defined as “Presence of 12 or more follicles in each ovary measuring 2-9mm in diameter, and/or increased ovarian volume (>10 ml).” 2
For reasons which will be detailed later in this paper we feel the definition should be the presence of irregular or absent ovulation in the presence of relative hyperandrogenism.
Relative hyperandrogenism can be diagnosed clinically or with laboratory studies. Many women with PCOS have significant hirsutism (excess hair growth)and the clinical diagnosis is straightforward. Laboratory studies will often confirm the clinical impression, but there is some debate as to the necessity of laboratory confirmation of a clinical or ultrasound based diagnosis of PCOS. Measurement of ovarian androgens (testosterone and androstenedione) will offer reassurance that the hirsutism is not the result of an androgen secreting ovarian tumor. DHEAS (dehydroepiandrosterone sulfate) will assess the adrenal contribution to the hyperandrogenism and rule out an adrenal tumor and 17-OH Progesterone will rule out congenital adrenal hyperplasia due to an enzymatic deficiency. Prolactin and thyroid stimulating hormone (TSH) should be checked in any woman with irregular menses, and mild abnormalities of one or both of these hormones is often detected in women with PCOS. LH and FSH will often be altered in PCOS, with LH levels being higher than FSH.
Suggested laboratory studies in PCOS
17 – hydroxy Progesterone
PCOS ovaries have a characteristic ultrasound appearance, with an increased number of pre-antral follicles. The ultrasound appearance in PCOS is definitive, and coupled with a clinical history of oligo- or anovulatory cycles (and relative hyperandrogenism), is diagnostic of PCOS.
It has been clearly demonstrated that both thin women and obese women with PCOS may be insulin resistant.2 Insulin resistance is a decreased capacity of insulin to stimulate glucose uptake by the cells of target tissues, resulting in increased pancreatic insulin production. Insulin resistance is so uniformly demonstrable in women with PCOS, particularly obese women, that we no longer test for this – insulin resistance is assumed in any individual with PCOS. It is the elevated insulin levels that result in the increased ovarian androgen production that is the hallmark of PCOS.3 While obese women may have more significant degrees of insulin resistance than thin women with PCOS, measurement offers little clinically useful information. Insulin resistance is associated with a significant risk of diabetes and heart disease, particularly in obese women with PCOS in whom the insulin resistance of PCOS is further aggravated by the insulin resistance associated with obesity.
TREATMENT - OBESE WOMEN
Treatment approaches differ significantly for the obese women and for the non-obese individuals with PCOS, and will therefore be discussed separately.
Normalization of insulin levels should be the first goal of treatment in obese women. This is true whether these women desire conception or not, given the dramatic increase in the risk of diabetes and heart disease these individuals face if the insulin resistance and resulting hyperinsulinemia are not addressed.
Metformin is clearly of value and is prescribed for all obese women with PCOS who can tolerate this medication. For obese women, the XR form of metformin is usually well tolerated, and dosages should be gradually increased until a total daily dose of 2000mg is achieved. This can be administered all at one time with dinner, or in divided doses of 1000mg twice a day. Metformin functions by improving peripheral insulin sensitivity and decreasing hepatic glucose production, thereby lowering glucose levels and decreasing insulin levels. Almost all studies of the effect of metformin have demonstrated that it improves cycle regularity and enhances conception rates.1, 4
Weight loss has been clearly demonstrated to be of value. Because of the insulin resistance, weight loss for women with PCOS is often extremely difficult if not impossible. We have found that a low amylose diet, as originally described by Dr. Ritchie Shoemaker, works extremely well for these individuals. This diet eliminates all simple (and virtually all complex) carbohydrates. This not only dramatically decreases insulin levels but when coupled with the use of metformin results in significant weight loss, often as much as ten pounds a month. The incorporation of a regular exercise routine results in even further improvement.
After at least three months of treatment with metformin, diet, and exercise, many obese women with PCOS will resume normal, ovulatory cycles and require no further intervention, even if pregnancy is the goal. For some, ovulatory function is improved but not quite normalized and for these women addition of small doses of clomiphene is often all that is required. For those who do not wish to conceive, use of oral contraceptives offers many advantages, including further suppression of the abnormal ovarian androgen production.
Rosiglitazone and pioglitazone have also been used to treat obese PCOS patients. They are, however, more expensive and not associated with the degree of weight loss seen with the use of metformin. We therefore have limited experience with their use and reserve it for those individuals who do not tolerate metformin.
TREATMENT - NON-OBESE WOMEN
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 months 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 performed 108 ovarian diathermy procedures. 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 was 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 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 letrozole and FSH is the most efficacious approach. Adequate endometrial development can be anticipated without risking the potentially excessive response encountered when using FSH alone.
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