Obesity, PCOS, and infertility Hartz et al.

(1979) found in a very large study obesity in the teenage years was more common among married women who never became pregnant then for married women who did become pregnant. In the Nurses Health Study studying 2527 married infertile nurses, the risk of ovulatory infertility increased from a RR of 1.3 (1.2-1.6) in the group with a BMI as low as 24 to a rate of 2.7 (2.0-3.7) in women with a BMI over 32 Rich Edwards et al. 1994. In the same year, Grodstein and colleagues (1994) showed that anovulatory infertility in 1880 infertile women and 4023 controls was higher in those with a BMI of > 26.9 (RR 3.1, 2.2-4.4) with a smaller non-significant risk of 1.2 (0.8-1.9) in those with BMI of 25-26. 9. So high normal to slightly overweight levels may have an effect on fertility. Howe et al.1985 Many multifarious women are obese and indeed most obese women are able to get pregnant readily. Initial study of the literature suggests that several excellent investigators have not been able to confirm the adverse effect of weight on reproductive performance. The oxford Family Planning Study did not show any relationship between conception rates and weight or BMI in women stopping contraception, but those women were a selected group of largely parlous subjects. Similar criticism applies to a wellconducted prospective study on fecundity in volunteer women who were followed for 6 months to examine the effect of environmental agent on reproduction. Zaadstra et al. (1993) found that the upper quartile of BMI (33.1) in a group of apparently normal women who were undergoing donor insemination had a reduced chance of pregnancy (OR 0.43). This was a particularly significant study because few of the women required medication to stimulate ovulation.

Balen et al. (1995) in the UK also found that obese women had higher infertility rates. In 204 North American women studied by Green et al. (1988) there was a reduced fertility rate among women with more than 20% of ideal body weight (OR 2.1) this did not apply to women who had previously been pregnant. The literature is therefore quite clear in associating increased body mass with a higher incidence of infertility. Most of the studies do not clearly classify women as having PCOS or normal ovaries but a large percentage of the obese female population are likely to have this condition. Lake et al. (1997) studied a cohort of women born in 1958 and followed up at 7, 11, 16, 23 and 33 years. They showed that weight during childhood did not predict subsequent fecundity but weight at 23 years did predict fecundity if the woman was obese (OR 0.69, 0.56-0.87). Results relating BMI at 33 years were weaker but consistent with those for 23 years. Obese women at 23 years were less likely to become pregnant within 12 months than women of normal weight (infertility rates=obese 33.6% vs. normal weight 18.6%). Lyttleton (2004), also identifies, Phlegm Damp accumulation and Kidney yang deficiency as a possible pattern, but goes on to state that many of those with PCOS now investigated using the wider index (see AES 2006, above) would show few (if any) signs of this pattern, and that in these cases a pattern of Kidney yin deficiency (either congenital or arising from qi Stagnation, or qi and Blood deficiency) may be more apparent. Lyttleton tends to use Western medicine investigative procedures to help inform diagnosis and in the case of PCOS she refers to using LH and FSH ratios as a guide. She believes that a ratio of LH to FSH greater than 2.5 suggests Kidney yang deficiency and Phlegm-Damp accumulation; whilst with a ratio of less than 2, Kidney yin deficiency is suspected. An extensive search has not revealed any

research to substantiate this approach, so one must assume that this is based upon her own clinical experience. Azziz (2006) not only found the Rotterdam 2003 criteria to be insufficient, but also found the same of the earlier diagnostic criteria used, that of the National Institutes of Health (NIH) 1990. In the comparison of the two formats conducted by Hsu et al., (2007), it was found that the NIH criteria only picked up the more severe symptoms, whereas the Rotterdam 2003 criteria picked up those with less severe symptoms, though flaws were still identified. The latest set of criteria used for identification of PCOS is that proposed by the Androgen Excess Society (AES). Called the AES diagnostic criteria, this takes into account the other aforementioned criteria and incorporates certain modifications in response to criticism of the previous two systems (see appendix 1 for comparisons and details) Lee Butler MBAcC, MRCHM BSc (Hons) Traditional Chinese Medicine: Acupuncture MSc Chinese Herbal Medicine Accredited Teacher in HE (SEDA The original criteria used for diagnosis was pathognomonic ovarian findings along with the presence of hirsuitism, obesity and amenorrhea (Lobo & Carmina, 2000). The advent of modern clinical investigative equipment has

subsequently expanded the required diagnostic criteria, though there is still some disagreement over which signs and symptoms have to be present in order to arrive at a firm diagnosis. The luteinizing hormone (LH)/follicle stimulating hormone (FSH) ratio has been used historically to help confirm diagnosis, however later research has found this to be of limited effectiveness (Cho et al., 2006).

General background of polycystic ovary syndrome (PCOS) As early as 1844, Chereau described sclerocystic changes in the human ovary (Chereau 1844). Although occasional reports on this condition continued to appear over the years, more interest was aroused in 1935 when bilateral polycystic ovaries were related by Stein and Leventhal in a clinical syndrome consisting of menstrual irregularity featuring amenorrhea, a history of infertility, masculine type hirsutism and, less consistently, obesity (Stein & Leventhal 1935). The condition was for a long time called the Stein-Leventhal syndrome. In 1958 McArthur and coworkers observed elevated LH levels in women with polycystic ovaries (MacArthur et al. 1958) and the introduction of radioimmunoassays (RIAs) in 1971 stimulated reliance on a biochemical diagnosis. Although it was suspected as early as 1962 that there was a wide variety of clinical presentation of PCOS, the concept of PCOS with normal LH concentrations was not conceived until 1976 (Rebar et al. 1976). The next milestone was the discovery of the association of PCOS and insulin resistance by Kahn and coworkers (Kahn et al. 1976) and Burghen et al. (Burghen et al. 1980). The ultrasonographic finding of polycystic ovaries was described for the first time in 1981 (Swanson et al. 1981). Adams and coworkers introduced a definition for the ultrasonographic appearance of PCO in 1985 as one diagnostic criterion of PCOS (Adams et al. 1985). This has been widely used thereafter, especially in Europe. Diet for POCS Toubro and Astrup 1997 A low fat, moderate protein and high carbohydrate intake diet (30:15:55) with a restricted calories input is the standard recommended diet in most countries. Concomitant exercise is essential

for weight maintenance and contributes to reducing stress and improves the sense of well-being. Weight loss is maintained more effectively and compliance is increased when an ad libitum low fat high carbohydrate dietary pattern is followed over longer periods of time, compared to fixed energy diets. There has also been increased community interest in a dietary protocol advocating a mode rate increase in protein (to approximately 30% of total energy intake) and concomitant reduction in dietary carbohydrates (Skov et al. 1999). Furthermore, altering the type of carbohydrate to produce a lower glycemic response (low glycemic index,(GI) is also proposed to improve satiety and metabolic parameters (Ludwig 2000). Moran ET al.2003 High protein diets range from the medically acceptable 30% protein, 40% carbohydrate, 30% fat to the Atkins-type diet which is much higher in protein (50%) and is high in fat. High protein diets are more likely to reduce ad libitum intake, increase subjective satiety, and decreased hunger compared to high carbohydrate diets. Weight loss may be more substantial in the short term but is no better in other diets in the longer term. The evidence for improved insulin sensitivity with high protein diets is debatable and metabolic improvements are not better in PCOS when caloric intake is matched for low protein diets. Overall it appears as if dietary composition is not a key component of diets for PCOS provide caloric intake is reduce substantially. Ultemately,weight loss will result from a decrease in energy intake are increase in energy expenditure and this should be the key approach. Reasons for weight-related menstrual problems Infertile, anovulatory obese women have higher plasma androgens, insulin, and LH concentrations and lower SHBG levels when compared to normal weight women or obese subjects with regular periods. It is possible that

the increased estrogen production from peripheral tissue leads to a disorder of the hypothalamic-pituitary-ovarian axis. Insulin resistance is common in anovulatory women and together with reduced hepatic clearance of insulin and increased sensitivity of the beta cell to secretory stimuli is thought to be the major cause of hyperinsulinemia. Insulin in turn can induce androgen secretion from an overy that is polycystic or genetically prone to excess androgen production. Current hypotheses suggest that hyperinsulinemia is a result of genetic or environmentally induced insulin resistance from peripheral tissues and this leads to increased androgen production from ovaries that are not resistant to the action of insulin. Reduction of hyperandrogeneia and restoration of reproduction function. This hypothesis is clearly supported by the

experimental observation by a number of investigators. Clark at al. 1995 We have followed women participating in a weight loss program and have shown that return of ovulation coincides with a reduction in insulin resistance and a fall in central adiposity. In a group of anovulatory subject who returned to ovulation with exercise and dietary restraint, waist circumference,central fat, LH, and insulin fell more than in those who remained anovulatory throughout (Buchholz et al. unpublished data).In a less extensive previous study we had shown that fasting insulin was significantly reduced by weight loss in anovulatory women who became ovulatory. While there is convincing evidence that insulin sensitivity can be restored in overweight women with PCOS who loss weight (Holte et al. 1994, 1995, Holte 1996), first phase insulin release remains significantly abnormal indicating an underlying problem in pancreatic secretion in these subjects. Other investigators have disputed his observation. The return to ovulation associated with a reduction in insulin rainforces studies with insulin sensitizing agents such as troglitazone where improved insulin sensitivity without weight loss promotes ovulation and fertility(Dunaif et al. 1996, Ehrmann et al. 1997).

Guzick et al.1994 Luteinizing hormone pulse frequency and amplitude does not appear to alter during weight loss in obese subjects although absolute values of LH do decrease significantly in responders to diet as judged by ovulation. Other factors involved may include androgens, hypothalamic endorphins, and leptin, all of which are increased in anovulatory overweight women. While leptin in increased in obese PCOS subjects, there is no increase over obesity not associated with PCOS and return of ovulation is not associated with a reduction in leptin concentration prior to return of periods. (Galletly et al.1996,a, b) Depression is frequent of women with PCOS and infertility as shown by assessments performed in Adelaide women. Participation in the program was associated with an improvement in well-being and psychological parameters that may indicate restoration of reproductive potential is closely tied in with psychological changes. These may have an effect through the endorphin system and other neurotransmitters in the hypothalamic-pituitary axis. Stress reduction Several studies have shown that women with PCOS are more likely to have a poor quality of life assessment, have eating disorders, and poor selfimage (Jahanfer et al. 1995, Coffey and Mason 2003). Intervention by counseling and reassurance leads to improvement in these parameters and should be part of any program.

Tiangui Fang recipe (TFR) Hou (et al., 2000) (see appendix 1, table 6) 6 out of 8 patients had resumed a normal menstrual cycle and double phase basal body temperature (BBT). There was also reported to be a lowering in serum testosterone, body mass index (BMI), and serum LH. This study was ran alongside a control group who were taking metformin, with this study apparently showing greater efficacy (only two of the metformin group had double phase BBT, and no change in BMI or LH). Analysis showed that TFR was better able to restore a normal menstrual cycle than metformin, however metformin was more effective at lowering insulin levels. Herbal formula Numerous studies have been conducted in Japan and China on the use of herbal formula for the treatment of PCOS. Some of these have been translated into English, though the majority have not. A selection of this research will be discussed below with the original name of the formula discussed in the research followed by the classical Chinese name where appropriate. Herbal formula A clinical study conducted in China (Hua et al., 2003) investigated the approach of Yishen Jianpi Yangxue tongli (translated as Tonify Kidney, strengthen Spleen, nourish Blood, dredge and eliminate) to treat PCOS. This publication illustrates the difficulty for the western researcher who cannot speak/read Chinese. At first glance the abstract appears to relate to a formula. It is only once the article has been translated that one can start to understand the design/rationale of the study. Hua et al., conclude that the formula used for this pattern, an experienced formula from Dr Cai Song Yan (see appendix 2, table 5), was able to improve pregnancy rate and clinical symptoms, especially in clomiphene resistant patients. It was also found to reduce serum levels of luteum hormone and testosterone, and lead to improvement in FerrimanGallway score (a questionnaire designed to measure PCOS symptoms). There

was a pregnancy rate of 65.7% compared to 25% in the control group using CC. Unfortunately there is no detail of the daily dosage or directions given.

Armanini et al., (2007) found in their trial involving 32 women with PCOS, that adding 265mg of gan cao (Radix Glycyrrhizae Uralensis) per day to the drug spironolactonereduced (SP) reduced the side effects of the SP and particularly the prevalence of metrorrhagia. Gan cao is also said ..to possess estrogen-like activity (p.67), which may be of value in treating those with PCOS. Full details were given of dosage and results, and analysis.