Impact of Obesity on Ovulatory Functions in Polycystic Ovarian Syndrome

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1 Med. J. Cairo Univ., Vol. 81, No. 1, December: , Impact of Obesity on Ovulatory Functions in Polycystic Ovarian Syndrome AHMED AL-SAWAF, M.D. and EMAN A. HUSSEIN, M.D. The Department of Obstetrics and Gynecology, Faculty of Medicine, Cairo University Abstract Background: Indeed the impact of obesity on female infertility is a topic of increasing importance in modern gynecological practice and extensive research is needed to reach well defined guidelines. In this current work the effect of obesity on ovulatory functions in pco was evaluated in 80 PCO patients attending the infertility outpatient clinic of Kasr Al-Aini Hospital. Patients and Methods: 80 PCO patients were selected according a restricted inclusion and exclusion criteria from Kasr Al-Aini infertility clinic in the period from July 2011 to March 2012, then divided into three groups according to BMI; Group (A) 38 patients with BMI <30Kg/m 2, Group (B) 24 patients with BMI 30-35kg/m 2, Group (C) 18 patients with BMI 35-40kg/m 2. Ovulatory function in the three groups was evaluated by folliculometry and day 21 progesterone. Basal hormonal profile on day 2 of the cycle (FSH, LH, E2, PRL and TSH) was also evaluated and statistically analyzed. Results: The results showed significant difference in the level of basal LH and prolactin (p-value <0.05) between the three groups; there was an inverse correlation between obesity and basal LH. PRL level was also significantly higher in the non obese groups. There was no significant difference in the level of basal FSH, E2 nor TSH. As regards to ovulatory functions; non obese group showed better ovulatory performance especially when monitored by day 21 progesterone (18.4% compared to 5.5% in the morbidly obese group). Conclusion: Obesity in PCO seems to increases the risk for anovulation most probably through the disruption of HPO axis by hyperandrogenism, and/or insulin resistance. Leptin may play a role through its direct effect on folliculogenesis. Weight reduction in PCO may improve ovulatory performance. Monitoring ovulation by folliculometry alone may not reflect accurate ovarian response and addition of day 21 progesterone should be considered to improve evaluation. Further studies and RCTs are needed to justify this conclusion. Key Words: Obesity PCO Hormonal profile Follicular maturation. Correspondence to: Dr. Ahmed Hussein Al Sawaf, hsawaf40@yahoo.com Introduction OBESITY is thought to result from a combination of environmental and genetic factors [1]. There are several methods for estimating body fat in adults; these include total body weight, waist circumference and hip circumference. Several indices of obesity have been derived from these measurements, including body mass index (BMI). BMI is the most widely used index of body fat in relation to body weight and height [2]. According to the WHO classification of obesity, increased BMI over 35, could be associated with serious health risks [1]. Obesity affects fertility through the presence of functional hyperandrogenism, hyperinsulinaemia and insulin resistant state, leading to increased free androgen availability, alterations of granulosa cell functions and follicular development [3]. Many studies have shown that many women with polycystic ovarian syndrome PCOS (between 38% and 88%) are overweight or obese [4]. Obesity is suggested to play a specific pathophysiological role in the development of PCOS [5]. The clinical features of PCOS are heterogenous and may change throughout the lifespan, starting from adolescence to post-menopausal age [3]. Many definitions were used to describe PCO syndrome, however, the most commonly used in clinical practice is the ROTERDAM CRITERIA which was used in the current study. In 2003 in Rotterdam, Netherlands, a consensus meeting between the European Society of Human Reproduction and Embryology and the American Society for Reproductive Medicine (ESHRE/ASRM) The Rotterdam ESHRE/ASRM Consensus Workshop defined PCOS; Affected individuals must have two out of the following three criteria: 1- Oligo- and/or ano- 983

2 984 Impact of Obesity on Ovulatory Functions in Polycystic Ovarian Syndrome vulation, 2- Hyperandrogenism (clinical and/or biochemical), and 3- Polycystic ovaries on sonographic examination with one ovary being sufficient for diagnosis [6]. Several studies have demonstrated higher rates of in-vitro fertilization IVF cycle cancellation prior to oocyte retrieval in overweight and obese women especially obese PCO [7-9]. A higher cancellation rate of 25.3% was found in the morbidly obese group compared to 10.8% in the normal weight and overweight women [10]. The precise mechanisms for increased gonadotrophins requirements and higher cancellation rate in obese women undergoing IVF remain unclear. However it has been suggested that abnormal LH and FSH levels may result in impaired ovarian response and decreased folicular maturation in this population [9]. Indeed the impact of obesity on female infertility is a topic of increasing importance in modern gynecological practice and extensive research is needed to reach well defined guidelines. In this current work the effect of obesity on ovulatory functions in pco was evaluated in 3 groups of women attending the infertility outpatient clinic of Kasr Al-Aini Hospital: (Group A: BMI <30kg/ m 2, Group B: BMI between kg/m 2, Group C: BMI between 35-40kg/m). Patients and Methods Place: Kasr AL-Aini infertility Outpatient Clinic, Cairo University, Egypt. Design: This is a prospective comparative study carried out on 80 PCO patients who underwent foliculometry and hormonal profile to assess their ovulation in the period from July 2011 to March 2012 at Kasr Al-Aini Infertility Outpatient Clinic. Inclusion criteria: Age group: years old. Parity: Variable. PCO patient according to Roterdam criteria. Agreement for participation in the study. Exclusion criteria: Age: <20 years and >35 years old. Any history of diseases that may affect ovulatory functions as thyroid, hepatic or renal problems problems. Patients who had previous operations on the ovary as cases with ovarian drilling. Written consents were taken from all cases according to the code of clinical research ethics of Kasr Al-Aini Hospitals. Methods: All participants were subjected to the following: - Full history taking with special emphasis on; age, parity, recent medications with specialy drugs that may affect ovulatory functions and special habits of medical importance e.g. smoking. - Full clinical examination including weight, height and BMI which was calculated as weight (in kilograms) divided by the height in meters squared [1]. Patients were divided into 3 groups according to BMI: Group A: 38 cases with BMI<30kg/m 2. Group B: 24 cases with BMI between 30 and 35kg/m 2. Group C: 18 cases with BMI between: 35 and 40kg/m 2. All participants were given induction of ovulation by clmiphene citrate 50mg twice daily for 5 days on day 2 or 3. Metformin 500mg tds was also given for one month. Ovulation was monitored in the 3 groups by serial songraphy (Toshiba Famio 5 6MHz) starting from day 9 or 10 and serum progesterone day 21. Ovulation was positive when the follicle size reached 16mm or more (16-21 mm) or day 21 progesterone exceeded 12ng/ml. Basal hormones (FSH, LH, E2, PRL and TSH) were also evaluated in the 3 groups and statistically analysed using computer programs Microsoft Excel version 7 (Microsoft corporation, NY, USA) and SPSS (Statistical package for the social science; SPSS Inc., Chicago, IL, USA) version 15 for Microsoft Windows. Statistical analysis of the data: The results were analyzed by ANOVA. Results The demographic data of the cases included in the study is presented in Table (1). It is evident that there is no significant difference between the three groups regarding their age or parity.

3 Ahmed Al-Saw af & Eman A. Hussein 985 Table (1): Age (years) and parity of the the three groups of patients classified according to BMI. BMI >30 38 patients BMI= patients BMI= patients p-value * Significance Age: Mean SD NS SE Parity: Mean SD I70 NS SE The basal hormonal profile on day 2 of the cycle is shown in Table (2). The results showed significant difference in the level of basal LH and prolactin (p-value <0.05). No significant difference was observed regarding basal FSH, E2 nor TSH (p-value >0.05). Table (2): Basal hormonal profile on day 2 of the cycle of FSH, LH, E2, PRL and TSH in the three groups of patient with different BMI. BMI >30 38 patients BMI= patients BMI= patients p-value* Significance FSH: Mean SD NS SE LH: Mean SD S SE E2: Mean SD NS SE PRL: Mean SD S SE TSH: Mean SD NS SE Upon studying ovulation in the three groups of patients with different BMI (Table 3), it was found that ovulation was better in the non obese group, however, this result did not show a statistical significance (p-value >0.05). Upon studying ovulation by day 21 progesterone (Table 4), it was obvious that ovulation was better in the non obese groups and this result was statistically significant. Table (3): U/S evidence of ovulation in the three groups according to follicular size. No Ovulation Yes Total p-value Groups: (23.6%) (20.8%) 24 > (22.2%) 18 Total ( 22.5%) 80

4 986 Impact of Obesity on Ovulatory Functions in Polycystic Ovarian Syndrome Table (4): U/S evidence of ovulation according to day 21 progesterone No Ovulation Yes Total p-value Groups: (18.42%) (16.66%) 24 > (5.55%) 18 Total (15%) 80 Discussion Most of the studies about obesity and infertility have been controversial and this may be attributed to a vast array of factors such as type of the study, sample size, variation in methodology and statistical analysis [11]. The present study was carried on 80 patients attending the infertility outpatient clinic of Kasr Al-Aini Hospitals. They were divided according to their BMI into three groups: First with BMI <30, second with BMI=30-35 and third group with BMI= Regarding the patient demographic data, there was no significant difference among the three groups included for their age and parity i.e. patients were matched as regards to age and parity. Regarding the basal hormonal profile, there was no significant difference in the levels of day 2 FSH, E2 nor TSH between the three groups, but there was a statistically significant increase regarding day 2 LH and PRL in the non obese group having BMI>30. This inverse correlation between BMI and basal LH was observed in similar studies; this result agrees with Pagán et al., [12] who studied twentyfour women with PCOS across a spectrum of BMIs with frequent blood sampling, IV administration of GnRH (75ng/kg), and SC administration of the NAL-GLU GnRH antagonist (5 gg/kg) in the General Clinical Research Center at an Academic Hospital coming out with results that illustrates the inverse correlation between BMI and mean LH, LH/FSH, and LH pulse amplitude. They also suggested that the effect of BMI on LH is mediated at a pituitary and not a hypothalamic level in PCOS as they noticed that the pituitary response to a weight-based dose of GnRH is inversely related to BMI in PCOS. This conclusion was also obtained by Bohlke et al., [13] who assessed the relationship between body mass index (BMI) and basal LH and the LH- FSH ratio revealing the same inverse association between BMI and basal LH levels but the study was on normally menstruating women and not on PCO patients. However, on the other hand Micah et al., [14] and Sathya et al., [15], who studied the impact of BMI on the outcome of ICSI cycles (they classified their patients only according to their BMI without focusing on pco patients), have stated in their results that the level of basal LH did not differ between obese and lean women. Our results also revealed significantly lower levels of prolactin in the obese group compared to the non-obese candidates. This finding is also an important secondary outcome observed in this study. As for basal FSH, E2 and TSH; results showed no significant difference between the three groups with different BMI. This result agrees with the findings observed by Sathya et al., [15]. In their study which focused on impact of obesity on IVF outcome, they recorded non significant difference in basal hormones with different BMI. On the contrary our findings may disagree with other studies as Loveland et al., who performed retrospective analysis on one hundred thirty-nine women <40 years old undergoing IVF cycles with fresh embryo transfers. They found that there is a decrease in basal FSH levels in the obese patients compared to non obese partners [16]. Also Giovanni et al., found lower basal FSH and estradiol levels in obese patients in their study that was carried on 22 patients with BMI >30 to document the hormonal differences in obese women [17]. In the second part of our work ovulation in the three groups was monitored by direct demonstration of a growing follicle using the trans-vaginal U/S. Although ovulation seemed to be better in non obese group (23.6%), yet, this result was not statistically significant. When ovulation was monitored by day 21 progesterone; ovulation was much better in the non obese group (18.3%), compared to the other groups. Ovulation was worst in the morbidly obese group (5.5%). Our results may agree with a prospective cohort study carried by Walter et al., These authors found that; in anovulatory women with PCOS resumption of ovulation was associated with early and consistent loss of intra-abdominal fat (12.4 versus 5.0% at 3 months and 18.5 versus 8.6% at 6 month) [18].

5 Ahmed Al-Saw af & Eman A. Hussein 987 There are also several studies that agree with our results such as those carried by Norman et al., who concluded that there is a definite relationship between anovulation and body BMI [19]. Our results may be attributed to abnormal leptin levels in obese patients which is believed to play a role in ovarian folliculogenesis. Human leptin is a protein of 167 amino acids. It is manufactured primarily in the adipocytes of white adipose tissue, and the level of circulating leptin is directly proportional to the total amount of fat in the body [20]. Leptin participates in regulation of ovarian folliculogenesis indirectly via control of LH and FSH secretion. More recent evidence suggests that leptin also has direct regulatory actions on the developing follicle. The presence of leptin receptors on follicular cells, including oocytes, and early pre-implantation embryos suggests that leptin may play a direct physiologic role in follicular maturation, oocyte development [21]. Because circulating leptin levels are directly related to body adiposity, elevated leptin concentrations associated with obesity may partly explain the negative impact of obesity on ovulation through its effect on FSH secretion and its direct effect on the follicles. There are several biological mechanisms through which obesity may increase the risk for anovulation. These mechanisms center on the HPO axis, which regulates both the menstrual cycle and ovulatory function through a complex hormonal regulation system. The two main disturbances to the HPO axis occur through either hyperandrogenism or insulin resistance [22]. Hyperandrogenism is a biological condition where there is an excess production or secretion of androgens, which include sex hormones [3]. Adipose tissue has been shown to have the potential to alter the secretion of sex hormones, given its essential role in both androgen production and in the conversion of androgens into other sex hormones [22]. In the same direction, insulin resistance and hyperinsulinemia can lead to disturbance in ovulatory function. The ovary is a target organ for insulin to stimulate the production of sex hormones [22]. This increased insulin level will negatively affect follicular maturation through increasing free insulin-like growth factor 1. In conclusion: There is a biological evidence supporting the hypothesis that obesity increases the risk for anovulation in PCOS through the disruption of HPO axis by hyperandrogenism, and/or insulin resistance [22] or through obnormal levels of leptin [21]. Therefore weight reduction in PCOS may improve ovulatory functions and should be advised complementary to induction protocols. However, further research studies are still required to elucidate the role of individual members of the complex endocrine system that controls these relationships. References 1- World Health Organization: Obesity: Preventing and managing the global epidemic, WHO technical report series 894. Geneva, Switzerland: World Health Organization, DOUGLAS T., NORRIS L.E. and OSTER R.A.: Difference in dietary intake between women with polycystic ovary syndrome and healthy controls Fertil. Steril., 86 (2): 411-7, PASQUALI R., PELUSI C., GENGHINI S., CACCIARI M. and GAMBINERI A.: Obesity and reproductive disorders in women. Hum. Reprod Update Online, 9: , LEGRO R.S.: The genetics of obesity, lessons for polycystic ovary syndrome. Annals of New York Acadmy of Sciences Online, 900: , GAMBINERI A., PELUS C., VICENNATI V., PAGOTTO U. and PASQUALI R.: Obesity and the polycystic ovary syndrome. Int. J. Obesity. Rel. Metab. 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6 988 Impact of Obesity on Ovulatory Functions in Polycystic Ovarian Syndrome luteinizing hormone and body mass index in polycystic ovarian syndrome: Investigation of hypothalamic and pituitary contributions. J. Clin. Endocrinol. Metab. Apr., 91 (4): Epub. Jan., 24, BOHLKE K., CRAMER D. and BARBIERI R.L.: Relation of luteinizing hormone levels to body mass index in premenopausal women. Fertil. Steril., 69: 500, MICAH J. HILL, STEVE HONG and JOHN L. FRAT- TARELLI: Body Mass Index Impacts in Vitro Fertilization Stimulation, ISRN Obstetrics and Gynecology, Volume, Article ID , 5 pages, SATHYA A., BALASUBRAMANYAM S., GUPTA S. and VERMA T.: Effect of body mass index on in vitro fertilization outcomes in women. J. Hum. Reprod. Sci. Sep., 3 (3): 135-8, LOVELAND J.B., MCCLAMROCK H.D., MALINOW A.M. and SHARARA F.I.: Increased body mass index has a deleterious effect on in vitro fertilization outcome. Journal of Assisted Reproduction and Genetics, 18: , GIOVANNI LAW D.C., MACLEHOSE R.F. and LONG- NECKER M.P.: Obesity and timeto pregnancy. Hum. Reprod., 22 (2): , WALTER K.H. KUCHENBECKER, HENK GROEN, SOPHIE J. VAN ASSELT, JOHANNA H.T. BOLSTER, J. ZWERVER, RIEMER H.J. SLART, ERIK J. VD JAGT, ANNEKE C. MULLER KOBOLD, BRUCE H.R. WOLFFENBUTTEL, JOLANDE A. LAND and ANNE- MIEKE HOEK: In Women With Polycystic Ovary Syndrome and Obesity, Loss of Intra-abdominal Fat is Associated with Resumption of Ovulation; Human Reproduction, 26 (9): , NORMAN R.J., NOAKES M., WU R., DAVIES M.J., MORAN L. and WANG J.M.: Improving reproductive performance in overweight/obese women with effective weight management. Hum. Reprod. Update Online, 10: , ZHANG F., BASINSKI M.B. and BEALS J.M.: Crystal structure of the obese protein leptin-e100. Nature May, 387 (6629): 206-9, BRANNIAN J.D. and HANSEN K.A.: Leptin and ovarian folliculogenesis: Implications for ovulation induction and ART outcomes. Semin. Reprod. Med., 20 (2): , BREWER C.J. and BALEN A.H.: The adverse effects of obesity on conception and implantation. Reproduction, 140 (3): , 2010

METABOLIC RISK MARKERS IN WOMEN WITH POLYCYSTIC OVARIAN MORPHOLOGY

Vuk Vrhovac University Clinic Dugi dol 4a, HR-10000 Zagreb, Croatia Original Research Article Received: February 18, 2010 Accepted: March 3, 2010 METABOLIC RISK MARKERS IN WOMEN WITH POLYCYSTIC OVARIAN