LITERATURE REVIEW OBESITY AND INFERTILITY

Supervised by: dr. Arie Polim, Sp. OG, K FER

Presented by: Fabian Jaya Junaidi Vivin Yohanna Achmad Gabriela Christy 2011-061-084 2011-061-086 2012-061-028

Department of Obstetric and Gynecology Faculty of Medicine Atma Jaya University Period October 28th 2013 January 11th 2013

FOREWORD First of all we would like to thank God because of Hiss blessing we can finished this referat. We also would like to thank our supervisor dr. Arie Polim Sp.OG (K) for giving us valuable advice and support always when needed. Other important persons considering our referat are our family for their support. Our colleagues whom we like to give our special thanks for giving us an opportunity to share their knowledge and the best available information.We choose Obesity and Infertility as our referat title. We realize this referat is far from perfect, therefore we hope any constructive advices or critics to make our referat better. As a final word we hope this referat is useful and enrich knowledge about poor ovarian response.

Jakarta, November 13th 2013

Authors

CONTENTS
Pages FOREWORD.............................................................................................................................ii CONTENTS..............................................................................................................................iii TABLES.....................................................................................................................................v CHAPTER I INTRODUCTION 1.1 Background..............................................................................................................1 1.2 Goal.......................................................................................................................2 CHAPTER II BASIC THEORY 2.1 Obesity..................................................................................................................3 2.1.1 Definition...............................................................................................................3 2.1.2 Etiology......................................................................................................................4 2.1.3 Clinical Presentation............................................................................................5 2.1.4 Treatment..............................................................................................................6 2.2 Infertility ...................................................................................................................7 2.2.1 Definition.................................................................................................................7 2.2.2 Epidemiology............................................................................................................8 2.2.3 Etiology................................................................................................................8 2.2.4 Diagnosis ..........................................................................................................10 2.2.5 Treatment ................................................................................................................13 2.3 Association between obesity and infertility in woman .............................................14 2.3.1 Obesity and Reproduction in Women .....................................................................14 2..3.1.1 Polycystic Ovarian Syndrome ........................................................................21 2.3.2 Obesity and Reproduction in Men.......................................................................... 22

2.3.3 Treatment of Reroductive Disorder in the Obese................................................... 25 2.3.3.1 Weight Loss..................................................................................................... 25 2.3.3.2 Managing hormonal imbalance........................................................................27 CHAPTER III CONCLUSION............................................................................................... 29 REFERENCE ..........................................................................................................................30

TABLES

Table 1. WHO classification of BMI for Asian........................................................................4 Table 2. Classification of disorders of ovulation.....................................................................10 Table 3. Table 3. Prevalence of Infertility in Obese Women...................................................17

CHAPTER 1 INTRODUCTION

1.1

Background Infertility is defined as one year of frequent, unprotected intercourse during which pregnancy has not occurred. According to data from the National Survey of Family Growth, an estimated 10 to 15 percent of couples in the United States are infertile. Infertility can be attributed to any abnormality in the female or male reproductive system. In most cases, the etiology is distributed fairly equally among male factors, ovarian dysfunction, and tubal factors. A smaller percentage of cases are atributed to endometriosis, uterine or cervical factors, or other causes. In approximately one fourth of couples, the cause is uncertain and is referred to as unexplained infertility. The etiology is multifactorial for some couples.1 In general, an infertility evaluation is initiated after 12 months of unprotected intercourse during which pregnancy has not been achieved. Evaluation also may be initiated earlier when the female partner is older than 35 years, because fertility rates decrease and spontaneous miscariage and chromosomal abnormality rates increase with advancing maternal age.1 There are two types of infertility, the primary infertility is when a couple have never had children, or have been unable to achieve pregnancy after one year of living together despite having unprotected sexual intercourse, the secondary infertility is when a couple have had children or achieved pregnancy previously, but are unable to conceive at this time, even after one year of having unprotected sexual intercourse.2 Obesity has reached epidemic proportions globally, and all this evidence sugggest that the situation is likely to get worse. In developed regions such Europe, the United States of America, Australia, and in Asia, the prevalence is high and increasing but in some developing countries even more extreme situations exist. For example, more than 70% of the adult Polynesian population in Samoa are Considered obese.3 Obesity is a health issue of epidemic proportions worldwide and in the United States. The World Health Organization (WHO) defines normal weight as a body mass

index (BMI) of 18.5-24.9 kg/m2, overweight as a BMI of 25-29.9 kg/m2, and obesity as a BMI of 30 kg/m2 or greater. When the BMI is greater than desire value it may lead to fertility problems among both males and females. It can disrupt the hormonal balance which is necessary for normal egg and sperm production.4 The association between increased weight and cardiometabolic disease is widely recognized, but obesity also plays a significant role in the development of reproductive disorders by increasing the risk of infertility, breast cancer, and endometrial cancer.5 Hence, we tried to collect evidence showing association between obesity and infertility because their association remains unclear.

1.2 Goal 1. Determine the correlation between obesity and infertility on women.

CHAPTER II BASIC THEORY

2.1 Obesity 2.1.1 Definition Obesity is defined as an excessive accumulation of energy in the body that are accumulated in the form of fat or adipose. Obesity is often caused by excess energy intake.6 In normal subjects the body fat content in men amounted to approximately 15-20% of the total body weight, whereas in women approximately 25-30% of the total body weight. But in men, body fat content exceeding 25% of total body weight called obesity, whereas in women whose body fat exceeds 30% of total body weight is defined as obese. In people who suffer from obesity, fat accumulation may reach 40-50% of total body weight.7 World Health Organization (WHO) divides the nutritional status based on body mass index (BMI), which is divide between body weight (kilograms) by height (meters)2. According to WHO, the first category is underweight with a BMI <18.50 kg/m2. The second category is the normal category with a BMI 18.50-24.99 kg/m2. The third category is overweight with a BMI 25.0-29.99 kg/m2. The fourth category is obese, with a BMI 30.0 kg/m2, which is divided into 3 classes: obese class I with a BMI 30.0-34.99 kg/m2, obese class II with a BMI 35.0-39.99 kg/m2, and obese class III with a BMI 40.0 kg/m2.3,8 International BMI according to WHO classification made using Caucasians as a model. The use of this classification have difficulties when BMI is used to assess the Mongoloid race in Asia. Mongoloid race has physical characteristics that are smaller than Caucasians and different body composition, so that the measurement results obtained being inaccurate when judged by category according to WHO standards. In the assessment using WHO standards, Mongoloid races tend to be in normal circumstances and overweight. Therefore, the WHO created a different categorization standards for use in the Mongoloid race in Asia. This standard is adjusted based on the physical characteristics and body composition in Asian Mongoloid race. the first

category is underweight with a BMI <18.50 kg/m2. The second category is the normal category with a BMI 18.50-22.99 kg/m2. The third category is overweight with a BMI > 23,0 kg/m2, which is divided into 3 classes: pre-obese with a BMI 23.0-24.99 kg/m2, obese class I with a BMI 25.0-29.99 kg/m2, and obese class II with a BMI 30.0 kg/m2.9 Table 1. WHO classification of BMI for Asian Classification Underweight Normal BMI (kg/m2) < 18,5 18,5 22,9

Overweight: Pre-obese Obese I Obese II

23 23 24,9 25 29,9 30

2.1.2 Etiology The cause of obesity can be affected by many factors such as metabolic factors, genetics, race, gender, age, ethnic, cultural, physical activity, neuroendocrine, socioeconomic, dietary habit, and psychological. However, in general, obesity is caused by two factors, external factors and internal factors. External factors are factors derived from the human environment that may affect the increase in energy intake and decrease of energy expenditure. External factors that increase the energy intake is the availability of enough food, many food choices, and many types of fast food that can increase the risk of obesity. Other external factors are increasing the quantity and quality of food, such as fast food that has a higher energy than the traditional foods that cause excessive energy intake, increased consumption of snacks (snacks) such as pastries, biscuits and others. External factors that inhibit energy expenditure is the development of technology such as transport and machines that

help people work so human energy expenditure tends to decrease. In addition there are also sports activities tend to decrease due to busy work. Another factor is the increasing number of entertainment factors that are passive activities such as electronic games, the spread of computers and televisions, resulting in reduced activity such as sports.10 Internal factors are factors that come from the man himself. Internal factors include genetic factors and ethnic factors. Genetic factors influence the susceptibility to external factors that lead to obesity. While the various ethnic groups there are differences in the pattern of weight gain, including body fat distribution and adiposity levels at the same BMI values.10 2.1.3 Clinical Presentation People with obesity may have some symptoms and predisposing factors for other diseases such as:6 Respiratory - Obstructive sleep apnea, greater predisposition to respiratory infections, and increased incidence of bronchial asthma Malignant - Association with endometrial, prostate, colon, breast, gall bladder, and possibly lung cancer Psychological - Social stigmatization and depression Cardiovascular - Coronary artery disease, essential hypertension, left ventricular hypertrophy, cor pulmonale, obesity-associated cardiomyopathy, accelerated atherosclerosis, and pulmonary hypertension of obesity Central nervous system (CNS) - Stroke, idiopathic intracranial hypertension Obstetric and perinatal - Pregnancy-related hypertension, fetal macrosomia, and pelvic dystocia Gastrointestinal (GI) - Gall bladder disease (cholecystitis, cholelithiasis), nonalcoholic steatohepatitis (NASH), fatty liver infiltration, and reflux esophagitis Orthopedic - Osteoarthritis, coxa vera, and chronic lumbago Metabolic - Type 2 diabetes mellitus, prediabetes, metabolic syndrome, and dyslipidemia Reproductive (in women) Anovulation, early puberty, infertility,

hyperandrogenism, and polycystic ovaries

Reproductive (in men) - Hypogonadotropic hypogonadism Cutaneous - Intertrigo, acanthosis nigricans, hirsutism, and increased risk for cellulitis and carbuncles Extremity - Venous varicosities, lower extremity venous and/or lymphatic edema Miscellaneous - Reduced mobility and difficulty maintaining personal hygiene

2.1.4 Treatment The goal of obesity therapy is not to lose weight to be normal, but to achieve significant weight loss and a gradual decrease complications and co-morbidities. Therapy consists of lifestyle modifications such as improved diet and increased physical activity, medication to lower the body's energy input, very low-calorie diet, as well as surgery. These therapies can be administered alone or together.3 Lifestyle changes3,6 o Diet Medication6 o Noradrenergic agonist (efedrin, kafein, phentermine, and dietilpropion). These drugs reduce weight by decreasing appetite and increasing thermogenesis body. The side effects of these drugs are central nervous system stimulation and should not be used more than three months o Serotoninergic and noradrenergic agonist (sibutramine). These drugs reduce re-uptake of serotonin and noradrenaline in the brain. Therefore, Reducing calorie diet of 500-1000 kcal / day Total fat consumed 30% total calories Reduce foods with a high saturated fat content Eating foods that contain high fiber

o Physical activity Exercise that is continuous, rhythmic, light-moderate intensity, and regular Walking 30 minutes/day as much as 3 days/week The intensity can be increased gradually to 45 minutes/day, 5 times/week Can also do other sports such as cycling, jogging, swimming, and other sports with low injury risk

these drugs decrease appetite, increase thermogenesis body, and increase energy expenditure. Side effects of these drugs minimal, including increased blood pressure and palpitations o Orlistat. Orlistat blocking lipase and phospholipase A2 produced by the stomach and pancreas. These drug inhibits fat absorption in the digestive tract by inhibiting the breakdown of fats into fatty acids. Side effects from the use of this drug include flatulen, steatorrhea, and increased frequency of bowel movements. In the long-term use, orlistat may inhibit the absorption of fat-soluble vitamins Surgery6 o Surgery is effective for weight loss. However, it is advisable for people with a BMI of 40 or 35 with comorbid illnesses. This method is the last alternative if the lifestyle changes and pharmacotherapy fail and suffer severe complications o Gastric bypass (Roux-en Y) is one of the interventions to lose weight with low operating risk

2.2 Infertility 2.2.1 Definition Infertility is inability to conceive a child. The clinical definition of infertility used by the World Health Organization (WHO) is a disease of the reproductive system defined by the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse. The American Society for Reproductive Medicine defines infertility as a disease, defined by the failure to achieve a successful pregnancy after 12 months or more appropriate, timed unprotected intercourse.11,
13,14,15

Infertility is synonymous to subfertility.16 Infertility is a critical component of reproductive health, and has often been neglected in these efforts. The inability to have children affects men and women across the globe. Infertility can lead to distress and depression, as well as discrimination.2

Conversely fecundability is the ability to conceive. Fecundability is the probability of achieving pregnancy within a single menstrual cycle, and fecundity is the probability of achieving a live birth within a single cycle. The fecundability of a normal couple is estimated to be at 20% to 25%. This means that about 80 to 90 percent of the couples should conceive after 12 months of unprotected intercourse.13,14 In those attempting conception, approximately 50 percent of women will be pregnant at 3 months, 75 percent will be pregnant at 6 months, and more than 85 percent will be pregnant by 1 year.1 There are two types of infertility, the primary infertility is when a couple have never had children, or have been unable to achieve pregnancy after one year of living together despite having unprotected sexual intercourse and the secondary infertility is when a couple have had children or achieved pregnancy previously regardless of the outcome or how long ago it was, but are unable to conceive at this time, even after one year of having unprotected sexual intercourse.2, 13,16 2.2.2 Epidemiology Infertility affects about 10% to 15% of reproductive-age couples in the United States.13 Infertility accounts fot 10% to 20% of all gynecologic office visits.15 Of those couples who undergo evaluation for infertility, approximately 45% to 55% is attributed to female factors and 35% attributed to male factors. In 10% to 20% of infertility cases, both male and female factors are detected. After evaluation, 10% of the couples will have no identifiable cause for their infertility.14 The incidence if infertility has increased in developed countries because of increasing sexually transmitted diseases (especially gonorrhea and Chlamydia, causing tubal damage, increasing number of sexual partners (increasing the potential for acquiring STDs), and smoking (1 pack/day decreases the chance of pregnancy by 20%).15 2.2.3 Etiology Successful pregnancy requires a complex sequence of events including ovulation, ovum pick-up by fallopian tube, fertilization, transport of a fertilized ovum into the uterus, and implantation into a receptive uterine cavity. Many of these couples present first to their primary care physician, who may initiate evaluation and treatment. The inability to have children affects men and women across the globe.1 Of

those couples who undergo evaluation for infertility, 40% are attributed purely to male factors and 40% to purely female factors. Both male and female factors are identified in 10% of the patient population. After evaluation, 10% of couples will have no identifiable cause for their infertility. Fortunately, modern technologies make it possible to identify the one or more possible causes for infertility in 90% cases. In these cases, appropriate therapy will result in pregnancy 50% of the time. It should be strongly urged that both partners be present for the initial consultation. Common causes of infertility of females include ovarian dysfunction, tubal disease, endometriosis, and uterine or cervical factors.1 A careful history and physical examination can suggest a single or multifactorial etiology and can direct further investigation.12 The causes of infertility may be classified as male-coital factors (40%), cervical (5%-10%), uterine-tubal (30%), ovulatory factors (15%-20%), and peritoneal or pelvic factors (40%). A few genetic causes (e.g. primary amenorrhea) are recognized.15 Male factors include abnormal spermatogenesis, abnormal motility, anatomic disorders, endocrine disorders, and sexual dysfunction. The anatomic abnormalities possibly responsible are congenital absence of the vas deferens, obstruction of the vas deferens, and congenital abnormalities of the ejaculatory system. Abnormal spermatogenesis may occur due to mumps orchitis, chromosomal abnormalities, cryptorchidism, chemical or radiation exposure, or varicocele. Abnormal motility is seen with absent cilia (Kartageners syndrome), varicocele, and antibody formation. The male factor endocrine disorders include thyroid disorders, adrenal hyperplasia, exogenous androgens, hypothalamic dysfunction, pituitary failure (may be caused by tumor, radiation, or surgery) and hyperprolactinemia (caused by tumor or druginduced). Cervical factors of female infertility may be congenital, such as diethylstilbestrol (DES) exposure and mullerian duct abnormality, or acquired (infection and surgical treatment).15 Uterine-tubal factors are most commonly structural abnormalities found in infertile women.15 Some of the disorders are myoma, failure of normal fusion of the reproductive tract, DES exposure, infections, intrauterine synechiae and previous ectopic pregnancy.14,15

Ovulatory factors involve central nervous system function, metabolic disease, or peripheral defects. Central nervous system defects include hyperandrogenemic anovulation, hyperprolactinemia, hypothalamic insufficiency, and pituitary

insufficiency. Metabolic diseases causing ovulatory factor defects are thyroid disease, liver disease, renal disease, obesity and androgen excess (adrenal or neoplastic). Peripheral defects may be gonadal dysgenesis, premature ovarian failure, ovarian tumor, or ovarian resistance. Table 2. Classification of disorders of ovulation5

The two most common pelvic or peritoneal factors are endometriosis and sequelae or infection (e.g. appendicitis and pelvic inflammatory disease). Laparoscopy in women with unexplained fertility will reveal previously unsuspected pathology in at least 30% of patients.15

2.2.4 Diagnosis Evaluations on infertility should follow a progression of testing and procedures. The basic evaluation usually requires 6-8 weeks to complete. Even if the history suggests a probable cause of infertility, completion of the evaluation of all major factors should be accomplished to avoid overlooking a secondary or

contributing factor. The initial assessment should include medical history for female infertility factors, including pubertal development, present menstrual cycle characteristics, contraceptive history, prior pregnancy and outcome, previous surgery (especially pelvic surgery), prior infection, abnormal Pap smears and therapy, drugs, diet, weight stability, exercise, and history of in utero DES exposure.15 The physician should guide the interview systematically while looking for symptoms related to ovarian, tubal, uterine, and cervical factors which can lead to infertility. Patients with ovulatory dysfunction may report amenorrhea, oligomenorrhea, or menorrhagia. Additional questioning should elicit symptoms related to PCOS, thyroid dysfunction, hyperprolactinemia, and ovarian failure. Patients with PCOS may report hirsutism, irregular menses, and/or weight changes. A detailed social history might reveal reasons for centrally mediated ovulatory dysfunctions including eating disorders, extreme exercise, or unusual stress. Women with endometriosis often give a history of cyclic pelvic pain, dysmenorrhea, and/or dyspareunia. Pelvic adhesions may be asymptomatic or may be associated with varying degrees o pelvic pain, especially with movement or lifting. The clinical presentation of uterine factor infertility varies with etiology. For many of these factors, infertility may be the only symptom. Among the most common causes, endometritis may present with pelvic pain and fever; submucosal fibroids and polyps may present with menorrhagia. Uterine anomalies such as uterine septum may present with a history of recurrent pregnancy loss. Cervical factor infertility may present with a history of prior cryotherapy, conization, cervical dilations, or in utero DES exposure.14 A physical examination should be performed to look for signs which may point toward a disorder associated with infertility. Careful evaluation may uncover signs of PCOS such as acne, hirsutism, acanthosis nigricans, achrochordons, and central obesity. Similar care should be taken in evaluating for thyroid dysfunction (goiter, changes in hair or nails, tachycardia). The examination should also look for breast development as a sign of past estrogen secretion. When performing a pelvic exam, premature ovarian failure might present with signs of estrogen deficiency such as vaginal atrophy. Visualization of the cervix may demonstrate cervical stenosis, signs of infection, or malformations. The finding associated with endometriosis or pelvic adhesions include a fixed or retroverted uterus, uterosacral nodularity, or tender fixed adnexa. With pelvic adhesions, the pain can sometimes be reproduced on abdominal or pelvic exam. Uterine size should be evaluated and the physician should

look for leiomyoma and any signs of current or prior pelvic infection. Endometriomas and other ovarian pathology may be palpated during the pelvic exam. The primary tests for the evaluation of ovulatory factor infertility involve looking for evidence of ovulation by tracking the menstrual cycle, measuring the basal body temperature, monitoring the cervical mucus, and measuring the midluteal progesterone (days 21 to 23 of the menstrual cycle). A clomiphene citrate challenge test (CCCT) can be used to assess for decreased ovarian reserve of the oocytes decline in fertility. The test involves administration of 100 mg of clomiphene citrate on days 5 through day 9 of the menstrual cycle. An FSH level is measured on days 3 and 10. Even small elevations in FSH levels correlate with decreased fecundity. This is especially useful in women over 30 years of age, those with prior ovarian surgery or having only one ovary, those with a history of prior chemotherapy or radiaton exposure, and in women who have had a poor response to ovulation induction. A progestin challenge test may be used to demonstrate endometriums ability to to respond with bleeding after progesterone is withdrawn from the system. This involves administration of a progestin over 5 to 10 days to build up the endometrium. When the progestin is stopped, the patient should experience a withdrawal bleeding within 1 week. If this test fails to produce bleeding, a combined estrogen and progesterone challenge can be performed. Endocrine evaluation may include measurement of FSH, LH, prolactin, thyroid function tests, and thyroid antibodies. If Cushing syndrome is suspected, serum testosterone, dehydroepiandrosterone sulphate (DHEAS), 17hydroxyprogesterone, 24-hour urine cortisol levels, and an overnight dexamethasone suppression test are helpful. When intracranial lesions are suspected, MRI or CT imaging of the head should be done. Endometriosis or pelvic adhesions may be strongly suspected based on the patients history, but direct visualization with laparoscopy or laparotomy is necessary to confirm the diagnosis. Ovarian endometriomas (cystic collections of endometrial cells on the ovaries) can be diagnosed on pelvic ultrasound. Tubal patency can be demonstrated with a hysterosalpingogram (HSG) performed during the follicular phase or tubal lavage (chromopertubation) performed during laparoscopy. HSG is one of the primary investigative tools for evaluation of anatomic abnormalities of the female reproductive tract. This involves installation of a contrast dye transcervically to evaluate for filling defects in the cavity and to test for tubal patency. The pelvic ultrasound is also useful in evaluating the uterus for structural defects such as fibroids,

polyps, adenomyosis, hyperplasia, and cancer. A saline sonohysterogram can complement the pelvic ultrasound by allowing better visualization of the uterine cavity. This is accomplished by transcervical infusion of saline into uterine cavity while the ultrasound examination of the uterus is performed. Hysteroscopy may be used to directly visualize the cavity of the uterus. MRI can also be useful in better delineation of adenomyosis and uterine anomalies. A Pap smear and cervical cultures for gonorrhea and Chlamydia should be performed in all women undergoing an infertility evaluation. Cervical mucus studies may be used to evaluate the quality of the cervical mucus.14

2.2.5 Treatment The underlying etiology of infertility should be identified and corrected. For uncorrectable cases, ovulation induction with fertility drugs, intrauterine insemination with sperm, or in vitro fertilization with placement of the embryo into the uterus can be used. Regular ovulation can be restored in 90% of infertility cases that are due to endocrine factors by treating the underlying disorder. The most common etiology of ovulatory infertility is PCOS. For PCOS patient, weight loss, metformin, and ovulation induction have been effective in establishing ovulation and producing viable pregnancies. In PCOS patients, even small amounts of weight loss can result in lowered fasting insulin, testosterone, and androstenedione levels. These

improvements can help promote the reestablishment of spontaneous ovulation in PCOS patients. If spontaneous ovulation cannot be established, ovulation inducing medications can be used to stimulate ovulation. If these treatments are unsuccessful, ovulation induction and pregnancy can be attempted with a combination of ovulation inducing medications or human gonadotropins with intrauterine insemination or in vitro fertilization. For patients with hypothalamic-pituitary failure (WHO group 1), ovulation can usually be achieved with pulsatile GnRH therapy or human gonadotropins. Of note, there is no treatment for WHO group 3 patients with ovarian failure because these patients lack viable oocytes. Patients with this diagnosis should be offered the options of egg donation, gestational surrogacy, or adoption. Symptomatic relief of endometriosis can be achieved medically or surgically. However, there is no role for medical management in the treatment of infertility caused by endometriosis. Medical treatments or continuous oral contraceptives can temporarily relieve symptoms but does not increase fertility rates. For patients with

endometriosis, fertility rates can be improved by surgical ligation of periadnexal adhesions during laparoscopy or laparotomy with excision, coagulation, vaporization, or fulguration of endometrial implants. Pregnancy rates after surgical treatment depend on the extent of the disease, with increased conception rates for severe endometriosis. Conflicting data exists regarding conception rates following surgical therapy for mild endometriosis. However, the consensus is that surgical adhesion lysis and ablation of endometrial implants does increase fertility. Microsurgical tuboplasty with tibal reanastomosis or neosalpingostomy has been proven to be effective for treating tubal occlusion due to prior infection or from prior tubal ligation. However, because it is more effective, most couples undergo IVF rather than attempt tuboplasty. The advantage of tuboplasty is that it allows for more than one future pregnancy without the cost and difficulty of multiple IVF cycles. When tubal occlusion, tubal damage, or hydrosalpinx results from prior salpingitis, reproductive endocrinologist will often remove the damaged tube and opt for IVF to treat the resulting infertility. Operative hysteroscopy is used to treat uterine factors such as uterine synechiae, septae, polyps, or submucosal fibroids. Following surgical ligation of synechiae or septae, estrogen therapy or intrauterine devices are often used to prevent recurrence of adhesions. Fertility is restored in 50% of these cases. Most surgeons reserve myomectomy for treatment after recurrent pregnancy loss or when symptomatic fibroids have been identified.14

2.3 Association between obesity and infertility 2.3.1 Obesity and Reproduction in Women There is some evidence of increased time to conception for obese compared with normal-weight women, particularly among women who smoke cigarettes Obesity is also a strong risk factor for polycystic ovarian syndrome, which results in menstrual irregularities and chronic anovulation. The central distribution of fat, as measured by waist-to-hip ratio, is also related to reproductive functioning, with higher rates of infertility associated with higher waist to- hip ratios. The menstrual cycle is influenced by body fat, and obesity can lead to irregularities in the menstrual cycle.18 Obesity in adolescence and young adulthood, as

opposed to during infancy, is more strongly associated with amenorrhea, oligomenorrhea, and long menstrual cycles.
19

Studies have indicated that 30-47% of

obese women have irregular cycles, although the incidence of infertility among obese women is not that high. Infertility in this population seems to be related to ovulatory dysfunction. A large case controlled study that compared obese, anovulatory women with fertile controls found a relationship between BMI at age 18 and subsequent anovulatory infertility.` The relative risk for anovulatory infertility was 1.3 (95% CI 1.2-1.6) in women with a BMI of 24 31 kg/m2, and 2.7 (95% CI 2.0 3.7) for those with a BMI > 32 kg/m2.18 Obesity decreases successful pregnancy rates in both natural and assisted conception cycles, with fertility being partially restored if weight loss can be achieved. The mechanism by which obesity reduces pregnancy rates are complex and likely multifactorial. Insulin resistance appears to be a key factor to obesity induced anovulation, with high levels of insulin leading to low levels of sex hormone-binding globulin, hyperandrogenaemia and high levels of free insulin-like growth factor 1. The loss of as little as 5% of body weight is accompanied by an increase in ovulation rates and reduces biochemical abnormalities. Elevated levels of leptin and low levels of adiponectin have also been implicated in the mechanism by which obesity reduces conception rates, but there is much less information on their role. Over and above a decrease in ovulation rates, obesity also increases the rate of miscarriage, thus further decreasing successful pregnancy rates among obese women. Potential mechanisms include poorer quality oocytes and/or a defect in endometrial receptivity with insulin resistance again implicated in the latter event. Given the above, it is not surprising that success rates of assisted reproductive technologies are lower in obese individuals. These data have led the British Fertility Society to recommend Women who are obese must initiate a weight reduction programme and those severely overweight (defined as having a BMI of 36 or more) should not receive treatment until their weight has reduced. In contrast to these effects on female fecundity, there is much less evidence that obesity adversely affects male fertility. Although obese men have lower total and free testosterone levels, meta-analyses have so far failed to confirm an effect of

obesity on semen parameters, indicating that if obesity does reduce male fertility then the effect is likely to be subtle . Once obese women are pregnant, their risk of pregnancy complications is significantly greater than their lean counterparts. Many of the adverse outcomes of obesity (including gestational diabetes and pre-eclampsia) occur as a result of increased insulin resistance. Even lean pregnant women are insulin resistant compared to their non-pregnant counterparts, with insulin resistance mediated downstream of the insulin receptor by defects in SLC2A4 (GLUT4) mobilisation. It is likely that this is induced by circulating factors, with cytokines such as tumour necrosis factor-a among the leading candidates. The increased insulin resistance in obese pregnant women leads not only to pregnancy complications for the mother, but also greater growth and disproportionally greater fat mass for the baby. Thus, high pre-pregnancy and early pregnancy BMI predisposes to the birth of an overweight baby. As reviewed by Drake & Reynolds , these overweight babies are themselves more likely to be obese as adults, and to have disordered glucose metabolism, vascular function and hypertension: the developmental overnutrition hypothesis. This transmission of obesity from generation to generation appears restricted to mothers, with paternal obesity having little effect. If this is true, it suggests that the in utero environment may be the key mediator to the maternal-offspring transmission of obesity. Again, this is an area of much research. The obvious question is whether any therapies can be introduced to treat this vicious cycle. The Institute of Medicine in the USA now recommends that obese pregnant women limit weight gain during pregnancy , but there is minimal evidence supporting intensive lifestyle interventions (improved diet and exercise) during

pregnancy. As Catalano states, lifestyle interventions are most likely to be effective if applied early in pregnancy or prior to conception in women who are planning to become pregnant ideally. Given that insulin resistance appears to be the key factor to many of the adverse consequences of obesity in pregnant women, therapies designed to improve insulin sensitivity in pregnancy could be effective. 20

Table 3. Prevalence of Infertility in Obese Women No. Author Year Title Journal Conclusion relative risk of

1. Pandey S. Et al

2010 The Impact of Female Journal of Human The Obesity Outcome Treartment on The Reproductive

anovulatory infertility is 2.7 (95% CI, 2.0-3.7) in women with BMI 32 kg/m2 at age while in ovulatory but

Fertility Science

subfertile woman the chance of spontaneous conception

decreases by 5% for each unit increase in the BMI. 2. AlHasani S, Zohni K 2008 The Overlooked Role Journal of Family A disproportionate number of of Obesity in and Reproductive women who seek treatment at

Infertility

Health Vol. 2, No. 3, infertility centers have a high September BMI. For example, among more than 5000 infertile

female patients seen at the Reproductive Medicine Unit at the University of Adelaide, Australia, 40% had a BMI exceeding 25 kg per m2 (borderline or overweight), and 17% had a BMI

exceeding 30 kg per m2 (obese). 3. Norman RJ, et al 2004 Improving reproductive performance overweight/ obese women with effective weight management Human Reproduction The Nurses' Health Study reported that in 2527 married

in Update,Vol.10, No.3 infertile nurses, the relative pp. 267-280 risk of ovulatory infertility was 1.3-fold higher (95% CI 1.21.6) in the group with a BMI range of 2431 kg/m2

and 2.7-fold higher (2.03.7) in women with a BMI >32 kg/m2.. More recent data from this group show that ovulatory infertility can be largely attributable to

overweight and a sedentary lifestyle. Grodstein et al

showed that anovulatory infertility in 1880 infertile women and 4023 controls was more common in those with a BMI of >26.9 kg/m2 (RR 3.1, 2.24.4). Even high normal to slightly may overweight an levels on

have

effect

fertility.

Weight

during

childhood did not predict adult fecundity, but weight at 23 years did if the woman was obese (OR 0.69, 0.56 0.87). Obese women at 23 years were less likely to become months normal pregnant within 12 than women of

weight,

while

infertility rate was 33.6% in obese women versus 18.6% in normal weight women. 4. Villiani R. R. et al 2013 Obesity among Infertil Quarterly Women Medical BMI calculation of 218

Channel MC Vol. 19 women attending infertility - No.1 - ( 48 - 50 ) clinic. It shows that 84 (38.53 %) women were of normal

BMI where as 73 (33.48%) of women were over weight. In our study No of women who were under weight were only 5 (2.29 %). According to grades of obesity, 41 (18.80 %) were of grade 1 obesity, 08 (3.66%) of grade II obesity and 07 (3.21%) were of grade III obesity. 5. Siega AM, al et 2009 Position American Association of The Journal of American It is stimated that 25% of Dietetic Dietetic Association and ovulation infertility in the United Stated may be

American Society for Nutrition: Reproduction, Obesity, and

atributable to overweight and obesity among women of repriductive age.

Pegnancy Outcomes 6. Kupka MS, et al 2010 Impact of female and Gynecological male obesity on Endocrinology; IVF/ICSI: results of Early Online, 16 700,000 ART-cycles In the group of obese women, the pregnancy rate decreased to 27.2%

in Germany

7. Sadia S, 2009 Characteristics et al

of J Ayub Med Coll Prevalence of amenorrhoea in obese women (BMI>29,9) is 4,4%. Prevalence in of obese

Infertile Patients with Abbottabad 2009;21 Ovulatroy Dysfunction and Their Relatyion Mass Index to Body

oligomenorrhoea women is 13%.

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Body Mass Index and of Social Sciences

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Infertility: A Cross Sectional

15 years the prevalence of obese-I (25,0-29,9) is 32% and obese-II (30,0) is 36%.

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2008 Risks

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ovulatory infertility at seven infertility clinics, obese women (BMI 27 kg/m2) have 3.1 times the risk of ovulatory infertility (95% CI: 2.2, 4.4) when compared with normal weight women (BMI 20.024.9 kg/m2). Moreover in a review of the literature on the impact of obesity on female reproduction, state that it is common for obese

conditional on body mass index?

women to not only require a higher dose of ovarian

stimulation drugs during IVF, but also to have fewer oocytes collected retrieval. at the time of

11. Akwasi NOP

2011 The Between

Correlation Department

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primary

Molecular Medicine, infertility is 30,23% in obese I and School of Medical women (BMI30-35) and

Anthropometry

Infertility in Women

Sciences College of 9,3% in obese II women. Health Sciences (BMI 35-40). The percentage of secondary infertility is 43,1% in obese I women (BMI30-35) and 8,62% in (BMI 35-

obese II women 40).

2..3.1.1 Polycystic Ovarian Syndrome Polycystic ovarian syndrome (PCOS) is the most common endocrinopathy seen in relation to obesity. Clinical features include obesity, anovulation, hirsutism, androgen excess, increased waist-to-hip ratio, and menstrual irregularities. But the true spectrum of PCOS is a continuum; patients do not have to exhibit all of these features, including obesity. To understand how body weight affects the menstrual cycle, it is first necessary to review the hormonal control of the normal functioning cycle. In an ovulatory cycle, follicle stimulating hormone (FSH) from the pituitary stimulates the growth of a follicle and the recruitment of granulosa cells which begin producing estradiol. The theca cells that surround the granulosa cells produce testosterone in response to luteinizing hormone (LH). Testosterone is the precursor to estradiol production. Insulin-like growth factor-II (IGF-II) is produced in the theca cells in response to gonadotropin stimulation, and this response is enhanced by estradiol and growth hormone. IGF-II increases luteinizing hormone stimulation of androgen production in the theca cells. As the follicle reaches full maturity and ovulates, there is more that transpires, but this will suffice to explain the impact of PCOS. PCOS is an imbalance in the delicate feedback system that normally takes place during an ovulatory cycle to allow for a single developing follicle to reach

maturity and be released. This system can be thwarted by obesity and PCOS in several ways. Fat cells are capable of making a weak estrogen,estrone, and releasing it into the circulation. Although weaker than estradiol, it is capable of suppressing FSH release and preventing the full development of a dominant follicle. When this occurs, developing follicles will progress to about 10 mm in size, add estradiol to the circulating pool of hormones, and be unable to grow further due to the decreasing levels of FSH occurring secondary to the negative feedback estrogens exert on FSH excretion. The ovaries will obtain a polycystic appearance due to the many small follicles present at the periphery which are unable to fully develop with the dropping FSH levels. Androgen levels rise with the falling FSH levels since FSH stimulates the aromatization of androgens to estrogens. A high androgen environment within the developing follicle leads to atresia. Elevated serum androgens exert an inhibitory effect on hepatic protein production, which leads to decreased production of sex hormone binding globulin (SHBG). SHBG binds estrogens and androgens in the serum making them less active. With less SHBG, the amount of free testosterone in the serum increases causing further atresia and hirsutism. Anovulation and unopposed estrogens can lead to endometrial hyperplasia and carcinoma. Some patients with obesity will have insulin resistance, a condition where their cells do not respond adequately to insulin so they must maintain elevated serum insulin levels in order to regulate glucose. One theory for this disorder is an insulin receptor defect. Insulin is capable of activating the IGF-II receptor and stimulating the theca cells to produce excess amounts of androgens leading to PCOS. Therefore, patients with insulin resistance can develop PCOS. 2.3.2 Obesity and Reproduction in Men The effects of obesity on male reproduction have been less well studied than those on female reproduction, but there is a growing body of evidence suggesting that obesity has an adverse effect on male reproduction. The incidence of oligospermia and azospermia increases as BMI increases, from 5.3% and 4.5% in normal weight men, to 9.5% and 8.9% in overweight men, and to 15.6% and 13.3% in obese men. Fat cells in men can produce estrone (as in women) via aromatization which suppresses gonadotropin secretion. These endocrine abnormalities are present in obese men and more pronounced in infertile obese men. In addition, in obese men, the scrotum remains closer to surrounding tissue than thinner men causing a thermogenic

effect on developing sperm.Various mechanisms can

influence and affect male

fertility. the effects manifestin both the endocrine and exocrine functioning of the male gonads. Altered semen parameters The relationship between male obesity and infertility can be attributed to more than just sexual dysfunction and other altered physical manifestations of obesity. Although spermatogenesis and fertility are not impaired in a majority of obese men, a disproportionate number of men seeking infertility treatment are obese . Sperm count and concentration Obese men are three times more likely than healthy men of normal weight to have a sperm count of fewer than 20 million/ml, also known as oligospermia. Chavarro et al. found that men with a BMI greater than 25 kg/m2 had a lower total sperm count than men of normal weight, and the measured volume of ejaculate decreased steadily with an increasing BMI. Among 1,558 Danish military recruits, there was a negative association between total sperm count and increasing BMI; there was also a consider able decrease in total sperm count and concentration.These findings have been corroborated by otherstudies although several reports exist of a considerable negative relationship between BMI and sperm count and concentration, some discrepancies have been noted; in these studies, a correlation between sperm count or concentration in obese men compared to controls was demonstrated, but was not deemed significant. Sperm motility Some consensus on the effects of obesity on sperm motility has been established, but overall there is no complete agreement. Hofny et al.found that the BMI correlated negatively with sperm motility, and Hammoud et al. concluded that the incidence of low progressively motile sperm count increased with increasing BMI. Fejes et al.concluded that the waist and hip circumference of men correlated negatively with the total motile sperm count as well as the rapid progressively motile sperm count. Despite this evidence,

not all studies have included sperm motility within their measurement parameters, and other studies have found no effect of BMI or obesity on sperm motility. DNA fragmentation Kort et al.45 found that an increase in the DNA fragmentation index (DFi) accompanied an increasing BMI, demonstrating that obesity might compromise the integrity of sperm chromatin. DFi is the percent of sperm in a semen sample that have increased levels of single or double strand breaks in nuclear DNA. a young and healthy man has about 35% of sperm with fragmented DNA while a level of 2530% DFi places a man attempting natural conception at a statistical risk for infertility. An increase in the BMI above 25 kg/m2 causes anincrease in sperm DFi and a decrease in the number of normal chromatin intact sperm cells per ejaculate, relative to the degree of obesity.Men with type 2 diabetes also present with a significantly higher number of severe structural defects in sperm compared with sperm from controls. Typically, males presenting with a high DFi will have reduced fertility and their partners will display an increased incidence of miscarriage asa consequence. Normal sperm morphology Measuring differences in the morphology of sperm between obese and normal weight men can be difficult owing to differences in what is classed as normalmorphology and high individual variability within indivi dual patient samples. However, most studies have shown no correlation between obesity and abnormal sperm morphology. Abnormal hormone profile o Decreased inhibin B Inhibin B is the most accurate marker for regular spermato genesis in all males, and so can be used to predict the quality of sperm and fertility of obese individuals. Inhibin B marks normal sertoli cell function and associated spermatogenic activity. Measurable decreases in inhibin B

levels are indicative of seminiferous tubule dysfunction, therefore subnormal levels clearly reflect irregular spermatogenesis. Studies carried out in normal monkeys revealed that inhibin B levels correlate positively with sertoli cell number (as well as function), and indicate that reduced levels of inhibin B in obese men are likely to signify fewer sertoli cells than in men of normal weight.The general consensus is that obese men have significantly lower than normal levels of inhibin B, and, indeed, inhibin B serum levels were 2532% lower in obese men compared with men of normal weight.This marked decrease in the most accurate marker of normal spermatogenesis indicates that the production of male gametesis seriously impaired in obese males.

o Decreased testosterone:estrogen A decrease in the testosterone:estrogen ratio is consistently displayed in obese infertile men. in a study by aggerholm et al.,obese men had 6% higher levels of estradiol and 2532% lower levels of testosterone than normal men. The severity of obesity determines the degree to which levels of estradiol are increased and testosterone decreased.The increased conversion of androgens into estrogens, which is characteristic of obesity, depresses the function of the pituitary gland by disturbing normal feedback in the testis 2.3.3 Treatment of Reroductive Disorder in the Obese 2.3.3.1 Weight Loss Treatments are aimed at correcting the imbalances that exist and allowing homeostasis to be restored. The first step is weight loss. Encouraging the patient to return to a more normal BMI often corrects the underlying hormonal imbalances allowing the menstrual cycle to restore itself. When the BMI moves closer to ideal, the peripheral production of estrone decreases, removing the inappropriate negative feedback on pituitary release of FSH. With the normal levels of FSH restored, ovulation can occur, or in the case of the male, normal spermatogenesis can commence or improve. it is important that treatment for infertility in obese men

differs from that of normalweight infertile men and that focus is placed on reproductive abnormalities that accompany or are associated with obesity. The unique physiological connections between obesity and the increased conversion of testosterone to estradiol, and the effect obesity has on suppressing GnrH release and spermatogenesis require different management when treating infertility in obese men.21 Studies carried out in subfertile females have shown that a reduction in obesity, particularly involving abdominal body fat, is associated with an improvement in reproductive function.Weight loss might be an obvious treatment to improve obesitylinked male infertility, but few controlled studies have been done to demonstrate any significant effects. Despite this lack of definitive evidence, there is general agreement among the few studies done. men who lost weight through natural (diet and/or exercise) methods experienced a high increase in androgen and inhibin B levels and an improvement in semen para meters.Kaukua et al.51 found that men who participated in a 4month weightloss program on a very low energy diet experienced increases in sHBG and testosterone, and decreases in the serum concentrations of insulin and leptin.21 Alternatives to weight loss as a means of regulating the menstrual cycle include oral contraceptives or cyclic progestins. By placing an anovulatory patient on oral contraceptives or giving her progestins on a monthly basis, one replaces the progesterone that the ovary fails to make when the ovulatory cycle is disrupted, and it is possible to lower the incidence of endometrial hyperplasia and carcinoma. Oral ontraceptives have the added advantage of lowering serum LH levels which lowers production of ovarian androgen. The estrogens in oral contraceptives stimulate the liver to increase production of SHBG and thereby lower the serum concentration of free androgens and improve hirsutism. Patients with insulin resistance can be placed on an insulin sensitizing agent to lower the serum level of insulin and alter its impact on ovarian androgen production through the IGF-II receptors. If patients are interested in having children, ovulation induction can be pursued through use of an estrogen receptor blocker, e.g. clomiphene citrate, which will inhibit the negative feedback of estrogen on the hypothalamus and pituitary and allow for increased FSH release. If this fails, FSH itself can be injected to induce

folliculogenesis. This can be combined with other therapies such as intrauterine insemination or in vitro fertilization (IVF). Studies on the effect of obesity on the response to ovarian stimulation have shown conflicting results, but overall they suggest that obesity has adverse effects. A retrospective study evaluating the outcomes in 5,019 IVF cycles revealed that obesity was associated with longer duration of the cycles, increased amounts of medications used, increased frequency of cancelled cycles, and lower numbers of oocytes retrieved. In another retrospective study of 3,586 IVF cycles, pregnancy rates were significantly lower in obese and very obese women compared to women who were not obese (OR 0.73, 95% CI 0.57 0.95 and 0.05, 95% CI 0.32 0.77 respectively)20

2.3.3.2 Managing hormonal imbalance Hormonal agonists If the patient presents with secondary infertility, successful current treatment options that might be considered involve a GnrH pump or human chorionic gonadotropin (HCG) injection, which acts as an lH analog in the testes,fostering testosterone production.Normal levels of lH stimulate the leydig cells to secrete testosterone, which might stimulate spermatogenesis. Aromatase inhibitors A new line of treatment that has undergone testing for the restoration of fertility in obese men has proven to be effective and less expensive than the use of the hormonalagonists mentioned above. aromatase inhibitors are designed to interfere with the aromatase P450 enzyme that is highly expressed in white adipose tissue. Currently available aromatase inhibitors include anastrozole and letrozole. Anastrozole treatment normalized the

testosterone:estradiol ratio and total testosterone levels, and improved semen parameters.Letrozole was reported to normalize serum testosterone levels in severely obese men with hypogonadotropic hypogonadism,59 and shortterm letrozole treatment normal ized serum testosterone levels in all obese men in a study carried out by loves et al.60 other studies have presented similar

findings using other aromatase inhibitors (for example, anastrozole). the

clinical significance of this intervention remains to be established in controlled, longterm studies. A case study by roth et al.10 confirmed that this line of treatment might also be effective in the treatment of infertility in morbidly obese men. a morbidly obese man (BMI 54.5 kg/m2) presenting with azoospermia as a consequence of months of testosterone replacement therapy to treat an expected hormonal imbalance was then treated with anastrozole. After as little as 2 months of therapy, positive treatment effects were seen; after 5 months, semen parameters and serum testosterone levels had normalized; and after 6 months of anastrozole therapy, his wife became pregnant. although this case is promising evidence for the use of aromatase inhibitors for obesitylinked male infertility, more data on the efficacy and safety of longterm treatment are still needed. 21

CHAPTER III CONCLUSION

Infertility is defined as one year of frequent, unprotected intercourse during which pregnancy has not occurred. There are two types of infertility, primary infertility and

secondary infertility. Obesity is defined as BMI of 30 kg/m2 or greater. Obesity has reached epidemic proportions globally and getting worse. There is association between obesity and infertility. Obesity make time for conception longer in women. Obesity is also a strong risk factor for polycystic ovarian syndrome. Obesity in adolescence and young adulthood is more strongly associated with amenorrhea, oligomenorrhea, and long menstrual cycles. Obesity decreases successful pregnancy rates in both natural and assisted conception cycles. In men, obesity increases incidence of oligospermia and azospermia, increase in the DNA fragmentation index , decreased inhibin B and decreased testosterone estrogen rasio. Management for infertility in obese population including weight loss and managing hormonal imbalance.

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