Sage Journals: Discover world-class research

Abstract

Obesity and overweight are common conditions that have consequences not only on general health but also to a great extent on reproductive health. There is a high prevalence of obese women in the infertile population and numerous studies have highlighted the link between obesity and infertility. Obesity contributes to anovulation and menstrual irregularities, reduced conception rate and a reduced response to fertility treatment. It also increases miscarriage and contributes to maternal and perinatal complication. Reduction of obesity, particularly abdominal obesity, is associated with improvements in reproductive functions; hence, treatment of obesity itself should be the initial aim in obese infertile women before embarking on ovulation-induction drugs or assisted reproductive techniques. While various strategies for weight reduction, including diet, exercise, pharmacological and surgical intervention exist, lifestyle modification continues to be of paramount importance.

Keywords

fertility fertility treatment obesity overweight

Obesity is a global issue. Despite efforts to confront it, the worldwide incidence of obesity continues to escalate [1]. The WHO estimates that approximately one billion people throughout the world are overweight and that over 300 million of these are obese. If current trends continue, the number of overweight persons will increase to 1.5 billion by the year 2015. The number of obese adults in Australia is estimated to have risen from 2 million in 1992 to 3.1 million in 2005 [2]. What contributes to the problem of obesity mainly stems from the imbalance between reduced exercise, overindulgence in energy-dense dietary intake, changing lifestyle and dietary composition. It has been known that obesity is related to systemic diseases such as diabetes mellitus, cardiovascular diseases, hyperlipidemia, sleep apnea, cancers and osteoarthritis.

Female obesity has a great impact on reproductive function and the hormonal milieu. As far back as 1934, the association between obesity and infertility was recognized when Irving Stein and Micheal Leventhal described a triad consisting of obesity, hirsutism and infertility: the ‘Stein–Leventhal Syndrome’ [3]. Overweight and obese women have more problems of menstrual irregularities, chronic or intermittent anovulation, infertility, signs of androgen excess, increased risk of miscarriages and hormone-sensitive carcinomas [4 –6]. In the Million Women Study, it was noted that increasing BMI was associated with an increased incidence of endometrial carcinoma (relative risk [RR] = 2.89; 95% CI: 2.62–3.18). Obesity also has important implications for the delivery of obstetric care. It is well recognized that maternal obesity is associated with an increased risk of maternal, peripartum and neonatal complications [7].

Defining obesity

Total body fat can be measured precisely using skin fold thickness, underwater weighing, dual energy x-ray absorptiometry (DEXA), MRI and infrared spectroscopy [8]; however, its usage is limited for research purposes. In daily clinical use, more simple measures are used to assess the degree of obesity including BMI (Table 1), waist circumference (WC) and waist–hip ratio (WHR). Central adiposity is particularly important in clinical sequelae associated with an increased BMI. In both male and female sexes, obesity, and in particular, the abdominal obesity phenotype, may impair fertility. Generally, a WHR of more than 0.9 for men and more than 0.8 for women defines an increased risk of cardiovascular disease. Also, in women with a WHR of more than 0.8, it was noted that the RRS of irregular menstruation and oligomenorrhea were 1.56 and 2.29, respectively [10]. In a prospective cohort study on women attending infertility clinics and requiring donor insemination, a high WHR was associated with a markedly lower conception rate [11]. A unit increase of 0.1 in WHR led to a 30% decrease in probability of conception per cycle (hazard ratio: 0.76; 95% CI: 0.562–0.887) after adjustment for age, size, reasons for artificial insemination, cycle length and regularity, smoking and parity. Emerging scientific interest has increased our understanding of the main metabolic and hormonal factors involved in the pathophysiology of different obesity phenotypes. Although for a long time it was suggested that these alterations were secondary to obesity, it has recently become evident that they conversely play a role in the development of different obesity phenotypes and associated metabolic abnormalities [12].

Table 1.

Classification of overweight in adults according to BMI.

Classification	BMI (kg/m²)	Risk of comorbidities
Underweight	<18.5	Low (but risk of other clinical problems increased)
Normal	18.5–24.9	Average
Overweight	> 25
Pre-obese	25–29.9	Increased
Obese class I	30–34.9	Moderate
Obese class II	35–39.9	Severe
Obese class III	> 40	Very severe

Adapted from [9].

Obesity & polycystic ovarian syndrome

Most obese women with infertility and signs or symptoms associated with androgen excess are affected by polycystic ovarian syndrome (PCOS), whose prevalence rates are suggested to be approximately 5–7% in western countries [13]. Prevalence of PCOS varies worldwide and this is mainly because different criteria are used for the diagnosis and there is also substantial heterogeneity of symptoms and signs among women with PCOS. Following a consensus held in Rotterdam, The Netherlands in 2003, an internationally accepted definition has been adopted by the European Society for Human Reproduction and Embryology and the American Society for Reproductive Medicine, known as the ESHRE/ASRM Rotterdam consensus [14]. Diagnosis of PCOS requires the presence of two of the following three diagnostic criteria:

Oligo- and/or an-ovulation

Clinical and/or biochemical evidence of hyperandrogenism

The presence of polycystic ovarian morphology on ultrasound

While the pathogenesis leading to the development of PCOS is not completely understood, it is increasingly recognized that in the majority of women with PCOS, insulin resistance and compensatory hyperinsulinemia plays an important role. Essentially, insulin resistance has a complex genetic and environment etiology. Insulin resistance appears to be selective with impaired glucose uptake, whilst other intracellular actions of insulin are preserved. At the ovarian level, by acting primarily through its own receptor and the IGF-1 receptor, insulin synergizes luteinizing hormone action and stimulates ovarian steroidogenesis both in thecal and granulosa cells [15]. Over a third to half of PCOS subjects are overweight or obese [16]. In PCOS women of Caucasian origin, it is noted that the severity of both metabolic and clinical symptoms is positively correlated with the BMI [16]. There is also evidence showing that even normal-weight PCOS women present with the abdominal phenotype of fat distribution [17]. Obesity acts as an amplifier of insulin resistance and hyperinsulinemia. The abdominal phenotype further worsens this. Obesity is therefore suggested as playing a specific pathophysiological role in the development of PCOS [18].

Obesity, menstrual disorders & infertility

The association between obesity and menstrual irregularities has been recognized. Obesity was present at a fourfold higher rate in women with menstrual irregularities compared with normally menstruating females [19]. Historical data from 26,638 women, aged 20–40 years, were used to study the association between obesity and menstrual abnormalities, including evidence of infertility. It was found that women with evidence of anovulatory cycles, in other words, irregular cycles greater than 36 days and hirsutism, were more than 30 lb (13.6 kg) heavier than women with no menstrual abnormalities after adjusting for height and age [19]. In adolescents and young women, the age of onset of obesity and that of menstrual irregularities are significantly correlated. In the 1958 British birth cohort, Lake et al. tracked 5799 females at the ages 7, 11, 16, 23 and 33 years and noted that obesity in childhood and early twenties increased the risk of menstrual problems [20]. Obesity at 23 years and obesity at 7 years both independently increased the risk of menstrual problems by age 33 years (odds ratio [OR] = 1.75; OR = 1.59, respectively) after adjusting for other confounding factors. Women who were overweight and obese at 23 years of age were less likely to conceive within 12 months of unprotected intercourse after adjustment for confounders (RR = 0.69). Overweight and obesity in early adulthood appears to increase the risk of menstrual problems and subfertility. There are also several epidemiological studies that suggest changes in bodyweight are critical factors regulating pubertal development in young women. A few studies have reported that obese girls had their menarche earlier than normal-weight girls. Similarly, the onset of ovarian failure and menopause occurs several years earlier in obese women than in normal-weight women [21].

The link between obesity and infertility is complex. The available knowledge supports the concept that androgen alterations and their balance with estrogen represent the most important mechanism responsible for the development of subfertility or infertility in obese women. Sex hormone binding globulin (SHBG) is a protein carrier that binds testosterone and dihydrotestosterone with high affinity and estrogens with a lower affinity. The degree of obesity is inversely related to SHBG levels. In addition, body fat distribution further influences SHBG concentrations. Females with central adiposity have lower SHBG concentrations in comparison with peripheral obesity [22], therefore the percentage of free testosterone fraction tends to be higher in women with central obesity. In addition, the adipose tissue is a site of active androgen production, converting androgens into estrogens, and of androgen and estrogen inter-conversion, which largely depends on the amount of fat [22]. Increased androgen production and reduced binding of androgens to SHBG contribute to hyperandrogenism, resulting in anovulation through inhibition of follicular maturation.

Hormones regulating energy metabolism have been shown to exert different effects on several reproductive events. The roles of insulin and insulin-like growth factors have been studied extensively and are well known for their effects on reproductive events, such as ovarian steroidogenesis, folliculogenesis and ovulation physiology. Insulin resistance plays a key pathogenic role in PCOS, and insulin-sensitizing drugs are now widely used to induce ovulation and improve fertility in these women [23].

In addition to insulin, novel hormones, such as leptin, ghrelin, adiponectin, resistin and peptide YY3–36 have been discovered as important regulators of appetite and energy homeostasis [24,25]. The close relationship between energy metabolism, nutritional state and reproductive physiology suggests that disorders or alterations in nutritional state (obesity, malnutrition, anorexia nervosa and so on) and metabolic disturbances can disrupt the complex interplay of gonadotropins and gonadal hormones, which are essential for fertility. Recent research has demonstrated that leptin plays an integral role in the normal physiology of the reproductive system with complex interactions at all levels of the hypothalamic–pituitary–gonadal axis. Observational studies have demonstrated that levels of leptin excess, deficiency or resistance can be associated with abnormal reproductive function [26]. Increased body weight and fat tissue substantially disrupt menstrual pattern and fertility potential. In obese women, weight loss alone improves insulin resistance and promotes fertility.

In addition, expression of leptin, ghrelin and their receptors in various reproductive organs, such as the ovary, testis, endometrium, embryo and placenta, have been demonstrated to have important roles in different stages of embryo development and implantation [26,27].

The Nurses' Health Study in 1994 compared 2527 married nulliparous nurses unable to become pregnant for at least 1 year owing to ovulatory disorder with controls comprising of 46,718 married parous nurses with no history of infertility [28]. The risk of ovulatory infertility for women at different BMI levels at age 18 years was compared with that for women at 18 years whose BMI was 20–21.9 (median for the cohort). Logistic regression was used to adjust for other confounding variables. Multivariate relative risks for infertility were: 1.2 (BMI: <16), 1.1 (BMI: 16–17.9), 1.0 (BMI: 18–19.9), 1.0 (BMI: 20–21.9), 1.1 (BMI: 22–23.9), 1.3 (BMI: 24–25.9), 1.7 (BMI: 26–27.9), 2.4 (BMI: 28–29.9), 2.7 (BMI: 30–31.9) and 2.7 (BMI: >32). These findings suggested that an elevated BMI at age 18 years, even at levels lower than those considered to be obese, is a risk factor for subsequent ovulatory infertility. More recent data from this group show that ovulatory infertility can be largely attributed to overweight and sedentary lifestyle [29]. Recent data by Gesink Law et al. from his study on more than 7327 pregnant women enrolled in the Collaborative Perinatal Project at 12 study centers in the USA showed that fecundity was reduced for overweight (OR: 0.92; 95% CI: 0.84, 1.01) and obese (OR: 0.82; 95% CI: 0.72, 0.95) women compared with optimal-weight women and was more evident for obese primiparous women (OR = 0.66; 95% CI: 0.49, 0.89) [30].

Obesity & infertility treatment

Most studies demonstrate conclusive evidence that increasing BMI is associated with an increased requirement of drugs to induce ovulation. Large doses of clomiphene of up to 200 mg per day were required to ensure ovulation in the heaviest women [31]. Similar trends were also observed in doses of gonadotrophins required to induce ovulation [32,33]. In a study of 335 women with WHO group ll anovulatory infertility [34], it was noted that with increasing BMI, a higher threshold dose of gonadotrophins was required (odds for needing a higher dose more than 75 IU was 1.47 [95% CI: 0.84–2.55] and 2.15 [95% CI: 1.17–3.94] for overweight and obese women, respectively) and there were more days of stimulation (OR: 1.8; 95% CI: 0.32–3.27 and OR: 2.91; 95% CI: 1.21–4.6) for overweight and obese women, respectively. In another study by Fedorcsak et al. involving 2660 IVF/intracytoplasmic sperm injection (ICSI) cycles, there was a positive correlation between BMI and the total follicle-stimulating hormone (FSH) required [35]. The higher the BMI, the more FSH is required for ovarian stimulation. Although the starting dose of FSH was not fixed in this report, the correlation between BMI and the length of stimulation suggests that the differences in FSH requirement were not caused solely by a deliberate subscription of higher FSH doses in obese women. Therefore, obesity represents a condition of resistance to agents used to stimulate ovulation. Linear association was observed between higher BMI and longer stimulation with FSH (p < 0.001), requirement for increased total doses of FSH (p < 0.001), increased frequency of cycle cancellations owing to insufficient follicular development (p < 0.001) and a lower number of collected oocytes (p < 0.001).

The value of obesity as a predictor of infertility treatment outcome is controversial. While some studies reported a decrease in pregnancy and implantation rates in obese women [35 –37], others reported no effects of extreme body weights [33,38]. Conflicting results may be related to the type of treatment, inconsistent definitions of obesity and smaller size of cohorts observed. In a study by Wang et al. on a large cohort of women seeking infertility treatment (n = 3586), it was noted that weight had a significant correlation on the outcome of assisted reproductive technique, with a significant linear reduction in fecundity from the moderate group to the very obese group (p < 0.001). The fecundity of the moderate group was almost 60% higher than that of the very obese group. Not only that, it was observed that bodyweight has an ‘inverted U’ effect on reproduction, which means that being either underweight or overweight has a deleterious effect on assisted reproductive techniques (ART) outcome [36].

There is evidence for an increased risk of miscarriage in obese women. Lashen et al. conducted a nested case–control study in which obese (BMI: > 30kg/m²) women were compared with an age-matched control group with normal BMI (19–24.9 kg/m²) [39]. A total of 1644 obese and 3288 age-matched normal-weight controls with a mean age of 26.6 years (95% CI: 26.5–26.7) were included in the study. The risk of early miscarriage was significantly higher among the obese patients (OR: 1.2; 95% CI: 1.01–1.46; p = 0.04). These data confirm that increasing obesity significantly reduces the chance of successful pregnancy. Obesity is also a risk factor for early miscarriage after assisted reproduction. Fedorcsak et al. noted that obesity was associated with an increased risk of early pregnancy loss occurring before 6 weeks gestation [40]. In another retrospective study on a large cohort of women (n = 2349) who were pregnant following ART [41], the overall incidence of spontaneous abortion was 20%. Compared with women with normal BMI, there was progressive increase in risk of spontaneous abortion in overweight, obese and very obese groups (OR: 1.29, [95% CI: 1.00–1.66]; OR: 1.71; [95% CI: 1.20–2.43] and OR: 2.19; [95% CI: 1.27–3.78] in the overweight, obese and very obese, respectively).

The poor reproductive performance in obese women, both in natural and assisted conception cycles, may be a result of a combination of lower implantation and pregnancy rates, higher preclinical and clinical miscarriage rates, and increased complications in pregnancy for both mother and fetus. These have been related to various endocrine and metabolic disturbances, such as effects on steroid metabolism and alterations in the secretion and action of insulin and other hormones, such as leptin, resistin, ghrelin and adiponectin [24], which may affect follicle growth, corpus luteum function, early embryo development, trophoblast function and endometrial receptivity.

The question remains as to the mechanism by which obesity may affect fecundity in women. Is it exclusively an ovarian effect, endometrial effect or a combined effect? The oocyte donation model is unique. By restricting study to oocytes donated by normal-weight women, the effect of obesity on oocyte development was eliminated, thus permitting an assessment of the extraovarian effect of excess bodyweight on successful pregnancy outcomes. However, data regarding the effects of BMI on the oocyte donation model are conflicting. While two authors observed no association between BMI, pregnancy rate and loss rate in oocyte donation cycles [42,43], others noted obesity to be an independent risk factor for miscarriage in women receiving donated oocytes [44,45]. Bellver et al., in his recent publication, studied 2656 first IVF cycles of ovum donation using good-quality embryos [36]. The recipients were divided into groups according to BMI: less than 20 kg/m² (n = 471), 20–24.9 kg/m² (n = 1613), 25–29.9 kg/m² (n = 450), and greater than or equal to 30 kg/m² (n = 122). The rates of implantation, pregnancy and miscarriage were similar among the BMI groups, although there was a negative trend when BMI increased. However, the ongoing pregnancy rates per cycle were poorer in the overweight and obese groups than in the underweight and normal groups. When the cut-off point of 25kg/m² was taken into account, the ongoing pregnancy rate per cycle initiated was significantly reduced in the overweight and obese groups (from 45.5% with <25kg/m² to 38.3% with >25kg/m², p = 0.002). The OR of ongoing pregnancy per started cycle among BMI groups was 0.85 (95% CI: 0.76–0.95, p = 0.003), showing a significant trend to decrease as BMI increased.

The ovary is not the only factor responsible for the poor reproductive outcome in obese patients: the endometrium or its environment also contributes to this discouraging prognosis, but in a more subtle manner. Thus, on the basis of many complications in pregnancies with obesity, it is justifiable to advise weight reduction in women contemplating pregnancy whether it is a cycle with their own oocyte or donated oocyte. The impact of obesity on reproduction is summarized in Table 2.

Table 2.

Impact of obesity on reproduction.

Condition	Associated risks
Menstruation and menorrhagia	↑ risk of menstrual dysfunction: amenorrhea, oligomenorrhea
Infertility	↑ risk ovulatory and anovulatory infertility
Infertility drug	↑ requirement for clomiphene/gonadotropin in ovulation induction and poor response to fertility drugs
Infertility treatment	↓ success rate for IVF/ICSI/GIFT pregnancies
Miscarriage	↑ risk of miscarriage, spontaneously or following treatment

GIFT: Gamete intrafallopian transfer; ICSI: Intracytoplasmic sperm injection.

Obesity & prioritizing fertility treatment

In many countries, IVF is still considered very costly and unaffordable to many patients. In New Zealand, balancing the cost and outcomes together, the New Zealand Ministry of Health restricted access to publicly funded IVF and ICSI using the clinical priority access criteria (CPAC) approach. Seven separate criteria were developed to select the couples with the worst prognosis for spontaneous conception for treatment priority [46]. The introduction of the CPAC model has allowed greater and fairer access to ARTs in New Zealand. Since obesity was considered to reduce a women's chance of successful ART, the CPAC could only be applied to women who were inside the BMI 18–32 kg/m² range. Women outside this range were only accepted on the basis that they had undergone weight improvement to within the agreed range. After 5 years of implementation, data from 1280 referred cases were analysed. A total of 38% of women with a BMI more than 32 kg/m² had a birth following a treatment-related pregnancy or spontaneous pregnancy, compared with 52% of women with a BMI less than 32 kg/m² [47]. The recent guidelines by UK NHS and British Fertility Society limiting ART services to those women with BMI less than 36 kg/m² is another example of the influence of obesity on decisions regarding ART provision [101].

Obesity & obstetric problems

An overweight maternal condition exists in more than 20% of all pregnancies and represents a major public health issue because of the numerous known pregnancy risks and complications [48]. A study that was conducted on 25,601 Finnish women with singleton pregnancies noted that pregnancy outcomes were impaired in overweight and obese patients with respective ORs as follows: low Apgar score at 5 min (OR: 1.54 [95% CI: 1.20–1.98] and OR: 1.64 [95% CI: 1.22–2.28], respectively), newborn admission to intentive care unit (OR: 1.20 [95% CI: 1.06–1.37] and OR: 1.38 [95% CI: 1.17–1.61], respectively), cesarean delivery (OR: 1.22 [95% CI: 1.10–1.35] and OR: 1.68 [95% CI: 1.48–1.91], respectively), perinatal death (OR: 1.54 [95% CI: 0.98–2.42] and OR: 2.19 [95% CI: 1.33–3.62], respectively). It is noted clearly in this large retrospective study that transition from overweight to obesity worsens pregnancy outcome in a BMI-dependant manner. Transition from overweight to obese condition also doubles the risk of perinatal death [48].

In another large review, involving 18,401 women who were booked for antenatal care in Queensland, Australia [49], it was noted that as BMI increases, cesarean section rates, maternal morbidity, neonatal morbidity, neonatal intensive care utilization and length of hospital stay all increase. There was also a doubling of birth defects from 1.9% in women with a BMI of 30–40kg/m² to 4% in women with a BMI above 40kg/m² (Table 3). Data from the Atlanta Birth Defects Risk Factor Surveillance Study from January 1993 until August 1997, noted that obese women were more likely than average-weight women to have an infant with spina bifida (unadjusted OR: 3.5; 95% CI: 1.2–10.3), omphalocele (OR: 3.3; 95% CI: 1.0–10.3), heart defects (OR: 2.0; 95% CI: 1.2–3.4), and multiple anomalies (OR: 2.0; 95% CI: 1.0–3.8) [50]. Overweight women were more likely than average-weight women to have infants with heart defects (OR: 2.0; 95% CI: 1.2–3.1) and multiple anomalies (OR: 1.9; 95% CI: 1.1–3.4). Several epidemiologic studies have suggested that being overweight before pregnancy is a risk factor for neural tube defects (NTDs) [51,52]. BMI of more than 29kg/m² doubles the risk of NTDs (OR 1.9; 95% CI: 1.1–3.4) [52]. Werler et al. compared 604 fetuses or infants with a NTD with 1658 fetuses or infants with other major malformations, all diagnosed within 6 months of delivery [53]. Compared with mothers weighing 50–59 kg, the RR of NTDs increased to 1.9 (95% CI: 1.2–2.9) for women weighing 80–89 kg and to 4.0 (95% CI: 1.6–9.9) for women weighing 110 kg or more. When women were classified according to daily intake above or below the recommended level of 400 μg of folate, an approximately threefold increase in risk was estimated for the heaviest weights in both groups. Intake of 400 μg or more of folate reduced the risk of NTDs by 40% among women weighing less than 70 kg, but no risk reduction was observed among heavier women [53].

Table 3.

Adjusted odds ratio for maternal, peripartum and neonatal outcomes, according to BMI.

	Normal (BMI 20.01–25)	Overweight (BMI 25.01–30)	Obese (BMI 30.01–40)	Morbidly obese (BMI >40)
Maternal outcomes
Hypertensive disease of pregnancy	1.00	1.74	3.00	4.87
Gestational diabetes	1.00	1.78	2.95	7.44
Caesarean section	1.00	1.50	2.02	2.54
Neonatal outcomes
Stillborn	1.00	1.16	1.19	0.89
Birth defect	1.00	1.26	1.58	3.41
Hypoglycaemia	1.00	0.78	2.57	7.14
Admission to intensive care	1.00	0.92	1.25	2.77

Adapted from [50].

The supposed mechanisms that increase the congenital anomaly rates include insulin resistance and its consequence, incipient hyperglycemia. In addition, the increased risk of congenital malformations, in particular NTDs, in children of obese women can be explained by difficulties in visualization when making the ultrasound scan and missing adjustment for weight when measuring biochemical markers [54].

Thus, preventive measures should be taken with overweight teenagers before their first pregnancy, and delivery wards should have an essential role in identifying women at high risk in their next pregnancy as a result of obesity. Modest weight loss would bring substantial advantages to the obstetric outcomes of these women.

Managing obesity

Treatment of obesity itself should be the initial aim in obese infertile women before embarking on ovulation-induction drugs or ART. Reduction of fat and abdominal fat should result in improved menstrual function and fertility and a reduction of metabolic risks. A reduction of 2–5% in body weight was associated with restoration of ovulation, an 11% reduction in abdominal fat, a 4 cm reduction in WC and a 71% increase in insulin sensitivity [55]. Weight loss results in an increase in SHBG, reduction in testosterone, improved menstrual function, improvement in conception rate and reduction in miscarriage rate. As central adiposity is associated with menstrual disorders and infertility, abdominal fat loss is critical in restoring ovulation.

Various strategies have been suggested to overcome the problem of obesity. Amongst these are dietary management, physical activity, behaviour modification, pharmacologic treatment and surgery. The issues are the long-term compliance to these strategies and maintaining the weight loss. The NIH recommends a multifaceted approach to treating obesity [56]. It emphasizes the importance of achievable and sustainable goals, notably a combination of diet, physical activity and behavior therapy (Box 1).

Dietary treatment

Bates and Whitworth were the first to show a reduction in plasma androgens with dieting, and associated return of menstrual cycle [57]. Subsequently other studies investigating dietary manipulation in subjects with obesity and PCOS [57], demonstrated that strict calorie restriction with 5% or greater weight loss led to changes in insulin, insulin-like growth factor, SHBG and menstruation.

Box 1.

NIH clinical guidelines for long-term treatment of overweight and obesity.

Sensible diet and changed eating habits for the long term

Effective physical activity programme sustainable long term

Behaviour modification, reduction of stress, well being

Social support by physician, family, spouse and peers

Smoking cessation and reduction in alcohol consumption

Avoidance of ‘crash diets’ and short-term weight loss

Minor roles for drugs involved in weight loss

Avoidance of aggressive surgical approaches for majority

Adaptation of weight loss programme to meet individual needs

Long-term observation, monitoring and encouragment of patients who have successfully lost weight

Adapted from [57].

The key component of diet should be calorie restriction rather than the composition of the diet itself. Dietary intervention in managing obesity should aim for gradual weight loss via reduced calorie consumption and increased physical activity, with the overall aim of energy expenditure exceeding energy intake. Sensible eating plans, tailoring to individual weight and current dietary and exercise pattern, increase the chance of sustained weight loss. Diets based on healthy eating principles have a better long-term outcome, which is important because weight-loss maintenance requires that changes in eating habits be sustained for life (Box 2) [59].

Lifestyle modification

Lifestyle modification is of paramount importance in achieving and maintaining weight loss. Dietary management with lifestyle modification as an objective should be adopted initially, with pharmacological and other surgical/medical interventions reserved for use when weight loss regimes have proved unsuccessful. Exercise should be an integral component in any weight-loss programme. Exercise increases insulin sensitivity both by acting directly on muscle metabolism [60] and indirectly by assisting in weight management [61].

Other lifestyle issues that need to be addressed are smoking, alcohol consumption and stress-related environment. Smoking is a major risk factor for reduced fertility in women, with consequences including extended time to pregnancy, preterm birth and low birth weight [62]. High levels of alcohol intake have been associated with reduced fertility and increased risk of spontaneous abortion [63]. Therefore, cessation of smoking, cessation or reduction of alcohol and reduction of psychosocial stressors are important issue that need to be addressed.

An analysis of the Nurses' Health Study, which began in 1976 and enrolled 121,700 female nurses who were followed by questionnaire biannually, clearly demonstrated the role of diet and lifestyle in the risk of development of Type 2 diabetes. Women were free of cardiovascular disease, diabetes and cancer at baseline and were followed up over 16 years. Overweight and obesity was the single most important predictor of development of diabetes. However, lack of exercise, a poor diet and smoking were all associated with a significantly increased risk of diabetes even after adjusting for BMI [64].

Box 2.

Dietary management for weight loss.

Energy deficit of 500–600 kcal/day

Low fat (30% of energy), moderate protein (15%) and high carbohydrate (55%)

Increased nonrefined carbohydrate, such as wholegrain bread and cereals

Increased fruits and vegetables

Low-glycemic index food may aid weight loss through increased satiation

No evidence for the strategy of increasing dietary protein to replace carbohydrate

Clark et al. conducted a study involving lifestyle modification through behavioral changes in relation to diet, exercise and stress management [65]. They noted that menstrual regularity can be restored and pregnancy achieved by lifestyle modification without so much emphasis on calorie restriction. In their follow-up study of 67 women [66], 60 resumed ovulation after weight reduction through 6 months of lifestyle modification and 18 became pregnant spontaneously. Huber-Buchholz et al. used a lifestyle modification approach that resulted in very modest weight reduction [55]. In the 18 subjects with PCOS and anovulation, nine became regularly ovulatory with weight loss ranging from 2 to 5%. Moran et al. demonstrated improvements in ovulation and menstrual status in 11 out of 25 women treated with dietary intervention resulting in weight loss [67].

Overall, the weight of evidence supports the role of lifestyle modification in weight reduction with a corresponding improvement in reproductive function. A group environment provides support and could make it easier for patients to implement these lifestyle changes [59].

Pharmacological treatment

Pharmacotherapy for the management of obesity is primarily aimed at weight loss, weight-loss maintenance and risk reduction, and has included thyroid hormone, phenylpropanolamine, mazindol, fenfluramines and, more recently, sibutramine and orlistat. These agents decrease appetite, reduce absorption of fat or increase energy expenditure. However, studies evaluating the long-term efficacy of anti-obesity agents are limited. Longer and more methodologically rigorous studies of anti-obesity drugs that are powered to examine the long-term effect and end points such as cardiovascular morbidities are awaited [68]. Despite rapid strides toward an ideal anti-obesity agent, the role of diet, exercise and behavior modification must be considered the cornerstone for any potential future pharmacotherapy.

Given the importance of hyperinsulinemia in the development of hyperandrogenism and disrupted folliculogenesis in obesity and PCOS, the use of insulin-sensitizing drugs seems reasonable in order to facilitate spontaneous ovulation and restore fertility. The most extensively studied insulin-lowering agent in the treatment of PCOS is metformin. Metformin is a biguanide oral antihyperglycemic agent that has been extensively used in the treatment of Type 2 diabetes mellitus. It lowers blood glucose mainly by inhibiting hepatic glucose production and increase in the peripheral glucose uptake. Several other actions may contribute to this effect, such as increased intestinal use of glucose and decreased fatty acid oxidation. Therefore, metformin can reduce peripheral insulin concentrations and improve glucose tolerance and metabolism. There are also preliminary in vitro data indicating that metformin may directly decrease ovarian androgen production. Tang et al. in a study on the effect of metformin compared with a combination of metformin and lifestyle modification [69], concluded that metformin alone does not improve weight loss or menstrual frequency in obese patients with PCOS. Weight loss alone through lifestyle changes improves menstrual frequency.

A meta-analysis of 13 randomized trials [70] comparing metformin with placebo or metformin plus clomiphene with clomiphene alone in women with PCOS concluded that metformin increased the ovulation rate by a factor of approximately four. It was discovered that pregnancy rate did not differ significantly between metformin and placebo, but pregnancy rates for metformin plus clomiphene were significantly higher than for clomiphene alone. However, in a multicenter, randomized trial involving 20 Dutch hospital and 228 patients, Moll concluded that metformin is not an effective addition to clomiphene citrate as the primary method of inducing ovulation in women with PCOS [71]. The ovulation rate in the metformin/clomiphene group was 64% compared with 72% in the clomiphene/placebo group, a nonsignificant difference. In a larger study, which involved 626 infertile women with PCOS assigned to either clomiphene, metformin or combination therapy, Legro et al. noted that although ovulation rate in the combination-therapy group was significantly higher than that in the other groups, the increase did not translate into a higher live birth rate [72]. He concluded that clomiphene is superior to metformin in achieving live birth in infertile women with PCOS, although multiple pregnancies are a complication.

Surgical treatment

In women with morbid obesity failing other interventions, weight loss may be induced with surgical intervention. Bariatric surgery today is the only effective therapy for morbid obesity. Bariatric operations are either restrictive, limiting the amount of food ingested; malabsorptive, limiting the amount of nutrient absorbed; or a combination of both [73]. Bariatric surgery dates back to the 1950s when jejunoileal bypass was introduced. Since then, numerous improvements have been made in procedures and techniques. Currently, the two most common bariatric procedures performed are laparoscopic adjustable gastric banding and laparoscopic Roux-en-Y gastric bypass. Both of these operations provide excellent results [74,75], with the majority of patients losing more than 50% of their excess weight and with most obesity-related comorbidities, such as diabetes and hypertension, reversed or prevented [76]. Morbidly obese patients considering such operations have to meet a strict criteria and must be evaluated by a multidisciplinary team. However, they would still need to commit to long-term dietary changes, behavioral modifications and medical supervision.

Eid et al. evaluated the outcomes of 24 women diagnosed with PCOS who had undergone weight loss surgery between July 1997 and November 2001 [77]. All of the women studied resumed normal menstrual cycles after a mean of 3.4 ± 2.1 months postoperatively. Five women had spontaneous conception after the surgery without the use of clomiphene. Tietelman et al. noted the effect of bariatric surgery on 98 patients who were anovulatory preoperatively [78]. A total of 70 patients (71.4%) regained normal menstrual cycles after surgery. Those patients who regained ovulation had greater weight loss than those who remained anovulatory (61.4 kg vs 49.9 kg, p = 0.02). Anovulation resulting in abnormal menses is a common problem in morbidly obese premenopausal women. The menstrual cycle disorders may completely resolve after bariatric surgery. Gastric bypass surgery and its consequent weight loss results in a significant improvement of menstrual problems and PCOS-related fertility. Thus, infertility owing to anovulation among morbidly obese women could potentially be viewed as an additional indication for bariatric surgery if other simple measures failed.

Executive summary

Obesity in women

Obesity is related to many systemic diseases and abnormalities in hormonal and reproductive function.

Obesity can be measured clinically by body mass index (BMI), waist circumference and waist–hip ratio. Waist–hip ratio greater than 0.8 defines an increased risk of cardiovascular disease and reduce cumulative pregnancy rate.

Obesity & PCOS

30–50% of PCOS women are overweight or obese. Obesity, particularly abdominal obesity amplifies hyperinsulinemia.

Obesity & reproduction

Obesity is related to menstrual abnormalities; amenorrhea, oligomenorrhea and menorrhagia are fourfold higher in obese women.

Obesity also contributes to anovulatory and ovulatory infertility via altered imbalance between estrogen, androgen and SHBG.

Hyperandrogenism and hyperleptinemia are also related to anovulatory and ovulatory infertility in obese women.

Obesity & assisted reproduction

Obesity is associated with a lower chance of live birth after IVF/intracytoplasmic sperm injection and with an impaired response to ovarian stimulation.

Obesity reduces the likelihood that a woman will be accepted for assisted reproductive techniques (ART) treatment, particularly in a nationally funded situation.

Obesity & obstetric care

Overweight and obesity increases obstetric risks in a BMI-dependent manner. The risk of perinatal death and congenital abnormalities double in the obese mother.

Managing obesity

Weight loss improves menstrual regularity, ovulation and fertility, and should be promoted as an initial treatment option for obese women with infertility. Only 3–5% weight loss is required.

Lifestyle modifications are the best way to achieve and sustain weight loss. These include sensible dieting, regular exercise, cognitive behavior therapy and a supportive group environment.

Pharmacological & surgical intervention

Pharmacologic intervention with metformin is not superior to clomiphene to induce ovulation and pregnancy/live birth rate in obese PCOS women.

Surgical intervention should be reserved if other measures of weight reduction fail. Although effective, it must be used together with dietary modifications and behavioral changes.

Future perspective

With an escalating figure of obesity worldwide, research in this area will definitely continue. While evidence from experimental, clinical and genetic research supporting the hypothesis for the fetal origins of PCOS has been documented, little is known about the possible contribution of ‘fetal programming’ to obesity. More research is needed at the molecular level to understand hormonal and biochemical associations with different obesity phenotypes. As obesity is not just an adult disease, with more children suffering from the problem lately, interventions in early life may have a great impact on adult health. Long-term follow up of childhood obesity and the impact of early interventions for weight reduction on the adult manifestation of reproductive disease is awaited. While it is acknowledged that obesity has a clear association with ART outcome, more research is needed to elucidate the mechanism underlying it, particularly to differentiate between endometrial or ovarian effect. Finally, there is no doubt that search for the ‘magic bullet’ to treat obesity will continue, but the importance of diet, exercise and lifestyle modification must continue to be the cornerstone of obesity management.

Footnotes

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

References

Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.

World Health Organization: Obesity preventing and managing the global epidemic. Report of a WHO consultation on Obesity WHO/NUT/NCD 98.1. World Health Organization, Geneva, Switzerland (1997).

Kouris-Blazos

Wahlqvist

: Health economics of weight management: evidence and cost. Asia Pac. J. Clin. Nutr. 16(l), 329–338 (2007).

Stein

Leventhal

: Amenorrhea associated with bilateral polycystic ovaries. Am. J. Obstet. Gynecol. 29, 181–191 (1934).

Kirschner

: Obesity, androgens, oestrogens, and cancer risk. Cancer Res. 42, 3281–3285 (1982).

Bjorge

Engeland

Tretli

: Body size in relation to cancer of the uterine corpus in 1 million Norwegian women. Int. J. Cancer. 120(2), 378–383 (2007).

Reeves

Pirie

Beral

: Cancer incidence and mortality in relation to body mass index in the Million Women Study: cohort study. BMJ 335(7630), 1134 (2007).

Wolfe

: High prepregnancy body mass index- a maternal-fetal risk factor. N. Engl. J. Med. 338, 191–192 (1998).

Moyad

: Current methods used for defining, measuring, and treating obesity. Semin. Urol. Oncol. 19(4), 247–256 (2001).

10.

Siedell

: The impact of obesity on health status: some implications for health care costs. Int. J. Obes. Relat. Metab. Disord. 19 (6), S13–S16 (1995).

11.

Hartz

Rupley

Rimm

: The association of girth measurements with disease in 32, 856 women. Am. J. Epidemiol. 119, 71–80 (1984).

12.

Zaadstra

Seidell

Van Noord

: Fat and female fecundity: prospective study of effect of body fat distribution on conception rates. Br. Med. J. 306, 484–487 (1993).

13.

Wajchenberg

: Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr. Rev. 21, 697–738 (2000).

14.

Ehrmann

: Polycyctic ovary syndrome. N. Engl. J. Med. 352, 1223–1236 (2005).

15.

The Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycyctic ovary syndrome. Hum. Reprod. 19, 41–47 (2004).

16.

Pasquali

: Obesity, fat distribution and infertility. Maturitas 54, 363–371 (2006).

17.

Balen

Conway

Kaltsas

: Polycystic ovary syndrome: the spectrum of the disorder in 1741 patients. Hum. Reprod. 10, 2107–2111 (1995).

18.

Norman

Masters

Hague

: Metabolic approaches to the subclassification of polycyctic ovary syndrome. Fertil. Steril. 63, 329–335 (1995).

19.

Pasquali

Gambineri

Pagotto

: The impact of obesity on reproduction in women with polycystic ovary syndrome. Br. J. Obstet. Gynaecol. 113, 1148–1159 (2006).

20.

In-depth discussion regarding the effect of obesity on reproduction in polycystic ovarian syndrome (PCOS) women.

21.

Hartz

Barboriak

Wong

Katayama

Rimm

: The association of obesity with infertility and related menstrual abnormalities in women. Int. J. Obes. 3, 57–73 (1979).

22.

Lake

Power

Cole

: Women's reproductive health: the role of body mass index in early and adult life. Int. J. Obes. Relat. Metab. Disord. 21, 432–438 (1997).

23.

Norman

Clark

: Obesity and reproductive disorders: a review. Reprod. Fertil. Dev. 10, 55–63 (1998).

24.

Pasquali

Pelusi

Genghini

Cacciari

Gambineri

: Obesity and reproductive disorders in women. Human Reprod. Update 9(4), 359–237 (2003).

25.

Nestler

Stovall

Akhter

Iuorno

Jakubowicz

: Strategies for the use of insulin-sensitizing drugs to treat infertility in women with polycystic ovary syndrome. Fertil. Steril. 77, 209–215 (2002).

26.

Budak

Sanchez

Bellver

Cervero

Simon

Pellicer

: Interactions of the hormones leptin, ghrelin, adiponectin, resistin, and PYY3–36 with the reproductive system. Fertil. Steril. 85, 1563–1581 (2006)

27.

Gosman

Katcher

Legro

: Obesity and the role of gut and adipose hormones in female reproduction. Hum. Reprod. Update 12(5), 585–601 (2006).

28.

Moschos

Chan

Mantzoros

: Leptin and reproduction: a review. Fertil. Steril. 77, 433–444 (2002).

29.

Gonzalez

Simon

Caballero-Campo

Norman

Chardonnens

Devoto

: Leptin and reproduction. Hum. Reprod. Update 6, 290–300 (2000).

30.

Rich-Edwards

Goldman

Willett

: Adolescent body mass index and infertility caused by ovulatory disorder. Am. J. Obstet. Gynecol. 171, 171–177 (1994).

31.

Rich-Edwards

Spiegelman

Garland

: Physical activity, body mass index and ovulatory disorder infertility. Epidemiology 13, 184–190 (2002).

32.

Gesink Law

Maclehose

Longnecker

: Obesity and time to pregnancy. Hum. Reprod. 22(2), 414–420 (2007).

33.

Dickey

Taylor

Curole

: Relationship of clomiphene dose and patient weight to successful treatment. Hum. Reprod. 12, 449–453 (1997).

34.

Loh

Wang

Matthews

: The influence of body mass index, basal FSH and age on the response to gonadotrophin stimulation in non-polycystic ovarian syndrome patients. Hum. Reprod. 17, 1207–1211 (2002).

35.

Dodson

Kunselman

Legro

: Association of obesity with treatment outcomes in ovulatory infertile women undergoing superovulation and intrauterine insemination. Fertil. Steril. 86, 642–646 (2006).

36.

Balen

Platteau

Anderson

: The influence of body weight on response to ovulation induction with gonadotrophins in 335 women with World Health Organization group ll anovulatory infertility. Br. J. Obstet. Gynaecol. 113, 1195–1202 (2006).

37.

Fedorcsák

Dale

Storeng

: Impact of overweight and underweight on assisted reproduction treatment. Hum. Reprod. 19(11), 2523–2528 (2004).

38.

Wang

Davies

Norman

: Body mass index and probability of pregnancy during assisted reproduction treatment: retrospective study. BMJ 321, 1320–1321 (2000).

39.

Nicholas

Crane

Higdon

Miller

Boone

: Extremes of body mass index reduce in vitro fertilization pregnancy rates. Fertil. Steril. 79, 645–647 (2003).

40.

Lashen

Ledger

Bernal

Barlow

: Extremes of body mass do not adversely affect the outcome of superovulation and invitro fertilization. Human Reprod. 14, 712–715 (1999).

41.

Lashen

Fear

Sturdee

: Obesity is associated with increased risk of first trimester and recurrent miscarriage: matched case control study. Hum. Reprod. 19(7), 1644–1646 (2004).

42.

Fedorcsák

Dale

Storeng

: Obesity is associated with early pregnancy loss after IvF or ICSI. Acta Obstet. Gynecol. Scand. 79, 43–48 (2000).

43.

Wang

Davies

Norman

: Obesity increases the risk of spontaneous abortion during infertility treatment. Obes. Res. 10(6), 551–554 (2002).

44.

Styne-Gross

Elkind-Hirsch

Scott

: Obesity does not impact implantation rates or pregnancy outcome in women attempting conception through oocyte donation. Fertil.Steril. 83, 1629–1634 (2005).

45.

Wattanakumtornkul

Damario

Stevens Hall

Thornhill

Tummon

: Body mass index and uterine receptivity in the oocyte donation model. Fertil. Steril. 80, 336–340 (2003).

46.

Bellver

Rossal

Bosch

Zuniga

Corona

Melendez

: Obesity and the risk of spontaneous abortion after oocyte donation. Fertil. Steril. 79, 1136–1140 (2003).

47.

Bellver

Melo

Bosch

Serra

Remohi

Pellicer

: Obesity and poor reproductive outcome: the potential role of the endometrium. Fertil. Steril. 88, 446–451 (2007).

48.

Discusses the controversial issue of the endometrial or oocyte role on the adverse effect of fertility in obese women.

49.

Farquhar

Gillett

: Prioritising for fertility treatments-should a high BMI exclude treatment. Br. J. Obstet. Gynaecol. 113, 1107–1109 (2006).

50.

Discusses the prioritization for IVF in a nationally funded situation.

51.

Gillet

Putt

Farquhar

: Prioritising for fertility treatments – the effect of excluding women with a high body mass index. Br. J. Obstet. Gynaecol. 113, 1218–1221 (2006).

52.

Raatikainen

Heiskanen

Heinonen

: Transition from overweight to obesity worsens pregnancy outcome in a BMI-dependant manner. Obesity 14, 165–171 (2006).

53.

Callaway

Prins

Chang

McIntyre

: The prevalence and impact of overweight and obesity in an Australian Obstetric population. Med. J. Aust. 184, 56–59 (2006).

54.

Watkins

Rasmussen

Honein

Botto

Moore

: Maternal obesity and risk for birth defects. Pediatrics 111(5), 1152–1158 (2003).

55.

Waller

Shaw

Rasmussen

: Prepregnancy obesity as a risk factor for structural birth defects. Arch. Pediatr. Adolesc. Med. 161(8), 745–750 (2007).

56.

One of the latest publications discussing the relationship between maternal obesity and congenital malformations.

57.

Watkins

Scanlon

Mulinare

Khoury

: Is maternal obesity a risk factor for anencephaly and spina bifida? Epidemiology 7(5), 507–512 (1996).

58.

Werler

Louik

Shapiro

Mitchell

: Prepregnant weight in relation to risk of neural tube defects. JAMA 275, 1089–1092 (1996).

59.

Tabor

Zdravkovic

Perslev

Møller

Pedersen

: Screening for congenital malformations by ultrasonography in the general population of pregnant women: factors affecting the efficacy. Acta Obstet. Gynecol. Scand. 83, 1092–1098 (2003).

60.

Huber-Buchholz

Carey

Norman

: Restoration of reproductive potential by lifestyle modification in obese polycystic ovary syndrome: role of insulin sensitivity and luteinizing hormone. J. Clin. Endocrinol. Metab. 84, 1470–1474 (1999).

61.

National Institutes of Health: Clinical guidelines on the identification, evaluation and treatment of overweight and obesity in adults: evidence report. Obes. Res. 6(S2), S51S–S209 (1998).

62.

Bates

Whitworth

: Effect of body weight reduction on plasma androgens in obese, infertile women. Fertil. Steril. 38, 406–409 (1982).

63.

Pettigrew

Hamilton-Fairley

: Obesity and female reproductive function. Br. Med. Bull. 53, 341–358 (1997).

64.

Moran

Norman

: The obese patient with infertility: a practical approach to diagnosis and treatment. Nutr. Clin. Care. 5(6), 290–297 (2002).

65.

Discussion on the practical approach to obese patients with infertility.

66.

Garrow

Summerbell

: Meta-analysis: effect of exercise, with or without dieting, on the body composition of overweight subjects. Eur. J. Clin. Nutr. 49, 1–10 (1995).

67.

Skender

Goodrick

Del Junco

: Comparison of 2 year weight loss trends in behavioural treatments of obesity: diet, exercise and combination interventions. J. Am. Diet Assoc. 96, 342–346 (1996).

68.

Satcher

: Women and smoking: a report of the Surgeon General, Atlanta, GA: Centers for Disease Control and Prevention (2001).

69.

Grodstein

Goldman

Cramer

: Infertility in women and moderate alcohol use. Am. J. Public Health. 84, 1429–1432 (1994)

70.

Manson

Stampfer

: Diet, lifestyle and the risk of type 2 diabetes mellitus in women. N. Engl. J. Med. 344(18), 1343–1350 (2001).

71.

Clark

Ledger

Galletly

: Weight loss results in significant improvement in pregnancy and ovulation rates in anovulatory obese women. Hum. Reprod. 10(10), 2705–2712 (1995).

72.

Clark

Thornley

Tomlinson

: Weight loss in obese infertile women results in improvement in reproductive outcome for all forms of fertility treatment. Hum. Reprod. 13(6), 1502–1505 (1998).

73.

Moran

Noakes

Clifton

: Dietary composition in restoring reproductive and metabolic physiology in overweight women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 88(2), 812–819 (2003).

74.

Padwal

Lau

DCW

: Long term pharmacotherapy for obesity and overweight. Cochrane Database of Systematic Review 2003. 335(7631), 1194–1199 (2007).

75.

Tang

Glanville

Hayden

: Combined lifestyle modification and metformin in obese patients with polycyctic ovary syndrome. A randomized, placebo-controlled, double-blind multicentre study. Hum. Reprod. 21(1), 80–89 (2006).

76.

Lord

Flight

IHK

Norman

: Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ 327, 951–953 (2003).

77.

Moll

Bossuyt

Korevaar

: Effects of clomiphene citrate plus metformin and clomiphene citrate plus placebo on induction of ovulation in women with newly diagnosed polycyctic ovary syndrome: randomized double blind clinical trial. BMJ 332, 1485–1492 (2006).

78.

Legro

Barnhart

Schlaff

: Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N. Engl. J. Med. 356, 551–566 (2007).

79.

Discusses the role of clomiphene in ovulation induction and its superiority to metformin in anovulatory PCOS patients.

80.

Salameh

: Bariatric surgery: past and present. Am. J. Med. Sci. 331, 194–199 (2006).

81.

Korenkov

: Bariatric surgery. Contrib. Nephrol. 151, 243–253 (2006).

82.

Kendrick

Dakin

: Surgical approaches to obesity. Mayo Clin. Proc. 81(10S), S18–S24 (2006).

83.

Escobar-Morreale

Jose

Botella

: The polycystic ovary syndrome associated with morbid obesity may resolve after weight loss induced by bariatric surgery. J. Clin. Endocrinol. Metab. 90(12), 6364–6369 (2005).

84.

Eid

Cottam

Velcu

: Effective treatment of polycystic ovarian syndrome with Roux-en-Y gastric bypass. Surg. Obes. Relat. Dis. 1(2), 77–80 (2005).

85.

Teitelman

Grotegut

Williams

Lewis

: The impact of bariatric surgery on menstrual pattern. Obes. Surg. 16(11), 1457–1463 (2006).

86.

Impact of bariatric surgery on menstrual pattern and return of fertility. Website

87.

British Fertility Society. NHS Funding of Assisted Conception. Bristol: The Soceity, 2006. Accessed February 8, 2007. Available at: www.fertility.org.uk/news/documents/NICEImplementationfollowup.pdf.

Impact of Obesity on Female Fertility and Fertility Treatment

Abstract

Keywords

Defining obesity

Obesity & polycystic ovarian syndrome

Obesity, menstrual disorders & infertility

Obesity & infertility treatment

Obesity & prioritizing fertility treatment

Obesity & obstetric problems

Managing obesity

Dietary treatment

Lifestyle modification

Pharmacological treatment

Surgical treatment

Future perspective

Footnotes

References