Abstract
Rising obesity rates around the world have had a profound impact on female reproductive health. Childhood obesity is associated with early onset of puberty, menstrual irregularities during adolescence and polycystic ovary syndrome. Women of reproductive age with high BMIs have a higher risk of ovulatory problems and tend to respond poorly to fertility treatment. Strategies for fertility control can also be complex since the efficacy and safety of hormonal contraceptives can be compromised by increased body weight. Obesity can aggravate symptoms of pelvic organ prolapse, stress urinary incontinence and increase the risk of endometrial polyps and symptomatic fibroids. Weight reduction enhances reproductive outcomes, diminishes symptoms of urinary incontinence and reduces morbidity following gynecological surgery. Sustained and substantial weight loss is difficult to achieve with the lifestyle and dietary measures that are currently available. A number of pharmacological treatment options are available, and there are emerging data on reproductive outcomes following surgical treatment for obesity.
Keywords
In 2005, approximately 1.6 billion adults worldwide were classed as overweight (BMI 25–30), and at least 400 million were obese (BMI >30). By 2015, these figures are expected to rise to 2.3 billion and 700 million, respectively [201]. Meanwhile, 56% of English [202] and 61% of American women are believed to be either overweight or obese [1]. Obesity is recognized as a major risk factor for a number of medical conditions, including cardiovascular disease, diabetes, osteoarthritis and malignancies of the colon and endometrium [201]. The aim of this review is to explore the impact of obesity on benign gynecological conditions.
A literature search was performed using MEDLINE and EMBASE from 1989 to July 2009. The search terms were: obesity, puberty, infertility, PCOS, fertility treatment, miscarriage, contraception, fibroid, endometrial polyp, urinary incontinence, pelvic floor dysfunction, menopausal transition, anesthesia, surgery and weight management. Relevant articles were identified and cross-references were checked.
Puberty
High BMI scores at 3 years of age has been identified as a risk factor for the early onset of puberty [2]. The impact of childhood weight gain on the time of the onset of puberty has been the focus of much research. Data from a large population-based study from Sweden suggest that for each unit increase in BMI, peak height velocity is brought forward by 0.11 years [3]. This phenomenon of accelerated pubertal development can be explained by the ‘critical weight hypothesis’, which proposes that menstruation is established once a threshold weight of 48 kg or 17% body fat composition is achieved [4,5]. A number of endocrine pathways linking childhood obesity with insulin resistance and early onset of puberty have been described [6]. Prenatal growth restriction can be accompanied by ‘catch-up’ growth in early infancy, resulting in increased deposition of visceral fat [7,8], insulin resistance and compensatory hyperinsulinemia [9]. Accelerated aromatization of adrenal and ovarian androgens in adipose tissue increases the bioavail-ability of sex steroids, which promotes earlier adrenarche, pubarche and thelarche [10,11]. It has been found that girls with an early onset of puberty are at increased risk of ovarian hyper-androgenism and polycystic ovary syndrome (PCOS) [12], as well as cardiovascular events in later life [13].
Subfertility & anovulatory infertility
Obese women have been shown to require a longer time to conceive [14] and are at increased risk of ovulatory disorders. In 18-year-old women, the relative odds of anovulation are 2.7 (95% CI: 2.0–3.7) in those with a BMI greater than or equal to 32 [15] and 3.1 (95% CI: 2.2-4.4) in those with a BMI greater than 27 [16]. Obesity is associated with an increase in leptin and a decrease in adiponectin levels in the circulation [17]. Leptin has a stimulatory effect on the hypothalamo–pitutary axis but inhibits ovarian folliculogenesis [18,19], as well as lutenizing hormone (LH)- and insulinmediated steroid production by granulosa and theca cells. Obesity related hyperinsulinemia causes hyperandrogenemia, which results in granulosa cell apoptosis, while peripheral conversion of androgens to estrogen in adipose tissue inhibits gonadotrophin secretion [17].
Polycystic ovary syndrome is a heterogeneous condition characterized by oligoovulation or anovulation, hyperandrogenism, menstrual irregularities and subfertilty [20,21]. Approximately 30–75% of women with PCOS are obese [22], with central obesity noted in 50–60% of women with PCOS, irrespective of BMI. Obesity encourages phenotypic expression of PCOS and causes deterioration of hormonal and metabolic parameters in those who are already symptomatic [21]. Serine phosphorylation of the insulin receptor prevents signal transduction to its substrate, causing insulin resistance [23,24] and compensatory hyperin-sulinemia – a situation that is exacerbated by obesity, particularly central obesity [25,26]. Hyperinsulinemia inhibits hepatic production of sex hormone-binding globulin, thus increasing serum free-androgen levels. Ovarian androgen production is facilitated by insulin, which, acting via IGF1, also enhances LH-mediated steroidogenesis in the theca-cell system of the ovary [27,28]. Serine phosphorylation of P450c17 increases 17,20-lyase activity, resulting in a further increase in ovarian and adrenal androgen production [23]. Increased androgen levels cause hirsutism, while peripheral conversion of excess androgens to estrogens by adipocytes leads to menstrual disorders and anovulatory infertility.
Fertility treatment & assisted reproduction technology
Obese women with ovulatory problems respond poorly to ovulation induction by means of anti-estrogens such as clomifene citrate. A systematic review of 13 studies also identified obesity and insulin resistance as predictors of treatment failure following gonadotrophin treatment. Obesity is positively correlated with gonadotrophin dose (weighted mean difference: 771 IU; 95% CI: 700-842) and cycle cancellation (OR: 1.86; 95% CI: 1.13-3.06), and negatively correlated with ovulation (OR: 0.44; 95% CI: 0.31-0.61) [29]. However, a multicenter study investigating 335 women with WHO type II anovulation showed that despite requiring higher doses of gonadotrophins and producing fewer follicles, women with high BMIs achieved similar rates of ovulation and clinical pregnancy compared with their low-BMI counterparts [30].
A systematic review of studies on the impact of obesity on assisted reproduction demonstrated that women with a BMI greater than or equal to 25 have lower pregnancy rates (OR: 0.71; 95% CI: 0.62-0.81), require higher doses of gonadotrophins (weighted mean difference:
210.08 IU; 95% CI: 149.12-271.05) and have a higher risk of miscarriage (OR: 1.33; 95% CI: 1.06-1.68). There was insufficient evidence to inform any meaningful conclusions about the effect of BMI on live birth, cycle cancellation, oocyte recovery and ovarian hyperstimulation syndrome [31].
Early pregnancy loss
A number of studies have demonstrated that the risk of miscarriage is higher in overweight and obese women in spontaneously conceived pregnancies, as well as those resulting from fertility treatment [32,33]. A recent systematic review suggests that women with a BMI greater than or equal to 25 have significantly higher risk of miscarriage regardless of the method of conception (OR: 1.67; 95% CI: 1.25-2.25). Overweight women are more likely to miscarry after ovulation induction (OR: 5.11; 95% CI: 1.76 – 14.83), as are high-BMI recipients of donated oocytes (OR: 1.52; 95% CI: 1.10-2.09). Obese women with a history of recurrent miscarriage also have significantly higher odds of miscarriage in subsequent pregnancies (OR: 1.71; 95% CI: 1.05-02.8) [34].
The reasons behind the association between high BMI and miscarriage are open to debate. It has been suggested that obesity impacts on the ovarian environment, resulting in impaired folliculogenesis and oogenesis. This hypothesis is supported by studies demonstrating comparable miscarriage rates in obese and nonobese women after adjusting for embryo and oocyte quality [35,36]. An alternative view is that obesity has a detrimental impact on the uterine environment. Some studies have reported lower pregnancy rates in obese women, even in cases where donated oocytes have been used or where adjustments have been made for embryo quality, suggesting a problem with the uterine environment [37,38].
Contraception
Pregnancy risks in obese women include pre-eclampsia, gestational hypertension, macrosomia, induction of labor and Caesarean section [39,40]. Over half of all maternal deaths reported by the seventh Confidential Enquiry into Maternal Deaths in the United Kingdom (CEMDUK) occurred in women who were overweight or obese (BMI >25) [203]. Despite the suggestion that obese women should use effective contraception while they try to lose weight [41], contraceptive use remains low in this group. In a large cross-sectional study, obesity was significantly associated with contraceptive nonuse (OR: 1.34; 95% CI: 1.16-1.55) [43], possibly owing to a perception among obese women that they have lower fertility, or fears (which are largely unsubstantiated) regarding hormonal contraception-related weight gain [42]. However, there is little evidence to link significant weight gain with either combined oral contraception [44], levonorgestrel-releasing intrauterine system (LNG-IUS) [45] or the progesterone-only pill [42]. On the other hand, depot medroxy progesterone acetate has been shown to cause a substantial weight gain of 9 kg over 5.5 years - possibly owing to increased appetite [46]. A number of studies have explored the efficacy of hormonal contraception in women with a high BMI. Analysis of data from a cohort of 755 female participants suggests that women with a body weight of 70.5 kg or more have a significantly increased risk of oral contraceptive failure (RR: 1.6; 95% CI: 1.1-2.4) compared with women who weigh less. The highest risk of contraception failure was observed among low-dose oral contraceptive users (RR: 2.6; 95% CI: 1.2–5.9) and very low-dose oral contraceptive users (RR: 4.5; 95% CI: 1.4–14.4) [47]. By comparison with women with a BMI less than 27.3, the risk of pregnancy was higher in women with a BMI greater than 27.3 (OR: 1.58; 95% CI: 1.11–2.24) and higher still in women with a BMI greater than 32.2 (OR: 1.72; 95% CI: 1.04–02.82) [48]. These results were not supported by the analysis of National Survey of Family Growth data [49] which suggested a complex relationship between obesity, socioeconomic factors and contraceptive use. A multicenter trial in China found a dose– response relationship between weight and failure rates associated with Norplant [50]. Results of secondary analyses of efficacy studies have suggested that contraceptive failure associated with the transdermal contraceptive patch (Ortho-Evra®) was increased in women whose bodyweight was greater than or equal to 90 kg (≥198 lb) [51]. Reduced efficacy of hormonal contraception in obese women could be due to lower plasma concentrations of the active agent. A recent study demonstrated significant differences in levonorgestrel half-life, clearance and time to reach a steady state between obese and normal-BMI women. Doubling of the time taken by levonorgestrel to reach a steady state in obese women created a ‘window of opportunity’ for follicular recruitment, development and ovulation [52]. In addition, the use of combined oral contraceptives by obese women is not without its hazards. Both the combined pill [53] and obesity
Menopausal transition
The mean weight gain during the period of menopausal transition is 2.1 kg [55]. This is mainly due to deposition of visceral fat [56] and results in an increased risk for diabetes, metabolic syndrome and cardiovascular disease. In a longitudinal study on menopausal women with constant body weight and unchanging levels of physical activity, subcutaneous and visceral abdominal fat deposits were noted to increase during the menopausal transition. The increase was approximately 32% for subcutaneous and 44% for visceral fat [57]. Increase in visceral adiposity is associated with insulin resistance, hypertension and hyperlipidemia [58]. Obesity also increases peripheral conversion of androgens to estrogens, while high serum levels of unopposed estrogens can encourage endometrial hyperplasia and cancer. In a study of abnormal perimenopausal bleeding, obesity was shown to be independently associated with heavy menstrual bleeding [59].
Obesity & specific benign gynecological problems
Menstrual problems
Women with PCOS, many of them obese [22], experience varying degrees of menstrual irregularity. Even in the absence of PCOS, obesity has been associated with long and irregular cycles. Women with a BMI of 35 have a fivefold higher risk of long cycles compared with those with a BMI between 22 and 23 (OR: 5.4; 95% CI: 2.1–13.7) [60]. Upper body obesity is associated with menstrual disorders in obese women, even in the absence of PCOS [61].
A cross-sectional study on 726 Australian women aged 26 to 36 years reported that the odds of having irregular cycles were 2.61 (95% CI: 1.28–5.35) for women with a BMI greater than 30 when compared with women with a BMI between 20 and 24.9; and 2.28 (95% CI: 1.16–4.49) for women with a waist circumference greater than 88 cm in comparison with women with a waist circumference less than 80 cm [62]. This further highlights the link between visceral adiposity and menstrual irregularities.
Endometrial polyps
Hormonal factors related to estrogen excess, such as obesity, have been implicated in the patho-genesis of endometrial polyps [63]. Onalan
Fibroids
Obesity has been linked with uterine fibroids. In a retrospective study, those presenting with uterine fibroids were more likely to be obese (50 vs 25%) or severely obese (16 vs 7.2%) than a general population of women [66]. In a prospective cohort study in the USA, BMI and weight gain exhibited a complex relationship with the risk of developing fibroids [67]. In a separate study, fibroids were associated with a BMI greater than 25, concurrent hypertension [68], occult obesity and upper body fat distribution [69]. The risk of developing fibroids is tripled in women with a bodyweight of 70 kg or more in comparison with those who weigh less than 50 kg [70]. It is possible that obesity causes a relative hyperestro-genic state, which encourages fibroid growth [70], although not all studies are in accordance with this hypothesis [71].
Urinary incontinence
A large cohort study demonstrated a link between BMI and urinary incontinence. Increased waist circumference, in particular, was associated with stress urinary incontinence, possibly as a result of raised intra-abdominal pressure caused by central obesity [72]. The severity of incontinence appears to be influenced by the duration of obesity. Women who had been overweight or obese since the age of 20 years were more likely to report severe incontinence than those who gained weight later in life [73].
The causal nature of the association between obesity and incontinence is supported by the results of a randomized, controlled trial that showed that a 6-month behavioral intervention targeting weight loss among overweight and obese women led to a reduction in the frequency of self-reported episodes of urinary incontinence [74].
A systematic review of 29 studies concluded that overweight and obesity increased the risk of urinary incontinence - especially stress urinary incontinence [75]. A second systematic review suggested that surgery for stress urinary incontinence in obese women was as safe, but less effective, than similar surgery performed in nonobese women [76].
Pelvic organ prolapse
Female pelvic organ prolapse is a common condition with a multifactorial etiology [77]. The prevalence of pelvic floor dysfunction is highest (57%) in morbidly obese women (BMI >40), and considerably higher (53%) in severely obese women (BMI >35) compared with that (44%) in obese women (BMI >30) [78]. Data from the Women's Health Initiative (WHI) study demonstrate that 55.7% women gained weight over a period of 5 years (mean: 4.43 kg ± 5.95), during which time the proportion of those with prolapse increased from 40.9-43.8% [79]. In this study, exacerbation of cystocele, rectocele and uterine prolapse was noted among women who were overweight (BMI between 25 and 29.9) or obese (BMI ≥30) at baseline. In overweight and obese women, worsening of symptoms of cystocele occurred in 32 and 48%; rectocele in 37 and 58%; and uterine prolapse in 43 and 69%, respectively [79]. Furthermore, a small degree of weight loss (10%) was associated with borderline worsening of uterine prolapse (OR: 0.93; 95% CI: 0.88-0.97), minimal regression of cystocele (OR: 1.03; 95% CI: 1.00–1.05) and rectocele (OR: 1.04; 95% CI: 1.01–1.07) [79]. This suggests that the damage to the pelvic floor caused by obesity is probably irreversible. Other studies have shown that surgically induced weight loss has a beneficial effect on symptoms of pelvic floor disorders in morbidly obese women [80]. The impact of obesity on different aspects of gynecology has been summarized in Table 1.
Impact of obesity on gynecology.
Gynecological surgery in the obese
Major gynecological surgery in obese women is technically challenging and associated with a high risk of morbidity.
Anesthesia
Anesthesia in morbidly obese women [81,82] is associated with problems in gaining vascular access, peripheral and neuraxial blockade [83] and intubation [84]. Obese patients are more likely to require thromboprophylaxis, aspiration prophylaxis and prolonged postanesthetic care in high-dependency units [82].
Abdominal, vaginal & laparoscopic surgery
Abdominal surgery in obese women takes lon-ger, is associated with greater blood loss, post-operative pyrexia, increased wound infection and increased hospital stay [85]. Since operative exposure is limited, panniculectomy could be considered in some situations [86] during a gyne-cological procedure. In these cases difficulty with operative exposure is reduced, and these patients are better served intraoperatively [87]. Mass closure [88], subcutaneous drains and prophylactic antibiotics [89] are recommended in order to minimize wound disruption. The vaginal route can be employed for hysterectomy, if appropriate. Compared with nonobese women, operating time and blood loss are higher during vaginal hysterectomy in obese women [90]; the risk of wound infection can be minimized.
Obesity has implications for laparoscopic entry [91], and open laparoscopy is a preferred option. Placement of additional ports may be technically challenging since obesity can make it difficult to visualize abdominal wall vessels. A high BMI increases the likelihood of conversion to open surgery during laparoscopy [92]. The benefits are reduced postoperative pain and morbidity, and quicker recovery [93].
Comorbidities
Obesity is associated with significant comorbidi-ties. The relative risks of these conditions that are relevant from a surgical point of view have been summarized from a large systematic review and meta-analysis in Table 2 [94]. This suggests that obese women undergoing gynecological surgery are potentially more likely to experience anesthetic and postoperative complications [82].
Weight management
Moderate weight reduction of 5–10% has been shown to reduce the risk of comorbidities [95] and encourage resumption of ovulation in anovulatory women [96,97]. Lifestyle modification, diet and exercise are still considered to be central to any obesity management strategy [98,99]. Pharmacological agents are useful adjuncts to exercise and dietary therapy [100] and bariatric surgery is increasingly being used as a final option by some women.
Lifestyle modification & dietary intervention
Lifestyle changes, such as a healthy diet and regular exercise help in weight reduction. The loss of 5–10% of body weight results in an improvement in ovarian morphology in women with PCO [101]. Weight loss can encourage resumption of spon-taneous ovulation and conception [96,101]. In a recent review of the literature, an expert panel appointed by the Androgen Excess and PCOS Society (AEPCOS) concluded that lifestyle modification was of paramount importance for treating metabolic complications and improving ovulatory function in overweight and obese women with PCOS [102]. In a meta-analysis of 18 RCTs, Wu
In addition to diet and exercise, behavior modification is of paramount importance. In a systematic review of studies, diet combined with aerobic training and behavioral therapy led to weight loss ranging between 7.9 and 12.4 kg [104]. Group therapy demonstrated better results than individual treatments [105].
Pharmacological interventions
Obesity guidelines currently recommend that drug therapy be considered in conjunction with nonpharmacological therapy for patients with a BMI greater than or equal to 30, or a BMI between 27 and 30 with one or more comorbidities [95]. The European Agency for the Evaluation of Medicinal Products has suggested a target placebo-subtracted weight loss of 10% for new antiobesity drugs [205].
This degree of weight loss has not been a requirement for approval of the currently marketed drugs, and none of the marketed antiobesity drugs produce weight losses of 10% or more [106].
Approved antiobesity medications include:
Orlistat, which inhibits pancreatic and other lipases, thus inhibiting fat absorption and thereby decreasing the progression of diabetes. It has gastrointestinal side-effects [107];
Sibutramine, which inhibits reuptake of serotonin and norepinephrine, is the most recently approved agent. It acts by increasing satiety and thermogenesis, primarily by modifying CNS neurotransmission. It is associated with increases in blood pressure and pulse rate [107] and is not recommended for use by women who are trying to conceive;
Rimonabant, which is a cannabinoid receptor antagonist, reduces the drive to eat. It reduces waist circumference and concentrations of high-density lipoprotein-cholesterol and trig-lyceride; however, an increased incidence of mood-related disorders has been reported with rimonabant [107].
Rucker
Metformin
The role of metformin in weight loss has been widely debated, and several authors have questioned its effectiveness [109,110]. A recent meta-analysis of 14 RCTs concluded that treatment with metformin resulted in a significant decrease in BMI compared with placebo (weighted mean difference: −0.68; 95% CI: −1.13–0.24). The magnitude of the effect was greater with highdose metformin (>1500 mg/day) and longer duration of therapy (>8 weeks) [111]. A recent Cochrane review concluded that metformin alone (OR: 2.12; 95% CI: 1.50-3.0) or in combination with clomifene (OR: 3.46; 95% CI: 1.97-6.07), increases ovulation rates in women with PCOS [112]. Metformin also increases the clinical pregnancy rate, but has no influence on the live birth rate [112]. A recent RCT concluded that menstrual patterns improved with metformin therapy in women with insulin resistance [113].
Surgical treatment (bariatric surgery)
Surgical treatment may be the last resort for some women who are unresponsive to other interventions for weight loss. A Swedish study demonstrated an estimated 24% reduction in the adjusted overall mortality rate in those treated surgically compared with conventionally treated controls [114]. Weight loss surgery reduces caloric intake by modifying the anatomy of the gastrointestinal tract via restriction, malabsorption or a combination of the two techniques. The ensuing changes alter peptides that may regulate appetite and satiety [115]. Bariatric surgical techniques include gastric bypass (open and laparoscopic), laparoscopic adjustable gastric banding and bili-opancreatic diversion (with or without duodenal switch) [116].
A systematic review of 136 studies involving 22,094 patients, 72.6% being women, with a mean age of 39 years (range: 16–64 years) showed that effective weight loss was achievable in morbidly obese patients following bariatric surgery. A substantial majority of patients with diabetes, hyperlipidemia, hypertension and obstructive sleep apnea experienced complete resolution or improvement [117]. In women of reproductive age, menstrual irregularities [118] and PCOS may be completely resolved after bariatric surgery [119]. Following bariatric surgery, morbidly obese women have improved fertility and a reduced risk of obstetric complications, such as gestational diabetes, macrosomia and hypertensive disorders of pregnancy [120]. However, pregnancy should be avoided during rapid weight loss [121]. Intrauterine growth retardation and nutritional deficiencies during pregnancy are the likely risks after bariatric surgery [120]. The impact of weight loss has been summarized in Table 3.
Impact of weight loss.
Executive summary
1.6 billion adults are currently overweight and 400 million are obese.
A total of 56% of women in England and 61 % of women in the USA are overweight or obese.
By 2050, 47–52% of women in the UK aged between 30 and 50 years of age will be obese.
BMI at 3 years of age and childhood obesity are associated with early onset puberty.
Postnatal catch-up growth following fetal growth restriction results in visceral adiposity and insulin resistance.
Obesity and insulin resistance are predictors of treatment failure following ovulation induction.
Obesity reduces the success rate of IVF intracytoplasmic sperm injection and increases the cycle cancellation rate.
Obesity is associated with increased early pregnancy loss.
Obesity impairs hormonal contraceptive efficacy and increases the risk of thromboembolism while taking combined oral contraceptive.
Use of depot provera is associated with weight gain.
Obesity is associated with irregular menstruation, endometrial polyps, stress urinary incontinence and pelvic organ prolapse.
Duration of obesity is correlated with severity of incontinence.
Cure rates following incontinence surgery are lower in obese women.
Pelvic surgery in obese women is technically challenging.
Both anesthesia and surgery have significant morbidity.
Lifestyle modification, diet and exercise are the cornerstones of any weight loss program.
Pharmacotherapy may aid weight loss.
Currently available medications result in a placebo-subtracted weight reduction of less than 5 kg.
Bariatric surgery is effective in morbidly obese women, and can regularize menstrual cycles and resolve polycystic ovary syndrome.
Future perspective
Modeling studies in the UK have predicted a substantial increase in obesity rates in women aged 30 to 50 years by the year 2050. With obesity affecting 47–52% of all women [204], a significant impact on gynecology is inevitable. More research is needed on how this dramatic increase can be halted, as are large multicenter trials on interventions for the prevention and treatment of obesity.
Footnotes