Endocrine effects of adipose tissue: leptin and insulin resistance

The adipocyte hormone leptin is secreted in proportion to fat content, and it plays a crucial role in regulating appetite, body weight and metabolism . It acts as a negative feedback signal relaying the magnitude of peripheral energy stores to the hypothalamus to alter energy expenditure and food intake . Apart from this, however, leptin may directly influence reproductive capacity in women. It acts as a signal of a nutritional status suitable for conception and pregnancy, and it is important in activating the hypothalamic–pituitary–ovarian (HPO) axis . In states of metabolic stress such as starvation or anorexia, a decline in circulating leptin may deactivate the HPO axis .

Obesity is a state characterized by hyperleptinaemia. However, in spite of these high levels of leptin, obesity “promotes multiple cellular processes that attenuate leptin signalling” leading to a leptin-resistant state, thereby increasing the risk of HPO axis deactivation, irregular menses and anovulation . Hyperleptinaemia itself may also directly inhibit ovarian granulosa and thecal cell steroidogenesis and “high leptin concentrations in the ovary may interfere with the development of a dominant follicle and oocyte maturation” .

Insulin resistance and its associated hyperinsulinaemia is another important feature of obesity, especially central obesity, that impacts fertility, and although the mechanisms are not fully elucidated, many aspects of adipocyte activity have been linked to its development. The adipocyte hormone adiponectin has been shown to increase insulin sensitivity but its concentration is negatively correlated with fat mass . Adipocyte proteins, resistin and retinol-binding protein-4 (RBP-4), have been implicated in the development of insulin resistance and they are positively correlated with adiposity . Inflammatory cytokines tumour necrosis factor alpha (TNF-α) and interleukin (IL)-6 are produced by adipose tissue macrophages and “increase in circulating levels of these macrophage-derived factors in obesity leads to a chronic low-grade inflammatory state that has been linked to the development of insulin resistance” .

Insulin resistance is associated with compensatory hyperinsulinaemia, and these elevated levels of insulin can contribute to subfertility in several ways. One of the major effects is hyperandrogenism arising from ovarian and other sources. At the level of the ovary, hyperinsulinaemia increases androgen production both directly and indirectly: it directly stimulates steroidogenesis within ovarian theca and granulosa cells and also increases the sensitivity of pituitary gonadotroph cells to gonadotrophin-releasing hormone (GnRH), thus indirectly enhancing ovarian steroidogenesis . In addition to this ovarian source of hyperandrogenism, hyperinsulinaemia may also suppress the hepatic synthesis of sex hormone-binding globulin (SHBG) leading to an increased free androgen index and it may also induce an increase in adrenal androgen production .

Direct effects of adipose tissue on steroid metabolism

In addition to the direct and indirect effects of adipocyte hormones on fertility, the adipocyte itself is a site of steroid metabolism and interconversion. The action of the enzyme 17β-hydroxysteroid dehydrogenase (17β-HSD) within the adipocyte in converting androstenedione into the active androgen testosterone, and of the enzyme 5α-reductase in converting testosterone into the more potent androgen 5α-dihydrotestosterone (DHT), can contribute to hyperandrogenaemia in the setting of increased adiposity . The fat-soluble nature of steroid hormones also means that the increased steroid pool within an increased adipose tissue mass augments this effect .

Polycystic ovary syndrome

PCOS is characterized by hyperandrogenism and chronic anovulation . The aetiology of PCOS is incompletely understood, and both genetic and environmental factors are thought to play a role . However, adiposity has been shown to play a profound role in the expression of the syndrome, and it is thought that the development of obesity may even unmask the condition . This important role of obesity in PCOS is demonstrated by the effect of weight loss on the manifestations of the syndrome. A strong association between the degree of adiposity and severity of PCOS has been observed , and as little as 5% weight loss has been noted to significantly improve hormonal abnormalities, menstrual cyclicity and fertility rates in women with PCOS .

The mechanisms by which obesity contributes to infertility in women with PCOS are incompletely understood and the aforementioned mechanisms of infertility in obesity have been implicated. However, insulin resistance, which consistently affects most women with PCOS, is thought to play a major role . The android body fat distribution (BFD) – characterized by a mainly visceral and abdominal subcutaneous distribution of adipose tissue and strongly associated with insulin resistance – has been observed to affect most women with PCOS . Hyperinsulinaemia contributes to anovulation by inducing hyperandrogenism via mechanisms previously detailed including increased ovarian steroidogenesis, reduced SHBG synthesis and increased adrenal androgen production . Further, hyperinsulinaemia itself has also been shown to arrest ovarian follicle development at 5–10 mm, thus contributing to anovulation in women with PCOS .

Lifestyle

Obesity, particularly when fat is disposed centrally, is associated with a host of metabolic, inflammatory and reproductive abnormalities. Abnormalities of the reproductive system can antedate the metabolic and inflammatory phenomena, and its spectrum spans disorders of ovulation, fertility, response to fertility treatment as well as adverse pregnancy outcomes (see Fig. 1 ) .

Clinical consequences of the insulin resistance syndrome on women’s health. Key: CVD = cardiovascular disease, GDM = gestational diabetes mellitus, PCOS = polycystic ovarian syndrome, T2DM = type 2 diabetes mellitus.

In a set of community-based studies, lifestyle interventions that control or reduce weight and weight gain have been shown to be effective in reducing the metabolic consequences of obesity. Thus, the Diabetes Prevention Program in the US , Da Qing in China and Diabetes Prevention Study in Scandinavia have all shown that it is possible to prevent the progression to type 2 diabetes in those at high risk of the disease when they adhere to dietary and exercise regimens. Can reproductive abnormalities in those with obesity experience similar benefit from such interventions?

The potential value of diet and physical activity upon ovulatory function may be implied from findings of the Nurses’ Health Study, which showed that healthier food choices are associated with a reduced risk of ovulatory infertility . Quite separately, those with the highest level of physical activity were also less likely to experience ovulatory infertility. Unfortunately, there is a paucity of data on the impact of lifestyle interventions from randomized control trials, and two recent meta-analyses in those with PCOS conclude that there are no current data demonstrating an effect of lifestyle on the fertility primary outcomes of pregnancy, ovulation or menstrual regularity , although benefits to body composition, hyperandrogenism and insulin resistance were observed.

Despite the foregoing, some early studies had demonstrated the potential benefits of lifestyle interventions on ovulation and pregnancy success. Thus, Clark et al. showed that it was possible to produce impressive improvement in ovulation, fertility and successful pregnancy rates as well as sustained weight gain through lifestyle coaching among a cohort of obese women compared with those who failed to adhere to the prescribed dietary and exercise regime. Since then, a number of randomized controlled trials have shown similar beneficial effects in obese pregnant women with benefit to both mother and baby. A meta-analysis of 44 such studies led to the following conclusions. Dietary advice influences a greater limit on gestational weight gain, whereas physical activity is more likely to impact positively upon fetal weight gain. Overall, lifestyle intervention is more likely to reduce the risk of both pre-eclampsia and shoulder dystocia . Another systematic review of both randomized and non-randomized controlled trials found that lifestyle interventions were successful in reducing gestational weight gain with a trend towards reduced prevalence of gestational diabetes mellitus (GDM), but there were no clear differences for impact upon caesarean section (CS), large for gestational age (LGA), birthweight or macrosomia . Moreover, there is no evidence of harm in the use of dietary- or physical activity-based interventions in pregnancy.

Despite the limited data, it seems fair to encourage lifestyle interventions that promote weight loss with some expectation of improvement in reproductive function especially as such interventions are very unlikely to be harmful. On the other hand, despite the proven benefits of lifestyle interventions on gestational weight gain, there are currently no data that support the notion that obese pregnant women should engage in weight-loss activities .

Pharmacotherapy

The treatment of infertility among the overweight/obese by pharmacologic means has been most studied in the setting of those with PCOS, and here the literature has been dominated by metformin, clomiphene citrate and, more recently, aromatase inhibitors. The use of gonadotrophin analogues is discussed in the context of in vitro fertilization (IVF).

Metformin is an inexpensive and widely available drug, which partly through an insulin-sensitizing action has found its place as a first-line pharmacologic agent in the treatment of type 2 diabetes. It offers potential in the treatment of many of the reproductive abnormalities associated with obesity . In 2003, a meta-analysis of the use of insulin-sensitizing agents was performed on >500 PCOS patients. This showed that metformin resulted in close to a fourfold increase in ovulation rates compared with placebo, and it was similarly effective in enhancing pregnancy rates when combined with clomiphene .

One decade later, its early promise remains unfulfilled and the evidence for true benefit from this drug in improving reproductive outcomes remains sketchy. In systematic reviews and meta-analyses, Siebert et al. and Xiao et al. compared whether metformin is superior to clomiphene as a primary ovulation induction agent in women with PCOS. They concluded that, as single agents, clomiphene citrate was superior to metformin with respect to both ovulation and pregnancy rates. These studies also found that the combination of clomiphene and metformin was superior to clomiphene alone in achieving pregnancy, but there was no difference in the live birth (LB) rate. A further conclusion by the authors is that the side-effect profile precludes metformin’s use as a first-line agent for ovulation induction. These findings were similar to an earlier systematic review of head-to-head randomized controlled trials and meta-analyses comparing clomiphene citrate and metformin as a first-step approach to treating anovulatory infertility in patients with PCOS . Acting on the suggestion that less obese women with PCOS might be more amenable to the benefits of metformin, another meta-analysis also failed to demonstrate a difference between metformin and clomiphene in terms of ovulation, pregnancy, LB, miscarriage and multiple pregnancy rates in women with BMI <32 kg/m ² . In addition, Palomba et al. evaluated the effect of the pre-gestational use of metformin on obstetric risk in PCOS and found no treatment effect in an analysis of 17 randomized controlled trials. With data of this sort, it is not surprising that learned societies and guideline committees in both the USA and the UK take conservative positions on the use of metformin in PCOS. A summary of the expected benefits of the various interventions on PCOS is shown in Table 1 .

Two new agents (lorcaserin and phentermine/topiramate) have recently entered the arena of pharmacotherapy following a succession of obesity treatments that have been limited by safety concerns. Until greater clinical experience and longer-term outcomes become available, the impact of these and other emerging therapies on primary fertility outcomes remains uncertain.

Bariatric surgery and fertility

Bariatric surgery is indicated in severe obesity (BMI ≥ 40 kg/m ² ) and in medically complicated obesity with BMI ≥35 kg/m ² when conservative treatment has failed . Women account for the majority of patients undergoing bariatric surgery in the 18–45-year age group . In an observational study, 32% of reproductive-age women were intending to conceive within 2 years following bariatric surgery .

Bariatric surgery can be classified into restrictive, malabsorptive and mixed procedures . Restrictive procedures include vertical banded gastroplasty or laparoscopic adjustable gastric banding (LAGB), and these methods promote weight loss by decreasing gastric volume. Malabsorptive procedures, as the name suggests, enhance weight loss by decreasing nutrient absorption and thereby inducing an iatrogenic malabsorptive state. These are very rarely used currently due to the severe nutritional deficiencies caused. Mixed procedures combine both decreased gastric capacity and malabsorption. In Roux-en-Y gastric bypass, a small gastric pouch is created and is anastomosed to empty directly into the distal jejunum. Sleeve gastrectomy involves resection of the majority of the greater curvature of the stomach. However, although technically this is a restrictive procedure, gastric hormonal levels and motility are affected and the resultant weight loss associated may be due to more than simply a restriction effect. Currently, Roux-en-Y, sleeve gastrectomy and adjustable gastric banding are the most common procedures in that order .

To date, there are no randomized controlled trials comparing the effects of bariatric surgery with conservative therapy in obese women wishing to conceive. The current literature suggests a trend to improved spontaneous pregnancy rates, although most studies are observational. In 2012, Legro et al. attempted to show that weight loss following Roux-en-Y would result in improved reproductive function, and although 29 patients were enrolled, only nine completed the study. They showed no change in endocrine menstrual parameters after weight loss in the study subjects; however, the length of the follicular phase of the menstrual cycle was shorter after weight loss – a change that was statistically significant. In a retrospective analysis, Musella et al. evaluated 110 women with obesity-related infertility who had undergone bariatric surgery (intragastric balloon, laparoscopic adjustable gastric banding, sleeve gastrectomy and gastric bypass) . Almost two-thirds of these women achieved pregnancy after their procedure and a weight loss of >5 BMI kg/m ² was predictive of pregnancy (OR 20.2). There was no statistical difference between procedures, although a limitation of this study was the absence of data on the cause of infertility or ovulatory status.

Obesity is associated with an increased risk of miscarriage. A meta-analysis in 2008 showed that, irrespective of the mode of conception, there was an increased risk of miscarriage (OR 1.67) in women with BMI >25 kg/m ² . It is unclear if weight loss after bariatric surgery results in improved miscarriage rates. Bilenka et al. showed decreased miscarriage rates after gastric banding. This was a small case series of nine patients with no control group for comparison. On the other hand, a retrospective survey of 700 women after biliopancreatic diversion showed no difference in self-reported miscarriage rates pre- and post-operatively .

It has been traditionally advised to delay pregnancy for 2 years after bariatric surgery. The time identified as the greatest risk to the fetus is between 12 and 18 months due to the rapid weight loss. The nutritional deficiencies associated with bariatric surgery are of greatest concern. However, in 2008, a systematic review of the timing of pregnancy after bariatric surgery could not define a clear policy due to insufficient data .

There are several studies that look at the change in the reproductive hormone profile before and after bariatric surgery. Bariatric surgery has shown to improve the levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), luteal pregnanediol glucuronide (Pdg), SHBG and GnRH . Obese women with subclinical hypothyroidism also have a decrease in thyroid-stimulating hormone (TSH) levels after bariatric surgery without replacement therapy . Unfortunately, such an improvement was not replicable for Müllerian-inhibiting substance (MIS), a marker for ovarian reserve. MIS levels were found to be lower in obese women. Interestingly, after bariatric surgery, MIS levels in women <35 years of age decreased, whereas premenopausal women older than 35 and postmenopausal women had no change in MIS levels . Table 2 summarizes some of the hormonal changes observed after bariatric surgery.

To date, the role of bariatric surgery in improving fertility in obese women remains unclear. While we know that obesity adversely affects female fertility and weight loss results in improved reproductive outcomes, the data on bariatric surgery achieving these goals come only from observational studies. Women also have to weigh the possible improved outcomes from bariatric surgery versus delaying conceiving after surgery, and many choose not to delay . Thus, further research is required to determine the role of bariatric surgery and reproductive outcomes.

Pregnancy after bariatric surgery

Young women who have undergone bariatric surgery are a unique obstetric population. Obesity increases both maternal and neonatal complications. The weight loss associated with bariatric surgery and its effect on subsequent pregnancies have been looked at in several retrospective studies. Galazis et al. performed a meta-analysis on 17 studies that evaluated obstetric and neonatal outcomes in post-bariatric pregnant women.

Assisted reproduction

It is accepted that female obesity is associated with decreased fecundity in both ovulatory and anovulatory patients . In a recent systematic review and meta-analysis of 33 studies (47,967 treatment cycles), women who were overweight or obese (BMI ≥ 25 kg/m ² ) had significantly lower clinical pregnancy (CP) rates (RR 0.90, p < 0.0001), LB rates (RR 0.84, p < 0.0002) and significantly higher miscarriage rates (RR 1.31, p < 0.0001) compared with women with BMI <25 kg/m ² .

Similarly, an analysis of 4609 women with first autologous fresh IVF or IVF–intracytoplasmic sperm injection (ICSI) cycles revealed that women with BMI ≥30.0 kg/m ² had significantly decreased odds of implantation, CP and LB. This study concluded that obese women had up to 65% lower odds of having an LB following their first assisted reproductive technology (ART) cycle, compared with women of BMI <30 kg/m ² .