Physical Address

304 North Cardinal St.
Dorchester Center, MA 02124

Obesity: male and female infertility


7.1

Introduction

  • Obesity has become a global epidemic, affecting more than 650 million adults worldwide.

  • The prevalence of obesity has consistently increased to the point where more than 35% of adults are now considered to be obese.

  • Women are generally more prone to obesity than men possibly because of their lower basal metabolic rate.

  • The effect of obesity on reproductive function reflects through complex endocrinological changes resulting from an interaction between the fat compartment and hypothalamic pituitary gonadal axis with an ultimate effect on sex steroids mediated through the effect of circulating adipokines.

  • Overweight is defined by the World Health Organization (WHO) as a body mass index (BMI) ≥25 kg/m 2 and obesity as ≥30 kg/m 2 .

  • Obesity brings out many problems such as social, psychological, demographic, and long-term health issues.

7.2

Epidemiology

  • The prevalence of obesity has increased in developed countries because of a change in lifestyle, including reduced physical activity, changes in nutrition style, and an increased calorie intake.

  • Other factors such as endocrine disorders, hormonal disorders, psychological disorders, and use of some drugs such as steroids and antidepressants may lead to obesity.

  • Rates of obesity in the United States are significantly higher than in other developed nations.

  • The number of obese Americans has doubled since 1960.

  • The WHO reported that in the United States and most European countries, 60% of women are overweight (≥25 kg/m 2 ), of these, 30% are obese (≥30 kg/m 2 ) and 6% are morbidly obese (≥35 kg/m2).

7.3

Female infertility

  • Obesity exerts a negative influence on female fertility.

  • Obese women are more likely to have ovulatory dysfunction due to dysregulation of the hypothalamic pituitary ovarian (HPO) axis.

  • Obese women have reduced fecundity even when eumenorrheic.

  • Obesity plays a significant role in reproductive disorders in women.

  • It is associated with anovulation, menstrual disorders, infertility, difficulties in assisted reproduction, miscarriage, and adverse pregnancy outcomes.

  • In obese women, gonadotrophin secretion is affected for the following reasons:

  • Increased peripheral aromatisation of androgens to oestrogens,

  • The insulin resistance and hyperinsulinaemia in obese women lead to hyperandrogenaemia.

  • The sex hormone binding globulin, growth hormone, and insulin-like growth factor binding proteins are decreased, and leptin levels are increased.

  • The neuroregulation of the HPO axis deteriorates.

  • These alterations may explain impaired ovulatory function and so reproductive health.

  • Because of lower implantation and pregnancy rates, higher miscarriage rates, and increased maternal and foetal complications during pregnancy, obese women have a lower chance to give birth to a healthy new-born.

7.3.1

Transgenerational inheritance

  • There is a mounting body of evidence suggesting that maternal obesity may confer a risk of metabolic dysfunction through multiple generations.

  • Children of obese mothers are more likely to develop obesity, type 2 diabetes, and cardiovascular disease as adults.

7.3.2

Pathophysiological basis of infertility in obese women

  • It is complex and multifactorial. Several mechanisms are involved in the relationship between fertility and obesity.

  • Adipokines are the signalling molecules (hormones) secreted by adipose tissue, and abnormalities in adipokines can cause inflammation and abnormal cell signalling, and thus can lead to deterioration in cell metabolism and function.

  • Some of these adipokines are leptin, adiponectin, interleukin-6 (IL-6), plasminogen activator inhibitor-1 (PAI-1), tumour necrosis factor-α (TNF-α), resistin, visfatin, chemerin, omentin, and ghrelin.

  • High levels of leptin seen in obesity may inhibit folliculogenesis. High levels of leptin interfere with endometrial receptivity and embryo implantation. Leptin levels have been found to be positively correlated with insulin resistance in women with polycystic ovarian syndrome (PCOS).

  • Adiponectin levels increase with weight loss. In the absence of adiponectin in obese women, plasma insulin levels increase. Consequently, high levels of insulin lead to hyperandrogenaemia.

  • IL-6, in the high levels seen in obese women, may contribute to impaired fertility in women with PCOS.

  • PAI-1 has been associated with miscarriage in women with PCOS.

  • TNF-α may affect several levels of the reproductive axis: inhibition of gonadotrophin secretion, ovulation, steroidogenesis, corpus luteum regression, and endometrial development.

  • The mechanism of other adipokines on reproductive functions such as resistin and ghrelin has not been fully understood.

  • Increased resistin levels seen in obesity leads to insulin resistance and leads to decreased insulin sensitivity.

  • Visfatin, shows insulin-mimetic effects, that increases glucose uptake in adipocytes and muscle cells, and decreases glucose release from hepatocytes.

  • Chemerin can impair follicle-stimulating hormone (FSH)-induced follicular steroidogenesis and thus can play a role in the pathogenesis of PCOS.

  • Almost all of the adipokines seem to have their effects on reproduction by causing insulin resistance ( Table 7.1 ).

    Table 7.1
    The effects of the adipokines on reproduction.
    Adipokines Effects on reproduction in obesity Serum levels in obesity
    Leptin

    • Inhibits insulin-induced ovarian steroidogenesis

    • Inhibits LH stimulated oestradiol production by the granulose cells

    		Increases
    Adiponectin Plasma insulin levels increase Decreases
    IL-6 Causes insulin resistance Increases
    PA1–1 Causes insulin resistance Increases
    TNF-α

    • Impairs insulin action-hyperinsulinaemia

    • Inhibits insulin signalling

    		Increases
    Resistin Causes insulin resistance Increases
    Visfatin Increased insulin sensitivity Increases
    Omentin Increased insulin sensitivity Decreases
    Chemerin Negatively regulates FSH-induced follicular steroidogenesis Increases
    FSH , Follicle-stimulating hormone; IL-6 , Interleukin-6; LH , Luteinising hormone; PA1–1 , Plasminogen Activator Inhibitor Type-1; TNF-α , tumour necrosis factor-α.

7.3.3

The clinical effects of obesity on female infertility

  • Obesity has a negative effect on reproductive potential, primarily thought to be due to functional alteration of the HPO axis.

  • Obese women often have higher circulating levels of insulin, which is a known stimulus for increased ovarian androgen production. These androgens are aromatised to oestrogen at high rates in the periphery owing to excess adipose tissue, leading to negative feedback on the HPO axis and affecting gonadotropin production.

  • This manifests as menstrual abnormalities and ovulatory dysfunction.

  • Obese women with a BMI >27 kg/m 2 have a relative risk of anovulatory infertility of 3.1 (95% CI, 2.2–4.4) compared with their lean counterparts with a BMI 20.0–24.9 kg/m 2 .

  • Obese women have a lower chance of conception within 1 year of stopping contraception compared with normal-weight women (i.e., 66.4% of obese women conceive within 12 months, compared with 81.4% of those of normal weight).

  • Multiple studies have demonstrated that obese women have increased time to pregnancy.

  • Obese women remain subfertile even in the absence of ovulatory dysfunction. Study showed reduced fecundity in eumenorrheic obese women and the probability of spontaneous conception declined linearly with each BMI point >29 kg/m 2 .

  • In normogonadotropic anovulatory women, increased BMI and abdominal obesity are associated with decreased odd ratios of ovulation in response to clomiphene citrate.

7.3.4

Effects on the oocyte

  • In women with obesity, there is high rates of meiotic aneuploidy with fragmented disorganised meiotic spindles and improper alignment of chromosomes.

  • Obesity appears to disrupt the mitochondrial function in the oocyte.

  • There is also evidence of endoplasmic reticulum (ER) stress in the obese state.

  • The continued dietary excess of fatty acids accumulates in the tissues and exerts toxic effects, which is termed lipotoxicity.

  • Obese women have higher levels of reactive oxygen species (ROS) that induce mitochondrial and ER stress leading to apoptosis.

  • Lipotoxicity plays a role in the development of insulin resistance and a heightened inflammatory state.

  • Obesity is considered to be a chronic low-grade inflammatory state.

  • Obese women have higher circulating levels of C-reactive protein, a marker of systemic inflammation.

  • The developing blastocyst produces adiponectin, IL-1, and IL-6. The altered inflammatory milieu in obese women likely exerts an influence on follicle rupture at the time of ovulation and invasion of the trophoblast into the receptive endometrium.

  • This effect of obesity at the level of the oocyte could have downstream effects on endometrial receptivity and embryo implantation.

7.3.5

Effects on the embryo

  • Obese women are more likely to create poor-quality embryos.

  • Embryos may also be susceptible to lipotoxicity.

  • Elevated leptin levels in obese women may exert a direct negative effect on the developing embryo.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here

Related Posts