Frontiers in Gynecological Endocrinology Volume 3: Ovarian Function and Reproduction - From Needs to Possibilities

10. Adipose Tissue and Menstrual Disturbances: Obesity Versus Anorexia Nervosa

Svetlana Vujovic¹ , Miomira Ivovic¹, Milina Tančić-Gajić¹, Ljiljana V. Marina¹, Zorana Arizanovic¹, Marija Barac¹, Maja Ivanisevic¹, Branko Barac¹, Milena Brkic¹, Marija Djurović¹ and Dragan Micić¹

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Medical Faculty, Clinic of Endocrinology, Diabetes and Diseases of Metabolism, Clinical Center of Serbia, University of Belgrade, Belgrade, Serbia

Svetlana Vujovic

Email: prof.svetlana.vujovic@gmail.com

Maintaining body homeostasis is a prerequisite for normal reproductive function, which is vital for the survival of the species and an important process of natural selection. Body weight is an independent regulator of the hypothalamic–pituitary–gonadal axis activity.

Eating disorders are psychological illnesses defined by abnormal eating habits that may involve either excessive or insufficient food intake to the detriment of an individual’s physical and mental health.

10.1 Obesity and Menstrual Disturbances

Obesity is an abnormal accumulation of body fat usually 20 % or more over an individual’s ideal body weight. The World Health Organization found that 9–25 % women were severely obese, meaning with grade IV obesity (body mass index (BMI) over 40 kg/m²).

Adipose tissue represents an endocrine organ. Adipocytes, immune cells, connective tissue matrix, nerve tissue, and stromal and vascular cells are involved in its function. White adipose tissue is made by 60–85 % lipid (90–95 % triglycerides). It provides as follows:

· Heat regulation

· Body cushioning

· Energy storage

Brown adipose tissue is important for non-shivering thermogenesis. In Table 10.1, the effects of adipose tissue on gonadal axis are presented.

Table 10.1

Effects of adipose tissue on gonadal axis

Gonadal axis is closely linked to the nutritional status. Critical percentage of body fat is necessary for maintaining regular menstrual cycles. Gaining weight can be detected as stressor influencing gonadal axis. On the other hand, adaptive mechanisms exist. In a moment of adaptive mechanism insufficiency, anovulation occurs and menstrual irregularities happen.

Lim et al. [1] showed the results of meta-analysis of overweight, obesity, central obesity in women with polycystic ovary syndrome (PCOS). They included 35 studies, on 15,129 women. Conclusion was made that women with PCOS had increased prevalence for overweight (1.95), obesity (2.77), central obesity (1.73), compared to controls.

The prevalence of obesity is increasing and has an important bearing on the phenotype of PCOS. Some studies suggested that higher body mass index is associated with greater prevalence of menstrual irregularities, hyperandrogenism, and hirsutism, but more studies are required to confirm this.

Increased BMI and visceral adiposity are associated with insulin resistance in the general population, but its effects on menstrual irregularities and hirsutism remain unclear. Lifestyle management results in weight loss and improve surrogate markers of metabolic disease [2].

Polycystic ovary disease results from the interaction between androgen excess with environmental factors, such as abdominal adiposity, obesity, and insulin resistance [3]. It represents the major risk factor for diabetes mellitus. Obesity is an exacerbating factor in the development of type II diabetes mellitus. The risk of type II diabetes mellitus is markedly elevated in women with PCOS (Table 10.2) at middle age and therefore reinforces the need for routine screening of PCOS for diabetes over time [4].

Table 10.2

Indications for screening for diabetes

Besides diabetes, cardiovascular diseases represent the most important diseases as a consequence of obesity (Table 10.3) [5].

Table 10.3

PCOS-related coronary vascular diseases risks

In obese women with PCOS, hyperinsulinism is detected. It influences gonadal axis (Table 10.4).

Table 10.4

Effects of hyperinsulinism

Insulin and LH influence steroidogenesis in theca cells from cholesterol to testosterone. These steps involve P450c17 alfa. Diamanti-Kandarakis E [6] showed insulin signaling defects in PCOS.

Growth hormone has a special role in maintaining body mass. Obesity is characterized by decreased growth hormone secretion, while chronic starvation is characterized by growth hormone resistance. IGF1 may be low in both extremes, and androgen levels may be abnormal. Free testosterone levels across the body weight spectrum are detected [7]. Pooled overnight, IGF1 levels were associated with pooled free testosterone levels across the body composition spectrum.

Visceral fat is the most significant variable correlating with metabolic dysfunction in women with polycystic ovary syndrome [8].

Adipose tissue secreted proteins are shown in Table 10.5.

Table 10.5

Adipose tissue secreted proteins

Leptin is a protein produced by adipocytes. Leptin receptors are detected in the hypothalamus in close proximity to median eminence. It regulates food intake, energy expenditure, and body weight.

Leptin stimulates gonadotropin secretion at the hypothalamic and pituitary levels. It directly modulates ovarian steroidogenesis. Pregnancy rate is modulated by leptin effects on the process of implantation and embryogenesis.

Beneficial adipokines are those increasing tissue sensitivity to insulin (Table 10.6) [9]. Adiponectin has a direct effect on the late stages of folliculogenesis. It interacts with insulin and gonadotropin in inducing periovulatory changes in ovaries. In obese women with PCOS, hypoadiponectinemia is present.

Table 10.6

Beneficial adipokines

Low adiponectin increases tissue necrosis factor alfa, interleukin 6, and leptin leading to insulin resistance, hyperinsulinism, androgen excess, and abdominal visceral adiposity. Hypoadiponectinemia is in the vicious circle, unifying hypothesis explaining the interplay between PCOS and abdominal obesity.

Weight loss decreases leptin levels, free fatty acids, resistin, PAI, TNF alfa and interleukin 6 and increases adiponectin, improving insulin sensitivity and reducing inflammation.

10.2 Anorexia Nervosa and Menstrual Disturbances

Menstrual cycles often cease after 10–15 % decrease in normal body weight representing 5 % of all amenorrhea. Mechanisms involved in amenorrhea in anorexia nervosa include as follows:

· Altered regulation of GnRH secretion

· Changes in the dopaminergic and opioidonergic system

Loss of weight can be understood as a stressor influencing the hypothalamic–pituitary–gonadal axis. In paraventricular nucleus and lateral hypothalamic area, cortico-releasing hormone (CRH) production increases, as well as proopiomelanocorticotropin and beta endorphin in arcuate nucleus, decreasing GnRH. Consequently, pituitary FSH and LH decrease and hypoestrogenism results with anovulatory cycles. Menstrual irregularities (oligomenorrhea and amenorrhea) represent stress disturbances that appeared due to maladaptive mechanisms (brake of adaptive mechanism) under the influences of too strong stressors or stressors of long duration.

Hormonal changes in anorexia nervosa are shown in Table 10.7.

Table 10.7

Anorexia nervosa–induced hormonal changes

Reduction of adipose tissue sirtuin 1 (SirT1) expression, which leads to histone hyperacetylation, ectopic inflammatory gene expression, is identified as a key regulatory component of macrophage influx into adipose tissue during overnutrition. It regulates proinflammatory transcription in response to fatty acids hypoxia and endoplasmatic reticulum stress. In anorexia nervosa, a completely opposite process occurs.

10.3 Conclusion

Normal body weight is an important factor in regulating menstrual cycle through the hypothalamic–pituitary–ovarian axis. Prior to ovulation induction, weight has to be normalized. Regulating body weight will stop metabolic and cardiovascular diseases, making better quality of healthier life.

References

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