**2.2. Incretin hormones**

**1. Introduction**

58 Debatable Topics in PCOS Patients

metabolic risk.

**2. Main body**

**2.1. Gut-brain axis in controlling eating behavior**

(CNS) in order to stop feeding [8].

is regulated also by cognitive functions and emotional inputs [8, 9].

Obesity is one of a key phenotype of polycystic ovary syndrome (PCOS). The risk for excess body weight in this population is up to 2.8 higher than in women without PCOS. About 60–70% of patients are being characterized as obese or overweight [1, 2]. The amount and distribution of fat is a major contributor to expression and severity of the syndrome [3, 4]. Obese women demonstrate more severe gynecological abnormalities and clinical and biochemical hyperandrogenism than normal weight or lean women with PCOS. Insulin resistance, glucose derangements including impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) and an increased overall cardiovascular risk are also more likely in obese PCOS [5–7]. Weight reduction is substantial for improvement of metabolic and androgen profile, reproductive function and reducing cardiovascular risk. Weight management by lifestyle intervention often remains unsatisfactory and nonsustainable. In the present chapter, we revised limited studies addressing the potential use of agents mediating through glucagon-like peptide 1 (GLP-1) in obese PCOS. We mainly focused on the available clinical trials of GLP-1 receptor agonists in this population. In addition, we challenged the original concept related to the enhancement of GLP-1–mediated action through phosphodiesterase 4 (PDE4). Nevertheless, we considered dipeptidyl peptidase 4 inhibitors as an alternative pharmacological intervention in subgroups of PCOS with high

An inability to control eating behavior is the main culprit for eating beyond metabolic needs that result in obesity. Eating behavior is a complex pattern based on communication between specific regulatory and hedonistic centers in hypothalamus and peripheral signals from gastrointestinal tract. The latter system consists of gastric emptying/distention signals and gastrointestinal regulatory (orexigenic and anorexigenic) hormones. In addition, eating behavior

Orexigenic hormone increases before meal and stimulates hunger and food intake. The most potent known orexigenic hormone ghrelin is released from specific endocrine cells in the stomach and stimulates food intake. On the opposite, hormones, such as cholecystokinin (CCK), peptide tyrosine-tyrosine (PYY) and glucagon-like polipeptide-1 (GLP-1), produce anorexigenic signals and affect peripheral organs and centers in the central nervous system

Reports about eating behavior in PCOS population are few and the results are not conclusive. It has not been established whether eating behavior is different in obese women with PCOS when compared to weight-matched non-PCOS controls. An increased food intake was reported in animal models and clinical studies with women with PCOS when compared to healthy controls [10–14]. Furthermore, bulimia was associated with an increased frequency Incretins are glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). They are polypeptide gut hormones secreted from endocrine cells in the small intestine under the influence of food intake and are responsible for 50–70% of postprandial insulin secretion. This is so-called incretin effect and is proportional to the current glycemia [8, 22].

GLP-1 is produced by L cells in distal intestine. It influences glucose hemostasis after food ingestion by insulin secretion and concurrent inhibition of glucagon release. GLP-1 is involved in the regulatory mechanisms of eating behavior with direct inhibitory effect on the homeostatic and hedonic centers of appetite in the central nervous system and indirect inhibitory effect on gastric emptying rates and gastrointestinal tract motility, which result in decreased food intake and consequently in body weight reduction [8, 23].

GIP is produced by K cells, which are located in the upper small intestine. It increases glucosedependent insulin release and has protective effect on beta cell. GIP also increases lipogenesis and has bone protective and neuroprotective effect. In contrast to GLP1, no additional effects on appetite and body weight are shown with GIP [22].

Both incretin hormones have a short half-life. They are rapidly inactivated by the enzyme dipeptidyl peptidase 4 (DPP4).

Obesity with the onset of insulin resistance and consequent metabolic diseases, such as impaired glucose tolerance and type 2 diabetes, impairs the effect of incretins. Postprandial GLP-1 concentration in obese people is lower than in people with normal body weight [24–27]. Similarly, lower postprandial GLP-1 values were measured in patients with type 2 diabetes, while the GIP response in this population was preserved [28–32].

#### **2.3. Incretin hormones in PCOS**

Current reports about GLP-1 secretion in PCOS are not consistent. Some studies found similar fasting GLP-1 levels in PCOS compared with age- and BMI-matched controls [21, 33–35], whereas others reported decreased or increased fasting levels of GLP-1 in PCOS [36, 37]. Regarding postprandial levels of GLP-1, some authors demonstrated that postprandial plasma levels of GLP-1 did not differ between subjects with and without PCOS [20, 34, 35]. On the other hand, another study demonstrated lower GLP-1 levels in PCOS at the end of oral glucose tolerance test (OGTT) compared to the control group, whereas fasting GLP-1 levels did not differ between two groups [21]. However, lower fasting GLP-1 levels and a weakened GLP-1 response to standardized mixed meal in women with PCOS versus healthy control group were also reported [37]. Contrary, another group found higher fasting GLP-1 levels in PCOS patients; while at the end of OGTT, GLP-1 levels did not differ between groups [36].

[49, 50]. No benefit regarding weight reduction was recognized when metformin was added on lifestyle changes. In a small study with 19 lean and 21 obese PCOS patients, the impact of metformin on incretin hormones was demonstrated with the increase of GLP-1 during

Incretin System: New Pharmacological Target in Obese Women with Polycystic Ovary Syndrome

http://dx.doi.org/10.5772/intechopen.70648

61

The available recent data offer new opportunity to include an adjunct management in obese PCOS patients who have not responded to lifestyle modification with or without

GLP-1 receptor agonists (GLP-1 RA) are class of antidiabetes medications, which are incretin mimetics. There are six GLP-1 RAs approved and available, of which only liraglutide and exenatide have been studied in PCOS [53–61]. Studies have been of short duration and have all shown the expected effective weight reduction with GLP-1Ras alone or in combination with metformin and improvement in glucose parameters with variable results on gynecologi-

Liraglutide is a long-acting GLP-1 RA analogue that is 97% homologous to human GLP-1. Its dose-dependent effect on weight loss was first observed in overweight patients with type 2 diabetes and later also in overweight subjects without diabetes. In dose of 3 mg, it was

> **Decreased fasting and/ or post-load glucose level**

x x x x x

x /

x / x / /

x x x

**Reduced hyperandrogenism** **Improved menstrual frequency**

**Decreased insulin resistance**

Jensterle et al. [60] x x x / x

OGTT with 8-month metformin intervention [35].

cal abnormalities and hyperandrogenism (**Table 1**).

recently approved for weight management in many countries [62–65].

**Improved eating behavior**

Kahal et al. [58] x / /

Jensterle et al. [57] x x x x

**Table 1.** Reported effects of GLP-1 agonist treatment in women with PCOS.

*2.4.3. GLP-1 receptor agonists in PCOS*

metformin [51, 52].

*2.4.3.1. Liraglutide in PCOS*

**Study Weight** 

Elkind-Hirsch et al. [59]

Rasmussen and Lindenberg [55]

Jensterle Sever et al. [53]

Nylander et al.

Note: x = yes; / = no effect.

[61]

Jensterle et al. [56] x x

**reduction**

Also studies concerning the GLP-1 response in PCOS patients in relation to body weight are not conclusive. Some authors demonstrated no difference in GLP-1 between lean and obese patients with PCOS during OGTT, whereas others reported lower levels of GLP-1 in obese PCOS patients compared to lean age-matched PCOS patients and healthy lean controls [20].

There are only few studies evaluating GIP levels in women with PCOS. Compared with BMI- and age-matched controls, most of them demonstrated no difference in fasting GIP levels [20, 33–35, 38], yet some have found increased fasting GIP [21]. The results of postprandial GIP levels in PCOS compared to matched controls are more inconsistent. While some studies did not find differences in GIP levels [34], other found increased [21, 38] or decreased [20, 35] GIP levels after OGTT.
