*2.4.3.2. Exenatide in PCOS*

The single report evaluating the effect of short-acting GLP-1 RA exenatide in PCOS was a 24-week randomized study demonstrated a mean weight loss of 3.2 kg with exenatide monotherapy in a dose of 10 μg twice daily, 6.0 kg with exenatide in adjunct to metformin and 1.6 kg with metformin alone. Combined therapy was superior to either monotherapy in improving menstrual frequency and ovulation rate. The ovulation rate was 86% in the combined group compared to 50% in exenatide monotherapy and 29% in metformin alone group. IR and insulin sensitivity were improved in all groups. Total cholesterol and triglyceride decreased with combined therapy compared to metformin alone [59]. Weight reductions with exenatide were of comparable magnitude to the liraglutide effect in PCOS, but achieved in a longer period of time with a larger drop out [53, 59]. The study with exenatide was the first study addressing intervention with GLP-1 Ras in PCOS population.

#### *2.4.3.3. Safety profile of GLP-RAs in PCOS*

GLP1Ras appear to be well tolerated in PCOS population. The main side effect was nausea, which was transient and did not result in study withdrawals. In studies when GLP-1RA liraglutide was dosed at 1.2 mg (the middle dose for diabetes therapy) and combined with metformin in maximum dose (1 g BID), nausea appeared to be less common, which may be due to the lower doses of liraglutide administered [57, 60]. So far, there is no safety data about GLP-1RA use in pregnancy. They are generally classified as pregnancy class C. Therefore, the use of these medications in this population would require use of contraception while on therapy. Counseling women who are planning pregnancy would include a washout period.

## *2.4.4. PDE4 inhibitors in PCOS*

Less recognized and completely distinct regulatory mechanisms related to the enhancement of GLP-1–mediated action represent an inhibition of phosphodiesterase (PDE) 4. The first drug specifically targeting PDE4 was roflumilast. It was approved for treatment of chronic inflammatory diseases, primarily chronic obstructive pulmonary disease (COPD), due to its efficient antiinflammatory effect [81]. Collaterally, 1-year treatment of COPD with roflumilast was associated with a weight loss of about 2 kg within 12 months [81]. Beneficial effect of roflumilast on metabolic parameters and glucose homeostasis accompanied with mean weight reduction of approximately 2 kg versus placebo was also demonstrated with a short-term use of roflumilast in newly diagnosed T2DM without COPD [82]. A small randomized study with obese PCOS women demonstrated that treatment with roflumilast 500 mg per day in combination with metformin 1000 mg twice per day significantly reduced body weight in obese PCOS when compared to metformin monotherapy. Weight loss was primarily due to visceral fat mass reduction with the between treatment difference of about 5 kg [83]. These observations gave rise to the hypothesis that PDE4 is involved in regulation of signaling pathways linked to GLP-1 release [84]. In line with this consideration are data from experimental rodent model where a single treatment with roflumilast enhanced plasma GLP-1 levels up to 2.5-fold [84]. A direct comparison of short-term intervention with liraglutide and roflumilast addressing weight management was performed in PCOS-related obesity [60]. It was demonstrated that both monotherapy with liraglutide and roflumilast were associated with significant weight reduction in obese PCOS when compared to metformin monotherapy. Reduction of weight with liraglutide was greater than with roflumilast [60].

#### *2.4.5. DPP4 inhibitors in PCOS*

period. The high rate of spontaneous pregnancies in COMBI after liraglutide discontinuation implies the potential role of GLP-1 in reproduction in the pre-conception period [79]. In line with these preliminary results, new data support a role for GLP-1RAs in fertility beyond merely weight reduction [51]. In animal models, GLP-1 and GLP receptors have been identi-

The single report evaluating the effect of short-acting GLP-1 RA exenatide in PCOS was a 24-week randomized study demonstrated a mean weight loss of 3.2 kg with exenatide monotherapy in a dose of 10 μg twice daily, 6.0 kg with exenatide in adjunct to metformin and 1.6 kg with metformin alone. Combined therapy was superior to either monotherapy in improving menstrual frequency and ovulation rate. The ovulation rate was 86% in the combined group compared to 50% in exenatide monotherapy and 29% in metformin alone group. IR and insulin sensitivity were improved in all groups. Total cholesterol and triglyceride decreased with combined therapy compared to metformin alone [59]. Weight reductions with exenatide were of comparable magnitude to the liraglutide effect in PCOS, but achieved in a longer period of time with a larger drop out [53, 59]. The study with exenatide was the first study addressing intervention with GLP-1 Ras in PCOS population.

GLP1Ras appear to be well tolerated in PCOS population. The main side effect was nausea, which was transient and did not result in study withdrawals. In studies when GLP-1RA liraglutide was dosed at 1.2 mg (the middle dose for diabetes therapy) and combined with metformin in maximum dose (1 g BID), nausea appeared to be less common, which may be due to the lower doses of liraglutide administered [57, 60]. So far, there is no safety data about GLP-1RA use in pregnancy. They are generally classified as pregnancy class C. Therefore, the use of these medications in this population would require use of contraception while on therapy. Counseling women who are planning pregnancy would include a washout period.

Less recognized and completely distinct regulatory mechanisms related to the enhancement of GLP-1–mediated action represent an inhibition of phosphodiesterase (PDE) 4. The first drug specifically targeting PDE4 was roflumilast. It was approved for treatment of chronic inflammatory diseases, primarily chronic obstructive pulmonary disease (COPD), due to its efficient antiinflammatory effect [81]. Collaterally, 1-year treatment of COPD with roflumilast was associated with a weight loss of about 2 kg within 12 months [81]. Beneficial effect of roflumilast on metabolic parameters and glucose homeostasis accompanied with mean weight reduction of approximately 2 kg versus placebo was also demonstrated with a short-term use of roflumilast in newly diagnosed T2DM without COPD [82]. A small randomized study with obese PCOS women demonstrated that treatment with roflumilast 500 mg per day in combination with metformin 1000 mg twice per day significantly reduced body weight in obese PCOS when compared to metformin monotherapy. Weight loss was primarily due to visceral fat mass reduction with the between treatment difference of about 5 kg [83]. These observations gave rise to the hypothesis that PDE4

fied directly in the hypothalamo-pituitary ovary axis [80].

*2.4.3.2. Exenatide in PCOS*

64 Debatable Topics in PCOS Patients

*2.4.3.3. Safety profile of GLP-RAs in PCOS*

*2.4.4. PDE4 inhibitors in PCOS*

The endogenous incretins are quickly degraded by DPP4 in serum. Degradation of endogenous incretins can be prevented by DPP4 inhibitors. DPP4 inhibitors are taken orally and are used as antidiabetic agents. They influence glucose homeostasis through the enhancement of endogenous incretion hormones. As incretin enhances insulin secretion in response to meal, DPP4 inhibitors do not cause hypoglycemia. They have been reported to cause a 0.5–1% HbA1c reduction [85, 86]. Five DPP4 inhibitors are approved in the treatment of type 2 diabetes: sitagliptin, alogliptin, saxagliptin, vildagliptin and linagliptin. The role of enhancement of endogenous GLP-1 with DPP4 inhibitors in the treatment of obese PCOS patient is yet to be established. So far, only sitagliptin, alogliptin and saxagliptin were studied in PCOS (**Table 2**).

The present evidences suggest that DPP4 inhibitors preserve beta cell function [23, 87]. The fact that body weight gain and associated insulin resistance lead to increased load of beta cells and consequent beta cell dysfunction give rise to thoughts that the use of DPP4 inhibitors in treatment of PCOS with high metabolic risk is reasonable.

Another aspect is weight management. The enhancement of endogenous incretin hormones by DPP4 inhibitors is generally described as being weight neutral, although modest weight reduction has been seen in some clinical trials, particularly when DPP4 inhibitors are used


**Table 2.** Reported effects of treatment with DPP4 inhibitors in women with PCOS.

in combination with metformin [88, 89]. Nevertheless, the mere fact that DPP4 inhibition is not associated with the weight gain that typically accompanies improved glycemic control in patients with T2DM suggests that DPP4 inhibitors may not be completely neutral in this respect [90]. Slowing of gastric emptying that might reinforce the sustained change of eating behavior was also demonstrated with treatment with DPP4 inhibitor sitagliptin [91].

[97–100]. Nevertheless, the mere fact that postoperative weight loss was significantly correlated to the magnitude of GLP1 response (57 Holst) suggests that GLP1 has major role in weight balance. There is currently no clear consensus on the role of bariatric surgery in the treatment of obese patients with PCOS. Studies in PCOS are very heterogeneous with a small number of patients. Beneficial observations were reported after laparoscopic Roux-en-Y gastric band (RYGB) operation, in two small studies, where post-operational weight loss was associated with resolution of hirsutism in 29–52% of patients, resolution of type 2 diabetes, improvement of hypertension and dyslipidemia was also reported. Moreover, in both studies, significant improvement in conception rate was observed [101, 102]. The same effects were also reported in small studies on obese PCOS patients who underwent gastric banding, gastric plication

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

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

67

Agents mediating through GLP-1 effects in combination with lifestyle intervention and metformin could potentially improve treatment outcomes in obese PCOS via co-targeting multifactorial origin of obesity and concomitant abnormalities intrinsically related to PCOS. Based on the limited available data, GLP-1RAs, in particular liraglutide, should be considered in obese PCOS. Enhanced understanding of the direct impact on GLP-1 beyond weight reducing and metabolic effects at the levels of pituitary and ovary are expected within the next 5 years [51]. Larger and longer randomized studies are needed to establish metabolic, reproductive and cardiovascular risk reduction and assess sustainability and safety profile of the benefits achieved by these potential new treatment

Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre

[1] Lim SS, Davies MJ, Norman RJ, Moran LJ. Overweight, obesity and central obesity in women with polycystic ovary syndrome: A systematic review and meta-analysis. Human Reproduction Update. 2012;**18**(6):618-637. DOI: 10.1093/humupd/dms030 [2] De Leo V, la Marca A, Petraglia F. Insulin-lowering agents in the management of polycystic ovary syndrome. Endocrine Reviews. 2003;**24**(5):633-667. DOI: 10.1210/er.2002-0015

and laparoscopic sleeve gastrectomy [103, 104].

Mojca Jensterle Sever\*, Simona Ferjan and Andrej Janez

\*Address all correspondence to: mojca.jensterlesever@kclj.si

**3. Conclusion**

strategies.

**Author details**

Ljubljana, Slovenia

**References**

The first study addressing the preservation of beta cell function in PCOS with DPP4 inhibitor reported an increase of insulin sensitivity and significant decrease of insulin resistance when alogliptin was added to metformin. Even greater improvement of these parameters was seen when triplet therapy with alogliptin, pioglitazone and metformin was used [92]. Beneficial effects of another DPP4 inhibitor sitagliptin were recently reported in metformin intolerant women with PCOS and high metabolic risk. After metformin withdrawal, a 12-week treatment with sitagliptin leads to significant improvement in beta cell function and prevented conversion rate from normal to impaired glucose tolerance and type 2 diabetes when compared to placebo [93]. Preliminary data suggest that DPP4 inhibitors seem to be a promising alternative in PCOS women with high metabolic risk who have failed with lifestyle intervention and are metformin intolerant. Future larger designs of longer duration should be powered.

A small single blind, randomized study on prediabetic PCOS women reported beneficial effect of DPP4 inhibitor saxagliptin on glucose homeostasis, metabolic parameters and clinical status. A 16-week intervention with saxagliptin/metformin (5 mg/2000 mg), monotherapy with saxagliptin (5 mg) and monotherapy with metformin (2000 mg) lead to normalization in glucose homeostasis in 91, 55 and 25% of patients, respectively. Improvement of metabolic parameters and clinical status was reported in all groups [94].

In a recent randomized study, another potential use of DPP4 inhibitors was demonstrated. Enhancement of endogenous GLP-1 signaling by sitagliptin prevented the expected weight regain after liraglutide 3.0 mg cessation in women with PCOS. During a 12-week follow-up period, sitagliptin in adjunct to metformin resulted in weight maintenance, whereas a switch to metformin alone resulted in a significant weight regain after liraglutide discontinuation. It was also demonstrated that the ability to resist emotional eating was greater in combined treatment than in monotherapy with metformin [95]. The observation provides first clinical findings suggesting that DPP4 inhibition may prevent weight regain after liraglutide cessation. This sequential treatment concept is particularly useful in patients who became intolerant, develop treatment resistance or decide to stop the antiobesity treatment with liraglutide. Further research is necessary to fully understand the cross talks between effects of peripheral signals of endogenous GLP-1 and central areas of satiety and reward in obese subjects.

#### *2.4.6. Bariatric surgery in PCOS*

Bariatric surgery is a well-established and effective method for the treatment of extreme obesity for well-informed and motivated patients with a BMI > 40 kg/m<sup>2</sup> or >35 kg/m<sup>2</sup> , with at least one comorbidity related to obesity and who have been previously unsuccessful with medical treatment for obesity [96]. The mechanism of weight loss induced by bariatric surgery is multifactorial. Beside reduced gastric volume [97, 98], weight reduction could be possibly explained with the changes in gut-brain axis. Gastrointestinal bypass surgery results in a quick delivery of nutrients to the small intestine associated with large increase in postprandial levels of GLP1 and PYY hormones [97–100]. Nevertheless, the mere fact that postoperative weight loss was significantly correlated to the magnitude of GLP1 response (57 Holst) suggests that GLP1 has major role in weight balance.

There is currently no clear consensus on the role of bariatric surgery in the treatment of obese patients with PCOS. Studies in PCOS are very heterogeneous with a small number of patients. Beneficial observations were reported after laparoscopic Roux-en-Y gastric band (RYGB) operation, in two small studies, where post-operational weight loss was associated with resolution of hirsutism in 29–52% of patients, resolution of type 2 diabetes, improvement of hypertension and dyslipidemia was also reported. Moreover, in both studies, significant improvement in conception rate was observed [101, 102]. The same effects were also reported in small studies on obese PCOS patients who underwent gastric banding, gastric plication and laparoscopic sleeve gastrectomy [103, 104].
