**5. What methods do we choose in order to obtain weight loss?**

#### **5.1. Pharmacological treatment for obesity**

In a relatively recent past, following multiple clinical trials, medical journals supported the benefit of adding anti-obesity drugs to lifestyle changes–both in terms of maintaining weight in the long-term and reducing associated co-morbidities. Drugs such as sibutramine, orlistat, and rimonabant have been shown to be effective in improving the lipid profile, lowering blood pressure, glycosylated hemoglobin (in diabetics), and pro-inflammatory cytokine levels, thus reducing cardiovascular risk [41]. Meanwhile, it has been shown that the majority of these drugs instead of lowering cardiovascular risk have the opposite effect, which has led to their removal from the market [42].

Currently, drugs used in the treatment of obesity are–orlistat, lorcaserin, phentermine-topiramate, bupropion naltrexone, liraglutide and noradrenergic sympathomimetic drugs but there are no specific studies with patients suffering from PCOS. A list of medication used to treat obesity is shown in **Table 1**.

*5.1.2. Serotonin agonists*

*5.1.3. Sympathomimetic drugs*

Lorcaserin is believed to activate serotonin 5-HT2c receptors stimulating pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus. Thus, it increases alphamelanocortin stimulating hormone resulting in satiety and consequently in a decreased food intake [45]. Lorcaserin is indicated for the treatment of obesity when it is associated with at least one comorbidity such as type 2 diabetes mellitus, high blood pressure, high cholesterol or sleep apnea [46]. This is an alternative to orlistat, with similar efficacy but fewer side effects. In addition to weight loss, studies show that it lowers: blood pressure, heart rate, total choles-

Diethylpropion Benzphetamine Phendimetrazine

Lifestyle Changes and Weight Loss: Effects in PCOS http://dx.doi.org/10.5772/intechopen.73298 47

Venlafaxine Desvenlafaxine Topiramate Zonisamide Lamotrigine Ziprasidone

Pramlintidine Exenatide Liraglutide

Bupropion-naltrexone

Noradrenergic sympathomimetics, of which we currently find phentermine, diethylpropion, benzphetamine, and phendimetrazine, cause early satiety and reduce food cravings.Although they have increased effectiveness and their use is widespread, they are indicated for a treatment of a maximum of 12 weeks and have large potential for abuse. We must mention that all sympathomimetic drugs have side effects such as tachycardia, increased blood pressure, cause insomnia, constipation, nervousness, and dry mouth. In fact, their side effects on the

terol, LDL cholesterol, fasting glucose, and insulin levels.

**Drugs that alter fat digestion Orlistat** Serotonin agonists Lorcaserin Sympathomimetic drugs Phentermine

Antidepressants and antiepileptic drugs Bupropion

Diabetes drugs Metformine

Combination drugs Phentermine-topiramate

**Table 1.** Medications used in the treatment of obesity and their classification.

#### *5.1.1. Drugs that alter fat digestion*

Orlistat, being an inhibitor of pancreatic and gastric lipases, inhibits the hydrolysis of triglycerides from the diet by up to 30%, thus reducing total caloric intake [41]. Hence, weight loss is not significant using this medication only and requires a calorie-restricted regimen. The X-PERT study establishes a 3-month weight loss that exceeds 5% of the initial weight as an accurate predictor of long-term weight loss. A 12-month meta-analysis concludes that patients undergoing lifestyle changes that also associate orlistat as an adjuvant medication will lose an average of 8–10 kg over 12 months as opposed to those who associate lifestyle change with a placebo who will lose an average of 3–6 kg [43]. In addition to weight loss, it has positive effects in reducing cardiovascular risk factors due to its effects on triglyceride and LDL cholesterol [41]. Moreover, in Orlistat treatment, a better glycemic control with decreasing fasting glucose and glycosylated hemoglobin is noticed [44]. This is considered to be a relatively safe drug, with adverse effects mainly upon the intestinal tract such as increased defecation, fatty stools, and fecal urgency.


**Table 1.** Medications used in the treatment of obesity and their classification.

#### *5.1.2. Serotonin agonists*

**4.2. What is the importance of physical exercise?**

46 Debatable Topics in PCOS Patients

**5.1. Pharmacological treatment for obesity**

their removal from the market [42].

obesity is shown in **Table 1**.

stools, and fecal urgency.

*5.1.1. Drugs that alter fat digestion*

physical activity of moderate intensity for 90 minutes per week [40].

**5. What methods do we choose in order to obtain weight loss?**

Physical exercise is definitely a part of the lifestyle changes. Studies show that the type, frequency or duration of the exercise do not influence the results that patients get from it. It has been shown that regular, aerobic exercise of moderate intensity does not only contribute to weight loss and improved insulin resistance, but also improves reproductive outcomes, including ovulation and regulation of menstrual cycles. The recommendation for patients with PCOS in view of the improve reproductive and cardio metabolic outcomes is – aerobic

In a relatively recent past, following multiple clinical trials, medical journals supported the benefit of adding anti-obesity drugs to lifestyle changes–both in terms of maintaining weight in the long-term and reducing associated co-morbidities. Drugs such as sibutramine, orlistat, and rimonabant have been shown to be effective in improving the lipid profile, lowering blood pressure, glycosylated hemoglobin (in diabetics), and pro-inflammatory cytokine levels, thus reducing cardiovascular risk [41]. Meanwhile, it has been shown that the majority of these drugs instead of lowering cardiovascular risk have the opposite effect, which has led to

Currently, drugs used in the treatment of obesity are–orlistat, lorcaserin, phentermine-topiramate, bupropion naltrexone, liraglutide and noradrenergic sympathomimetic drugs but there are no specific studies with patients suffering from PCOS. A list of medication used to treat

Orlistat, being an inhibitor of pancreatic and gastric lipases, inhibits the hydrolysis of triglycerides from the diet by up to 30%, thus reducing total caloric intake [41]. Hence, weight loss is not significant using this medication only and requires a calorie-restricted regimen. The X-PERT study establishes a 3-month weight loss that exceeds 5% of the initial weight as an accurate predictor of long-term weight loss. A 12-month meta-analysis concludes that patients undergoing lifestyle changes that also associate orlistat as an adjuvant medication will lose an average of 8–10 kg over 12 months as opposed to those who associate lifestyle change with a placebo who will lose an average of 3–6 kg [43]. In addition to weight loss, it has positive effects in reducing cardiovascular risk factors due to its effects on triglyceride and LDL cholesterol [41]. Moreover, in Orlistat treatment, a better glycemic control with decreasing fasting glucose and glycosylated hemoglobin is noticed [44]. This is considered to be a relatively safe drug, with adverse effects mainly upon the intestinal tract such as increased defecation, fatty

Lorcaserin is believed to activate serotonin 5-HT2c receptors stimulating pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus. Thus, it increases alphamelanocortin stimulating hormone resulting in satiety and consequently in a decreased food intake [45]. Lorcaserin is indicated for the treatment of obesity when it is associated with at least one comorbidity such as type 2 diabetes mellitus, high blood pressure, high cholesterol or sleep apnea [46]. This is an alternative to orlistat, with similar efficacy but fewer side effects. In addition to weight loss, studies show that it lowers: blood pressure, heart rate, total cholesterol, LDL cholesterol, fasting glucose, and insulin levels.

#### *5.1.3. Sympathomimetic drugs*

Noradrenergic sympathomimetics, of which we currently find phentermine, diethylpropion, benzphetamine, and phendimetrazine, cause early satiety and reduce food cravings.Although they have increased effectiveness and their use is widespread, they are indicated for a treatment of a maximum of 12 weeks and have large potential for abuse. We must mention that all sympathomimetic drugs have side effects such as tachycardia, increased blood pressure, cause insomnia, constipation, nervousness, and dry mouth. In fact, their side effects on the cardiovascular system were those that caused the withdrawal of some drugs of this class from the market, such as sibutramine (removed from the market in 2010 [47] after it was shown to increase the risk of myocardial infarction and stroke [48]) or phenylpropanolamine (removed from the market due to association with increased risk of hemorrhagic stroke in women [49]).

even orlistat when administered in high doses [55]. Among its adverse effects when administered at high doses are included nausea and vomiting, which may in part contribute to the weight-loss effect [55]. This drug is quite often avoided due to its route of administration (subcutaneous injection) but also due to its potential adverse effects, that although rare, they are severe (pancreatitis, renal impairment and gallbladder disease). Further, we consider important to mention that rodent studies have demonstrated the association of this drug with the increased frequency of thyroid C-cell tumors (benign and malignant), which is why it is not recommended in the case of the patients with personal or family history of medullary thyroid cancers [56].

The combination of phentermine and topiramate is another two drug combination with good effect in terms of weight loss, being pharmacologically included in the sympathomimetic anorexia class. Being a two drug combination, it has a complex mechanism of action. Thus, phentermine, which is a sympathomimetic amine, like amphetamines, will reduce the appetite after the stimulation of the hypothalamus and the release of the norepinephrine. Topiramate also has appetite suppressing effects and causes rapid satiety. Studies show that after a 1-year administration, the effect of this combination drug on weight loss decreases, but nevertheless it seems to contribute in maintaining the weight obtained up to that point [57, 58]. Side effects of this drug include dry mouth, constipation, paresthesia, psychiatric and cognitive impairment. It is also contraindicated during pregnancy, having teratogenic effects [59].

The bupropion-naltrexone combination, though effective in weight loss, seems to have cardiovascular side effects, such as high blood pressure or tachycardia, so if it would be adminis-

equal to 35 kg/m<sup>2</sup> associated with different comorbidities). A study that enrolled obese patients who underwent bariatric surgery divided the treated patients into 3 groups; obese with PCOS, obese with hyperandrogenemia characteristics but with regular menstrual cycles and a third group with obese patients without hyperandrogenic traits. After applying the exclusion criteria, the group of patients with PCOS was studied in detail and the results were surprising. Within 12 +/− 5 months, the weight loss was of 41 +/− 9 kg, associated with the improvement of clinical and biochemical markers of hyperandrogenism. It was noted that an improvement in hirsutism had been observed and from a biochemical point of view markers such as: free testosterone, total testosterone, androstenedione and dehydroepiandrostenedione sulfate have been normalized while the level of SHBG increased. From a metabolic point of view, the improved insulin sensitivity was proved by the decrease in fasting insulin levels. With regard to the reproductive

or BMI greater than or

Lifestyle Changes and Weight Loss: Effects in PCOS http://dx.doi.org/10.5772/intechopen.73298 49

tered it would fail in addressing the underlying reason for initiating this therapy.

system, the restoration of regular menstrual cycles and ovulation were noticed [60].

A newer study, conducted in 2012, concludes that weight loss after bariatric surgery is not associated with significant changes in the menstrual cycle, the luteal phase length or the amount of blood lost during menstruation. A relatively modest improvement was found with respect to biochemical hyperandrogenism but without effects on the clinical markers

Bariatric surgery is indicated in cases of morbid obesity (BMI = 40 kg/m<sup>2</sup>

**5.2. Surgical treatment of obesity–bariatric surgery**

*5.1.6. Combination drugs*

#### *5.1.4. Antidepressants and antiepileptic drugs*

Antidepressants and antiepileptics can affect weight in different ways, while some lead to weight gain, others to loss. Among the drugs that lead to weight loss, we mention: bupropion, venlafaxine, desvenlafaxine, topiramate, zonisamide, lamotrigine, and ziprasidone [45].

Bupropion is an antidepressant commonly used in cases of smoking cessation, to prevent weight gain [50]. It can also be used in combination with naltrexone, although there are currently no data on an augmenting the effect of bupropion by naltrexone.

Topiramate is an antiepileptic agent that blocks neuronal voltage-dependent sodium channels, enhances gamma-aminobutyric acid (GABA) A activity and inhibits carbonic anhydrase, generating appetite suppression and satiety enhancement. Amongs its adverse effects, we mention paresthesia, somnolence, and metabolic acidosis. Studies recommend its use in combinations with other substances and not as a sole agent in the treatment of obesity.

Zonisamide is another antiepileptic with serotoninergic and dopaminergic activity, which has effect on weight loss. Randomized trials in obese patients demonstrate that zonisamide at high doses is superior to placebo, while at low doses has effects similar to placebo [51].

#### *5.1.5. Diabetes drugs*

Metformin is an anti-hyperglycemic biguanide, used in the treatment of type 2 diabetes mellitus. It reduces liver production and intestinal absorption of glucose and therefore insulin secretion. By its anti-lipolytic effect, free fatty acid concentrations and gluconeogenesis decrease [52, 53]. Numerous studies have been performed on obese patients with PCOS, who received metformin. While the first studies seemed to demonstrate its effects in terms of weight loss, decreased serum androgen levels (and implicitly hirsutism), restoration of menstrual cycles, and induction of ovulation [54], further studies concluded its ineffectiveness in treating hirsutism or increasing live birth rates, even if it is effective in increasing the ovulatory rates and pregnancy rates. Metformin is no longer used as a first-line treatment for oligomenorrhea or weight loss.

Pramlintide is a synthetic analog of human amylin whose effect in terms of weight loss is relatively modest, due to its slowing effect on gastric emptying and the reduction in postprandial blood glucose concentration it causes.

Exenatide is a long-acting synthetic peptide (GLP-1 -glucagon-like polypeptide-1-agonist receptor), the effect of which is the increased secretion of dose-dependent and glucosedependent insulin. Its' use is avoided because of the relatively low weight loss effect in conjunction with its mode of administration by subcutaneous injection [45].

Liraglutide, like exenatide, is a GLP-1 analog with significant weight-reducing effects. Studies in obese, non-diabetic patients have shown better efficacy against placebo at normal doses and even orlistat when administered in high doses [55]. Among its adverse effects when administered at high doses are included nausea and vomiting, which may in part contribute to the weight-loss effect [55]. This drug is quite often avoided due to its route of administration (subcutaneous injection) but also due to its potential adverse effects, that although rare, they are severe (pancreatitis, renal impairment and gallbladder disease). Further, we consider important to mention that rodent studies have demonstrated the association of this drug with the increased frequency of thyroid C-cell tumors (benign and malignant), which is why it is not recommended in the case of the patients with personal or family history of medullary thyroid cancers [56].

## *5.1.6. Combination drugs*

cardiovascular system were those that caused the withdrawal of some drugs of this class from the market, such as sibutramine (removed from the market in 2010 [47] after it was shown to increase the risk of myocardial infarction and stroke [48]) or phenylpropanolamine (removed from the market due to association with increased risk of hemorrhagic stroke in women [49]).

Antidepressants and antiepileptics can affect weight in different ways, while some lead to weight gain, others to loss. Among the drugs that lead to weight loss, we mention: bupropion, venlafaxine, desvenlafaxine, topiramate, zonisamide, lamotrigine, and ziprasidone [45].

Bupropion is an antidepressant commonly used in cases of smoking cessation, to prevent weight gain [50]. It can also be used in combination with naltrexone, although there are cur-

Topiramate is an antiepileptic agent that blocks neuronal voltage-dependent sodium channels, enhances gamma-aminobutyric acid (GABA) A activity and inhibits carbonic anhydrase, generating appetite suppression and satiety enhancement. Amongs its adverse effects, we mention paresthesia, somnolence, and metabolic acidosis. Studies recommend its use in com-

Zonisamide is another antiepileptic with serotoninergic and dopaminergic activity, which has effect on weight loss. Randomized trials in obese patients demonstrate that zonisamide at high doses is superior to placebo, while at low doses has effects similar to placebo [51].

Metformin is an anti-hyperglycemic biguanide, used in the treatment of type 2 diabetes mellitus. It reduces liver production and intestinal absorption of glucose and therefore insulin secretion. By its anti-lipolytic effect, free fatty acid concentrations and gluconeogenesis decrease [52, 53]. Numerous studies have been performed on obese patients with PCOS, who received metformin. While the first studies seemed to demonstrate its effects in terms of weight loss, decreased serum androgen levels (and implicitly hirsutism), restoration of menstrual cycles, and induction of ovulation [54], further studies concluded its ineffectiveness in treating hirsutism or increasing live birth rates, even if it is effective in increasing the ovulatory rates and pregnancy rates. Metformin is no longer used as a first-line treatment for

Pramlintide is a synthetic analog of human amylin whose effect in terms of weight loss is relatively modest, due to its slowing effect on gastric emptying and the reduction in postprandial

Exenatide is a long-acting synthetic peptide (GLP-1 -glucagon-like polypeptide-1-agonist receptor), the effect of which is the increased secretion of dose-dependent and glucosedependent insulin. Its' use is avoided because of the relatively low weight loss effect in

Liraglutide, like exenatide, is a GLP-1 analog with significant weight-reducing effects. Studies in obese, non-diabetic patients have shown better efficacy against placebo at normal doses and

conjunction with its mode of administration by subcutaneous injection [45].

binations with other substances and not as a sole agent in the treatment of obesity.

rently no data on an augmenting the effect of bupropion by naltrexone.

*5.1.4. Antidepressants and antiepileptic drugs*

48 Debatable Topics in PCOS Patients

*5.1.5. Diabetes drugs*

oligomenorrhea or weight loss.

blood glucose concentration it causes.

The combination of phentermine and topiramate is another two drug combination with good effect in terms of weight loss, being pharmacologically included in the sympathomimetic anorexia class. Being a two drug combination, it has a complex mechanism of action. Thus, phentermine, which is a sympathomimetic amine, like amphetamines, will reduce the appetite after the stimulation of the hypothalamus and the release of the norepinephrine. Topiramate also has appetite suppressing effects and causes rapid satiety. Studies show that after a 1-year administration, the effect of this combination drug on weight loss decreases, but nevertheless it seems to contribute in maintaining the weight obtained up to that point [57, 58]. Side effects of this drug include dry mouth, constipation, paresthesia, psychiatric and cognitive impairment. It is also contraindicated during pregnancy, having teratogenic effects [59].

The bupropion-naltrexone combination, though effective in weight loss, seems to have cardiovascular side effects, such as high blood pressure or tachycardia, so if it would be administered it would fail in addressing the underlying reason for initiating this therapy.

#### **5.2. Surgical treatment of obesity–bariatric surgery**

Bariatric surgery is indicated in cases of morbid obesity (BMI = 40 kg/m<sup>2</sup> or BMI greater than or equal to 35 kg/m<sup>2</sup> associated with different comorbidities). A study that enrolled obese patients who underwent bariatric surgery divided the treated patients into 3 groups; obese with PCOS, obese with hyperandrogenemia characteristics but with regular menstrual cycles and a third group with obese patients without hyperandrogenic traits. After applying the exclusion criteria, the group of patients with PCOS was studied in detail and the results were surprising. Within 12 +/− 5 months, the weight loss was of 41 +/− 9 kg, associated with the improvement of clinical and biochemical markers of hyperandrogenism. It was noted that an improvement in hirsutism had been observed and from a biochemical point of view markers such as: free testosterone, total testosterone, androstenedione and dehydroepiandrostenedione sulfate have been normalized while the level of SHBG increased. From a metabolic point of view, the improved insulin sensitivity was proved by the decrease in fasting insulin levels. With regard to the reproductive system, the restoration of regular menstrual cycles and ovulation were noticed [60].

A newer study, conducted in 2012, concludes that weight loss after bariatric surgery is not associated with significant changes in the menstrual cycle, the luteal phase length or the amount of blood lost during menstruation. A relatively modest improvement was found with respect to biochemical hyperandrogenism but without effects on the clinical markers

of hyperandrogenism. Instead, an 8–9 day follicular phase shortening associated with decreased fertility, was observed. What was new in this study was the finding that patients undergoing bariatric surgery after weight loss improve their sex life [61].

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