Obesity 2025 PDF

# Pharmacology-2 ## Dietitian Program 2024-2025 ### Prof Dr Manar A Nader ## Obesity - Obesity is defined as an excess of total body fat. - Body mass index (BMI) is useful in assessing accurate body weight status, degree of adiposity, and risk for obesity-related conditions. ### The Benefits of W...

# Pharmacology-2 ## Dietitian Program 2024-2025 ### Prof Dr Manar A Nader ## Obesity - Obesity is defined as an excess of total body fat. - Body mass index (BMI) is useful in assessing accurate body weight status, degree of adiposity, and risk for obesity-related conditions. ### The Benefits of Weight Loss Include: 1. Reduction in the rate of progression of diabetes 2. Reduction in blood pressure in hypertensive patients 3. Decrease the lipid profile in high-risk patients ### Non-Cardiac Benefits of Weight Loss 1. Reduction in urinary incontinence, sleep apnea, asthma, and depression 2. Improvement in quality of life, mobility, and physical activity ### Common Symptoms of Obesity in Adults Include: - Excess body fat, particularly around the waist - Shortness of breath - Sweating more than usual - Snoring - Trouble sleeping - Skin problems from moisture accumulating in the folds of the skin - Fatigue, which can range from mild to extreme - Pain, especially in the back and joints ## Causes of Obesity - The balance between calorie intake and energy expenditure determines a person's weight. - If a person eats more calories than they burn (metabolize), the person gains weight since the body will store the excess energy as fat. - If a person eats fewer calories than they metabolize, the person will lose weight. - Therefore, overeating and physical inactivity are the most common causes of obesity. - **Genetics:** A person is more likely to develop obesity if one or both parents are obese. - Genetics also affect hormones involved in fat regulation. - For example, one genetic cause of obesity is leptin deficiency. - Leptin is a hormone produced in fat cells and in the placenta. - Leptin controls weight by signaling the brain to eat less when body fat stores are too high. - If, for some reason, the body cannot produce enough leptin or leptin cannot signal the brain to eat less, this control is lost, and obesity occurs. - **Physical Inactivity:** Sedentary people burn fewer calories than people who are active. - **Diet High in Simple Carbohydrates:** Carbohydrates increase blood glucose levels, which in turn stimulate insulin release by the pancreas, and insulin promotes the growth of fat tissue and can cause weight gain. - **Frequency of Eating:** People who eat small meals four or five times daily have lower cholesterol levels and more stable blood sugar levels than people who eat less frequently (two or three large meals daily). - One possible explanation is that small frequent meals produce stable insulin levels, whereas large meals cause large spikes of insulin after meals. - **Certain Medications:** Medications associated with weight gain include certain antidepressants, anticonvulsants (medications used in controlling seizures such as carbamazepine, Tegretol), some diabetes medications such as insulin, sulfonylureas, certain hormones such as oral contraceptives, and most corticosteroids such as prednisone. - Some high blood pressure medications and antihistamines cause weight gain. - **Psychological Factors:** For some people, emotions such as sadness, stress, or anger influence eating habits. - **Diseases:** Diseases such as hypothyroidism, insulin resistance, polycystic ovary syndrome, and Cushing's syndrome are also contributors to obesity. ## Risk Factor - Insulin resistance - Type 2 diabetes - High blood pressure (hypertension) - High cholesterol (hypercholesterolemia) - Stroke - Gallstones - Gout and gouty arthritis - Osteoarthritis (degenerative arthritis) of the knees, hips, and the lower back ## Goal of Therapy - Weight loss initial goal: 5-10% decrease from baseline weight every 3 months or over 6 months. - Example, if a patient weighs 100 kg, it is recommended to be 80 after 1 year. ## Management of Obesity - Weight-reduction therapies aimed at affecting one or more steps in the energy intake, storage, and expenditure cycle. - Typical treatment strategies include diet restriction, exercise, behavior modification, pharmacologic procedures, and even invasive procedures. - There is no single standard weight-loss strategy that is effective for all individuals suffering from obesity. - Weight-reduction programs must be designed to fulfill the needs and fit the lifestyle of each individual. The critical element or goal for any program is to have energy expenditures exceed caloric demands. - These changes must be maintained to achieve the desired weight. - Candidates for pharmacological therapy include adults with a BMI greater than 30 kg/m2 or BMI 27-29.9 Kg/m2 with comorbidities who have not met weight loss goals. - **BMI Calculations:** - Normal BMI-18.5-24.9 Kg/m2 - Overweight-25-29.9 Kg/m2 - **Obesity:** - Class I-30-34.9 Kg/m2 (low risk-behavioral therapy) - Class II-35-39.9 Kg/m2 (moderate risk- add drug therapy) - Class III-40 Kg/m2 or greater (high risk- bariatric surgery) - Candidate for bariatric surgery: include adults with BMI $\geq$ 40 Kg/m2 or BMI 35-39.9 Kg/m2 with at least one serious comorbidity who have not met weight loss goals with diet, exercise, and drug therapy. ## Non-Pharmacological Treatment for Obesity - Non-pharmacological techniques can be used to manage obesity, such as diets, cognitive behavioral interventions, exercise, and transcranial direct current stimulation. - Combining these techniques may allow improving quality of life of obese patients. - **Diet:** Diet modification, low-carbohydrate diet, low-fat diet, hypo-caloric diet. - **Exercise:** Walking, jogging, bicycle riding (stationary or on path), running, swimming. - **Cognitive Behavioral Interventions:** Such as self-monitoring during eating, realistic and achievable goal setting, control of dangerous stimuli, and triggers. - **Transcranial Direct Current Stimulation (tDCS):** Is a neuromodulation technique with potential to treat eating disorders and obesity. - **Hydrogels:** Considered medical devices, hydrogels are orally administered products, taken twice daily before meals, which expand in the stomach and intestines to create a sensation of satiety. - They are not systemically absorbed and are eliminated through the feces. - Hydrogels are indicated for use as weight management aids for adults with a BMI of 25 to 40 kg/m² and are to be used in conjunction with diet and exercise. - **Dietary Supplements:** Although over-the-counter dietary supplements are widely used by individuals attempting to lose weight, we advise against their use because evidence to support their efficacy and safety are limited. Examples of dietary supplements include ephedra, green tea, chromium, chitosan, Vitamin B-12, and guar gum. ## Anti-Obesity Medications **Indications for use of obesity drugs:** - BMI of 30 kg/m2 or more or a BMI of 27 kg/m2 or more with comorbid conditions. - Dietary and physical activity therapy not successful. - Understand that drug therapy is adjunctive to lifestyle intervention. - Have realistic expectations about weight loss goals and outcome - Demonstration readiness for change - Are unable to loss/maintain weight with lifestyle change alone - Comply with medical use - Have no medical or psychiatric contraindications. - **The most commonly used medications approved by the U.S. Food and Drug Administration (FDA) for the treatment of obesity include:** - Phentermine - Liraglutide & Semaglutide - Orlistat - Phentermine-topiramate - Sibutramine - **Diethylpropion:** Is a sympathomimetic amine exudes similar pharmacologic activity as the amphetamines, resulting in central nervous system stimulation and appetite suppression, it is indicated for short-term use in conjunction with a reduced calorie diet and exercise in obese patients. - Phentermine's and diethylpropion's main side effects are related to their sympathomimetic properties, including elevation in blood pressure and pulse, insomnia, constipation, and dry mouth. - **Liraglutide & Semaglutide:** It is a glucagon-like peptide-1 (GLP-1) analogue that activates the GLP-1 receptor. - Administration of liraglutide results in uptake in specific brain regions regulating appetite, including the hypothalamus and brain stem suppressed food intake, subjective hunger, and delayed gastric emptying. - Side effects: gastrointestinal symptoms, such as nausea, vomiting and abdominal pain. - **Tirzepatide:** Is a novel GLP-1 and GIP receptor agonist administered by once-weekly subcutaneous injection. It is effective in the treatment of obesity in patients with and without diabetes mellitus. - However, this is not approved by the US Food and Drug Administration (FDA) for the treatment of obesity. - **Orlistat:** Promotes weight loss by inhibiting gastrointestinal lipases, thereby decreasing the absorption of fat from the gastrointestinal tract. It has been shown to improve insulin sensitivity and lower serum glucose levels, and reduced total cholesterol. - Side effects of orlistat, including fatty oily stool and reduce the absorption of fat-soluble vitamins A, D, E, and K, which can be mitigated with separate administration of vitamin supplementation. - **Cetilistat:** It acts in the same way as orlistat and significantly reduced weight and was better tolerated than orlistat - **Phentermine Topiramate:** Promote weight loss by increasing norepinephrine release and decreasing its uptake in hypothalamic nuclei, leading to a decrease in food intake. - It also acts as an adrenergic agonist that activates the sympathetic nervous system to possibly increase energy expenditure. - Not recommended for patients with significant cardiac history such as coronary disease and uncontrolled hypertension. - **Sibutramine:** Effect by inhibiting the reuptake of serotonin, norepinephrine, and dopamine. - Appetite becomes suppressed because patients feel a sense of satiety, concerned in energy balance. - Contraindicated in patients with psychiatric conditions such as anorexia depression. - Main side effects: are feeling nervous, depressed, headache, dry mouth, constipation. - **Metformin (trade name Glucophage):** Is an antihyperglycemic agent that acts by suppressing gluconeogenesis and increasing peripheral insulin sensitivity. ## Potential Weight Loss Mechanisms Include: 1. Activation of AMP-activated protein kinase (AMPK) to mimic an "energy deficient" state. 2. Increasing anorexigenic hormones GLP-1, growth-differentiation factor- 15 (GDF-15), neuropeptide Y (NPY). 3. Increasing leptin sensitivity. - The most common side effects of metformin are nausea, flatulence, diarrhea, and bloating. The most serious side effect is lactic acidosis, but this is rare (<1/100,000). - Monitoring for vitamin B12 deficiency is recommended as long-term use of metformin has been associated with low vitamin B12 levels and neuropathy. ## Surgical Therapies - Surgical techniques share two fundamental designs: intestinal malabsorption and gastric restriction. - Weight-loss surgery, also known as bariatric surgery, limits the amount of food you're able to comfortably eat or decreases the absorption of food and calories. However, this can also result in nutritional and vitamin deficiencies. - **Consider bariatric surgery:** - In adults with clinically severe obesity (BMI>40 kg/m2). It is the most effective treatment for morbid obesity; it leads to durable weight loss and improvement of comorbidities. - In adults with BMI >35 kg/m2 with concomitant obesity-related conditions after failure of conventional treatment including insulin resistance and type 2 diabetes mellitus, hypertension, dyslipidemia, cardiovascular disease, stroke, sleep apnea, gallbladder disease, hyperuricemia and gout, and osteoarthritis. - In adults with BMI>30kg/m 2 who have poorly controlled type 2 diabetes and are at increased cardiovascular risk. - In "post pubertal adolescents with very severe to extreme obesity and severe comorbidities. - Bariatric surgery in adolescents is to be limited to exceptional cases and performed only by experienced teams. - In cases of failure of significant and sustained improvement of obesity-related comorbidities with lifestyle interventions alone. - **Gastric Bypass Surgery:** In gastric bypass (Roux-en-Y), the surgeon creates a small pouch at the top of the stomach. The small intestine is then cut a short distance below the main stomach and connected to the new pouch. Food and liquid flow directly from the pouch into this part of the intestine, bypassing most of the stomach. - **Gastric Sleeve:** In this procedure, part of the stomach is removed, creating a smaller reservoir for food. It's a less complicated surgery than gastric bypass. - **Vertical Sleeve Gastrectomy** - **Intragastric Balloon:** The balloon partially fills the stomach to provide a feeling of satiety. It reduces the amount of food you can eat, increases the feeling of being fuller longer, designed to fit comfortably in the stomach, managed weight loss system team of experts. The balloon is removed after six months, at which time patients remain in a structured dietary program to maintain weight loss. - **The Intragastric Balloon:** The balloon is partially fills the stomach to provide a feeling of satiety. Reduces the amount of food you can eat, increases the feeling of being fuller longer, designed to fit comfortably in the stomach, managed weight loss system team of experts. The balloon is removed after six months, at which time patients remain in a structured dietary program to maintain weight loss. ## Minerals Aid in Weight Reduction (Not Approved) 1. **Chromium:** - It is important in the metabolism of fats and sugar. It regulates insulin levels. Meat, whole grains, fruits are good sources. - The effect of chromium on individuals is dependent on the dose, diet, and duration. 2. **Magnesium:** - It influences muscle function, energy production and immunity. - Green leafy vegetables, nuts, grains and cereals are good sources. - Magnesium supplementation or sufficient magnesium intake from dietary sources can help improve exercise performance. 3. **Zinc:** - It regulates enzyme activity. Grains, legumes, poultry, seafood and meat contribute to dietary zinc requirements. - Zinc plays a role in nutrition by interacting with leptin. - Zinc supplementation resulted in a significant decrease in BMI and body weight. - Serum zinc levels were improved and zinc supplementation significantly decreased triglyceride levels. 4. **Selenium:** - It helps the body in producing antioxidant enzymes and improving immunity. - Vegetables, grains, seafoods and chicken can provide you with selenium. - A positive relation was found between selenium and obesity-related parameters like cholesterol. - The link between selenium and cardiovascular disease has been proven. - Cardiovascular diseases are the main outcomes of metabolic syndrome and obesity. 5. **Calcium:** - It is required for healthy bones and teeth. - Dairy products are the top sources of calcium followed by green leafy vegetables. - A diet deficient in calcium is associated with higher body weight. - 1000mg of calcium per day along with a moderately restricted diet. - Weight loss outcomes were higher with high calcium diets and even better with high dairy diets. - Fat loss was found to be higher in groups consuming high calcium and high dairy diets. 6. **Vanadium:** - It is a trace element found in mushrooms, shellfish and grains. - Vanadium influences cholesterol levels and glucose metabolism. - Vanadium is proven to influence leptin signaling in a rat model. - Chronic vanadium administration is found to enhance weight-reducing effects of leptin in animals. - Vanadium supplementation led to reduced body weights and decrease in elevated glucose levels in diabetic rats. - It also brought about a decrease in antioxidant enzyme levels. - Vanadium is a potential agent to guard against diabetic complications. ## Lines of Therapy Approved by FDA - **1st line** is the administration of Liraglutide or Semaglutide for 3 months. - **If no benefit** (not reaching the target, 5% reduction of weight) or not tolerated, switch to the **2nd line of therapy** orlistat. - **3rd line of therapy:** Phentermine-topiramate. - **4th line of therapy:** Bupropion-naltrexone. - **5th line of therapy:** Lorcaserin. - **Increasing dose or switch is done every 3 months.** - **The target is to induce weight loss 5% of max body weight** - **Only liraglutide increasing dose every one week till reach 3 mg/day, then continue to 3 months.** - **In the USA, Phentermine is of label use in small dose without a prescription.** - **Not recommended using dietary supplements unless lad assessment is done.** ## Off-Label Medication (Only 1-2% of patients can benefit so not involved in guidelines): - SSRI (All except paroxetine); fluoxetine drug of choice in bulimia nervosa - Zonisamide - Metformin - Pramlintide - Empagliflozin - Herbs (green tea, Garcinic Cambogia, chitosan, gambisan, chromium, hoodia gordonii, cynanchum auriculatum, human chorionic gonadotropin) ## I. Liraglutide & Semaglutide: - Liraglutide considered as 1st line especially in diabetes. - (Saxenda approved by FDA for obesity) - Initial starting dose is 0.6 mg once daily then increased by 0.6 mg at weekly interval; target dose for obesity is 3 mg daily. - Discontinue if less than 5% weight loss is not achieved in 12 weeks or the patient can't tolerate 3 mg daily dose. - The obesity formulation should be avoided in patients receiving insulin (increased the risk of hypoglycemia) - FDA has recently approved semaglutide for obesity management. Evidence suggests it can help people lose weight by suppressing appetite, as long as they keep taking it. ## II. Orlistat - Taken during, or up to one hour after, a meal. - **Side effect:** - Decrease vitamins E, D & A absorption - Hepatotoxic - Kidney stone - Oily & greasy stool and diarrhea which is offensive to patients - Become 2nd line because of Oily & greasy stool and diarrhea. - Discontinue if less than 5% weight loss is not achieved in 12 weeks. ## III. Phentermine + Topiramate - Combined extended release preparation. - Phentermine is schedule IV - Act as appetite suppressant - Must be taken in the morning to avoid insomnia. - Initial dose is 3.75/23 mg daily for 2 weeks, then double the dose until reaching 15/92mg/day. - Must taper when discontinuing to avoid seizures. - Discontinue if less than 5% weight loss is not achieved in 12 weeks, or the patient can't tolerate 3 mg daily dose. ## IV. Bupropion/Naltrexone - SE: Nausea, constipation, headache, vomiting, dizziness, insomnia, and dry mouth. - Contraindication in hypertension. - Avoid use with chronic use of opioids. - Discontinue if less than 5% weight loss is not achieved in 12 weeks, or the patient can't tolerate 3 mg daily dose. ## V. Diethyl Propion, Phentermine, Phendimetrazine, and Benzphenteramine: - Last line therapy - Taken up to 12 weeks. - However, Phentermine is the most widely prescribed weight loss drug in the USA; clinical guidelines recommend against the use of these 4 drugs. ## VI. Lorcaserin: - Schedule IV, increase serotonin and decrease hunger - Not available in the Middle East. - Discontinue if less than 5% weight loss is not achieved in 12 weeks. - **Side Effect:** - Dry mouth, nausea, attention disturbance, constipation, hypoglycemia, fetal toxicity needs pregnancy test. - Avoid concurrent use with serotonergic drugs such as citalopram to avoid serotonergic syndrome. - Increasing dose or switch is done every 3 months. - The target is to induce weight loss 5% of max body weight. - Only liraglutide increasing dose every one week till reach 3 mg/day, the continue to 3 months. - In the USA, Phentermine is of label use in small dose without a prescription. - Not recommended using dietary supplements unless an assessment is done. ## Polycystic Ovary Syndrome ### Introduction - Polycystic ovary syndrome (PCOS) is a condition that affects a woman's hormone levels where they produce higher-than-normal amounts of male hormones. - This hormone imbalance causes them to skip menstrual periods and makes it harder for them to get pregnant. It also affects the ovary forming many cysts. - PCOS also causes hair growth on the face and body, and baldness. And it can contribute to long-term health problems like heart disease. - In PCOS, many small, fluid-filled sacs grow inside the ovaries. The word "polycystic" means "many cysts." These sacs are actually follicles; each one contains an immature egg. The eggs never mature enough to trigger ovulation. - The lack of ovulation alters levels of estrogen, progesterone, FSH, and LH. - Estrogen and progesterone levels are lower than usual, while androgen levels are higher than usual. - Extra male hormones disrupt the menstrual cycle, so women with PCOS get fewer periods than usual. ### Pathophysiology - Doctors don't know exactly what causes PCOS. - They believe that high levels of male hormones prevent the ovaries from producing hormones and making eggs normally. Genes, insulin resistance, and inflammation have all been linked to excess androgen production. ### Genes - Studies show that PCOS runs in families. - It's likely that many genes contribute to the condition. ### Insulin Resistance - Up to 70 percent of women with PCOS have insulin resistance, meaning that their cells can't use insulin properly. - When cells can't use insulin properly, the body's demand for insulin increases. - The pancreas makes more insulin to compensate. - Extra insulin triggers the ovaries to produce more male hormones. - Obesity is a major cause of insulin resistance. - Both obesity and insulin resistance can increase your risk for type 2 diabetes. ### Inflammation - Women with PCOS often have increased levels of inflammation in their body. - Being overweight can also contribute to inflammation. - Studies have linked excess inflammation to higher androgen levels. ### Common Symptoms of PCOS: - **Irregular periods:** A lack of ovulation prevents the uterine lining from shedding every month. Some women with PCOS get fewer than eight periods a year. - **Heavy bleeding:** The uterine lining builds up for a longer period of time, so the periods you do get can be heavier than normal. - **Hair growth:** More than 70 percent of women with this condition grow hair on their face and body - including on their back, belly, and chest (hirsutism). - **Acne:** Male hormones can make the skin oilier than usual and cause breakouts on areas like the face, chest, and upper back. - **Weight gain:** Up to 80 percent of women with PCOS are overweight or obese. - **Male-pattern baldness:** Hair on the scalp gets thinner and falls out. - **Darkening of the skin:** Dark patches of skin can form in body creases like those on the neck, in the groin, and under the breasts. - **Headaches:** Hormone changes can trigger headaches in some women. ### How PCOS Affects Your Body - Having higher-than-normal androgen levels can affect your fertility and other aspects of your health. ### Infertility - To get pregnant, you have to ovulate. - Women who don't ovulate regularly don't release as many eggs to be fertilized. - PCOS is one of the leading causes of infertility in women. ### Metabolic Syndrome:  - Up to 80 percent of women with PCOS are overweight or obese. - Both obesity and PCOS increase your risk for high blood sugar, high blood pressure, low HDL ("good") cholesterol, and high LDL ("bad") cholesterol - Together, these factors are called metabolic syndrome, and they increase the risk for heart disease, diabetes, and stroke. ### Sleep Apnea - This condition causes repeated pauses in breathing during the night, which interrupt sleep. - Sleep apnea is more common in women who are overweight, especially if they also have PCOS. - The risk for sleep apnea is 5 to 10 times higher in obese women with PCOS than in those without PCOS. ### Endometrial Cancer - During ovulation, the uterine lining sheds. If you don't ovulate every month, the lining can build up. - A thickened uterine lining can increase your risk for endometrial cancer. ### Depression - Both hormonal changes and symptoms like unwanted hair growth can negatively affect your emotions. Many with PCOS end up experiencing depression and anxiety. ### How PCOS Is Diagnosed: - Doctors typically diagnose PCOS in women who have at least two of these three symptoms: - High androgen levels - Irregular menstrual cycles - Cysts in the ovaries - Your doctor should also ask whether you've had symptoms like acne, face and body hair growth, and weight gain. - A pelvic exam can look for any problems with your ovaries or other parts of your reproductive tract. - Blood tests check for higher-than-normal levels of male hormones. - You might also have blood tests to check your cholesterol, insulin, and triglyceride levels to evaluate your risk for related conditions like heart disease and diabetes. - An ultrasound uses sound waves to look for abnormal follicles and other problems with your ovaries and uterus. ### Management of PCOS - Treatment for PCOS usually starts with lifestyle changes like weight loss, diet, and exercise. - Losing just 5 to 10 percent of your body weight can help regulate your menstrual cycle and improve PCOS symptoms. - Weight loss can also improve cholesterol levels, lower insulin, and reduce heart disease and diabetes risks. - Any diet that helps you lose weight can help your condition. However, some diets may have advantages over others. - Studies comparing diets for PCOS have found that low-carbohydrate diets are effective for both weight loss and lowering insulin levels. - A low glycemic index (low-GI) diet that gets most carbohydrates from fruits, vegetables, and whole grains helps regulate the menstrual cycle better than a regular weight loss diet. - A few studies have found that 30 minutes of moderate-intensity exercise at least three days a week can help women with PCOS lose weight. - Losing weight with exercise also improves ovulation and insulin levels. - Exercise is even more beneficial when combined with a healthy diet. Diet plus exercise helps you lose more weight than either intervention alone, and it lowers your risks for diabetes and heart disease. - There is some evidence that acupuncture can help with improving PCOS, but more research is needed. ### Common Medical Treatments - Birth control pills and other medicines can help regulate the menstrual cycle and treat PCOS symptoms like hair growth and acne. ### Birth Control: - Taking combined oral contraceptive (estrogen and progestin) daily can restore a normal hormone balance, regulate ovulation, relieve symptoms like excess hair growth, and protect against endometrial cancer. - **Choice of oral contraceptive:** We typically start with a COC containing 20 mcg of ethinyl estradiol combined with a progestin such as norethindrone or norethindrone acetate, progestins that have lower androgenicity. - **Progestins with lower androgenicity** include desogestrel, cyproterone acetate, and drospirenone, but all have been associated with a possible higher risk of venous thromboembolism (VTE). Norgestimate is a progestin with low androgenicity and similar venous thrombosis risk to norethindrone and levonorgestrel. ### Antiandrogens: - After six months, if the patient is not satisfied with the clinical response to COC monotherapy (for hyperandrogenic symptoms), we typically add spironolactone 50 to 100 mg twice daily. 1. **Finasteride:** Other available antiandrogens, which inhibits 5-alpha-reductase type 2, the enzyme that converts testosterone to dihydrotestosterone (DHT). 2. **Dutasteride:** An inhibitor of both 5-alpha-reductase types 1 and 2. - No clinical trial data are available for dutasteride use in hirsute women. - These drugs should never be used in women who are not using reliable contraception, as there is a substantial risk of preventing the development of normal male external genitalia during early pregnancy. 3. **Cyproterone acetate:** Is an antiandrogen that is available in most countries, but not the United States. 4. **Flutamide:** Is also effective, but we recommend not using it because of its potential hepatotoxicity. 5. **Other - Gonadotropin-releasing hormone (GnRH) agonists:** Are also sometimes used to suppress ovarian androgen production; "add-back" estrogen-progestin therapy is necessary to avoid bone loss and estrogen deficiency symptoms. Clomiphene can also be used to enhance ovulation but it has a high risk of multiple births. ### Metformin - Although some clinicians use metformin to treat hirsutism, the Endocrine Society Clinical Practice Guidelines suggest against its routine use as it is associated with minimal or no benefit and is less effective than treatment with COCs and/or antiandrogens. - Biguanides (metformin) and thiazolidinediones (pioglitazone, rosiglitazone) can reduce insulin levels in women with PCOS. - These drugs may also reduce ovarian androgen production (and serum free testosterone concentrations) and restore normal menstrual cyclicity. ### Hair Removal Medicines: - A few treatments can help get rid of unwanted hair or stop it from growing. Eflornithine (Vaniqa) cream is a prescription drug that slows hair growth. - Laser hair removal and electrolysis, can get rid of unwanted hair on your face and body. ### Surgery - Surgery can be an option to improve fertility if other treatments don't work. - Ovarian drilling is a procedure that makes tiny holes in the ovary with a laser or thin heated needle to restore normal ovulation. ### Management Algorithm for Lean PCOS - **Lifestyle Modifications:** - Weight maintenance/avoidance of weight gain through dietary modifications (Consumption of ample amounts of vegetables, some fruits, vitamin D, calcium, and herbs) - Regular exercises. - **Inadequate clinical response:** - Add on metformin + / - myoinositol along with additional management for following conditions when necessary. - **Hirsutism:** - Mechanical (e.g., shaving, electrolysis, laser, etc.) - Pharmacologic (e.g., OCP, androgen receptor blockers, finasteride, etc.) - **Menstrual dysfunction:** - Progestin alone, or combined OCP - **Acne:** - Topical (e.g., benzoyl peroxide and/or retinoids, etc.) - Antibiotic (e.g., dorycycline) - Isotretinoin in severe cases - **Infertility:** - Pharmacotherapy (Clomiphene citrate and/or gonadotropins) - Surgery (bilateral or unilateral laparoscopic ovarian drilling) - In vitro fertilization