Menopause, Obesity & PCOS PDF

Menopause Obesity & PCOS Menopause ✓ Menopause is signaled by a woman's last menstrual period ✓ The permanent cessation of menstruation resulting from loss of ovarian follicular activity. ✓ The occurrence of the last menstruation can only be diagnosed retrospectively and is usually taken as be...

Menopause Obesity & PCOS Menopause ✓ Menopause is signaled by a woman's last menstrual period ✓ The permanent cessation of menstruation resulting from loss of ovarian follicular activity. ✓ The occurrence of the last menstruation can only be diagnosed retrospectively and is usually taken as being final if it is followed by a 12-month bleed-free interval; such women are defined as being post-menopausal. ✓ The mean age of menopause in the UK is 51 years, and by the age of 54 years, around 80% of women will be post-menopausal. If menopause occurs before 40 years, it would be classed as a premature menopause. Many women will experience erratic periods before the final cessation due to inadequate ovarian estrogen secretion (peri- menopausal). This transitional phase usually lasts around 4–5 years. Causes ▪ The problems associated with menopause result from estrogen deprivation. ▪ Hormone replacement therapy (HRT) reduces the effects of this deprivation and overcomes the associated symptoms. ▪ Menopause is a natural event in the anatomical, physiological and psychological changes which form the female climacteric. ▪ Some women will go from the transition of being pre- menopausal to post-menopausal with no symptoms at all. Symptoms Many will experience the symptoms associated with estrogen lack, whether in the peri-menopausal or post-menopausal phase, which include: 1)vasomotor symptoms 2)localized atrophy of urogenital tissues 3)osteoporosis 4)psychological problems 5)Coronary heart disease. Initially, the symptoms are more likely to include Vasomotor symptoms such as 1. Hot flushes, 2. Night sweats 3. Palpitations, Psychological problems such as 1. Mood changes 2. Irritability 3. Sleep disturbance 4. Depression 5. Decreased libido. Localized atrophy of urogenital tissues 1.Vaginal dryness 2.Dyspareunia, which serve to enhance the loss of libido, and this in turn, can adversely affect psychological well-being. 3.The urethral mucosa may become atrophied, leading to an increased incidence of urinary tract infections or urinary incontinence. 4.In some women, the urethra may eventually become fibrosed, leading to dysuria, frequency and urgency (urethral syndrome). Osteoporosis 1. The long-term consequences of estrogen deprivation are often symptomless. There is a significant loss of calcium from the bones, which may give rise to frequent fractures, 2. Typical morbidities after a vertebral fracture include: back pain Loss of height Deformity (kyphosis, protuberant abdomen) reduced pulmonary function Diminished quality of life: loss of self-esteem, distorted body image, dependence on narcotic analgesics, sleep disorder, depression, loss of independence. To contextualize risk, the remaining lifetime probability in women at menopause of a fracture at any one of these sites exceeds that of breast cancer (~12%). Also, the likelihood of a fracture at any of these sites is 40% or more in developed countries. Cardiovascular system 1) Young adult women are protected against the development of hypertension and its deleterious consequences in the cardiovascular system. 2) Levels of low-density lipoprotein cholesterol (LDL-C) and very-low- density lipoprotein cholesterol (VLDL-C) are decreased by estrogen, and the levels of high-density lipoprotein cholesterol (HDL-C) are increased, thereby giving some protection against atherosclerosis. 3) HDL-C is known to promote cholesterol efflux from macrophages in the arterial wall, thereby reducing atheromatous plaque and conferring a protective effect against heart disease. 4) After menopause, this protection is lost and the incidence of high blood pressure and associated cardiovascular disease increases to levels similar to those found in age-matched men. 5) Estrogen has direct beneficial effects in the control of blood pressure, possibly via regulating endothelium-mediated control of arteriolar tone. 1) In women deprived of estrogen, endothelium-dependent vasodilation is impaired. This dysfunction is largely associated with a reduction in nitric oxide availability. 2) Estrogen increases nitric oxide availability by stimulating endothelial nitric oxide synthase (eNOS). 3) Estrogen also stimulates the production of other endothelium-derived relaxing factors such as prostacyclin (prostaglandin I2). 4) Research suggests that the estrogen receptor (ER) α is important in mediating the vascular effects of estrogen. Studies using selective ERα agonists are being undertaken. However, many pathways are stimulated by estrogen receptor activation and the relative importance of these different pathways varies from tissue to tissue.  Miscellaneous 1)Thinning of the skin, 2)Brittle nails, 3)Hair loss 4)Generalized aches and pains are also associated with reduced estrogen levels. Management 1) Hormone replacement therapy A. HRT is a complicated clinical issue requiring an in-depth risk/ benefit assessment. B. One important factor is age, as data have shown that if a woman aged less than 35 has a hysterectomy and a bilateral oophorectomy, her risk of non-fatal myocardial infarction is nearly eight times that of her age- matched counterpart who has retained her ovaries. C. Age at time of HRT prescription in relation to menopausal age, that is, number of years of oestrogen deprivation before replacement, is also of importance when considering outcomes. D. Individual differences in hormone metabolism (both endogenous and exogenous) are also likely to be important as several different cytochrome enzymes metabolize estrogen and may be affected by inherited polymorphisms. E. Therefore, some women may produce estrogenic metabolites possessing considerable estrogenic activity, whilst others produce metabolites which are relatively non-estrogenic. F. Body mass index (BMI) also influences response to HRT, with increased plasma estradiol levels observed in women with higher BMIs. G. HRT is effective for symptomatic relief of menopausal symptoms, and its use is justified when symptoms adversely affect quality of life. H. Current advice is that the lowest effective dose for a particular woman should be used for the shortest period of time. I. Local estrogen replacement may be used to reverse the symptoms of urogenital atrophy as it appears to be more effective than systemic therapy. There is no evidence to suggest that local estrogen treatment is associated with significant risks. J. Treatment with HRT should be reviewed at least annually, with alternative therapies considered for the management of osteoporosis. K. In the treatment of menopausal symptoms, the benefits of short-term HRT outweigh the risks in the majority of women, but in healthy women without symptoms, the risks outweigh the benefits. Contraindications to the use of HRT include 1) Undiagnosed vaginal bleeding in post-menopausal women, 2) The presence of an estrogen-dependent tumor, 3) Liver disease (where liver function tests have failed to return to normal), 4) Active thrombophlebitis, 5) Active or recent arterial thromboembolic disease as angina or myocardial infarction. 6) A history of deep vein thrombosis and pulmonary embolism requires careful evaluation before the use of estrogen therapy. 7) Use in patients with Dubin–Johnson and Rotor syndromes may also be contraindicated. Estrogen therapy Since the symptoms and long-term effects of menopause are due to estrogen deprivation, the mainstay of HRT is estrogen. This may be administered orally or parenterally but, in either case, the estrogens used are naturally occurring and include: estradiol estriol estrone estropipate conjugated equine estrogen (estrone sulphate 40%, equilin sulphate 60%) estradiol valerate. The use of ‘natural’ estrogens reduces the risk of the potentially dangerous estrogenic effects such as 1) Raised blood pressure, 2) Alteration in coagulation factors 3) An undesirable lipid profile, which sometimes occur with the more potent synthetic estrogens used in the oral contraceptive agents. Natural VS Synthetic Estrogen 1) A ‘natural’ estrogen is defined as one that is normally found in the human female and has a physiological effect. 2) Natural estrogens are less potent (up to 200 times) than synthetic estrogens. As they are naturally occurring compounds, 3) The plasma half-life of these estrogens is similar to that of the ovarian-secreted estrogens and 4) The duration of action is shorter than the synthetic estrogens, such as ethinylestradiol, used in many formulations of the contraceptive pill. 5) The plasma ratio of estradiol to estrone is normally about 1:1 to2:1,  There are four main routes of administration for estrogens in HRT: Oral Transdermal (patches/gels/cream) Subcutaneous (implants) Vaginal (creams and medicated rings). Progestogen therapy A.The only proven reason for adding a progestogen to estrogen therapy for HRT in women with an intact uterus is to protect the endometrium from hyperplasia and possible neoplasia. B.There are many preparations which contain progestogens added to oestrogen for a number of days per month. However C.To effectively prevent endometrial hyperplasia, the progestogen must be taken for a minimum of 12 days. D.The minimum dose of progestogen required to protect against hyperplasia depends on the potency of the compound used. E. The progestogens commonly available in HRT preparations are either derivatives of progesterone, such as medroxyprogesterone and dydrogesterone, or 19-nortestosterone substitutes such as norethisterone or levonorgestrel. F. All these synthetic progestogens are active following oral administration and provide adequate protection of the endometrium against estrogen stimulation. G. Some transdermal preparations also incorporate a progestogenic compound in the regimen. As with all semisynthetic or synthetic hormones, these compounds may act on receptors other than the progesterone receptor, and the long term consequence of this is not predictable. H. Progesterone is the only progestogen to act solely on the progesterone receptor, but it has poor oral bioavailability and so it is difficult to achieve satisfactory plasma concentrations. However, the micronised preparations are better absorbed. I. Progesterone may also be administered at night in the form of a pessary or suppository, or by injection in the form of a longlasting subdermal implant. II. The progestogen in HRT is most commonly administered orally or transdermally and usually one of the synthetic progestogens is used. Estrogen and progestogen regimens The monthly withdrawal bleed is perceived by some post-menopausal patients to be an unacceptable side effect of HRT, and this has resulted in the development of a number of regimens in an effort to minimise this effect. Formulations have been produced with which bleeding only occurs every 3 months instead of every 4 weeks, or it does not occur at all. Regimens of combined estrogen and progestogen therapy Estrogen 28 days + progestogen 12 or 14 days, then repeat without interval (bleed every 4 weeks) Estrogen 70 days + progestogen 14 days followed by 7 days placebo tablets (bleed every 3 months) Estrogen + progesterone continuously (no bleed) Estrogen continuously + Mirena IUS (bleed variable but levonorgestrel likely to reduce bleed and can provoke amenorrhoea) Tibolone 1) Tibolone is a synthetic steroid that has estrogenic, progestogenic and androgenic effects that alleviate menopausal symptoms without a monthly bleed. 2) The estrogenic effects are weak and should not promote endometrial hyperplasia, but 10–15% of women on this treatment experience breakthrough bleeding. 3) The drug is given continuously but is not suitable for women within 1 year of menopause or immediately after estrogen therapy because in such cases breakthrough bleeding is most likely to occur. 4) The evidence suggests that this drug is protective against osteoporosis, but the long-term cardioprotective effects remain unclear as there is some evidence of a lowering of HDL-C. 5) It should also be withdrawn if signs of thromboembolic disease occur. 6) The androgenic action of tibolone tends to increase libido. 7) It has been reported that tibolone does have fewer breast-related adverse effects than estrogenic or estrogenic–progestogenic HRT regimens. Raloxifene 1) Raloxifene is a non-steroidal benzothiophene that binds to some estrogen receptors and belongs to a class of drugs referred to as selective estrogen receptor modulators (SERMs). 2) These compounds act selectively on some estrogen receptors to increase bone mineral density and antagonise estrogen- dependent effects on breast and endometrial tissues in post-menopausal women. 3) However, there is a reported increased risk of thromboembolism, particularly in the first 4 months of use. 4) Raloxifene cannot be used to treat vasomotor symptoms in peri-menopausal women. 5) In fact, it is reported to induce hot flushes. It has little or no stimulatory effect on the uterine endometrium and is not associated with uterine bleeding. In summary, raloxifene is a compound that selectively stimulates one group of estrogen receptors and may be considered a curative treatment for osteoporosis and a preventive agent in the development of estrogen- dependent breast tumors. OBESITY The term obesity is given to individuals with a body mass index (BMI) of 30 kg/m2 or greater. Obesity is due in part to an energy imbalance. Simply put, calorie consumption exceeds calorie expenditure. However, it is now well understood that genetics, metabolism, behavior, environment, culture, and socioeconomic status play a role in obesity. An individual whose BMI is greater than 30 or greater than 27 with at least two comorbidities (for example, hypertension and diabetes) is considered a potential candidate for pharmacological treatment of obesity. The majority of drugs approved to treat obesity have short-term indications for usage. However, some of the newer medications have been approved for long-term weight management. − The older medications approved for short-term usage are the anorexiants phentermine and diethylpropion. − There is a much larger list of anorexiants used off-label for weight loss; The lipase inhibitor, orlistat, has been available for several years, and other lipase inhibitors are being considered for approval. − Recently, a serotonin agonist, lorcaserin, and a combination drug, phentermine and topiramate, were also approved for the treatment of obesity. − Drugs for obesity are considered effective if they demonstrate at least a 5% greater reduction in body weight as compared to placebo (no treatment). B. Classification 1. Based on BMI 2. Normal: BMI 18.5–24.9 kg/m2 3. Overweight: BMI 25.0–29.9 kg/m2 4. Obesity a. Class I: BMI 30.0–34.9 kg/m2 b. Class II: BMI 35.0–39.9 kg/m2 c. Class III: BMI 40 kg/m2 or greater C. Therapy Goals 1. Weight loss: Initial goal 5%–10% decrease from baseline weight over 6 months 2. Maintain lower weight in the long term. 3. Limit weight-induced comorbidities (e.g., T2D, hypertension, cardiovascular disease). D. Nonpharmacologic Therapy (aimed at providing an energy deficit) 1. Increased physical activity: 200–300 minutes per week 2. Dietary options: Any diet that has proven weight reduction data available is appropriate. No specific recommendations of one diet over another. Individualize according to patient preferences. a. Strive for at least a 500-kcal/day deficit. b. 1200–1800 kcal/day for women c. 1500–1800 kcal/day for men 3. Behavioral intervention: (at least 14 sessions in 6 months) comprehensive weight-loss intervention through group or individual sessions with a professional (e.g., dietitian, exercise specialist, health counselor) 4. Surgery: Usually reserved for patients with severe obesity (BMI greater than 40 kg/m2) or lower BMIs with existing comorbidities a. Gastric bypass b. Gastric banding E. Pharmacotherapy 1. Always in conjunction with diet, physical activity, and behavioral therapy 2. Medications should be reserved for those not achieving or sustaining weight reduction with adequate lifestyle modifications, in those with obesity, or with a BMI of at least 27 kg/m2 with significant weight-related comorbidities (e.g., diabetes, hypertension). 3. Medication selected according to risk-benefit profile should be U.S. Food and Drug Administration (FDA) approved. After 1 year, approved agents should provide at least a statistically significant 5% weight-loss difference from placebo, and at least 35% of treated subjects should achieve at least a 5% weight loss from baseline and twice that of placebo-treated subjects. 1. Orlistat a. Mechanism of action: Reduced absorption of fat by inhibition of gastric and pancreatic lipases b. Dosing i. Prescription: 120 mg three times daily during or up to 1 hour after meals ii. Over the counter: 60 mg three times daily during or up to 1 hour after meals c. Adverse effects i. Gastrointestinal (GI) tract: Flatulence, oily stools, loose stools, fecal urgency or incontinence (very dependent on fat content of meal) ii. Reduced absorption of fat-soluble vitamins (A, D, E, and K): Use vitamin supplement before or well after use. iii. Hepatotoxicity, kidney stones d. Efficacy: 35%–54% of patients taking a prescription-strength product attained at least a 5% weight loss after 1 year of therapy, and 16%–25% attained at least a 10% weight loss. 2. Lorcaserin (schedule IV) a. Mechanism of action: Reduced hunger by stimulating serotonin-2C receptors in the brain. Previous serotonin agonists used for obesity (e.g., fenfluramine) were nonselective and caused cardiac and pulmonary problems. b. Dosing: 10 mg twice daily c. Adverse effects: Headache, dizziness, nausea, dry mouth, constipation, memory or attention disturbances, hypoglycemia in patients with diabetes d. Efficacy: 4.5%–6% weight loss from baseline; 47% attained at least a 5% loss, and 23% attained at least a 10% weight loss. In overweight patients with diabetes, up to a 1% reduction in A1C e. Discontinue use if at least a 5% weight loss is not achieved after 12 weeks of use. f. Avoid concurrent use with serotonergic drugs, including selective serotonin reuptake inhibitors. 3. Phentermine/extended-release topiramate (schedule IV) a. Mechanism of action: Phentermine promotes appetite suppression and decreased food intake secondary to its sympathomimetic activity. Mechanism of topiramate is unknown, but it may cause appetite suppression and satiety through increased γ-aminobutyrate activity. b. Dosing (phentermine/topiramate): Should be taken in the morning to avoid insomnia i. Initial: 3.75/23 mg daily for 2 weeks; then increase to 7.5/46 mg daily ii. If at least a 3% weight loss not achieved after 12 weeks, can discontinue or increase to 11.25/ 69 mg daily for 2 weeks; then increase to 15/92 mg daily if tolerated iii. If at least a 5% weight loss not achieved with 15/92 mg daily, discontinue use. Taper when discontinuing to avoid seizures. iv. Dosing in moderate hepatic or renal impairment: Do not exceed 7.5/46 mg daily. c. Adverse effects: Dry mouth, paresthesia, constipation, dysgeusia, insomnia, attention and memory disturbances, increased heart rate d. In women of childbearing age, obtain a negative pregnancy test before initiating and monthly thereafter because of fetal toxicity. Stress the importance of adequate contraception during use. e. Efficacy: 9%–10% weight loss from baseline; 60%–70% attained at least a 5% weight loss after 1 year of treatment, and 37%–48% attained at least a 10% weight loss 4. Bupropion/naltrexone a. Mechanism of action: Reuptake inhibitor of dopamine and norepinephrine (bupropion) and opioid antagonist (naltrexone) b. Dosing (8 mg naltrexone/90 mg bupropion tablets) i. Dosage escalation at weekly intervals by 1 tablet daily ii. Initially, 1 tablet once daily iii. Target dosage 2 tablets twice daily c. Adverse effects: Nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth d. Precautions and contraindications: Uncontrolled hypertension, seizure disorders, anorexia nervosa or bulimia, drug or alcohol withdrawal. Avoid with chronic use of opioids. e. Efficacy: 5%–6% weight loss from baseline; 40%–55% attained at least a 5% weight loss after 56 weeks of therapy, 20%–25% attained at least a 10% weight loss f. Discontinue use if at least a 5% weight loss is not achieved after 12 weeks of use. 5. Liraglutide a. Mechanism of action: Glucagon-like peptide-1 (GLP-1) agonist (part of incretin system). Thought to cause satiety and delay gastric emptying. Used in treatment of T2D. b. Dosing (administered subcutaneously by pen device) i. Target dosage higher in obesity than in treatment of diabetes. Brand- name product for obesity is not approved for diabetes and vice versa. ii. Initially, 0.6 mg once daily; increase by 0.6 mg at weekly intervals iii. Target dosage for obesity is 3 mg daily. c. Adverse effects: Nausea, vomiting, diarrhea, constipation, dyspepsia ii. Obesity formulation should be avoided in patients receiving insulin (increased risk of hypoglycemia). iii. Do not use with other GLP-1 agonists used in the treatment of diabetes mellitus (DM). e. Efficacy i. Patients without diabetes: 8%–9% weight loss from baseline; 60%–65% attained at least a 5% weight loss after 56 weeks of treatment, and about 33% attained at least a 10% weight loss ii. Patients with diabetes: 6% weight loss from baseline; 54% attained at least a 5% weight loss after 56 weeks of treatment, and 25% attained at least a 10% weight loss. Only minimally more effective at A1C reduction than standard diabetes dosage (see text that follows for diabetes dosing) f. Discontinue use if the patient does not achieve at least a 4% weight loss after 16 weeks of therapy or if the patient cannot tolerate the target 3-mg daily dosage. 6. Diethylpropion (schedule IV), phentermine (schedule IV), phendimetrazine (schedule III) a. Should be used only for a limited time, up to 3 months, and avoid in those with abuse potential b. Adverse effects: Increased blood pressure, constipation, increased heart rate, dysrhythmias, abuse potential (avoid in patients with hypertension or history of cardiovascular disease) Other issues a. Concurrent use of obesity medications has not been studied. b. Comparative studies between agents are lacking (although liraglutide has been shown to reduce weight better than orlistat). c. Long-term safety of all agents is unknown. d. Consider chronic medication. Weight loss after continuation of agent is not sustained 11. Off-label medications used but not well studied specifically for obesity: Selective serotonin reuptake inhibitors, zonisamide, metformin, pramlintide POLYCYSTIC OVARY SYNDROME A. Background and Classification 1. May be a cause of infertility in up to 20% of infertile couples 2. Mainly considered to be caused by androgen excess or hyperandrogenism 3. Underlying cause appears to be insulin resistance (in patients with and without obesity), with subsequent compensatory insulin hypersecretion or increased insulin action. This increased action stimulates androgen secretion by the ovaries or adrenal cells, leading to increased luteinizing hormone (LH) secretion but normal or low follicle-stimulating hormone (FSH) concentrations, with a subsequent decrease in follicular maturation and anovulation. 4. Has several potential comorbidities with endocrine and cardiovascular implications (e.g., T2D, obesity) 5. May affect 6%–10% of women (higher depending on diagnostic criteria used), making it one of the most prevalent endocrine disorders in young women 6. No clear consensus on classifying polycystic ovary syndrome (PCOS), although some rate it from mild to severe 7. Endocrine Society has the only recent guideline on PCOS diagnosis and treatment. B. Diagnosis 1. Still somewhat under debate; no clear consensus 2. 1990 National Institutes of Health (NIH) criteria a. Hyperandrogenism or hyperandrogenemia b. Oligoovulation (infrequent or irregular ovulation) c. Exclusion of other secondary causes, particularly adrenal hyperplasia, Cushing syndrome, hyperprolactinemia 3. 2003 Rotterdam criteria: Presence of at least two of the following and ruling out secondary causes a. Menstrual irregularity (oligoovulation or anovulation) b. Hyperandrogenism (clinical or biochemical signs) c. Polycystic ovaries (by trans vaginal ultrasonography) d. Recommended by the Endocrine Society guideline 4. 2006 Androgen Excess Society: Follow 1990 NIH criteria, but recognize concerns brought about from the Rotterdam criteria. C. Clinical Presentation 1. Clinical signs of hyperandrogenism: Hirsutism, acne, pattern alopecia (can vary by ethnicity) 2. Biochemical signs of hyperandrogenism (should not be used as the sole criterion because 20%–40% of patients with PCOS may be in the normal range) a. Elevated free or total serum testosterone b. LH/FSH ratio greater than 2 3. Infrequent, irregular (e.g., late), or no ovulation, leading to irregular menses 4. Infertility despite unprotected and frequent intercourse during the past year 5. In patients with obesity (50%–80% of cases), prediabetes (impaired glucose tolerance) or T2D may be present. D. Therapy Goals 1. Normalize ovulation and menses. 2. Improve fertility in those who want to become pregnant. 3. Limit clinical signs. 4. Reduce progression to T2D (perhaps cardiovascular disease). E. Nonpharmacologic Therapy 1. Weight loss (5%–10%) important in patients who are overweight or obese 2. Mechanical hair removal for hirsutism F. Pharmacotherapy 1. Fertility improvement a. Clomiphene citrate i. Mechanism of action: Induces ovulation as a selective estrogen receptor modulator that improves LH-FSH secretion. ii. Dosing (a) 50 mg/day for 5 days starting on the third or fifth day of the menstrual cycle (b) Increase to 100 mg if ovulation does not occur after first cycle of treatment. (c) Maximal daily dosage 150–200 mg/day iii. Adverse effects: Flushing, GI discomfort, vision disturbances, vaginal dryness, multiple pregnancies iv. Drug of choice for infertility according to the Endocrine Society guideline b. Gonadotropin (e.g., recombinant FSH) or recombinant gonadotropin-releasing hormone therapy with or without clomiphene i. Mechanism of action: Normalizes LH/FSH ratio to stimulate ovulation ii. Dosing: Many dosing strategies used iii. Adverse effects: Multiple pregnancies, ovarian hypertrophy, miscarriage, mood swings, breast discomfort 2. Symptomatic improvement a. Hormonal contraceptives (estrogen/progestin combination): Endocrine Society first-line therapy for menstrual abnormalities, hirsutism, or acne b. Metformin i. Effective for metabolic and glycemic abnormalities, if present, but only modestly effective for hirsutism ii. Alternative to hormonal contraception for irregular menses when hormonal contraceptives are contraindicated iii. Few data to support use for increased fertility (may improve pregnancy rate but not shown to improve rates of live births) c. Spironolactone i. Often added to hormonal contraceptives ii. May help with hirsutism d. Pioglitazone: Questionable whether benefits outweigh risks in PCOS. Not recommended in Endocrine Society guidelines