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InternalMed_Harrison. In addition to addressing the negative impact of smoking on fertility and pregnancy outcome, counseling about nutrition and weight is a fundamental component of infertility and pregnancy management. Both low and increased body mass index (BMI) are associated with infertility in women and with increased morbidity during pregnancy. Obesity has also been associated with infertility in men. The treatment of infertility should be tailored to the problems unique to each couple. In many situations, including unexplained infertility, mild-to-moderate endometriosis, and/or borderline semen parameters, a stepwise approach to infertility is optimal, beginning with low-risk interventions and moving to more invasive, higher risk interventions only if necessary. After determination of all infertility factors and their correction, if possible, this approach might include, in increasing order of complexity: (1) expectant management, (2) clomiphene citrate or an aromatase inhibitor (see below) with or


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InternalMed_Harrison. and their correction, if possible, this approach might include, in increasing order of complexity: (1) expectant management, (2) clomiphene citrate or an aromatase inhibitor (see below) with or without intrauterine insemination (IUI), (3) gonadotropins with or without IUI, and (4) in vitro fertilization (IVF). The time used for evaluation, correction of problems identified, and expectant management can be longer in women age <30 years, but this process should be advanced rapidly in women age >35 years. In some situations, expectant management will not be appropriate.


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InternalMed_Harrison. Treatment of ovulatory dysfunction should first be directed at identification of the etiology of the disorder to allow specific management when possible. Dopamine agonists, for example, may be indicated in patients with hyperprolactinemia (Chap. 403); lifestyle modification may be successful in women with obesity, low body weight, or a history of intensive exercise.


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InternalMed_Harrison. Medications used for ovulation induction include agents that increase FSH through alteration of negative feedback, gonadotropins, and pulsatile GnRH. Clomiphene citrate is a nonsteroidal estrogen antagonist that increases FSH and LH levels by blocking estrogen negative feedback at the hypothalamus. The efficacy of clomiphene for ovulation induction is highly dependent on patient selection. In appropriate patients, it induces ovulation in ~60% of women with PCOS and has traditionally been the initial treatment of choice. Combination with agents that modify insulin levels such as metformin does not appear to improve outcome. Clomiphene citrate is less successful in patients with hypogonadotropic hypogonadism. Aromatase inhibitors have also been investigated for the treatment of infertility. Studies suggest they may have advantages over clomiphene, but these medications have not been approved for this indication.


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InternalMed_Harrison. Gonadotropins are highly effective for ovulation induction in women with hypogonadotropic hypogonadism and PCOS and are used to induce the development of multiple follicles in unexplained infertility and in older reproductive-age women. Disadvantages include a significant risk of multiple gestation and the risk of ovarian hyperstimulation, particularly in women with polycystic ovaries, with or without other features of PCOS. Careful monitoring and a conservative approach to ovarian stimulation reduce these risks. Currently available gonadotropins include urinary preparations of LH and FSH, highly purified FSH, and recombinant FSH. Although FSH is the key component, LH is essential for steroidogenesis in hypogonadotropic patients, and LH or human chorionic gonadotropin (hCG) may improve results through effects on terminal differentiation of the oocyte. These methods are commonly combined with IUI.


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InternalMed_Harrison. None of these methods are effective in women with premature ovarian failure, in whom donor oocyte or adoption is the method of choice. If hysterosalpingography suggests a tubal or uterine cavity abnormality or if a patient is age ≥35 at the time of initial evaluation, laparoscopy with tubal lavage is recommended, often with a hysteroscopy. Although tubal reconstruction may be attempted if tubal disease is identified, it is generally being replaced by the use of IVF. These patients are at increased risk of developing an ectopic pregnancy.


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InternalMed_Harrison. Although 60% of women with minimal or mild endometriosis may conceive within 1 year without treatment, laparoscopic resection or ablation appears to improve conception rates. Medical management of advanced stages of endometriosis is widely used for symptom control but has not been shown to enhance fertility. In moderate and severe endometriosis, conservative surgery is associated with pregnancy rates of 50 and 39%, respectively, compared with rates of 2389 25 and 5% with expectant management alone. In some patients, IVF may be the treatment of choice.


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InternalMed_Harrison. The treatment options for male factor infertility have expanded greatly in recent years (Chap. 411). Secondary hypogonadism is highly amenable to treatment with gonadotropins or pulsatile gonadotropin-releasing hormone (GnRH) where available. In vitro techniques have provided new opportunities for patients with primary testicular failure and disorders of sperm transport. Choice of initial treatment options depends on sperm concentration and motility. Expectant management should be attempted initially in men with mild male factor infertility (sperm count of 15 to 20 × 106/ mL and normal motility). Moderate male factor infertility (10 to 15 × 106/mL and 20–40% motility) should begin with IUI alone or in combination with treatment of the female partner with ovulation induction, but it may require IVF with or without intracytoplasmic sperm injection (ICSI). For men with a severe defect (sperm count of <10 × 106/mL, 10% motility), IVF with ICSI or donor sperm should be used. If ICSI is


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InternalMed_Harrison. require IVF with or without intracytoplasmic sperm injection (ICSI). For men with a severe defect (sperm count of <10 × 106/mL, 10% motility), IVF with ICSI or donor sperm should be used. If ICSI is performed because of azoospermia due to congenital bilateral absence of the vas deferens, genetic testing and counseling should be provided because of the risk of cystic fibrosis.


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InternalMed_Harrison. The development of assisted reproductive technologies (ARTs) has dramatically altered the treatment of male and female infertility. IVF is indicated for patients with many causes of infertility that have not been successfully managed with more conservative approaches. IVF or ICSI is often the treatment of choice in couples with a significant male factor or tubal disease, whereas IVF using donor oocytes is used in patients with premature ovarian failure and in women of advanced reproductive age. Success rates are influenced by cause of infertility and age, varying between 15 and 40%. Success rates are highest in anovulatory women and lowest in women with decreased ovarian reserve. In the United States, success rates are higher in white than in black, Asian, or Hispanic women. Although often effective, IVF is expensive and requires careful monitoring of ovulation induction and invasive techniques, including the aspiration of multiple follicles. IVF is associated with a significant risk


InternalMed_Harrison

InternalMed_Harrison. effective, IVF is expensive and requires careful monitoring of ovulation induction and invasive techniques, including the aspiration of multiple follicles. IVF is associated with a significant risk of multiple gestation, particularly in women age <35, in whom the rate can be as high as 30%, which has led to specific recommendations for numbers of embryos or blastocysts to transfer based on age and specific prognostic factors.


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InternalMed_Harrison. Although use of contraception worldwide has increased in the last two decades, as of 2010, 146 million women worldwide age 15–49 years who were married or in a union had an unmet need for family planning. The absolute number of married women who use contraception or have an unmet need for family planning is projected to grow from 900 million (876–922 million) in 2010 to 962 million (927–992 million) in 2015. Only 15% of couples in the United States report having unprotected sexual intercourse in the past 3 months. However, despite the wide availability and widespread use of a variety of effective methods of contraception, approximately one-half of all births in the United States are the result of unintended pregnancy. Teenage pregnancies continue to represent a serious public health problem in the United States, with >1 million unintended pregnancies each year—a significantly greater incidence than in other industrialized nations.


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InternalMed_Harrison. Of the contraceptive methods available (Table 414-1), a reversible form of contraception is used by >50% of couples, whereas sterilization (male or female) has been used as a permanent form of contraception by over one-third of couples. Pregnancy termination is relatively safe when directed by health care professionals but is rarely the option of choice. 2390 surgical interruption of the fallopian tubes in women or the vas deferens in men. TAblE 414-1 EffECTivEnESS of DiffEREnT foRmS of ConTRACEPTion Method of Theoreticala Actuala Percent Continuing Methods Used by are potentially reversible, these proce- Contraception Effectiveness, % Effectiveness, % Use at 1 Yearb U.S. Womenc patient counseling. Several methods of tubal ligation Cervical cap 94 82 50 <1 have been developed, all of which are Spermicides 97 79 43 1 highly effective with a 10-year cumulative pregnancy rate of 1.85 per 100 women. However, when pregnancy does occur, the


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InternalMed_Harrison. Male 99.9 99.9 100 9 risk of ectopic pregnancy may be as high Female 99.8 99.6 100 27 as 30%. The success rate of tubal reanasto- 1 mosis depends on the method of ligationCopper T380 99 97 78 used, but even after successful reversal, the risk of ectopic pregnancy remains high. In Mirena 99.9 99.8 addition to prevention of pregnancy, tubal Hormonal 99.7 92 72 31 ligation reduces the risk of ovarian cancer, contraceptives possibly by limiting the upward migration of potential carcinogens. Vasectomy is a highly effective outpa- tient surgical procedure that has little risk. The development of azoospermia may be delayed for 2–6 months, and other forms sterility. Reanastomosis may restore fertilaAdapted from J Trussel et al: Obstet Gynecol 76:558, 1990. bAdapted from Contraceptive Technology Update. Contraceptive ity in 30–50% of men, but the success rateTechnology, Feb. 1996, Vol 17, No 1, pp 13–24. cAdapted from LJ Piccinino, WD Mosher: Fam Plan Perspective 30:4, 1998.


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InternalMed_Harrison. declines with time after vasectomy and may be influenced by factors such as the development of antisperm antibodies.


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InternalMed_Harrison. No single contraceptive method is ideal, although all are safer than INTRAUTERINE DEVICES carrying a pregnancy to term. The effectiveness of a given method of IUDs inhibit pregnancy through several mechanisms, primarily via a contraception does not just depend on the efficacy of the method itself. spermicidal effect caused by a sterile inflammatory reaction induced Discrepancies between theoretical and actual effectiveness emphasize by the presence of a foreign body in the uterine cavity (copper IUDs) the importance of patient education and compliance when consider-or by the release of progestins (Progestasert, Mirena). IUDs provide aing various forms of contraception (Table 414-1). Knowledge of the high level of efficacy in the absence of systemic metabolic effects, and advantages and disadvantages of each contraceptive is essential for ongoing motivation is not required to ensure efficacy once the devicecounseling an individual about the methods that are safest and most has been


InternalMed_Harrison

InternalMed_Harrison. disadvantages of each contraceptive is essential for ongoing motivation is not required to ensure efficacy once the devicecounseling an individual about the methods that are safest and most has been placed. However, only 1% of women in the United States consistent with his or her lifestyle. The WHO has extensive family use this method compared to a utilization rate of 15–30% in much ofplanning resources for the physician and patient that can be accessed Europe and Canada, despite evidence that the newer devices are notonline. Similar resources for determining medical eligibility are avail-associated with increased rates of pelvic infection and infertility, asable through the Centers for Disease Control and Prevention (CDC). occurred with earlier devices. An IUD should not be used in women at Considerations for contraceptive use in obese patients and after bariat-high risk for development of STI or in women at high risk for bacterialric surgery are discussed below. endocarditis. The


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InternalMed_Harrison. at Considerations for contraceptive use in obese patients and after bariat-high risk for development of STI or in women at high risk for bacterialric surgery are discussed below. endocarditis. The IUD may not be effective in women with uterine leiomyomas because they alter the size or shape of the uterine cavity.


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InternalMed_Harrison. IUD use is associated with increased menstrual blood flow, althoughBarrier contraceptives (such as condoms, diaphragms, and cervical this is less pronounced with the progestin-releasing IUD, which iscaps) and spermicides are easily available, reversible, and have fewer associated with a more frequent occurrence of spotting or amenorrhea. side effects than hormonal methods. However, their effectiveness is highly dependent on adherence and proper use (Table 414-1). A major advantage of barrier contraceptives is the protection pro-Oral Contraceptive Pills Because of their ease of use and efficacy,vided against sexually transmitted infections (STIs) (Chap. 163).


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InternalMed_Harrison. oral contraceptive pills are the most widely used form of hormonalConsistent use is associated with a decreased risk of HIV, gonorcontraception. They act by suppressing ovulation, changing cervical rhea, nongonococcal urethritis, and genital herpes, probably due mucus, and altering the endometrium. The current formulations arein part to the concomitant use of spermicides. Natural membrane made from synthetic estrogens and progestins. The estrogen com-condoms may be less effective than latex condoms, and petroleumponent of the pill consists of ethinyl estradiol or mestranol, whichbased lubricants can degrade condoms and decrease their efficacy for is metabolized to ethinyl estradiol. Multiple synthetic progestins arepreventing HIV infection. Barrier methods used by women include used. Norethindrone and its derivatives are used in many formuthe diaphragm, cervical cap, and contraceptive sponge. The cervical lations. Low-dose norgestimate and the more recently developedcap and sponge are


InternalMed_Harrison

InternalMed_Harrison. and its derivatives are used in many formuthe diaphragm, cervical cap, and contraceptive sponge. The cervical lations. Low-dose norgestimate and the more recently developedcap and sponge are less effective than the diaphragm, and there have (third-generation) progestins (desogestrel, gestodene, drospirenone)been rare reports of toxic shock syndrome with the diaphragm and have a less androgenic profile; levonorgestrel appears to be the mostcontraceptive sponge.


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InternalMed_Harrison. androgenic of the progestins and should be avoided in patients with STERILIzATION hyperandrogenism. The three major formulations of oral contracep-Sterilization is the method of birth control most frequently chosen tives are (1) fixed-dose estrogen-progestin combination, (2) phasic by fertile men and multiparous women >30 years old (Table 414-1). estrogen-progestin combination, and (3) progestin only. Each of these Sterilization refers to a procedure that prevents fertilization by formulations is administered daily for 3 weeks followed by a week of Absolute Previous thromboembolic event or stroke History of an estrogen-dependent tumor Active liver disease Pregnancy Undiagnosed abnormal uterine bleeding Hypertriglyceridemia Women age >35 years who smoke heavily Coronary heart disease—increased in smokers >35; no relation to proges Hypertension—relative risk 1.8 (current users) and 1.2 (previous users)


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InternalMed_Harrison. Coronary heart disease—increased in smokers >35; no relation to proges Hypertension—relative risk 1.8 (current users) and 1.2 (previous users) Venous thrombosis—relative risk ~4; may be higher with third-generation progestin, drospirenone, and patch; compounded by obesity (tenfold increased risk compared with nonobese, no OCP); markedly increased with factor V Leiden or prothrombin gene mutations Stroke—slight increase; unclear relation to migraine headache Cerebral vein thrombosis—relative risk ~13–15; synergistic with prothrombin gene mutation Breast cancer—may increase risk in carriers of BRCA1 and possibly BRCA2 Abbreviation: OCP, oral contraceptive pill.


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InternalMed_Harrison. no medication during which menstrual bleeding generally occurs. Two extended oral contraceptives are approved for use in the United States; Seasonale is a 3-month preparation with 84 days of active drug and 7 days of placebo, whereas Lybrel is a continuous preparation. Current doses of ethinyl estradiol range from 10 to 50 μg. However, indications for the 50-μg dose are rare, and the majority of formulations contain 30–35 μg of ethinyl estradiol. The reduced estrogen and progestin content in the secondand third-generation pills has decreased both side effects and risks associated with oral contraceptive use (Table 414-2). At the currently used doses, patients must be cautioned not to miss pills due to the potential for ovulation. Side effects, including breakthrough bleeding, amenorrhea, breast tenderness, and weight gain, often respond to a change in formulation. Even the lower dose oral contraceptives have been associated with an increased risk of cardiovascular disease (myocardial


InternalMed_Harrison

InternalMed_Harrison. breast tenderness, and weight gain, often respond to a change in formulation. Even the lower dose oral contraceptives have been associated with an increased risk of cardiovascular disease (myocardial infarction, stroke, venous thromboembolism [VTE]), but the absolute excess risk is extremely low. VTE risk is higher with the third-generation than the second-generation progestins, and the risk of stroke and VTE is also higher with drospirenone (although not cyproterone), but the absolute excess risk is small and may be outweighed by contraceptive benefits and reduction in ovarian and endometrial cancer risk.


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InternalMed_Harrison. The microdose progestin-only minipill is less effective as a contraceptive, having a pregnancy rate of 2–7 per 100 women-years. However, it may be appropriate for women at increased risk for cardiovascular disease or for women who cannot tolerate synthetic estrogens.


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InternalMed_Harrison. Alternative Methods A weekly contraceptive patch (Ortho Evra) is available and has similar efficacy to oral contraceptives. Approximately 2% of patches fail to adhere, and a similar percentage of women have skin reactions. Efficacy is lower in women weighing >90 kg. The amount of estrogen delivered may be comparable to that of a 40-μg ethinyl estradiol oral contraceptive, raising the possibility of increased risk of 2391 VTE, which must be balanced against potential benefits for women not able to successfully use other methods. A monthly contraceptive estrogen/progestin injection (Lunelle) is highly effective, with a first-year failure rate of <0.2%, but it may be less effective in obese women. Its use is associated with bleeding irregularities that diminish over time. Fertility returns rapidly after discontinuation. A monthly vaginal ring (NuvaRing) that is intended to be left in place during intercourse is also available for contraceptive use. It is highly effective, with a 12-month


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InternalMed_Harrison. after discontinuation. A monthly vaginal ring (NuvaRing) that is intended to be left in place during intercourse is also available for contraceptive use. It is highly effective, with a 12-month failure rate of 0.7%. Ovulation returns within the first recovery cycle after discontinuation.


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InternalMed_Harrison. Long-Term Contraceptives Long-term progestin administration acts primarily by inhibiting ovulation and causing changes in the endometrium and cervical mucus that result in decreased implantation and sperm transport. Depot medroxyprogesterone acetate (Depo-Provera, DMPA), the only injectable form available in the United States, is effective for 3 months, but return of fertility after discontinuation may be delayed for up to 12–18 months. DMPA is now available for both SC and IM injection. Irregular bleeding, amenorrhea, and weight gain are the most common side effects. This form of contraception may be particularly good for women in whom an estrogen-containing contraceptive is contraindicated (e.g., migraine exacerbation, sickle cell anemia, fibroids).


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InternalMed_Harrison. The probability of pregnancy without relation to time of the month is 8%, but the probability varies significantly in relation to proximity to ovulation and may be as high has 30%. In order of efficacy, methods of postcoital contraception include the following: 1. Copper IUD insertion within a maximum of 5 days has a reported efficacy of 99–100% and prevents pregnancy by its spermicidal effect; insertion is frequently available through family planning clinics. 2. Oral antiprogestins (ulipristal acetate, 30 mg single dose, available worldwide, or mifepristone, 600 mg single dose, not available for this indication in the United States) prevent pregnancy by delaying or preventing ovulation; when administered, ideally within 72 h but up to 120 h after intercourse, they have an efficacy of 98–99%; require a prescription. 3.


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InternalMed_Harrison. 3. Levonorgestrel (1.5 mg as a single dose) delays or prevents ovulation and is not effective after ovulation; should be taken within 72 h of unprotected intercourse, and has an efficacy that varies between 60 and 94%; it is available over the counter. Combined estrogen and progestin regimens have lower efficacy and are no longer recommended. A pregnancy test is not necessary before the use of oral methods, but pregnancy should be excluded before IUD insertion. Risk factors for failure of oral regimens include close proximity to ovulation and unprotected intercourse after use. In addition, there is an increased risk of pregnancy in obese and overweight women using levonorgestrel for postcoital contraception and an increased risk in obese women using an antiprogestin.


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InternalMed_Harrison. Approximately one-third of adults in the United States are obese. Although obesity is associated with some reduction in fertility, the vast majority of obese women can conceive. The risk of pregnancy-associated complications is higher in obese women. Intrauterine contraception may be more effective than oral or transdermal methods for obese women. The WHO guidelines provide no restrictions (class 1) for the use of intrauterine contraception, DMPA, and progestin-only pills for obese women (BMI ≥30) in the absence of coexistent medical problems, whereas methods that include estrogen (pill, patch, ring) are considered class 2 (advantages generally outweigh theoretical or proven risks) due to the increased risk of thromboembolic disease. There are no restrictions to the use of any contraceptive methods following restrictive bariatric surgery procedures, but both combined and progestin-only pills are relatively less effective following procedures associated with malabsorption.


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InternalMed_Harrison. 415e-1 SECTiOn 3 OBESiTy, DiABETES MElliTuS, AnD METABOliC SynDROME intraabdominal and abdominal subcutaneous fat have more significanceBiology of Obesity than subcutaneous fat present in the buttocks and lower extremities. This distinction is most easily made clinically by determining


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InternalMed_Harrison. Jeffrey S. Flier, Eleftheria Maratos-Flier the waist-to-hip ratio, with a ratio >0.9 in women and >1.0 in men being abnormal. Many of the most important complications of obesity, such as insulin resistance, diabetes, hypertension, hyperlipid-In a world where food supplies are intermittent, the ability to store emia, and hyperandrogenism in women, are linked more stronglyenergy in excess of what is required for immediate use is essential for to intraabdominal and/or upper body fat than to overall adipositysurvival. Fat cells, residing within widely distributed adipose tissue (Chap. 422). The mechanism underlying this association is unknowndepots, are adapted to store excess energy efficiently as triglyceride but may relate to the fact that intraabdominal adipocytes are more lipoand, when needed, to release stored energy as free fatty acids for use at lytically active than those from other depots. Release of free fatty acidsother sites. This physiologic system, orchestrated through


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InternalMed_Harrison. needed, to release stored energy as free fatty acids for use at lytically active than those from other depots. Release of free fatty acidsother sites. This physiologic system, orchestrated through endocrine into the portal circulation has adverse metabolic actions, especially onand neural pathways, permits humans to survive starvation for as the liver. Adipokines and cytokines that are differentially secreted by adilong as several months. However, in the presence of nutritional abunpocyte depots may play a role in the systemic complications of obesity.


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InternalMed_Harrison. dance and a sedentary lifestyle, and influenced importantly by genetic endowment, this system increases adipose energy stores and produces PREVALENCE adverse health consequences. Data from the National Health and Nutrition Examination Surveys (NHANES) show that the percentage of the American adult population Obesity is a state of excess adipose tissue Weight Height kg lb cm in. mass. Although often viewed as equivalent to increased body weight, this need not be 340 the case—lean but very muscular individu-150 dards without having increased adiposity. 130 Body weights are distributed continuously 130 in populations, so that choice of a medi-120 and obese is somewhat arbitrary. Obesity is therefore defined by assessing its linkage to morbidity or mortality.


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InternalMed_Harrison. Although not a direct measure of adi posity, the most widely used method to gauge obesity is the body mass index (BMI), which is equal to weight/height2 (in kg/m2) (Fig. 415e-1). Other approaches to quanti-75 fold thickness), densitometry (underwater weighing), computed tomography (CT) or magnetic resonance imaging (MRI), and electrical impedance. Using data from the


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InternalMed_Harrison. Metropolitan Life Tables, BMIs for the mid-55 point of all heights and frames among both men and women range from 19 to 26 kg/m2; at a similar BMI, women have more body fat than men. Based on data of substantial morbidity, a BMI of 30 is most commonly used as a threshold for obesity in both men 40 85 and women. Most but not all large-scale epidemiologic studies suggest that all-cause, metabolic, cancer, and cardiovascular mor-35 bidity begin to rise (albeit at a slow rate) when BMIs are ≥25. Most authorities use the term overweight (rather than obese) to describe individuals with BMIs between 25 and 30. A BMI between 25 and 30 should be viewed as medically significant and wor-25 thy of therapeutic intervention in the pres ence of risk factors that are influenced by adiposity, such as hypertension and glucose FIgURE 415e-1 Nomogram for determining body mass index. To use this nomogram, intolerance. place a ruler or other straight edge between the body weight (without clothes) in


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InternalMed_Harrison. hypertension and glucose FIgURE 415e-1 Nomogram for determining body mass index. To use this nomogram, intolerance. place a ruler or other straight edge between the body weight (without clothes) in kilograms or


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InternalMed_Harrison. The distribution of adipose tissue in dif-pounds located on the left-hand line and the height (without shoes) in centimeters or inches ferent anatomic depots also has substan-located on the right-hand line. The body mass index is read from the middle of the scale and is tial implications for morbidity. Specifically, in metric units. (Copyright 1979, George A. Bray, MD; used with permission.)


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InternalMed_Harrison. CHAPTER 415e Biology of Obesity with obesity (BMI >30) has increased from 14.5% (between 1976 and 1980) to 35.7% (between 2009 and 2010). As many as 68% of U.S. adults aged ≥20 years were overweight (defined as BMI >25) between the years of 2007 and 2008. Extreme obesity (BMI ≥40) has also increased and affects 5.7% of the population. The increasing prevalence of medically significant obesity raises great concern. Overall, the prevalence of obesity is comparable in men and women. In women, poverty is associated with increased prevalence. Obesity is more common among blacks and Hispanics. The prevalence in children and adolescents has been rising at a worrisome rate, reaching 15.9% in 2009/2010, but may be leveling off.


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InternalMed_Harrison. Substantial evidence suggests that body weight is regulated by both endocrine and neural components that ultimately influence the effector arms of energy intake and expenditure. This complex regulatory system is necessary because even small imbalances between energy intake and expenditure will ultimately have large effects on body weight. For example, a 0.3% positive imbalance over 30 years would result in a 9-kg (20-lb) weight gain. This exquisite regulation of energy balance cannot be monitored easily by calorie-counting in relation to physical activity. Rather, body weight regulation or dysregulation depends on a complex interplay of hormonal and neural signals. Alterations in stable weight by forced overfeeding or food deprivation induce physiologic changes that resist these perturbations: with weight loss, appetite increases and energy expenditure falls; with overfeeding, appetite falls and energy expenditure increases. This latter compensatory mechanism frequently fails,


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InternalMed_Harrison. with weight loss, appetite increases and energy expenditure falls; with overfeeding, appetite falls and energy expenditure increases. This latter compensatory mechanism frequently fails, however, permitting obesity to develop when food is abundant and physical activity is limited. A major regulator of these adaptive responses is the adipocyte-derived hormone leptin, which acts through brain circuits (predominantly in the hypothalamus) to influence appetite, energy expenditure, and neuroendocrine function (see below).


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InternalMed_Harrison. Appetite is influenced by many factors that are integrated by the brain, most importantly within the hypothalamus (Fig. 415e-2). Signals that impinge on the hypothalamic center include neural afferents, hormones, and metabolites. Vagal inputs are particularly important, bringing information from viscera, such as gut distention. Hormonal signals include leptin, insulin, cortisol, and gut peptides. Among the latter is ghrelin, which is made in the stomach and stimulates feeding, and peptide YY (PYY) and cholecystokinin, which is made in the small intestine and signals to the brain through direct action on hypothalamic control centers and/or via the vagus nerve. Metabolites, including glucose, can influence appetite, as seen by the effect of hypoglycemia to induce hunger; however, glucose is not


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InternalMed_Harrison. FIgURE 415e-2 The factors that regulate appetite through effects on central neural circuits. Some factors that increase or decrease appetite are listed. AgRP, Agouti-related peptide; CART, cocaineand amphetamine-related transcript; CCK, cholecystokinin; GLP-1, glucagonrelated peptide-1; MCH, melanin-concentrating hormone; α-MSH, α-melanocyte-stimulating hormone; NPY, neuropeptide Y.


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InternalMed_Harrison. normally a major regulator of appetite. These diverse hormonal, metabolic, and neural signals act by influencing the expression and release of various hypothalamic peptides (e.g., neuropeptide Y [NPY], Agoutirelated peptide [AgRP], α-melanocyte-stimulating hormone [α-MSH], and melanin-concentrating hormone [MCH]) that are integrated with serotonergic, catecholaminergic, endocannabinoid, and opioid signaling pathways (see below). Psychological and cultural factors also play a role in the final expression of appetite. Apart from rare genetic syndromes involving leptin, its receptor, and the melanocortin system, specific defects in this complex appetite control network that influence common cases of obesity are not well defined.


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InternalMed_Harrison. Energy expenditure includes the following components: (1) resting or basal metabolic rate; (2) the energy cost of metabolizing and storing food; (3) the thermic effect of exercise; and (4) adaptive thermo-genesis, which varies in response to long-term caloric intake (rising with increased intake). Basal metabolic rate accounts for ~70% of daily energy expenditure, whereas active physical activity contributes 5–10%. Thus, a significant component of daily energy consumption is fixed.


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InternalMed_Harrison. Genetic models in mice indicate that mutations in certain genes (e.g., targeted deletion of the insulin receptor in adipose tissue) protect against obesity, apparently by increasing energy expenditure. Adaptive thermogenesis occurs in brown adipose tissue (BAT), which plays an important role in energy metabolism in many mammals. In contrast to white adipose tissue, which is used to store energy in the form of lipids, BAT expends stored energy as heat. A mitochondrial uncoupling protein (UCP-1) in BAT dissipates the hydrogen ion gradient in the oxidative respiration chain and releases energy as heat. The metabolic activity of BAT is increased by a central action of leptin, acting through the sympathetic nervous system that heavily innervates this tissue. In rodents, BAT deficiency causes obesity and diabetes; stimulation of BAT with a specific adrenergic agonist (β3 agonist) protects against diabetes and obesity. BAT exists in humans (especially neonates), and although its physiologic


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InternalMed_Harrison. and diabetes; stimulation of BAT with a specific adrenergic agonist (β3 agonist) protects against diabetes and obesity. BAT exists in humans (especially neonates), and although its physiologic role is not yet established, identification of functional BAT in many adults using positron emission tomography (PET) imaging has increased interest in the implications of the tissue for pathogenesis and therapy of obesity. Beige fat cells, recently described, resemble BAT cells in expressing UCP-1. They are scattered through white adipose tissue, and their thermogenic potential is uncertain.


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InternalMed_Harrison. Adipose tissue is composed of the lipid-storing adipose cell and a stromal/vascular compartment in which cells including preadipocytes and macrophages reside. Adipose mass increases by enlargement of adipose cells through lipid deposition, as well as by an increase in the number of adipocytes. Obese adipose tissue is also characterized by increased numbers of infiltrating macrophages. The process by which adipose cells are derived from a mesenchymal preadipocyte involves an orchestrated series of differentiation steps mediated by a cascade of specific transcription factors. One of the key transcription factors is peroxisome proliferator-activated receptor γ (PPARγ), a nuclear receptor that binds the thiazolidinedione class of insulin-sensitizing drugs used in the treatment of type 2 diabetes (Chap. 418).


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InternalMed_Harrison. Although the adipocyte has generally been regarded as a storage depot for fat, it is also an endocrine cell that releases numerous molecules in a regulated fashion (Fig. 415e-3). These include the energy balance–regulating hormone leptin, cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-6, complement factors such as factor D (also known as adipsin), prothrombotic agents such as plasminogen activator inhibitor I, and a component of the blood pressure–regulating system, angiotensinogen. Adiponectin, an abundant adipose-derived protein whose levels are reduced in obesity, enhances insulin sensitivity and lipid oxidation and has vascular-protective effects, whereas resistin and RBP4, whose levels are increased in obesity, may induce insulin resistance. These factors, and others not yet identified, play a role in the physiology of lipid homeostasis, insulin sensitivity, blood pressure control, coagulation, and vascular health, and are likely to contribute to


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InternalMed_Harrison. and others not yet identified, play a role in the physiology of lipid homeostasis, insulin sensitivity, blood pressure control, coagulation, and vascular health, and are likely to contribute to obesity-related pathologies.


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InternalMed_Harrison. FIgURE 415e-3 Factors released by the adipocyte that can affect peripheral tissues. IL-6, interleukin 6; PAI, plasminogen activator inhibitor; RBP4, retinal binding protein 4; TNF, tumor necrosis factor. Although the molecular pathways regulating energy balance are beginning to be illuminated, the causes of obesity remain elusive. In part, this reflects the fact that obesity is a heterogeneous group of disorders. At one level, the pathophysiology of obesity seems simple: a chronic excess of nutrient intake relative to the level of energy expenditure. However, due to the complexity of the neuroendocrine and metabolic systems that regulate energy intake, storage, and expenditure, it has been difficult to quantitate all the relevant parameters (e.g., food intake and energy expenditure) over time in human subjects.


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InternalMed_Harrison. Role of genes Versus Environment Obesity is commonly seen in families, and the heritability of body weight is similar to that for height. Inheritance is usually not Mendelian, however, and it is difficult to distinguish the role of genes and environmental factors. Adoptees more closely resemble their biologic than adoptive parents with respect to obesity, providing strong support for genetic influences. Likewise, identical twins have very similar BMIs whether reared together or apart, and their BMIs are much more strongly correlated than those of dizygotic twins. These genetic effects appear to relate to both energy intake and expenditure. Currently, identified genetic variants, both common and rare, account for less than 5% of the variance of body weight.


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InternalMed_Harrison. Whatever the role of genes, it is clear that the environment plays a key role in obesity, as evidenced by the fact that famine prevents obesity in even the most obesity-prone individual. In addition, the recent increase in the prevalence of obesity in the United States is far too rapid to be due to changes in the gene pool. Undoubtedly, genes influence the susceptibility to obesity in response to specific diets and availability of nutrition. Cultural factors are also important—these relate to both availability and composition of the diet and to changes in the level of physical activity. In industrial societies, obesity is more common among poor women, whereas in underdeveloped countries, wealthier women are more often obese. In children, obesity correlates to some degree with time spent watching television. Although the role of diet composition in obesity continues to generate controversy, it appears that high-fat diets may, when combined with simple, rapidly absorbed carbohydrates,


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InternalMed_Harrison. watching television. Although the role of diet composition in obesity continues to generate controversy, it appears that high-fat diets may, when combined with simple, rapidly absorbed carbohydrates, promote obesity. Specific genes are likely to influence the response to specific diets, but these genes are largely unidentified.


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InternalMed_Harrison. Additional environmental factors may contribute to the increasing obesity prevalence. Both epidemiologic correlations and experimental data suggest that sleep deprivation leads to increased obesity. Changes in gut microbiome with capacity to alter energy balance are receiving experimental support from animal studies, and a possible role for obesigenic viral infections continues to receive sporadic attention. Specific genetic Syndromes For many years, obesity in rodents has been known to be caused by a number of distinct mutations distributed through the genome. Most of these single-gene mutations cause both hyperphagia and diminished energy expenditure, suggesting a physiologic link between these two parameters of energy homeostasis. Identification of the ob gene mutation in genetically obese (ob/ob) mice represented a major breakthrough in the field. The ob/ob mouse


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InternalMed_Harrison. FIgURE 415e-4 The physiologic system regulated by leptin. Rising or falling leptin levels act through the hypothalamus to influence appetite, energy expenditure, and neuroendocrine function and through peripheral sites to influence systems such as the immune system.


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InternalMed_Harrison. develops severe obesity, insulin resistance, and hyperphagia, as well as efficient metabolism (e.g., it gets fat even when ingesting the same number of calories as lean litter mates). The product of the ob gene is the peptide leptin, a name derived from the Greek root leptos, meaning thin. Leptin is secreted by adipose cells and acts primarily through the hypothalamus. Its level of production provides an index of adipose energy stores (Fig. 415e-4). High leptin levels decrease food intake and increase energy expenditure. Another mouse mutant, db/db, which is resistant to leptin, has a mutation in the leptin receptor and develops a similar syndrome. The ob gene is present in humans where it is also expressed in fat. Several families with morbid, early-onset obesity caused by inactivating mutations in either leptin or the leptin receptor have been described, thus demonstrating the biologic relevance of the leptin pathway in humans. Obesity in these individuals begins shortly after


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InternalMed_Harrison. mutations in either leptin or the leptin receptor have been described, thus demonstrating the biologic relevance of the leptin pathway in humans. Obesity in these individuals begins shortly after birth, is severe, and is accompanied by neuroendocrine abnormalities. The most prominent of these is hypogonadotropic hypogonadism, which is reversed by leptin replacement in the leptin-deficient subset. Central hypothyroidism and growth retardation are seen in the mouse model, but their occurrence in leptin-deficient humans is less clear. Mutations in the leptin or leptin receptor genes do not play a prominent role in common forms of obesity.


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InternalMed_Harrison. Mutations in several other genes cause severe obesity in humans (Table 415e-1); each of these syndromes is rare. Mutations in the gene encoding proopiomelanocortin (POMC) cause severe obesity through failure to synthesize α-MSH, a key neuropeptide that inhibits appetite in the hypothalamus. The absence of POMC also causes secondary adrenal insufficiency due to absence of adrenocorticotropic hormone (ACTH), as well as pale skin and red hair due to absence of α-MSH. Proenzyme convertase 1 (PC-1) mutations are thought to cause obesity by preventing synthesis of α-MSH from its precursor peptide, POMC. α-MSH binds to the type 4 melanocortin receptor (MC4R), a key hypothalamic receptor that inhibits eating. Heterozygous loss-of-function mutations of this receptor account for as much as 5% of severe obesity. Loss of function of MRAP2, a protein required for normal MC4R signaling, has been found in rare cases of severe obesity. These six genetic defects define a pathway through which leptin


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InternalMed_Harrison. obesity. Loss of function of MRAP2, a protein required for normal MC4R signaling, has been found in rare cases of severe obesity. These six genetic defects define a pathway through which leptin (by stimulating POMC and increasing α-MSH) restricts food intake and limits weight


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InternalMed_Harrison. CHAPTER 415e Biology of Obesity mouse deficient in the peptide MCH, whose administration causes feeding, is lean. Gene Gene Product Mechanism of Obesity In Human In Rodent A number of complex human syndromes Leptin, a fat-derived hormone Proopiomelanocortin, a precursor of several hormones and neuropeptides Agouti-related peptide, a neuropeptide expressed in the hypothalamus Prohormone convertase 1, a processing enzyme Carboxypeptidase E, a processing enzyme Tub, a hypothalamic protein of unknown function TrkB, a neurotrophin receptor Mutation prevents leptin from delivering satiety signal; brain perceives starvation Same as above Mutation prevents synthesis of melanocyte-stimulating hormone (MSH), a satiety signal Mutation prevents reception of satiety signal from MSH Mutation prevents synthesis of neuropeptide, probably MSH Same as above


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InternalMed_Harrison. Mutation prevents reception of satiety signal from MSH Mutation prevents synthesis of neuropeptide, probably MSH Same as above Hyperphagia due to uncharacterized hypothalamic defect (Fig. 415e-5). The results of genomewide association studies to identify genetic loci responsible for obesity in the general population have so far been disappointing. More than 40 replicated loci linked to obesity have been identified, but together they account for less than 3% of interindividual variation in BMI. The most replicated of these is a gene named FTO, which is of unknown function, but like many of the other recently described candidates, is expressed in the brain. Because the heritability of obesity is estimated to be 40–70%, it is likely that many more loci remain to be identified. It is possible that epistatic interactions between causative loci or unknown gene-environment interactions explain the poor success at identifying causal loci.


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InternalMed_Harrison. In addition to these human obesity genes, studies in rodents reveal several other molecular candidates for hypothalamic mediators of human obesity or leanness. The tub gene encodes a hypothalamic peptide of unknown function; mutation of this gene causes late-onset obesity. The fat gene encodes carboxypeptidase E, a peptide-processing enzyme; mutation of this gene is thought to cause obesity by disrupting production of one or more neuropeptides. AgRP is coexpressed with NPY in arcuate nucleus neurons. AgRP antagonizes α-MSH action at MC4 receptors, and its overexpression induces obesity. In contrast, a


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InternalMed_Harrison. FIgURE 415e-5 A central pathway through which leptin acts to regulate appetite and body weight. Leptin signals through proopiomelanocortin (POMC) neurons in the hypothalamus to induce increased production of α-melanocyte-stimulating hormone (α-MSH), requiring the processing enzyme PC-1 (proenzyme convertase 1). α-MSH acts as an agonist on melanocortin-4 receptors to inhibit appetite, and the neuropeptide AgRp (Agouti-related peptide) acts as an antagonist of this receptor. Mutations that cause obesity in humans are indicated by the solid green arrows. At least 12 genetic loci have been identified, and most of the encoded proteins form two multiprotein complexes that are involved in ciliary function and microtubule-based intracellular transport. Some evidence suggests that mutations might disrupt leptin receptor trafficking in key hypothalamic neurons, causing leptin resistance. Other Specific Syndromes Associated with Obesity • CUSHING’S SYNDROME


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InternalMed_Harrison. Other Specific Syndromes Associated with Obesity • CUSHING’S SYNDROME Although obese patients commonly have central obesity, hypertension, and glucose intolerance, they lack other specific stigmata of Cushing’s syndrome (Chap. 406). Nonetheless, a potential diagnosis of Cushing’s syndrome is often entertained. Cortisol production and urinary metabolites (17OH steroids) may be increased in simple obesity. Unlike in Cushing’s syndrome, however, cortisol levels in blood and urine in the basal state and in response to corticotropinreleasing hormone (CRH) or ACTH are normal; the overnight 1-mg dexamethasone suppression test is normal in 90%, with the remainder being normal on a standard 2-day low-dose dexamethasone suppression test. Obesity may be associated with excessive local reactivation of cortisol in fat by 11β-hydroxysteroid dehydrogenase 1, an enzyme that converts inactive cortisone to cortisol.


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InternalMed_Harrison. HYPOTHYROIDISM The possibility of hypothyroidism should be considered, but it is an uncommon cause of obesity; hypothyroidism is easily ruled out by measuring thyroid-stimulating hormone (TSH). Much of the weight gain that occurs in hypothyroidism is due to myxedema (Chap. 405). INSULINOMA Patients with insulinoma often gain weight as a result of overeating to avoid hypoglycemic symptoms (Chap. 420). The increased substrate plus high insulin levels promote energy storage in fat. This can be marked in some individuals but is modest in most.


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InternalMed_Harrison. Whether through tumors, trauma, or inflammation, hypothalamic dysfunction of systems controlling satiety, hunger, and energy expenditure can cause varying degrees of obesity (Chap. 402). It is uncommon to identify a discrete anatomic basis for these disorders. Subtle hypothalamic dysfunction is probably a more common cause of obesity than can be documented using currently available imaging techniques. Growth hormone (GH), which exerts lipolytic activity, is diminished in obesity and is increased with weight loss. Despite low GH levels, insulin-like growth factor (IGF) I (somatomedin) production is normal, suggesting that GH suppression may be a compensatory response to increased nutritional supply.


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InternalMed_Harrison. Pathogenesis of Common Obesity Obesity can result from increased energy intake, decreased energy expenditure, or a combination of the two. Thus, identifying the etiology of obesity should involve measurements of both parameters. However, it is difficult to perform direct and accurate measurements of energy intake in free-living individuals; and the obese, in particular, often underreport intake. Measurements of chronic energy expenditure are possible using doubly labeled water or metabolic chamber/rooms. In subjects at stable weight and body composition, energy intake equals expenditure. Consequently, these techniques allow assessment of energy intake in free-living individuals. The level of energy expenditure differs in established obesity, during periods of weight gain or loss, and in the preor postobese state. Studies that fail to take note of this phenomenon are not easily interpreted.


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InternalMed_Harrison. There is continued interest in the concept of a body weight “set point.” This idea is supported by physiologic mechanisms centered around a sensing system in adipose tissue that reflects fat stores and a receptor, or “adipostat,” that is in the hypothalamic centers. When fat stores are depleted, the adipostat signal is low, and the hypothalamus responds by stimulating hunger and decreasing energy expenditure to conserve energy. Conversely, when fat stores are abundant, the signal is increased, and the hypothalamus responds by decreasing hunger and increasing energy expenditure. The recent discovery of the ob gene, and its product leptin, and the db gene, whose product is the leptin receptor, provides important elements of a molecular basis for this physiologic concept (see above).


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InternalMed_Harrison. What Is the Status of Food Intake in Obesity? (Do the Obese Eat More Than the Lean?) This question has stimulated much debate, due in part to the methodologic difficulties inherent in determining food intake. Many obese individuals believe that they eat small quantities of food, and this claim has often been supported by the results of food intake questionnaires. However, it is now established that average energy expenditure increases as individuals get more obese, due primarily to the fact that metabolically active lean tissue mass increases with obesity. Given the laws of thermodynamics, the obese person must therefore eat more than the average lean person to maintain their increased weight. It may be the case, however, that a subset of individuals who are predisposed to obesity have the capacity to become obese initially without an absolute increase in caloric consumption.


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InternalMed_Harrison. What Is the State of Energy Expenditure in Obesity? The average total daily energy expenditure is higher in obese than lean individuals when measured at stable weight. However, energy expenditure falls as weight is lost, due in part to loss of lean body mass and to decreased sympathetic nerve activity. When reduced to near-normal weight and maintained there for a while, (some) obese individuals have lower energy expenditure than (some) lean individuals. There is also a tendency for those who will develop obesity as infants or children to have lower resting energy expenditure rates than those who remain lean. The physiologic basis for variable rates of energy expenditure (at a given body weight and level of energy intake) is essentially unknown.


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InternalMed_Harrison. Another component of thermogenesis, called nonexercise activity thermogenesis (NEAT), has been linked to obesity. It is the thermogenesis that accompanies physical activities other than volitional exercise such as the activities of daily living, fidgeting, spontaneous muscle contraction, and maintaining posture. NEAT accounts for about two-thirds of the increased daily energy expenditure induced by overfeeding. The wide variation in fat storage seen in overfed individuals is predicted by the degree to which NEAT is induced. The molecular basis for NEAT and its regulation is unknown.


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InternalMed_Harrison. Leptin in Typical Obesity The vast majority of obese persons have increased leptin levels but do not have mutations of either leptin or its receptor. They appear, therefore, to have a form of functional “leptin resistance.” Data suggesting that some individuals produce less leptin per unit fat mass than others or have a form of relative leptin deficiency that predisposes to obesity are at present contradictory and unsettled. The mechanism for leptin resistance, and whether it can be overcome by raising leptin levels or combining leptin with other treatments in a subset of obese individuals, is not yet established. Some data suggest that leptin may not effectively cross the blood-brain barrier as levels rise. It is also apparent from animal studies that leptin-signaling inhibitors, such as SOCS3 and PTP1b, are involved in the leptinresistant state.


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InternalMed_Harrison. (See also Chap. 416) Obesity has major adverse effects on health. Obesity is associated with an increase in mortality, with a 50–100% increased risk of death from all causes compared to normal-weight CHAPTER 415e Biology of Obesity individuals, mostly due to cardiovascular causes. Obesity and overweight together are the second leading cause of preventable death in the United States, accounting for 300,000 deaths per year. Mortality rates rise as obesity increases, particularly when obesity is associated with increased intraabdominal fat (see above). Life expectancy of a moderately obese individual could be shortened by 2–5 years, and a 20to 30-year-old male with a BMI >45 may lose 13 years of life. It is likely that the degree to which obesity affects particular organ systems is influenced by susceptibility genes that vary in the population.


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InternalMed_Harrison. Insulin Resistance and Type 2 Diabetes Mellitus Hyperinsulinemia and insulin resistance are pervasive features of obesity, increasing with weight gain and diminishing with weight loss (Chap. 422). Insulin resistance is more strongly linked to intraabdominal fat than to fat in other depots. Molecular links between obesity and insulin resistance in fat, muscle, and liver have been sought for many years. Major factors include: (1) insulin itself, by inducing receptor downregulation; (2) free fatty acids that are increased and capable of impairing insulin action; (3) intracellular lipid accumulation; and (4) several circulating peptides produced by adipocytes, including the cytokines TNF-α and IL-6, RBP4, and the “adipokines” adiponectin and resistin, which have altered expression in obese adipocytes and can modify insulin action. Additional mechanisms are obesity-linked inflammation, including infiltration of macrophages into tissues including fat, and induction of the endoplasmic


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InternalMed_Harrison. adipocytes and can modify insulin action. Additional mechanisms are obesity-linked inflammation, including infiltration of macrophages into tissues including fat, and induction of the endoplasmic reticulum stress response, which can bring about resistance to insulin action in cells. Despite the prevalence of insulin resistance, most obese individuals do not develop diabetes, suggesting that diabetes requires an interaction between obesity-induced insulin resistance and other factors such as impaired insulin secretion (Chap. 417). Obesity, however, is a major risk factor for diabetes, and as many as 80% of patients with type 2 diabetes mellitus are obese. Weight loss and exercise, even of modest degree, increase insulin sensitivity and often improve glucose control in diabetes.


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InternalMed_Harrison. Reproductive Disorders Disorders that affect the reproductive axis are associated with obesity in both men and women. Male hypogonadism is associated with increased adipose tissue, often distributed in a pattern more typical of females. In men whose weight is >160% ideal body weight (IBW), plasma testosterone and sex hormone– binding globulin (SHBG) are often reduced, and estrogen levels (derived from conversion of adrenal androgens in adipose tissue) are increased (Chap. 411). Gynecomastia may be seen. However, masculinization, libido, potency, and spermatogenesis are preserved in most of these individuals. Free testosterone may be decreased in morbidly obese men whose weight is >200% IBW.


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InternalMed_Harrison. Obesity has long been associated with menstrual abnormalities in women, particularly in women with upper body obesity (Chap. 412). Common findings are increased androgen production, decreased SHBG, and increased peripheral conversion of androgen to estrogen. Most obese women with oligomenorrhea have polycystic ovarian syndrome (PCOS), with its associated anovulation and ovarian hyperandrogenism; 40% of women with PCOS are obese. Most nonobese women with PCOS are also insulin-resistant, suggesting that insulin resistance, hyperinsulinemia, or the combination of the two are causative or contribute to the ovarian pathophysiology in PCOS in both obese and lean individuals. Increasing evidence supports a role for adipokines in mediating a link between obesity and the reproductive dysfunction of PCOS. In obese women with PCOS, weight loss or treatment with insulin-sensitizing drugs often restores normal menses. The increased conversion of androstenedione to estrogen, which occurs to a


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InternalMed_Harrison. of PCOS. In obese women with PCOS, weight loss or treatment with insulin-sensitizing drugs often restores normal menses. The increased conversion of androstenedione to estrogen, which occurs to a greater degree in women with lower body obesity, may contribute to the increased incidence of uterine cancer in postmenopausal women with obesity.


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InternalMed_Harrison. Cardiovascular Disease The Framingham Study revealed that obesity was an independent risk factor for the 26-year incidence of cardiovascular disease in men and women (including coronary disease, stroke, and congestive heart failure). The waist-to-hip ratio may be the best predictor of these risks. When the additional effects of hypertension and glucose intolerance associated with obesity are included, the adverse impact of obesity is even more evident. The effect of obesity on cardiovascular mortality in women may be seen at BMIs as low as 25. Obesity, especially abdominal obesity, is associated with an atherogenic lipid profile; with increased low-density lipoprotein cholesterol, very-low-density lipoprotein, and triglyceride; and with decreased high-density lipoprotein cholesterol and decreased levels of the vascular protective adipokine adiponectin (Chap. 421). Obesity is also associated with hypertension. Measurement of blood pressure in the obese requires use of a larger cuff


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InternalMed_Harrison. decreased levels of the vascular protective adipokine adiponectin (Chap. 421). Obesity is also associated with hypertension. Measurement of blood pressure in the obese requires use of a larger cuff size to avoid artifactual increases. Obesity-induced hypertension is associated with increased peripheral resistance and cardiac output, increased sympathetic nervous system tone, increased salt sensitivity, and insulin-mediated salt retention; it is often responsive to modest weight loss.


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InternalMed_Harrison. Pulmonary Disease Obesity may be associated with a number of pulmonary abnormalities. These include reduced chest wall compliance, increased work of breathing, increased minute ventilation due to increased metabolic rate, and decreased functional residual capacity and expiratory reserve volume. Severe obesity may be associated with obstructive sleep apnea and the “obesity hypoventilation syndrome” with attenuated hypoxic and hypercapnic ventilatory responses. Sleep apnea can be obstructive (most common), central, or mixed and is associated with hypertension. Weight loss (10–20 kg) can bring substantial improvement, as can major weight loss following gastric bypass or restrictive surgery. Continuous positive airway pressure has been used with some success.


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InternalMed_Harrison. Hepatobiliary Disease Obesity is frequently associated with nonalcoholic fatty liver disease (NAFLD), and this association represents one of the most common causes of liver disease in industrialized countries. The hepatic fatty infiltration of NAFLD progresses in a subset to inflammatory nonalcoholic steatohepatitis (NASH) and more rarely to cirrhosis and hepatocellular carcinoma. Steatosis typically improves following weight loss, secondary to diet or bariatric surgery. The mechanism for the association remains unclear. Obesity is associated with enhanced biliary secretion of cholesterol, supersaturation of bile, and a higher incidence of gallstones, particularly cholesterol gallstones (Chap. 369). A person 50% above IBW has about a sixfold increased incidence of symptomatic gallstones. Paradoxically, fasting increases supersaturation of bile by decreasing the phospholipid component. Fasting-induced cholecystitis is a complication of extreme diets.


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InternalMed_Harrison. Cancer Obesity is associated with increased risk of several cancer types, and in addition can lead to poorer treatment outcomes and increased cancer mortality. Obesity in males is associated with higher mortality from cancer of the esophagus, colon, rectum, pancreas, liver, and prostate; obesity in females is associated with higher mortality from cancer of the gallbladder, bile ducts, breasts, endometrium, cervix, and ovaries. Some of the latter may be due to increased rates of conversion of androstenedione to estrone in adipose tissue of obese individuals. Other possible mechanistic links may involve hormones, growth factors, and cytokines whose levels are linked to nutritional state, including insulin, leptin, adiponectin, and IGF-I, as well as activation of signaling pathways linked to both obesity and cancer. It has been estimated that obesity accounts for 14% of cancer deaths in men and 20% in women in the United States.


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InternalMed_Harrison. Bone, Joint, and Cutaneous Disease Obesity is associated with an increased risk of osteoarthritis, no doubt partly due to the trauma of added weight bearing, but potentially linked as well to activation of inflammatory pathways that could promote synovial pathology. The prevalence of gout may also be increased (Chap. 395). One of the skin problems associated with obesity is acanthosis nigricans, manifested by darkening and thickening of the skinfolds on the neck, elbows, and dorsal interphalangeal spaces. Acanthosis reflects the severity of underlying insulin resistance and diminishes with weight loss. Friability of skin may be increased, especially in skinfolds, enhancing the risk of fungal and yeast infections. Finally, venous stasis is increased in the obese. 2392 SEC Tion 3 obESiT y, DiAbETES mElliTuS, AnD mETAboliC SynDRomE Evaluation and management of Robert F. Kushner


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InternalMed_Harrison. 2392 SEC Tion 3 obESiT y, DiAbETES mElliTuS, AnD mETAboliC SynDRomE Evaluation and management of Robert F. Kushner More than 66% of U.S. adults are categorized as overweight or obese, and the prevalence of obesity is increasing rapidly in most of the industrialized world. Children and adolescents also are becoming more obese, indicating that the current trends will accelerate over time. Obesity is associated with an increased risk of multiple health problems, including hypertension, type 2 diabetes, dyslipidemia, obstructive sleep apnea, nonalcoholic fatty liver disease, degenerative joint disease, and some malignancies. Thus, it is important for physicians to identify, evaluate, and treat patients for obesity and associated comorbid conditions.


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InternalMed_Harrison. Physicians should screen all adult patients for obesity and offer intensive counseling and behavioral interventions to promote sustained weight loss. The five main steps in the evaluation of obesity, as described below, are (1) a focused obesity-related history, (2) a physical examination to determine the degree and type of obesity, (3) assessment of comorbid conditions, (4) determination of fitness level, and (5) assessment of the patient’s readiness to adopt lifestyle changes. The Obesity-Focused History Information from the history should address the following seven questions: What factors contribute to the patient’s obesity? How is the obesity affecting the patient’s health? What is the patient’s level of risk from obesity? What does the patient find difficult about managing weight? What are the patient’s goals and expectations? Is the patient motivated to begin a weight management program? What kind of help does the patient need?


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InternalMed_Harrison. What are the patient’s goals and expectations? Is the patient motivated to begin a weight management program? What kind of help does the patient need? Although the vast majority of cases of obesity can be attributed to behavioral factors that affect diet and physical activity patterns, the history may suggest secondary causes that merit further evaluation. Disorders to consider include polycystic ovarian syndrome, hypothyroidism, Cushing’s syndrome, and hypothalamic disease. Drug-induced weight gain also should be considered. Common causes include medications for diabetes (insulin, sulfonylureas, thiazolidinediones); steroid hormones; psychotropic agents; mood stabilizers (lithium); antidepressants (tricyclics, monoamine oxidase inhibitors, paroxetine, mirtazapine); and antiepileptic drugs (valproate, gabapentin, carbamazepine). Other medications, such as nonsteroidal anti-inflammatory drugs and calcium channel blockers, may cause peripheral edema but do not increase body fat.


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InternalMed_Harrison. The patient’s current diet and physical activity patterns may reveal factors that contribute to the development of obesity and may identify behaviors to target for treatment. This type of historic information is best obtained by the combination of a questionnaire and an interview. Body Mass Index (BMI) and Waist Circumference Three key anthropometric measurements are important in evaluating the degree of obesity: weight, height, and waist circumference. The BMI, calculated as weight (kg)/height (m)2 or as weight (lbs)/height (inches)2 × 703, is used to classify weight status and risk of disease (Tables 416-1 and 416-2). BMI provides an estimate of body fat and is related to disease risk. Lower BMI thresholds for overweight and obesity have been proposed for the Asia-Pacific region since this population appears to be at risk for glucose and lipid abnormalities at lower body weights.


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InternalMed_Harrison. Excess abdominal fat, assessed by measurement of waist circumference or waist-to-hip ratio, is independently associated with a higher risk for diabetes mellitus and cardiovascular disease. Measurement of the waist circumference is a surrogate for visceral adipose tissue and should be performed in the horizontal plane above the iliac crest (Table 416-3). Physical Fitness Several prospective studies have demonstrated that physical fitness, reported by questionnaire or measured by a maximal treadmill exercise test, is an important predictor of all-cause mortality rate independent of BMI and body composition. These observations highlight the importance of taking a physical activity and exercise history during examination as well as emphasizing physical activity as a treatment approach.


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InternalMed_Harrison. Obesity-Associated Comorbid Conditions The evaluation of comorbid conditions should be based on presentation of symptoms, risk factors, and index of suspicion. For all patients, a fasting lipid panel should be performed (total, low-density lipoprotein, and high-density lipoprotein cholesterol and triglyceride levels) and a fasting blood glucose level and blood pressure determined. Symptoms and diseases that are directly or indirectly related to obesity are listed in Table 416-4. Although individuals vary, the number and severity of organ-specific comorbid conditions usually rise with increasing levels of obesity. Patients at very high absolute risk include those with the following: established coronary heart disease; presence of other atherosclerotic diseases, such as peripheral arterial disease, abdominal aortic aneurysm, and symptomatic carotid artery disease; type 2 diabetes; and sleep apnea.


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InternalMed_Harrison. Assessing the Patient’s Readiness to Change An attempt to initiate lifestyle changes when the patient is not ready usually leads to frustration and may hamper future weight-loss efforts. Assessment includes patient motivation and support, stressful life events, psychiatric status, A helpful method to begin a readiness assessment is to use the motitime availability and constraints, and appropriateness of goals and vational interviewing technique of “anchoring” the patient’s interest expectations. Readiness can be viewed as the balance of two opposing and confidence to change on a numerical scale. With this technique, forces: (1) motivation, or the patient’s desire to change; and (2) resis-the patient is asked to rate—on a scale from 0 to 10, with 0 being not so tance, or the patient’s resistance to change. important (or confident) and 10 being very important (or confident)— his or her level of interest in and confidence about losing weight at this time. This exercise helps establish


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InternalMed_Harrison. to change. important (or confident) and 10 being very important (or confident)— his or her level of interest in and confidence about losing weight at this time. This exercise helps establish readiness to change and also serves as a basis for further dialogue.


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InternalMed_Harrison. Underweight <18.5 — — TREATmEnT obesity Healthy weight 18.5–24.9 — — Overweight 25.0–29.9 — Increased The primary goals of treatment are to improve obesity-related Obesity 30.0–34.9 I High comorbid conditions and to reduce the risk of developing future Obesity 35.0–39.9 II Very high comorbidities. Information obtained from the history, physical examination, and diagnostic tests is used to determine risk and Source: Adapted from the National Institutes of Health, National Heart, Lung, and Blood develop a treatment plan (Fig. 416-1). The decision of how aggres-Institute: Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight sively to treat the patient and which modalities to use is determined and Obesity in Adults. U.S. Department of Health and Human Services, U.S. Public Health Service, 1998. by the patient’s risk status, expectations, and available resources. Evaluation and Management of Obesity


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InternalMed_Harrison. Service, 1998. by the patient’s risk status, expectations, and available resources. Evaluation and Management of Obesity Eastern (Arab) populations Source: From KGMM Alberti et al for the IDF Epidemiology Task Force Consensus Group: Lancet 366:1059, 2005. Not all patients who are deemed obese by BMI alone need to be treated, as exemplified by the concepts of obesity paradox or the metabolically healthy obese. However, patients who present with obesity-related comorbidities and who would benefit from weight loss intervention should be managed proactively. Therapy for obesity always begins with lifestyle management and may include pharmacotherapy or surgery, depending on BMI risk category (Table 416-5). Setting an initial weight-loss goal of 8–10% over 6 months is a realistic target. Integument Dementia Striae distensae Stasis pigmentation of legs Lymphedema Cellulitis Intertrigo, carbuncles Acanthosis nigricans Acrochordons (skin tags) Hidradenitis suppurativa


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InternalMed_Harrison. Integument Dementia Striae distensae Stasis pigmentation of legs Lymphedema Cellulitis Intertrigo, carbuncles Acanthosis nigricans Acrochordons (skin tags) Hidradenitis suppurativa Obesity care involves attention to three essential elements of lifestyle: dietary habits, physical activity, and behavior modification. Because obesity is fundamentally a disease of energy imbalance, all patients must learn how and when energy is consumed (diet), how and when energy is expended (physical activity), and how to incorporate this information into their daily lives (behavioral therapy). Lifestyle management has been shown to result in a modest (typically 3–5 kg) weight loss when compared with no treatment or usual care.


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InternalMed_Harrison. Diet Therapy The primary focus of diet therapy is to reduce overall calorie consumption. Guidelines from the National Heart, Lung, and Blood Institute recommend initiating treatment with a calorie deficit of 500–1000 kcal/d compared with the patient’s habitual diet. This reduction is consistent with a goal of losing ~1–2 lbs per week. The calorie deficit can be instituted through dietary substitutions or alternatives. Examples include choosing smaller portion sizes, eating more fruits and vegetables, consuming more whole-grain cereals, selecting leaner cuts of meat and skimmed dairy products, reducing consumption of fried foods and other foods with added fats and oils, and drinking water instead of sugar-sweetened beverages. It is important that dietary counseling remain patient centered and that the goals set be practical, realistic, and achievable.


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InternalMed_Harrison. The macronutrient composition of the diet will vary with the patient’s preference and medical condition. The 2010 U.S. Department of Agriculture Dietary Guidelines for Americans (Chap. 95e), which focus on health promotion and risk reduction, can be applied to treatment of overweight or obese patients. The recommendations include maintaining a diet rich in whole grains, fruits, vegetables, and dietary fiber; consuming two servings (8 oz) of fish high in omega 3 fatty acids per week; decreasing sodium intake to <2300 mg/d; consuming 3 cups of milk (or equivalent low-fat or fat-free dairy products) per day; limiting cholesterol intake to <300 mg/d; and keeping total fat intake at 20–35% of daily calories and saturated fat intake at <10% of daily calories. Application of these guidelines to specific calorie goals can be found on the website www.choosemyplate.gov. The revised Dietary Reference Intakes for Macronutrients released by the Institute of Medicine recommends that 45–65% of


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InternalMed_Harrison. to specific calorie goals can be found on the website www.choosemyplate.gov. The revised Dietary Reference Intakes for Macronutrients released by the Institute of Medicine recommends that 45–65% of calories come from carbohydrates, 20–35% from fat, and 10–35% from protein. The guidelines also recommend daily fiber intake of 38 g (men) and 25 g (women) for persons over 50 years of age and 30 g (men) and 21 g (women) for those under age 50.


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InternalMed_Harrison. Since portion control is one of the most difficult strategies for patients to manage, the use of pre-prepared products such as meal replacements is a simple and convenient suggestion. Examples include frozen entrees, canned beverages, and bars. Use of meal replacements in the diet has been shown to result in a 7–8% weight loss.


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InternalMed_Harrison. Patient encounter Hx of ˜ 25 BMI? BMI measured in past 2 years? No • Measure weight, height and waist circumference • Calculate BMI BMI ˜ 25 OR waist circumference > 88 cm (F) >102 cm (M) Hx BMI ˜ 25? Brief reinforcement/ educate on weight management Advise to maintain weight, address other risk factors Assess risk factors BMI ˜ 30 OR {[BMI 26 to 29.9 OR waist circumference > 88 cm (F) >102 cm (M)] AND ˜ 2 risk factors} Does patient want to lose weight? Progress being made/goal achieved? Maintenance counseling: • Dietary therapy • Behavior therapy • Physical therapy Assess reasons for failure to lose weight Periodic weight check 4 5 6 Yes 7 Yes Yes No 8 9 12 11 10 No Yes 1315 14 No Yes 16 No No Clinician and patient devise goals and treatment strategy for weight loss and risk factor control


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InternalMed_Harrison. FIGURE 416-1 Algorithm for the treatment of obesity. This algorithm applies only to assessment for overweight and obesity and subsequent decisions based on that assessment. It does not reflect initial overall assessment for other conditions that the physician may wish to perform. BMI, body mass index; Hx, history. (From the National, Heart, Lung, and Blood Institute: Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: The evidence report. Washington, DC, US Department of Health and Human Services, 1998.) Evaluation and Management of Obesity


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InternalMed_Harrison. Evaluation and Management of Obesity Numerous randomized trials comparing diets of different macro-patient’s taste preferences, cooking style, and culture. However, the nutrient composition (e.g., low-carbohydrate, low-fat, Mediterranean) patient’s underlying medical problems are also important in guiding have shown that weight loss depends primarily on reduction of total the recommended dietary composition. The dietary prescription will caloric intake and adherence to the prescribed diet, not the spe-vary according to the patient’s metabolic profile and risk factors. A cific proportions of carbohydrate, fat, and protein in the diet. The consultation with a registered dietitian for medical nutrition therapy macronutrient composition will ultimately be determined by the is particularly useful in considering patient preference and treatment of comorbid diseases.


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InternalMed_Harrison. Another dietary approach to consider is based on the concept of energy density, which refers to the BMI Category (kg/m2) number of calories (i.e., amount of energy) a food Treatment 25–26.9 27–29.9 30–34.9 35–39.9 ≥40 contains per unit of weight. People tend to ingest a constant volume of food regardless of caloric or Diet, exercise, With With + + + behavioral therapy comorbidities comorbidities macronutrient content. Adding water or fiber to a food decreases its energy density by increasing weight without affecting caloric content. Examples of foods with low-energy density include soups, fruits, vegetables, oatmeal, and lean meats. Dry foods and high-fat foods such as pretzels, cheese, egg


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InternalMed_Harrison. Source: From the National Heart, Lung, and Blood Institute, North American Association for the Study of Obesity (2000). yolks, potato chips, and red meat have a high-energy 2396 density. Diets containing low-energy-dense foods have been shown to control hunger and thus to result in decreased caloric intake and weight loss. Occasionally, very low-calorie diets (VLCDs) are prescribed as a form of aggressive dietary therapy. The primary purpose of a VLCD is to promote a rapid and significant (13to 23-kg) short-term weight loss over a 3to 6-month period. The proprietary formulas designed for this purpose typically supply ≤800 kcal, 50–80 g of protein, and 100% of the recommended daily intake for vitamins and minerals. According to a review by the National Task Force on the Prevention and Treatment of Obesity, indications for initiating a VLCD include the involvement of well-motivated individuals who are moderately to severely obese (BMI, >30 kg/m2), have failed at more conservative


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InternalMed_Harrison. Treatment of Obesity, indications for initiating a VLCD include the involvement of well-motivated individuals who are moderately to severely obese (BMI, >30 kg/m2), have failed at more conservative approaches to weight loss, and have a medical condition that would be immediately improved with rapid weight loss. These conditions include poorly controlled type 2 diabetes, hypertriglyceridemia, obstructive sleep apnea, and symptomatic peripheral edema. The risk for gallstone formation increases exponentially at rates of weight loss >1.5 kg/week (3.3 lb/week). Prophylaxis against gallstone formation with ursodeoxycholic acid (600 mg/d) is effective in reducing this risk. Because of the need for close metabolic monitoring, VLCDs usually are prescribed by physicians specializing in obesity care.


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InternalMed_Harrison. Physical Activity Therapy Although exercise alone is only moderately effective for weight loss, the combination of dietary modification and exercise is the most effective behavioral approach for the treatment of obesity. The most important role of exercise appears to be in the maintenance of the weight loss. The 2008 Physical Activity Guidelines for Americans (www.health.gov/paguidelines) recommend that adults should engage in 150 min of moderate-intensity or 75 min a week of vigorous-intensity aerobic physical activity per week, performed in episodes of at least 10 min and preferably spread throughout the week. Focusing on simple ways to add physical activity into the normal daily routine through leisure activities, travel, and domestic work should be suggested. Examples include walking, using the stairs, doing housework and yard work, and engaging in sports. Asking the patient to wear a pedometer or accelerometer to monitor total accumulation of steps or kcal expended as part of the


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InternalMed_Harrison. using the stairs, doing housework and yard work, and engaging in sports. Asking the patient to wear a pedometer or accelerometer to monitor total accumulation of steps or kcal expended as part of the activities of daily living is a useful strategy. Step counts are highly correlated with activity level. Studies have demonstrated that lifestyle activities are as effective as structured exercise programs for improving cardiorespiratory fitness and weight loss. A high level of physical activity (>300 min of moderate-intensity activity per week) is often needed to lose weight and sustain weight loss. These exercise recommendations are daunting to most patients and need to be implemented gradually. Consultation with an exercise physiologist or personal trainer may be helpful.


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InternalMed_Harrison. Behavioral Therapy Cognitive behavioral therapy is used to help change and reinforce new dietary and physical activity behaviors. Strategies include self-monitoring techniques (e.g., journaling, weighing, and measuring food and activity); stress management; stimulus control (e.g., using smaller plates, not eating in front of the television or in the car); social support; problem solving; and cognitive restructuring to help patients develop more positive and realistic thoughts about themselves. When recommending any behavioral lifestyle change, the patient should be asked to identify what, when, where, and how the behavioral change will be performed. The patient should keep a record of the anticipated behavioral change so that progress can be reviewed at the next office visit. Because these techniques are time-consuming to implement, their supervision is often undertaken by ancillary office staff, such as a nurse-clinician or registered dietitian.


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InternalMed_Harrison. Adjuvant pharmacologic treatments should be considered for patients with a BMI ≥30 kg/m2 or—for patients who have concomitant obesity-related diseases and for whom dietary and physical activity therapy has not been successful—a BMI ≥27 kg/m2. When an antiobesity medication is prescribed, patients should be actively engaged in a lifestyle program that provides the strategies and skills needed to use the drug effectively, since such support increases total weight loss.


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InternalMed_Harrison. Medications for obesity have traditionally fallen into two major categories: appetite suppressants (anorexiants) and gastrointestinal fat blockers. Appetite-suppressing medications have primarily targeted three monoamine receptor systems in the hypothalamus: noradrenergic, dopaminergic, and serotonergic receptors. Two new appetite suppressants were approved by the U.S. Food and Drug Administration (FDA) in 2012: lorcaserin and phentermine/topiramate (PHEN/TPM) extended release. Gastrointestinal fat blockers reduce the absorption of selective macronutrients, such as fat, from the gastrointestinal tract.


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InternalMed_Harrison. Centrally Acting Anorexiant Medications Anorexiants affect satiety (the absence of hunger after eating) and hunger (the biologic sensation that prompts eating). By increasing satiety and decreasing hunger, these agents help patients reduce caloric intake without a sense of deprivation. The target site for the actions of anorexiants is the ventromedial and lateral hypothalamic regions in the central nervous system (Chap. 415e). The biologic effect of these agents on appetite regulation is produced by augmentation of the neurotransmission of three monoamines: norepinephrine; serotonin (5-hydroxytryptamine, or 5-HT); and, to a lesser degree, dopamine. The classic sympathomimetic adrenergic agents (benzphetamine, phendimetrazine, diethylpropion, mazindol, and phentermine) function by stimulating norepinephrine release or by blocking its reuptake. Among the anorexiants, phentermine has been the most commonly prescribed; there is limited long-term data on its effectiveness. A 2002 review of


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InternalMed_Harrison. norepinephrine release or by blocking its reuptake. Among the anorexiants, phentermine has been the most commonly prescribed; there is limited long-term data on its effectiveness. A 2002 review of six randomized, placebo-controlled trials of phentermine for weight control found that patients lost 0.6–6.0 additional kilograms of weight over 2–24 weeks of treatment. The most common side effects of the amphetamine-derived anorexiants are restlessness, insomnia, dry mouth, constipation, and increased blood pressure and heart rate.


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InternalMed_Harrison. PHEN/TPM is a combination drug that contains a catecholamine releaser (phentermine) and an anticonvulsant (topiramate). Topiramate is approved by the FDA as an anticonvulsant for the treatment of epilepsy and for the prophylaxis of migraine headaches. Weight loss was identified as an unintended side effect of topiramate during clinical trials for epilepsy. The mechanism responsible for weight loss is uncertain but is thought to be mediated through the drug’s modulation of γ-aminobutyric acid receptors, inhibition of carbonic anhydrase, and antagonism of glutamate. PHEN/TPM has undergone two 1-year pivotal randomized, placebo-controlled, double-blind trials of efficacy and safety: EQUIP and CONQUER. In a third study, SEQUEL, 78% of CONQUER participants continued to receive their blinded treatment for an additional year. All participants received diet and exercise counseling. Participant numbers, eligibility, characteristics, and weight loss outcomes are displayed in Table 416-6.


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InternalMed_Harrison. treatment for an additional year. All participants received diet and exercise counseling. Participant numbers, eligibility, characteristics, and weight loss outcomes are displayed in Table 416-6. Intention-to-treat 1-year placebo-subtracted weight loss for the PHEN/TPM 15-mg/92-mg dose was 9.3% and 8.6%, respectively, in the EQUIP and CONQUER trials. Clinical and statistical dose-dependent improvements were seen in selected cardiovascular and metabolic outcome measurements that were related to the weight loss. The most common adverse events experienced by the drug-randomized group were paresthesias, dry mouth, constipation, dysgeusia, and insomnia. Because of an increased risk of congenital fetal oral-cleft formation from topiramate, the FDA approval of PHEN/TPM stipulated a Risk Evaluation and Mitigation Strategies requirement to educate prescribers about the need for active birth control among women of childbearing age and a contraindication for use during pregnancy.


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InternalMed_Harrison. Lorcaserin is a selective 5-HT2C receptor agonist with a functional selectivity ~15 times that of 5-HT2A receptors and 100 times that of 5-HT2B receptors. This selectivity is important, since the drug-induced valvulopathy documented with two other serotonergic agents that were removed from the market—fenfluramine No. of participants (ITT-LOCF) 3182 4008 1230 2448 Age (years) 18–65 18–65 ≥35 27–45 BMI (kg/m2) 27–45 27–45 18–70 18–70 Comorbid conditions (cardio-≥1 ≥1 ≥1 ≥2


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InternalMed_Harrison. No. of participants (ITT-LOCF) 3182 4008 1230 2448 Age (years) 18–65 18–65 ≥35 27–45 BMI (kg/m2) 27–45 27–45 18–70 18–70 Comorbid conditions (cardio-≥1 ≥1 ≥1 ≥2 Mean weight loss (%) with 5.8 vs. 2.2 4.8 vs. 2.8 11 vs. 1.6 10.4 vs. 1.8 treatment vs. placebo Placebo-subtracted weight 3.6 3.0 9.3 8.6 loss (%) Categorical change in 5% 47.5 vs. 20.3 47.2 vs. 25 67 vs. 17 70 vs. 21 weight loss with treatment vs. placebo Completion rate (%) Lorcaserin, 55.4; placebo, 45.1 55.5 59.9 62 aTable shows a comparison of two 1-year prospective, randomized, double-blind trials of lorcaserin (BLOOM and BLOSSOM) and phentermine-topiramate extended release (EQUIP and CONQUER). bLorcaserin dose: 10 mg bid. cLorcaserin dose: 10 mg bid or qd. dPhentermine-topiramate extended release dose: 15 mg/92 mg. Abbreviations: BMI, body mass index (see Table 416-1); ITT-LOCF, intention to treat, last observation carried forward; PHEN/TPM, phentermine-topiramate extended release.


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InternalMed_Harrison. Abbreviations: BMI, body mass index (see Table 416-1); ITT-LOCF, intention to treat, last observation carried forward; PHEN/TPM, phentermine-topiramate extended release. and dexfenfluramine—was due to activation of the 5-HT2B receptors expressed on cardiac valvular interstitial cells. By activating the 5-HT2C receptor, lorcaserin is thought to decrease food intake through the pro-opiomelanocortin system of neurons.


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InternalMed_Harrison. Lorcaserin has undergone two randomized, placebo-controlled, double-blind trials for efficacy and safety. Participants were randomized to receive lorcaserin (10 mg bid) or placebo in the BLOOM study and to receive lorcaserin (10 mg bid or qd) or placebo in the BLOSSOM study. All participants received diet and exercise counseling. Participant numbers, eligibility, characteristics, and weight loss outcomes are displayed in Table 416-6. Overweight or obese subjects had at least one coexisting condition (hypertension, dyslipidemia, cardiovascular disease, impaired glucose tolerance, or sleep apnea)—medical conditions that are commonly seen in the office setting. Intention-to-treat 1-year placebo-subtracted weight loss was 3.6% and 3.0%, respectively, in the BLOOM and BLOSSOM trials. Echocardiography was performed at the screening visit and at scheduled time points over the course of the studies. There was no difference in the development of FDA-defined valvulopathy between drug-treated


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InternalMed_Harrison. was performed at the screening visit and at scheduled time points over the course of the studies. There was no difference in the development of FDA-defined valvulopathy between drug-treated and placebo-treated participants at 1 year or 2 years. Modest statistical improvements consistent with the weight loss were seen in selected cardiovascular and metabolic outcome measurements. The most common adverse events experienced by the drug group were headache, dizziness, and nausea.


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InternalMed_Harrison. In approving both PHEN/TPM and lorcaserin, the FDA introduced a new provision with important clinical relevance: a prescription trial period to assess effectiveness. Response to both medications should be assessed after 3 months of treatment. For lorcaserin, the medication should be discontinued if the patient has not lost at least 5% of body weight by that point. For PHEN/TPM, if the patient has not lost at least 3% of body weight at 3 months, the clinician can either escalate the dose and reassess progress at 6 months or discontinue treatment entirely.


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InternalMed_Harrison. Peripherally Acting Medications Orlistat (XenicalTM) is a synthetic hydrogenated derivative of a naturally occurring lipase inhibitor, lipostatin, that is produced by the mold Streptomyces toxytricini. This drug is a potent, slowly reversible inhibitor of pancreatic, gastric, and carboxylester lipases and phospholipase A2, which are required for the hydrolysis of dietary fat into fatty acids and monoacylglycerols. Orlistat acts in the lumen of the stomach and small intestine by forming a covalent bond with the active site of these lipases. Taken at a therapeutic dose of 120 mg tid, orlistat blocks the digestion and absorption of ~30% of dietary fat. After discontinuation of the drug, fecal fat content usually returns to normal within 48–72 h.


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InternalMed_Harrison. Multiple randomized, double-blind, placebo-controlled studies have shown that, after 1 year, orlistat produces a weight loss of ~9–10%, whereas placebo recipients have a 4–6% weight loss. Because orlistat is minimally (<1%) absorbed from the gastrointestinal tract, it has no systemic side effects. The drug’s tolerability is related to the malabsorption of dietary fat and the subsequent passage of fat in the feces. Adverse gastrointestinal effects, including flatus with discharge, fecal urgency, fatty/oily stool, and increased defecation, are reported in at least 10% of orlistat-treated patients. These side effects generally are experienced early, diminish as patients control their dietary fat intake, and only infrequently cause patients to withdraw from clinical trials. When taken concomitantly, psyllium mucilloid is helpful in controlling orlistat-induced gastrointestinal side effects. Because serum concentrations of the fat-soluble vitamins D and E and β-carotene may be reduced by


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InternalMed_Harrison. psyllium mucilloid is helpful in controlling orlistat-induced gastrointestinal side effects. Because serum concentrations of the fat-soluble vitamins D and E and β-carotene may be reduced by orlistat treatment, vitamin supplements are recommended to prevent potential deficiencies. Orlistat was approved for over-the-counter use in 2007.


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InternalMed_Harrison. Antiobesity Drugs in Development Two additional medications are currently in development. Bupropion and naltrexone (ContraveTM)—a dopamine and norepinephrine reuptake inhibitor and an opioid receptor antagonist, respectively—are theoretically combined to dampen the motivation/reinforcement that food brings (dopamine effect) and the pleasure/palatability of eating (opioid effect). In the COR-1 randomized, double-blind, placebo-controlled trial, 1742 enrolled participants, who were 18–65 years of age and had BMIs of 30–45 kg/m2, were randomized to receive naltrexone (16 mg/d) plus bupropion (360 mg/d), naltrexone (32 mg/d) plus bupropion (360 mg/d), or placebo. Mean change in body weight for the three groups was 5.0%, 6.1%, and 1.3%, respectively. The most common adverse events were nausea, headache, constipation, dizziness, vomiting, and dry mouth. However, the FDA rejected the drug in 2011 because of cardiovascular concerns and concluded that a large-scale study of the long-term