Megan McNamara, MD, MSc
Judith Walsh, MD, MPH
The field of women’s health encompasses more than the reproductive health issues commonly addressed by obstetricians and gynecologists; it evaluates diseases and conditions only seen or experienced in women or experienced by women in ways different than men, as well as the evidence-based prevention and treatment of risk factors and diseases in women. Hence, all primary care providers, including internists and family physicians, should be well versed in women’s health issues. While this chapter refers to other disease-based chapters in the textbook, it also emphasizes the understanding of issues from the particular perspective of women.
PREVENTIVE HEALTH CARE
Prevention of disease can be primary (preventing disease before it happens as well as identifying and modifying risk factors), secondary (identifying early disease), or tertiary (treating complications of the disease or limiting the impact of established disease). Important areas for primary prevention include encouraging women to exercise regularly to reduce the risk of coronary heart disease (CHD) and breast cancer as well as counseling women to discontinue smoking to reduce the risk of cardiac and lung diseases. Cancer screening in women focuses on secondary prevention, so that disease is detected early when prompt treatment improves outcome.
CARDIOVASCULAR DISEASE PREVENTION
Although cardiovascular disease is the leading cause of death in women, they are often more concerned about developing breast cancer (see below) than about developing heart disease. While some heart disease risk factors such as age and family history are not modifiable, as with men, other risk factors such as hypertension, hyperlipidemia, smoking, obesity, and diabetes are potentially modifiable (see alsoChapter 1). The Framingham risk calculator (http://hp2010.nhlbihin.net/atpiii/calculator.asp?usertype=prof) can be used to estimate a woman’s 10-year risk of CHD based on her age, smoking status, blood pressure, and cholesterol levels.
Modifiable Risk Factors
Hypertension is a risk factor for CHD and stroke in both men and women (see Chapter 1). Approximately 70–80% of women over age 70 have hypertension. A woman with high blood pressure is at lower risk for CHD than a similar aged man. For many young and otherwise healthy women, medication treatment can be deferred, since their absolute risk of CHD in the next 10 years is likely to be low. When pharmacotherapy is started, the choice of medication is similar to those used in men (see Chapter 11).
Hyperlipidemia is a CHD risk factor in both men and women, but low levels of high-density lipoprotein (HDL) are more predictive of CHD risk in women. The US Preventive Services Task Force (USPSTF) recommends screening all women aged 45 and older for hyperlipidemia, whereas the National Cholesterol Education Program (NCEP) recommends screening all individuals aged 20 and over. Before screening a woman for hyperlipidemia, an important consideration is whether or not treatment recommendations will change based on the results. Since therapeutic lifestyle changes are recommended for all women, the question is at what point pharmacotherapy should be considered.
There is clear evidence that medication treatment of hyperlipidemia reduces CHD events in women who already have CHD, but when lipid-lowering medications are used in women who do not already have CHD, the evidence of benefit is less clear (see also Chapter 28). Decisions about when to initiate medication treatment should include an assessment of an individual’s absolute risk of CHD in the next 10 years. Medication treatment should be targeted toward women with CHD and high-risk women who are most likely to benefit. The NCEP recommends different thresholds at which to initiate medication therapy based on individual CHD risk. For example, for a woman with known CHD, lipid-lowering medication is initiated at a low-density lipoprotein (LDL) cholesterol of > 130 mg/dL, whereas for a woman with 0–1 risk factor, medication therapy is not initiated until the LDL cholesterol measures > 190 mg/dL.
Diabetes is a CHD risk factor in both men and women. Studies have reached conflicting conclusions about the effect of tight control of diabetes on CHD outcomes in both men and women, although lipid lowering is clearly associated with a reduction in CHD events in diabetic women. All women should focus on primary prevention of diabetes with avoidance of obesity and maintenance of regular exercise. Women with diabetes also should focus on treatment of hypertension given the impact on CHD events (see Chapter 27).
Obesity has been established as an independent risk factor for CHD in women. It is not known whether or not weight loss will decrease CHD risk. Since most obese women who lose weight gain it back, the overall goal should be ongoing avoidance of weight gain above normal weight (see Chapters 1 and 29).
The use of high-sensitivity C-reactive protein (hsCRP) has increased in recent years. CRP is an inflammatory biomarker that has been shown to predict cardiovascular events. However, there is currently no evidence that screening for hsCRP improves cardiac outcomes. It has been suggested that measuring hsCRP may be useful in women for whom it would change treatment outcomes, but there is currently no evidence to support this. The USPSTF has published guidelines outlining the use of nontraditional risk factors in the evaluation of CHD. The risk factors included in the recommendation were hsCRP, ankle-brachial index, leukocyte count, fasting blood glucose, periodontal disease, carotid intima media thickness, coronary artery calcification score, electron beam CT, homocysteine, and lipoprotein (a). The USPSTF concluded that there is insufficient evidence to balance the benefits and harms of screening asymptomatic men and women with no history of CHD to predict CHD events and did not recommend routine screening.
Therapeutic Options for Reducing Risk Factors
Aspirin is clearly useful for secondary prevention of CHD in women. Among women who do not have CHD, aspirin reduces the risk of stroke, whereas in men, it reduces the risk of CHD. Before starting an aspirin regimen to reduce the risk of the stroke, women should be assessed for their risk of gastrointestinal bleeding, which is the most common adverse side effect of aspirin use. The USPSTF recommends aspirin in women aged 55–79 years when the potential benefit of a reduction in ischemic strokes outweighs the potential harms of a gastrointestinal hemorrhage. For healthy or at-risk women, 81 mg/d or 100 mg every other day is the suggested dose. For high-risk women, a dose of 75–325 mg/d is recommended.
Exercise has been associated with a reduction in all causes of cardiovascular mortality. Women often want to know how much exercise is necessary for health benefits. Studies have shown that walking 2.5–3 hours a week is associated with a reduction in cardiovascular disease. The Centers for Disease Control and Prevention and the American College of Sports Medicine recommend that all women accumulate at least 30 minutes a day of moderate intensity physical activity on most if not all days of the week. The Institute of Medicine recommends an hour a day for the goal of maintaining health and ideal body weight. See also Chapter 1.
Gutierrez J et al. Statin therapy in the prevention of recurrent cardiovascular events: a sex-based meta-analysis. Arch Intern Med. 2012 June 25;172(12):909–19. [PMID: 22732744]
Mosca L et al. Effectiveness-based guidelines for the prevention of cardiovascular disease in women—2011 update: a guideline from the American Heart Association. Circulation. 2011 Mar 22;123(11):1243–62. [PMID: 21325087]
U.S. Preventive Services Task Force. Screening for Lipid Disorders in Adults: U.S. Preventive Services Task Force recommendation statement.http://www.uspreventiveservicestaskforce.org/uspstf08/lipid/lipidrs.htm
Risk Factors & Risk Assessment
Breast cancer is the most commonly detected cancer in women and the second leading cause of cancer death (see also Chapter 17). Breast cancer risk is increased with age and with a family history of breast cancer. Women who drink more than two alcoholic drinks per day are at increased risk for breast cancer, and exercise is associated with a decreased risk of breast cancer. Dietary intake has not been conclusively associated with breast cancer risk. Breast density is an emerging risk factor for breast cancer; women with denser breasts as measured with mammography are at increased breast cancer risk. Although some states now mandate that women with increased breast density on mammography be notified, it is not currently known what women can do to decrease this risk.
Various models have been used to predict a woman’s risk for breast cancer. The National Cancer Institute has developed the Breast Cancer Risk Assessment Tool (http://www.cancer.gov/bcrisktool/), which is based on the Gail Model, and calculates the woman’s risk of developing breast cancer in the next 5 years by considering the following factors: (1) the woman’s age, (2) age at which she had her first menstrual period, (3) age at delivery of first live child, (3) number of first-degree relatives with breast cancer, (4) history of any breast biopsies, and (5) history of atypical hyperplasia. The model has been validated in white women and has been evaluated in black women and found to be relatively accurate, although it may underestimate the risk in black women with a history of previous breast biopsies. It has yet to be validated in women of other ethnicities.
In addition to lifestyle modifications, such as exercise and moderation of alcohol intake, chemoprevention of breast cancer is an option for some women. The selective estrogen receptor modifiers (SERMS) tamoxifen and raloxifene have both been shown to reduce invasive breast cancer in high-risk women. However, there are risks associated with SERM treatment. Tamoxifen is associated with an increased risk of endometrial cancer and deep venous thrombosis (DVT). Although raloxifene is not associated with an increased risk of endometrial cancer, the risk of DVT remains. Aromatase inhibitors, such as exemestane, show promise for breast cancer prevention but are not currently FDA approved for this indication. The USPSTF recommends that clinicians discuss chemoprevention with women at high risk for breast cancer and at low risk for the adverse effects of chemoprevention. Clinicians should inform patients of the potential benefits and harms of chemoprevention. Breast cancer risk increases with age, but the risk of adverse effects does as well. Since the clinical trials of tamoxifen and raloxifene for breast cancer prevention used a 1.66% 5-year risk, this risk level is often used as a guide for medication treatment.
Breast Cancer Screening
Traditional breast cancer screening modalities include screening mammography, clinical breast examination, and breast self-examination (see also Chapter 17). Teaching women to do routine breast self-examination has not been shown to reduce breast cancer mortality. The USPSTF recommends against teaching women to do breast self-examination. The American Cancer Society states that it is acceptable not to do it, but that if women are performing breast self-examination, it is important to ensure that they are doing it correctly. The combination of breast examination done by a clinician and mammography is associated with a decrease in breast cancer mortality, but there is insufficient evidence to recommend clinical breast examination alone.
Mammography reduces breast cancer mortality in women aged 50–74 years and routine mammographic screening is recommended for women in this age group. For women aged 40–49 years, screening has been more controversial. Guidelines published by the USPSTF recommend that clinicians not routinely order mammography among 40- to 49-year-old women but rather that they individualize the decision to begin screening, since the number needed to invite to screen to prevent one breast cancer death is much higher in younger women and the number of false-positive and false-negative test results are much higher. Since women over age 75 have not been included in clinical trials and since the likelihood of comorbid diseases limiting life expectancy increases, routine screening of women in this age group is not recommended, but rather the decision making should be individualized.
Hubbard et al. Cumulative probability of false-positive recall or biopsy recommendation after 10 years of screening mammography: a cohort study. Ann Intern Med. 2011 Oct 18;155(8):481–92. [PMID: 22007042]
Nelson HD et al. Risk factors for breast cancer for women aged 40 to 49 years: a systematic review and meta-analysis. Ann Intern Med. 2012 May 1;156(9):635–48. [PMID: 22547473]
Colorectal cancer is the third leading cause of cancer death in both men and women. In 2013 an estimated 9% of cancer deaths in women were caused by colorectal cancer. Since the risk of colorectal cancer increases with age, all women should be screened for colorectal cancer starting at the age of 50. The USPSTF recommends routine screening in men and women age 50–75, individualized decision making about screening in individuals aged 76–85, and no screening after the age of 85. Details of the screening options and suggested screening intervals are described in Chapter 1.
U.S. Preventive Services Task Force. Screening for Colorectal Cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2008 Nov 4;149(9):627–37. [PMID: 18838716]
In contrast to most other cancers for which routine screening is recommended, the incidence of cervical cancer is higher in younger women and decreases with age. The major risk factor for cervical cancer is exposure to the human papillomavirus (HPV). Primary prevention of cervical cancer includes avoidance of smoking, postponing sexual debut, and limiting the number of sexual partners. Condom use may also be protective.
A quadrivalent HPV vaccine that includes capsid proteins against four HPV types (6, 11, 16, and 18) has been approved for use in girls and women aged 9–26 years to prevent disease associated with these HPV types (see also Chapter 18). A bivalent vaccine (Cervarix) is also available. The Advisory Committee on Immunization Practices (ACIP) recommends routine vaccination for girls aged 11 or 12 up to age 26, whereas the American Cancer Society recommends the vaccine for girls aged 11–18 but states that there is insufficient evidence to recommend for or against routine vaccination for women aged 19–26. Unanswered questions about the vaccine include the long-term effects and the length of protection. Receipt of vaccine should not change cervical cancer screening intervals in women.
An important focus of cervical cancer prevention is screening using the Papanicolaou smear. Cervical cancer screening is the biggest success in the history of cancer screening. Cervical cancer mortality has been reduced by about 70% with routine cervical cancer screening. One of the reasons that screening has been so successful is that there is a long preclinical phase where early changes can be detected and treated so as to avoid the development of cancer. The USPSTF updated their screening recommendations in 2012 (see Chapter 18).
U.S. Preventive Services Task Force. Screening for cervical cancer: U.S. Preventive Services Task Force recommendation statement.http://www.uspreventiveservicestaskforce.org/uspstf11/cervcancer/cervcancerrs.htm
Although lung cancer is not typically considered a “women’s cancer,” it is the leading cause of cancer mortality in both men and women. Primary prevention of lung cancer should be a high priority with encouragement of tobacco cessation among women who smoke (see Chapters 1 and 39). Consistent with a 2012 joint recommendation from the American Academy of Chest Physicians and the American Society of Clinical Oncology in December 2013, the USPSTF updated its screening recommendation based on NLST data recommending “annual screening for lung cancer with low-dose computed tomography in adults ages 55 to 80 years who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years.”
Humphrey LL et al. Screening for lung cancer with low-dose computed tomography: a systematic review to update the U.S. Preventive services task force recommendation. Ann Intern Med. 2013 Sep 17;159(6):411–20. [PMID: 23897166]
National Lung Screening Trial Research Team; Aberle DR et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011 Aug 4;365(5):395–409. [PMID: 21714641]
Ovarian cancer is a relatively rare but dreaded cancer, with a lifetime incidence of about 1.2% in women with no family history of ovarian cancer. Because it is often detected late, treatment options may be limited.
Many of the risk factors for ovarian cancer such as age and family history are not modifiable, but there are protective factors, including having more than one full-term pregnancy, breast-feeding, and oral contraceptive use. Women at high-risk for ovarian cancer should consider the use of oral contraceptives for as long as it is feasible.
Although screening for ovarian cancer with either the serum marker CA-125 or with transvaginal ultrasound is theoretically appealing, the rarity of the disease limits their use and leads to many false-positive test results (see also Chapter 18). The USPSTF does not recommend screening for ovarian cancer.
Buys SS et al. Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial. JAMA. 2011 Jun 8;305(22):2295–303. [PMID: 21642681]
Osteoporotic fractures are increasing as the population ages. Age and female sex are major risk factors for osteoporotic fractures. Hip and vertebral fractures are associated with premature mortality. Osteoporosis risk can be assessed by measuring bone mineral density (BMD). See also Chapter 26.
The World Health Organization has developed a fracture risk assessment tool (FRAX, available at http://www.shef.ac.uk/FRAX/index.jsp) that can predict a woman’s 10-year risk of having any osteoporotic fracture and the 10-year risk of hip fracture. Risk factors used in the FRAX tool include age, gender, personal history of fracture, parental history of hip fracture, low body mass index, use of oral corticosteroids, secondary osteoporosis, current smoking, and alcohol intake of three or more drinks per day. It can be used with or without BMD. The FRAX tool is particularly helpful in determining which women with osteopenia are most likely to benefit from treatment. Based on the World Health Organization algorithm adopted for the United States, treatment is recommended when there is a 10-year risk of hip fracture ≥ 3% or a 10-year risk of a major osteoporotic fracture ≥ 20%.
Although calcium supplementation is routinely recommended, evidence from the Women’s Health Initiative showed that calcium supplementation did not reduce fracture risk in healthy postmenopausal women and other research has highlighted potential risks of calcium supplementation. Calcium appears to be necessary but not sufficient for fracture prevention. The USPSTF recommendations state that the evidence is insufficient to assess the balance of benefits and harms for the combination of vitamin D and calcium for primary prevention of fractures in men or premenopausal women. Recommended calcium intake for women younger than 50 years is 1000 mg/d and for women aged 51 and over, it is 1200 mg/d. Dietary calcium may be safer than calcium supplements, but calcium supplements can be given as either calcium citrate or calcium carbonate and should be given with vitamin D. Regular weight bearing exercise has also been associated with an increase in bone density although the effect is lost when the exercise is not continued.
Increasing evidence suggests that vitamin D supplementation is associated with a reduction in fracture risk. Vitamin D can be given as either D2 or D3 formulations. Recommendations are that women aged 70 and younger should consume 600 international units of vitamin D per day, whereas women aged 71 and older should consume 800 international units per day. Individuals with vitamin D deficiency (25-OH vitamin D < 20 mg/mL) may require higher doses, although most recommendations for vitamin D supplementation are based on achieving a serum 25-OH vitamin D concentration of a particular level, rather than on a clinical outcome. Whether or not women should be routinely screened for vitamin D deficiency remains an ongoing question. However, given the association of vitamin D and fractures, checking a 25-OH vitamin D level in women with osteopenia or osteoporosis is reasonable.
Bone Mineral Density Screening
The biggest risk factor for developing osteoporosis is increasing age. Although many women expect to be screened around the time of menopause, routine BMD screening is not recommended until the age of 65. The National Osteoporosis Foundation recommends screening all women age 65 and older and screening younger postmenopausal women if there is a concern based on their risk-factor profile. The USPSTF recommends screening women aged 65 and older and only screening younger women whose fracture risk is equal to or greater than that of a 65-year-old white woman who has no additional risk factors. The Fracture Risk Assessment tool (FRAX) tool can be used to calculate 10-year risk of osteoporotic fracture. Most guidelines do not specifically address how often a woman should undergo BMD testing. However, decisions about when to rescreen should probably be based on the results of initial screening. Women with normal BMD or mild osteopenia at baseline can be screened less often than women who are near the threshold for osteoporosis.
Treatment is generally recommended in women who have a t score < –2.5, who have already had a fracture or who have a t score in the osteopenic range but are at high risk for fracture. Treatment options for osteoporosis are described in Chapter 26.
Gourlay ML et al; Study of Osteoporotic Fractures Research Group. Bone-density testing interval and transition to osteoporosis in older women. N Engl J Med. 2012 Jan 19;366(3):225–33. [PMID: 22256806]
Institute of Medicine (IOM). Dietary reference intakes for calcium and vitamin D. http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D.aspx
Li K et al. Associations of dietary calcium intake and calcium supplementation with myocardial infarction and stroke risk and overall cardiovascular mortality in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition study (EPIC-Heidelberg). Heart. 2012 Jun;98(12):920–5. [PMID: 22626900]
U.S. Preventive Services Task Force. Screening for osteoporosis: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2011 Mar 1;154(5):356–64. [PMID: 21242341]
U.S. Preventive Services Task Force. Vitamin D and calcium supplementation to prevent cancer and osteoporotic fractures. http://www.uspreventiveservicestaskforce.org/uspstf/uspsvitd.htm
World Health Organization Collaborating Centre for Metabolic Bone Diseases. Fracture Risk Assessment Tool (FRAX). http://www.shef.ac.uk/FRAX/tool.jsp
PREVENTION OF SEXUALLY TRANSMITTED INFECTIONS
Many sexually transmitted infections are asymptomatic in women and some can lead to significant consequences. Primary prevention of sexually transmitted infections includes postponing sexual debut, limiting number of sexual partners, and regular condom use.
The USPSTF and the Centers for Disease Control and Prevention recommend annual screening for Chlamydia trachomatis and gonorrhea in sexually active women age 25 and younger (see Chapter 30). Screening should continue in women over age 25 and in women who have high-risk sexual behaviors. The USPSTF recommends screening all women for HIV: including adolescents and women of age 15-65 years, others at high risk, as well as pregnant women. All patients who have a sexually transmitted infection or who seek testing for a sexually transmitted infection should be offered HIV testing. The CDC currently recommends screening all women born between 1945 and 1965 for hepatitis C infection.
Since depression is approximately two times more common in women than in men, clinicians should be alert to symptoms suggesting depression in women. Symptoms include depressed mood, loss of interest in activities, sleep disturbance, change in appetite or weight, psychomotor retardation, difficulty concentrating, feelings of worthlessness, and thoughts of suicide (see also Chapter 25). Low energy or fatigue is a particularly common symptom in women.
There are several clinical surveys for depression screening. The two question screen appears to be effective. Patients are asked “Over the past 2 weeks, have you felt down, depressed or hopeless?” and “Over the past 2 weeks, have you felt little interest or pleasure in doing things?” There is no evidence to suggest that any particular screening tool is superior. A positive screening test should lead to more extensive evaluation.
The USPSTF recommends screening for depression if staff-assisted depression care supports are in place to ensure accurate diagnosis, effective treatment, and follow-up. If these supports are not in place, screening is not recommended.
U.S. Preventive Services Task Force. Screening for Depression in Adults. http://www.uspreventiveservicestaskforce.org/uspstf/uspsaddepr.htm
SPECIFIC ISSUES & CONDITIONS
INTIMATE PARTNER VIOLENCE
Intimate partner violence (IPV) is a pattern of abusive behavior by a person who is in some type of intimate relationship with the victim. The abuse can be physical, sexual, or emotional and can include economic deprivation. Although anyone can be a victim of IPV, women are much more likely than men to be victims. Regardless of the type of abuse, the goal of the abuser is to gain control over the victim. IPV is common but is often not diagnosed, in part because patients try to hide the abuse.
The prevalence estimate of IPV varies depending on the setting. Rates are higher when measured in emergency departments than when measured in the general population. In a randomized controlled trial of IPV screening in emergency departments, the prevalence over 12 months ranged from 4% to 18%.
Risk factors for abuse include being young (under age 35 years); being pregnant; being single, divorced, or separated; alcohol or drug abuse in the victim or the partner; smoking; and being poor.
Since patients often do not volunteer that they have been abused, clinicians must be alert to clues that suggest abuse, including an explanation of the injuries that do not fit with what is being seen; frequent visits to the emergency department; and somatic complaint such as chronic headache, abdominal pain, and fatigue. The patient may be vague about some of her symptoms and may avoid eye contact. If the abusing partner is present, he or she may answer all the questions or may decline to leave the room. It is critical that the patient have the opportunity to speak with the clinician alone. The patient’s description of the events should be carefully detailed in case there are any subsequent legal issues.
Physical examination often reveals injuries in the central area of the body. There may be injuries on the forearms as well if the patient tried to defend herself. As with any situation of expected abuse, bruises that are in various stages of healing may be an important clue. All physical examination findings should be well documented.
In addition to the physical consequences, abuse can have psychological consequences. Posttraumatic stress disorder, depression, anxiety, and alcohol or other substance abuse can develop in victims. Somatization is also very common among victims.
Several instruments have been developed to screen for IPV. These include the HITS (Hurt, Insult, Threaten, Screamed at) tool, the Women Abuse Screening tool (WAST), the Partner Violence Screen (PVS), the Abuse Assessment Screen (AAS), and the Women’s Experience with Battering (WEB) scale. A systematic review of these screening tools showed that most tools only had been evaluated in a relatively small number of studies and the sensitivities and specificities varied widely within and between the tools.
Inclusion of one question in the context of the medical history, “Have you ever been hit, kicked, punched or otherwise hurt by someone within the past year? If so, by whom?” has been shown to increase identification of IPV.
Many studies have addressed how the questions about IPV are asked. In one randomized trial, women preferred written questionnaires over face to face interviewing.
Screening for IPV (in contrast to asking questions when IPV is suspected) has been advocated by many experts, although there has been controversy about whether or not it improves outcomes. In January 2013, the USPSTF updated its previous guidelines and currently recommends that clinicians screen women of childbearing age for IPV including domestic violence, and provide or refer women who screen positive to intervention services.
Interventions for IPV
Interventions can include encouraging the woman to leave the abusive situation, ensuring that she has a safe place to go, and counseling so that she can adequately assess her risk of danger and create a plan for safety. There is no evidence that treatment of the abuser changes abuser behavior.
When to Refer
Moyer VA. Screening for intimate partner violence and abuse of elderly and vulnerable adults: U.S. preventive services task force recommendation statement. Ann Intern Med. 2013 Mar 19;158(6):478–86. [PMID: 23338828]
Nelson HD et al. Screening women for intimate partner violence and elderly and vulnerable adults for abuse: systematic review to update the 2004 U.S. Preventive Services Task Force Recommendation. Evidence synthesis No. 92. AHRQ Publication No. 12-05167-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; May 2012. [PMID: 22675737]
Eating disorders are common in women. Anorexia nervosa and bulimia nervosa are described in detail in Chapter 29. The female athlete triad, disordered eating in diabetics, and binge eating disorders are other eating disorders that should be considered in appropriate women.
ESSENTIALS OF DIAGNOSIS
Female athletes who participate in sports and activities valuing thinness are at increased risk for developing the female athlete triad. The definition of the triad includes disordered eating (a spectrum of abnormal patterns of eating, including bingeing; purging; food restriction; prolonged fasting; and the use of diet pills, diuretics, or laxatives), menstrual disorders, and low BMD. Half of all athletes with amenorrhea have bone density at least 1.0 standard deviation below the mean. The bone density is decreased even in those areas subjected to stress during exercise. The diagnosis is made when the individual meets the three criteria of the triad.
Individuals with the female athlete triad display some pattern of disordered eating and have some menstrual irregularities. Many women have amenorrhea but others have irregular menses. Typically, the patient has concerns about weight and body image. A history of stress fractures should also raise the clinician’s concern.
Depending on the severity of the symptoms and whether or not the patient is bingeing and purging, the laboratory abnormalities can be similar to those seen in anorexia nervosa or bulimia nervosa. BMD, if measured, is decreased.
The main differential diagnoses include anorexia nervosa, bulimia nervosa as well as endocrine disorders such as hyperthyroidism and diabetes mellitus.
Little evidence is currently available about treatment of the female athlete triad. Strategies such as counseling, cognitive behavior therapy, and possibly exercise restriction may be helpful. A multidisciplinary approach, including consultation with a nutritionist and communication with the coach and trainers, may enable common goal setting. The desire to participate in sports and the lure of a performance enhancing diet may motivate some patients to pursue treatment.
ESSENTIALS OF DIAGNOSIS
Purging with laxatives or vomiting.
Taking less insulin than prescribed to lose weight.
Eating disturbances have been estimated to be present in up to one-third of young women with diabetes. Eating disorders are more common in adolescents with diabetes than in their non-diabetic peers. Mortality is particularly high in individuals with both diabetes and eating disorders.
For diabetes, the dietary regimen emphasizes intense meal timing and consistency. In addition, the hunger associated with hypoglycemia encourages binge eating. Diabetics with disordered eating have been shown to have an increased risk of retinopathy. Given the emphasis that young women often place on body weight, maintaining optimal diabetes control is a particular challenge. The diagnosis is typically made in a diabetic who has worsening diabetic control, when other causes of worsening control have been ruled out.
Diabetics may report polydipsia, polyuria, or weight loss. In addition, upon questioning, they may report disturbed eating patterns. Other symptoms associated with eating disorders, such as disturbance of body image and menstrual irregularities, may also be present.
The main laboratory finding will be a trend of increasing levels of hemoglobin A1C.
The main differential diagnosis includes looking for other causes of worsening glycemic control such as underlying infection or metabolic disease such as hyperthyroidism.
There is currently no evidence to support any particular strategies for the treatment of disordered eating in diabetic patients. Proposed strategies for at risk diabetic patients include nutritional counseling to promote healthy eating instead of dietary restraint, regular (instead of fixed) meal and snack times, less intensive insulin therapy to reduce weight gain, and family counseling to improve communication.
No studies have evaluated the optimal treatment of diabetic patients with established eating disorders. Presumably, strategies that are effective for patients without diabetes, such as cognitive behavioral therapy and medications, will be effective. In addition, diabetic management strategies that do not require the patient to constantly think about food may be beneficial.
ESSENTIALS OF DIAGNOSIS
Binge eating disorder consists of episodes of eating a large amount of food in a discreet period of time with a sense of lack of control.
Binge episodes characterized by at least three of the following:
– Eating large amounts of food when not feeling hungry.
– Eating more rapidly than normal.
– Eating until feeling uncomfortably full.
– Eating alone because of embarrassment about the amount of food consumed.
– Feeling disgusted, depressed, or guilty after eating.
Episodes occur at least two times a week for at least 6 months.
No compensatory behavior (purging, fasting, or excessive exercise) after eating.
Binge eating disorder is more common than either anorexia nervosa or bulimia nervosa, and, with the publication of the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-V), it is recognized formally as a diagnosable eating disorder.
Binge eating disorder is much more common in women and is associated with obesity, although not all individuals with binge eating disorder are obese. Obesity-related complications are likely to occur, and the disorder may be more common in weight cycling patients.
The patient may present with weight gain or may describe disordered eating patterns and binge eating episodes. There are no specific laboratory findings for binge eating disorder.
The main differential diagnosis includes other psychiatric and eating disorders. Other diagnostic possibilities include hypothyroidism and Prader-Willi syndrome.
Treatment goals focus on decreasing the patient’s binge eating episodes and may include weight loss and treatment of other psychiatric comorbidities. As in bulimia nervosa, cognitive behavioral therapy is the mainstay of treatment. Interpersonal therapy has also been shown to be effective. Pharmacotherapy with selective serotonin reuptake inhibitors is also helpful, but does not appear to be better than cognitive behavioral therapy.
National Institute for Health and Clinical Excellence. Eating disorders: core interventions in the treatment and management of anorexia nervosa, bulimia nervosa and related eating disorders.http://www.nice.org.uk/CG009
Young V et al. Eating problems in adolescents with Type 1 diabetes: a systematic review with meta-analysis. Diabet Med. 2013 Feb;30(2):189–98. [PMID: 22913589]
SEXUALITY & SEXUAL HEALTH
Sexual health is defined by the World Health Organization as a state of physical, emotional, mental, and social well-being in relation to sexuality. Healthy sexual functioning therefore depends on a complex interplay of physical, psychological, and societal factors. Among the more than 30,000 women who were surveyed about their sexuality in the PRESIDE study, 9–12% reported having a sexual problem that caused personal distress or interpersonal difficulties. The female sexual disorders identified in the DSM-V include female sexual interest/arousal disorder, sexual aversion disorder, female orgasmic disorder, and genito-pelvic pain/penetration disorder (these are discussed in detail in Chapters 18 and 25). Several medical conditions (depression, diabetes, urinary incontinence, and multiple sclerosis) and medications (antidepressants, hormonal therapy, antihypertensives) can contribute to the development of female sexual disorders. Clinicians should routinely assess patients’ sexual health during office visits; even a brief assessment provides patients with reassurance that this is an important topic. Providers can broach the subject using a broad question, such as “What concerns or questions do you have about your sexual functioning?” and then follow-up with more specific questions, including “Do you have difficulty with desire, arousal, or orgasm?” and “If you are not currently sexual, are there any particular problems that are contributing to your lack of sexual behavior?” Patient concerns can then be delineated more fully during the complete sexual assessment, which encompasses details about medical, surgical, and psychiatric problems, as well as medications and reproductive history. Treatment options depend on the diagnosed disorder and can include psychosexual and hormonal therapy (seeChapter 18).
Kingsberg SA et al. Female sexual disorders: assessment, diagnosis, and treatment. CNS Spectr. 2011 Feb;16(2):49–62. [PMID: 21419070]
World Health Organization. Measuring sexual health: conception and practical considerations and related indicators. World Health Organization, 2010, Geneva, Switzerland.http://www.who.int/reproductivehealth/publications/monitoring/who_rhr_10.12/en/index.html
CHRONIC PELVIC PAIN
ESSENTIALS OF DIAGNOSIS
Duration of 6 months or more.
Localized to anatomic pelvis, anterior abdominal wall at or below the umbilicus, the lumbosacral back, or buttocks.
Associated with functional disability.
Chronic pelvic pain (CPP) is defined as noncyclic pain lasting at least 6 months that localizes to the pelvic girdle region; it must be of sufficient severity to cause functional disability or necessitate medical care. CPP may result from gynecologic, urologic, gastrointestinal, musculoskeletal, or neurologic disorders. Although endometriosis is the most common gynecologic condition associated with CPP, postoperative adhesions, pelvic congestion, and chronic pelvic inflammatory disease should also be considered. Interstitial cystitis, irritable bowel syndrome, and myofascial pain syndrome arising from trigger points in the abdominal musculature or pelvic floor have all been associated with CPP. Sensation to the pelvis is supplied by nerves arising from thoracolumbar and sacral nerve roots. Thus, spinal pathology or direct injury to the pudendal nerve can produce CPP. It is important to remember that most women with CPP have multiple diagnoses contributing to their pain.
Certain features of the history and physical examination can provide clues to the underlying diagnosis. Patients should be asked about the location, quality, and intensity of their pain as well as the relationship with the menstrual cycle, sexual activity, urination, and defecation. Dysmenorrhea and dyspareunia are often experienced by patients with endometriosis, whereas dysuria, urgency, and frequency in association with pelvic pain are characteristic of interstitial cystitis. Pain related to pelvic varices is usually postural, worsening with prolonged standing and improving with leg elevation. Patients with irritable bowel syndrome often report abdominal pain, distention, and diarrhea or constipation. Clinicians should ask patients about surgery or direct trauma involving the spine or pelvis, which may suggest musculoskeletal sources of pain. The physical examination, including the pelvic examination, is usually quite painful in the patient with CPP and should be done carefully. Palpation of the thoracic and lumbar spine, pelvic girdle, and abdomen can reveal areas of discomfort that refer to the pelvic area. A positive Carnett test (constituted by an increase in tenderness when the abdominal muscles are tensed) can be helpful for identifying abdominal wall trigger points. A single-digit internal vaginal examination should be done to localize the exact area of pain and to assess for trigger points along the pelvic floor muscles. Palpation of the pelvic viscera can help identify localized areas of tenderness in women with endometriosis or chronic pelvic inflammatory disease. The external genitalia should also be examined carefully to identify areas of vulvar discomfort because vulvodynia often coexists in patients with CPP. Notably, the absence of physical examination findings does not rule out significant pathology.
Women who are at high risk for pelvic infection should be screened with cervical swabs for chlamydia and gonorrhea.
Pelvic ultrasonography is useful for evaluating the pelvic anatomy, investigating localized areas of tenderness, and identifying pathology. Laparoscopy may be helpful for diagnosing endometriosis or pelvic adhesions, although 35% of diagnostic laparoscopies are normal in patients with CPP.
CPP is frequently a manifestation of another disease, as noted above. When considering various diagnoses, it is important to differentiate extra-pelvic from intra-pelvic sources of pain. Musculoskeletal disorders involving the spine, hips, and sacroiliac joints may cause referred pelvic pain, whereas endometriosis, chronic pelvic inflammatory disease, and pelvic congestion are typically associated with tenderness of the pelvic viscera. Similarly, abdominal wall or hip girdle trigger points that cause CPP can be easily differentiated from trigger points in the levator ani and perineal muscles.
Medical treatment may focus on managing the chronic pain, the underlying condition, or both. Analgesics are commonly used, and nonsteroidal anti-inflammatory drugs (NSAIDs) are typically helpful. However, patients and clinicians should be cautious about long-term use of these medications because long-term NSAID therapy can be associated with significant gastric toxicity. Antidepressants (eg, amitriptyline) and antiseizure medications (eg, gabapentin) (see Table 5–4), which have demonstrated efficacy in the treatment of other pain syndromes, may also be useful for CPP. Opioid therapy improves pain but not functional or psychological outcomes and should generally be avoided.
Hormonal therapies are used primarily for treating gynecologic sources of CPP. Women with endometriosis often benefit from treatment with combined oral contraceptive pills, which suppress ovulation and reduce dysmenorrhea. Gonadotropin-releasing hormone (GnRH) agonists and progestins improve pain associated with endometriosis and pelvic varices. The decrease in BMD associated with GnRH agonist treatment can be mitigated with estrogen or progesterone add-back therapy. Treatment with medroxyprogesterone improved pain scores in women with pelvic congestion, but symptoms returned with cessation of treatment.
Medical therapies directed at the treatment of nongynecologic sources of CPP, including interstitial cystitis and irritable bowel syndrome, are discussed in Chapters 15 and 23. Physical therapy and injection of identified trigger points provide significant pain relief in patients with musculoskeletal sources of pain. Psychological evaluation and treatment should also be strongly considered as many women with CPP experience anxiety and depression.
Surgical treatment of CPP requires referral to a gynecologist. Condition-specific surgical treatments include ovarian or pelvic vein embolization in women with pelvic congestion syndrome or adhesiolysis in patients with pelvic adhesions. Women with endometriosis may be offered laparoscopic surgical destruction of implants or laparoscopic utero-sacral (LUNA) nerve ablation for relief of their chronic pain. Importantly, the efficacy of some of these surgical techniques is controversial. According to a recent systematic review, lysis of adhesions and LUNA were no more effective than diagnostic laparoscopy for improvement in pain scores. Women with endometriosis who have persistent disease after medical and surgical therapies may benefit from hysterectomy, although it is controversial as to whether concomitant oopherectomy improves symptoms further.
When to Refer
Patients should be referred to a gynecologist for diagnostic or therapeutic surgical procedures, if the underlying diagnosis is unclear, or if the provider feels uncomfortable managing side effects associated with medical treatments (ie, GnRH agonist therapy).
Andrews J et al. Noncyclic chronic pelvic pain therapies for women: comparative effectiveness [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2012 Jan. Available fromhttp://www.ncbi.nlm.nih.gov/books/NBK84586/[PMID: 22439157]
Engler D et al; European Association of Urology. Guidelines on chronic pelvic pain, 2012. http://www.uroweb.org/gls/pdf/24_Chronic_Pelvic_Pain_LR%20II.pdf
Shin JH et al. Management of chronic pelvic pain. Curr Pain Headache Rep. 2011 Oct;15(5):377–85. [PMID: 21556711]
Stacy J et al. Persistent pelvic pain: rising to the challenge. Aust N Z J Obstet Gynaecol. 2012 Dec;52(6):502–7. [PMID: 22998335]
ESSENTIALS OF DIAGNOSIS
Infection, malignancy, and extramammary conditions can cause breast pain.
Abnormal physical examination findings, such as a breast mass or skin abnormalities, should prompt radiographic imaging.
Breast pain, or mastalgia, is categorized as cyclical, noncyclical, or extramammary. Although minor breast discomfort is commonly associated with the normal menstrual cycle, women with cyclical mastalgia typically have moderate to severe pain that can last more than 5 days. Cyclical mastalgia can be diagnosed only in reproductive-age women who experience breast pain as a result of the hormonally-mediated proliferation in breast tissue that occurs with ovulation. In contrast, noncyclical mastalgia has no relationship to the menstrual cycle and can occur in premenopausal or postmenopausal women. Causes of noncyclical mastalgia include large breast size (with stretching of Cooper ligaments), medications, pregnancy, thrombophlebitis, or inflammatory breast cancer. Extramammary mastalgia is caused by pain that is referred from other anatomic locations, including the chest wall, heart, gallbladder, or spine. Trauma or previous surgery may also produce extramammary pain.
Cyclical mastalgia is often described as a deep, heavy, aching pain, which is typically diffuse and bilateral and is clearly associated with the menstrual cycle. Conversely, noncyclical pain, which may be constant or intermittent, is variable in location and can involve one or both breasts. Chest wall pain, a frequent cause of extramammary mastalgia, typically causes unilateral, burning pain that may be either localized or diffuse. Malignancy-associated mastalgia is often severe, progressive, and unilateral.
Breast cancer may be associated with mastalgia, and thus a careful physical examination is essential in all women who report breast pain. Large, pendulous breasts may be observed in women who have noncyclical pain caused by stretching of Cooper ligaments. Chest wall pain is usually related to inflammation or injury to the pectoralis major muscle; it may be reproduced by palpation or by having the patient place her hand on her hip and push inward. Any palpable breast mass must be evaluated further with radiologic imaging.
An ultrasound, mammogram, or both should be obtained in women who have a palpable breast mass or localized breast pain or who are at an increased risk for breast cancer. Women with diffuse breast pain who are at average risk for breast cancer and who have a normal physical examination do not require further imaging and can be reassured. However, the clinician should ensure that all patients with mastalgia are up to date on routine screening mammography, as appropriate for their age and personal risk factors.
Malignancy must be ruled out in all patients with mastalgia, and this is usually accomplished through a careful history, physical examination, and diagnostic imaging in patients with clinical abnormalities, such as a palpable breast mass. Extramammary causes of breast pain include chest wall pain, spinal or gallbladder disease, and myocardial ischemia.
Women with cyclical mastalgia who have a normal physical examination and are up to date on routine mammographic screening should be reassured about the benign nature of their symptoms and monitored closely. Cyclical and noncyclical mastalgia often improve with use of a supportive bra. Although there is conflicting evidence regarding the benefit of vitamin E, some experts advocate its use (at a dose of 2000–3000 mg daily) for women with cyclical breast pain. Topical NSAIDs, such as diclofenac gel or patch, improve localized breast pain.
Women who experience severe and persistent cyclical mastalgia despite adherence to conservative measures may be offered hormonal treatment. Danazol, a synthetic androgen that inhibits ovulation, is the only medication that has been approved by the Food and Drug Administration (FDA) for the treatment of cyclical mastalgia. However, side effects associated with treatment are common and include weight gain, menstrual irregularities, voice deepening, and hot flashes. Tamoxifen therapy is tolerated well by most women, and many experts recommend it as first-line therapy for the treatment of cyclical mastalgia. Patients treated with tamoxifen should be counseled about the possibility of hot flashes and menstrual irregularities (experienced by up to 10% of women), as well as the risk for more serious adverse events, such as thromboembolic disease and endometrial cancer.
Symptoms of cyclical and noncyclical mastalgia improve without pharmacologic treatment in most women.
When to Refer
Patients with mastalgia and a palpable breast mass should be referred to a breast surgeon, even if the results of diagnostic imaging are normal.
Rungruang B et al. Benign breast diseases: epidemiology, evaluation, and management. Clin Obstet Gynecol. 2011 Mar; 54(1):110–24. [PMID: 21278510]
Salzman B et al. Common breast problems. Am Fam Physician. 2012 Aug 15;86(4):343–9. [PMID: 22963023]
THE PALPABLE BREAST MASS
ESSENTIALS OF DIAGNOSIS
Diagnostic imaging is essential for any women with a palpable dominant breast mass, regardless of her age.
Ultrasound is the initial test of choice for women under the age of 30; diagnostic mammography with or without ultrasonography is performed initially in women over the age of 30.
Palpable breast masses may be detected by a patient during breast self-examination, or may be identified by the provider during a routine physical examination. A breast mass may be a presenting symptom of breast cancer, and thus a thorough work-up of any palpable breast mass is essential, regardless of age and personal risk factors for breast cancer (see Chapter 17). Common benign causes of palpable breast masses include fibrocystic condition, cysts, and fibroadenomas.
In general, the benign causes of a palpable breast mass have a favorable prognosis. Many women with breast pain and palpable masses due to fibrocystic condition have spontaneous resolution or have improvement in their symptoms with menopause. Benign simple cysts that are asymptomatic may be followed clinically, and symptomatic cysts should resolve with aspiration.
Certain pathologic diagnoses increase the risk of breast cancer, including papillary lesions, radial scars, atypical ductal or lobular hyperplasia, and lobular carcinoma in situ. FNA biopsy or core-needle biopsy results that indicate one of these diagnoses necessitate referral to a breast surgeon for further evaluation and management.
When to Refer
– If diagnostic imaging indicates that the mass \has suspicious features.
– If the mass persists and diagnostic imaging is normal.
– If the mass is categorized as probably benign on diagnostic imaging, but there are worrisome features on physical examination or there is a high clinical suspicion for malignancy.
– If diagnostic imaging demonstrates a complex cyst, or aspiration of a simple cyst reveals a bloody aspirate.
– If the biopsy demonstrates a lesion with an increased risk of breast cancer (papillary lesions, radial scars, atypical hyperplasia, lobular carcinoma in situ).
– If the biopsy results are discordant with the physical examination and radiographic findings.
Ferrara A. Benign breast disease. Radiol Technol. 2011 May–Jun;82(5):447M–62M. [PMID: 21572066]
Rungruang B et al. Benign breast diseases: epidemiology, evaluation, and management. Clin Obstet Gynecol. 2011 Mar; 54(1):110–24. [PMID: 21278510]
Salzman B et al. Common breast problems. Am Fam Physician. 2012 Aug 15;86(4):343–9. [PMID: 22963023]
Nipple discharge is a common breast complaint but is rarely indicative of malignancy. Nipple discharge that comes from multiple ducts, is bilateral, and is produced only with squeezing is considered physiologic, and no further work-up is necessary. Milky discharge that is bilateral, spontaneous, and not associated with pregnancy or breastfeeding is termed “nonlactational galactorrhea.” The most common cause of nonlactational galactorrhea is an elevated prolactin level, which may be associated with pituitary or hypothalamic lesions, systemic diseases (hypothyroidism, renal disease), or medications. Women who have bloody discharge, persistent spontaneous unilateral discharge from a single duct, or discharge associated with a palpable breast mass should be referred for diagnostic mammography and ultrasonography and surgical consultation. These features are suggestive of a pathologic diagnosis, such as papilloma, duct ectasia, or malignancy. Surgical excision of the involved duct is the gold standard for diagnosis. See also Chapter 17.
Huang W et al. Evaluation and management of galactorrhea. Am Fam Physician. 2012 Jun1;85(11):1073–80. [PMID: 22962879]
Salzman B et al. Common breast problems. Am Fam Physician. 2012 Aug 15;86(4):343–9. [PMID: 22963023]
FEMALE PATTERN HAIR LOSS
Female pattern hair loss (FPHL) affects more than 20 million women in the United States. This type of alopecia is characterized by shortening of the anagen (growth) phase and follicle miniaturization. Clinically, presenting signs include diffuse thinning over the central scalp and a prominent midline part; the frontal hairline is typically spared. Although occasionally FPHL may be a sign of hyperandrogenism associated with congenital adrenal hyperplasia, androgen-secreting tumors, or polycystic ovarian syndrome, most women have normal levels of serum testosterone.
Topical minoxidil is currently the only medication that has been approved by the FDA for the treatment of FPHL. In a systematic review of several treatments for FPHL, treatment with topical minoxidil was consistently shown to result in moderate hair re-growth in affected women. When both are applied twice daily, the 2% solution of minoxidil is as effective as the 5% solution and is associated with fewer adverse events. The most common side effect of minoxidil is facial hypertrichosis, which can affect 3–5% of women, but this typically resolves after 1 year of treatment. Spironolactone and cyproterone acetate are oral antiandrogens that have been used for the treatment of FPHL, although there are limited data to support this practice. Importantly, both of these medications can cause feminization of a male fetus and should be used cautiously in reproductive-age women.
Atanaskova Mesinkovska N et al. Hair: what is new in diagnosis and management? Female pattern hair loss update: diagnosis and treatment. Dermatol Clin. 2013 Jan;31(1):119–27. [PMID: 23159181]
van Zuuren EJ et al. Evidence-based treatments for female pattern hair loss: a summary of a Cochrane systematic review. Br J Dermatol. 2012 Nov;167(5):995–1010. [PMID: 23039053]
AGE-RELATED FACIAL CHANGES
Minimally invasive aesthetic procedures are now commonly used to treat mild to moderate age-related changes in the face. These procedures are generally safe and are associated with long-lasting and natural results.
Visible signs of aging in the face result from changes in muscular tone and balance, volume loss, decreased skin elasticity, and changes in skin color and texture. Facial rejuvenation procedures can be grouped into three categories based on their mechanism of action. Neuromodulators are used to produce temporary chemodenervation of hyperactive facial muscles, thereby smoothing facial wrinkles. Soft-tissue fillers restore volume loss, and laser and light-energy based devices improve skin laxity and reflectance. Chemical peels and topical medications are considered adjunctive treatments for improving skin appearance.
For each of the three treatment categories, several options are available. The injectable neuromodulators currently approved by the FDA include various formulations of botulinum toxin A. Dermal fillers include collagen, hydroxylapatite, hyaluronic acid, and injectable poly-L-lactic acid, and differ from each other in their degree of cross-linking, gel hardness, and ability to resist dilution. Among these, hyaluronic acid fillers have become increasingly popular and have been approved by the FDA for treatment of nasolabial folds and lip augmentation; they have also been used off-label to treat wrinkles and improve facial volume. Combination therapy with botulinum toxin A and hyaluronic acid is often used in the eyebrow and eyelid regions to achieve more satisfying cosmetic results. Light-based therapy, which includes laser, radiofrequency, and infrared devices, is typically used to improve elasticity in in the upper eye area. Skin laxity may improve by as much as 30–50% with one treatment, depending on the device used.
Kontis TC et al. Contemporary review of injectable facial fillers. JAMA Facial Plast Surg. 2013 Jan;15(1):58–64. [PMID: 23183718]
Sundaram H et al. Nonsurgical rejuvenation of the upper eyelid and brow. Clin Plast Surg. 2013 Jan;40(1):55–76. [PMID: 23186756]
Wollina U et al. Minimally invasive aesthetic procedures in young adults. Clin Cosmet Investig Dermatol. 2011;4:19–26. [PMID: 21673871]