Influenza-related hospitalizations were approximately twice as high among residents of areas where at least 20% of the population lived below the federal poverty level, compared with areas of less poverty, based on data from more than 27 million individuals in the United States.

Census and hospitalization data included 14 states and spanned two flu seasons (2010-2011 and 2011-2012). Overall, the incidence of flu-related hospitalizations was approximately 21 per 100,000 person-years in high-poverty areas, compared with approximately 11 per 100,000 person-years in census areas where less than 5% of the population lived below the poverty level. The data were consistent across all age groups and ethnicities.

Flu vaccination rates were inversely associated with poverty level, ranging from a high of 48% in high-income areas to a low of 35% in areas with the most poverty. This finding, however, was probably caused by lower vaccination rates among adults aged 65 years and older in higher-poverty areas, compared with high-income areas (80% vs. 94%) noted Dr. James L. Hadler of the Yale School of Public Health in New Haven, Conn., and colleagues.

“Enhanced influenza outreach to improve influenza vaccination coverage for persons living in poorer neighborhoods and efforts to increase use of antivirals by clinicians serving these neighborhoods could reduce poverty-related disparities in severe influenza outcomes,” the researchers noted.

The findings were published in the Morbidity and Mortality Weekly Report (MMWR 2016;65[5]:101-5). Read the full article here.

Influenza-related hospitalizations were approximately twice as high among residents of areas where at least 20% of the population lived below the federal poverty level, compared with areas of less poverty, based on data from more than 27 million individuals in the United States.

Census and hospitalization data included 14 states and spanned two flu seasons (2010-2011 and 2011-2012). Overall, the incidence of flu-related hospitalizations was approximately 21 per 100,000 person-years in high-poverty areas, compared with approximately 11 per 100,000 person-years in census areas where less than 5% of the population lived below the poverty level. The data were consistent across all age groups and ethnicities.

Flu vaccination rates were inversely associated with poverty level, ranging from a high of 48% in high-income areas to a low of 35% in areas with the most poverty. This finding, however, was probably caused by lower vaccination rates among adults aged 65 years and older in higher-poverty areas, compared with high-income areas (80% vs. 94%) noted Dr. James L. Hadler of the Yale School of Public Health in New Haven, Conn., and colleagues.

“Enhanced influenza outreach to improve influenza vaccination coverage for persons living in poorer neighborhoods and efforts to increase use of antivirals by clinicians serving these neighborhoods could reduce poverty-related disparities in severe influenza outcomes,” the researchers noted.

The findings were published in the Morbidity and Mortality Weekly Report (MMWR 2016;65[5]:101-5). Read the full article here.

Influenza-related hospitalizations were approximately twice as high among residents of areas where at least 20% of the population lived below the federal poverty level, compared with areas of less poverty, based on data from more than 27 million individuals in the United States.

Census and hospitalization data included 14 states and spanned two flu seasons (2010-2011 and 2011-2012). Overall, the incidence of flu-related hospitalizations was approximately 21 per 100,000 person-years in high-poverty areas, compared with approximately 11 per 100,000 person-years in census areas where less than 5% of the population lived below the poverty level. The data were consistent across all age groups and ethnicities.

Flu vaccination rates were inversely associated with poverty level, ranging from a high of 48% in high-income areas to a low of 35% in areas with the most poverty. This finding, however, was probably caused by lower vaccination rates among adults aged 65 years and older in higher-poverty areas, compared with high-income areas (80% vs. 94%) noted Dr. James L. Hadler of the Yale School of Public Health in New Haven, Conn., and colleagues.

“Enhanced influenza outreach to improve influenza vaccination coverage for persons living in poorer neighborhoods and efforts to increase use of antivirals by clinicians serving these neighborhoods could reduce poverty-related disparities in severe influenza outcomes,” the researchers noted.

The findings were published in the Morbidity and Mortality Weekly Report (MMWR 2016;65[5]:101-5). Read the full article here.

The Diagnosis: Stinkbug Staining

After discussing management options with the patient including biopsy, we decided that we would photograph the lesion and follow-up in clinic. While dressing, the patient discovered the source of the pigment, a stinkbug, stuck to the corresponding area of the sock.

The brown marmorated stinkbug (Halyomorpha halys)(Figure) is a member of the Pentatomidae family. This insect is native to East Asia and has become an invasive species in the United States. Their presence has recently increased in the eastern United States and they have become an important agricultural pest as well as a household nuisance. Stinkbugs most commonly interact with humans during the fall and winter months when they enter homes because of cooler temperatures outdoors. They can fit into many unexpected places because of their thin profile.¹

Stinkbugs earned their name because of their defensive release of a malodorous chemical. This chemical is comprised of trans-2-decenal and trans-2-octenal, which are both aldehydes and are chemically related to formaldehyde. Based on the material safety data sheet, trans-2-decenal also may be responsible for the orange-brown color seen on the patient’s skin.² Contact dermatitis caused by direct excretion of this chemical onto human skin has been reported³; anecdotal reports of irritation in agricultural workers have been noted. Stinkbugs are becoming a more common household and agricultural pest and should be recognized as possible causes of some presentations in the dermatology clinic.

The Diagnosis: Stinkbug Staining

After discussing management options with the patient including biopsy, we decided that we would photograph the lesion and follow-up in clinic. While dressing, the patient discovered the source of the pigment, a stinkbug, stuck to the corresponding area of the sock.

The brown marmorated stinkbug (Halyomorpha halys)(Figure) is a member of the Pentatomidae family. This insect is native to East Asia and has become an invasive species in the United States. Their presence has recently increased in the eastern United States and they have become an important agricultural pest as well as a household nuisance. Stinkbugs most commonly interact with humans during the fall and winter months when they enter homes because of cooler temperatures outdoors. They can fit into many unexpected places because of their thin profile.¹

Stinkbugs earned their name because of their defensive release of a malodorous chemical. This chemical is comprised of trans-2-decenal and trans-2-octenal, which are both aldehydes and are chemically related to formaldehyde. Based on the material safety data sheet, trans-2-decenal also may be responsible for the orange-brown color seen on the patient’s skin.² Contact dermatitis caused by direct excretion of this chemical onto human skin has been reported³; anecdotal reports of irritation in agricultural workers have been noted. Stinkbugs are becoming a more common household and agricultural pest and should be recognized as possible causes of some presentations in the dermatology clinic.

The Diagnosis: Stinkbug Staining

After discussing management options with the patient including biopsy, we decided that we would photograph the lesion and follow-up in clinic. While dressing, the patient discovered the source of the pigment, a stinkbug, stuck to the corresponding area of the sock.

The brown marmorated stinkbug (Halyomorpha halys)(Figure) is a member of the Pentatomidae family. This insect is native to East Asia and has become an invasive species in the United States. Their presence has recently increased in the eastern United States and they have become an important agricultural pest as well as a household nuisance. Stinkbugs most commonly interact with humans during the fall and winter months when they enter homes because of cooler temperatures outdoors. They can fit into many unexpected places because of their thin profile.¹

Stinkbugs earned their name because of their defensive release of a malodorous chemical. This chemical is comprised of trans-2-decenal and trans-2-octenal, which are both aldehydes and are chemically related to formaldehyde. Based on the material safety data sheet, trans-2-decenal also may be responsible for the orange-brown color seen on the patient’s skin.² Contact dermatitis caused by direct excretion of this chemical onto human skin has been reported³; anecdotal reports of irritation in agricultural workers have been noted. Stinkbugs are becoming a more common household and agricultural pest and should be recognized as possible causes of some presentations in the dermatology clinic.

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In recent years, resistance to antimicrobial drugs has become increasingly widespread, resulting in a health threat of epidemic proportions. The long list of drug-resistant bacteria continues to expand at an accelerated pace. What does this mean in the dermatology world? We are not the only problem but are certainly part of the problem, representing 5% of all antibiotic prescriptions annually even though we represent only 1% of all physicians in the United States. These prescriptions certainly do not just include skin and soft tissue functions, as a survey-based study by Chouake et al (J Drugs Dermatol. 2014;13:119-124.) showed that dermatologists are overusing antibiotics in the treatment of simple skin abscesses such as acne vulgaris, one of the most common inflammatory skin diseases.

Although the inappropriate utilization of antibiotics for acne has been a subject of great discourse for years, it recently reentered the limelight in a study by Nagler et al published online in October 2015 in the Journal of the American Academy of Dermatology. They showed that patients who ultimately were treated with isotretinoin had been receiving antibiotics for months without any sign of therapeutic life or course end in sight. This retrospective chart review evaluated the duration of systemic antibiotic use prior to starting isotretinoin in 137 patients with inflammatory/nodulocystic acne. Antibiotic use continued for a mean of 331.3 days (median, 238 days). Duration of antibiotic use was divided into categories: 3 months or less (15.3%), 6 months or more (64.2%), or 1 year or more (33.6%).

Let’s take a broad look at antimicrobial resistance. Bacterial drug resistance has numerous negative effects on medicine and society. Drug-resistant bacterial infections result in higher doses of drugs, the addition of treatments with higher toxicity, longer hospital stays, and increased mortality. In the United States, infections due to antibiotic-resistant bacteria add $20 billion to total health care costs plus $35 billion in costs to society.

Unfortunately, it is relatively easy for bacterium to develop drug resistance through 3 simple steps: acquisition by microbes of resistance genes, expression of those resistance genes, and selection for pathogens expressing those resistance genes. The selective pressure in favor of resistance occurs whenever microbes are exposed to a drug but not eradicated, either by the killing effects of the drug itself or by inhibitory effects of the drug followed by killing by the host’s immune system. In any setting that creates this selective pressure in favor of drug resistance, such as poor patient compliance (ie, infrequent dosing, taking an antibiotic for too long as we see with the use of antibiotics for the treatment of inflammatory skin diseases such as acne), the likelihood of that resistance actually developing is increased. In addition, drugs that inhibit but do not kill microbes are more likely to allow some microbial cells to live and therefore develop resistance when exposed to a drug, which accounts for the majority of antibiotics in our armament. Lastly, abuse of broad-spectrum antibiotics has further spurred the emergence of many antibiotic-resistant strains. For instance, Pseudomonas aeruginosa is one of many evolving multidrug-resistant microorganisms that have been collectively coined the “ESKAPE” pathogens (Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, P aeruginosa, Enterobacter species) to emphasize the fact that they “escape” the effects of many antibacterial agents.

All of the above does not take into account the environmental factors that play a role in this resistance. The close quarters, mass/public transportation, and stressful pace of life of urban living not only bring these organisms together to share resistance genes but also increase our susceptibility.

What’s the issue?

We can all do our part in the fight against microbial resistance and join the antimicrobial stewardship. Here are a couple tips for dermatologists:

1. Stop using over-the-counter antibiotic ointment for every biopsy or minor procedure, which is one of the recommendations of the American Academy of Dermatology based on the ABIM Foundation’s Choosing Wisely campaign.
2. Oral and topical antibiotics for inflammatory skin diseases such as acne, rosacea, and hidradenitis suppurativa should only be used temporarily or at subantimicrobial dosing. Always combine a benzoyl peroxide–containing wash with a topical or oral antibiotic to hit the bacteria with multiple mechanisms of antibacterial activity to limit resistance. Don’t use benzoyl peroxide stronger than 2.5% for the face; make sure to wash it off completely to avoid staining your towels, sheets, and clothing.

We can all play our part in the fight against antimicrobial resistance. How do you fight the resistance?

We want to know your views! Tell us what you think.

In recent years, resistance to antimicrobial drugs has become increasingly widespread, resulting in a health threat of epidemic proportions. The long list of drug-resistant bacteria continues to expand at an accelerated pace. What does this mean in the dermatology world? We are not the only problem but are certainly part of the problem, representing 5% of all antibiotic prescriptions annually even though we represent only 1% of all physicians in the United States. These prescriptions certainly do not just include skin and soft tissue functions, as a survey-based study by Chouake et al (J Drugs Dermatol. 2014;13:119-124.) showed that dermatologists are overusing antibiotics in the treatment of simple skin abscesses such as acne vulgaris, one of the most common inflammatory skin diseases.

Although the inappropriate utilization of antibiotics for acne has been a subject of great discourse for years, it recently reentered the limelight in a study by Nagler et al published online in October 2015 in the Journal of the American Academy of Dermatology. They showed that patients who ultimately were treated with isotretinoin had been receiving antibiotics for months without any sign of therapeutic life or course end in sight. This retrospective chart review evaluated the duration of systemic antibiotic use prior to starting isotretinoin in 137 patients with inflammatory/nodulocystic acne. Antibiotic use continued for a mean of 331.3 days (median, 238 days). Duration of antibiotic use was divided into categories: 3 months or less (15.3%), 6 months or more (64.2%), or 1 year or more (33.6%).

Let’s take a broad look at antimicrobial resistance. Bacterial drug resistance has numerous negative effects on medicine and society. Drug-resistant bacterial infections result in higher doses of drugs, the addition of treatments with higher toxicity, longer hospital stays, and increased mortality. In the United States, infections due to antibiotic-resistant bacteria add $20 billion to total health care costs plus $35 billion in costs to society.

Unfortunately, it is relatively easy for bacterium to develop drug resistance through 3 simple steps: acquisition by microbes of resistance genes, expression of those resistance genes, and selection for pathogens expressing those resistance genes. The selective pressure in favor of resistance occurs whenever microbes are exposed to a drug but not eradicated, either by the killing effects of the drug itself or by inhibitory effects of the drug followed by killing by the host’s immune system. In any setting that creates this selective pressure in favor of drug resistance, such as poor patient compliance (ie, infrequent dosing, taking an antibiotic for too long as we see with the use of antibiotics for the treatment of inflammatory skin diseases such as acne), the likelihood of that resistance actually developing is increased. In addition, drugs that inhibit but do not kill microbes are more likely to allow some microbial cells to live and therefore develop resistance when exposed to a drug, which accounts for the majority of antibiotics in our armament. Lastly, abuse of broad-spectrum antibiotics has further spurred the emergence of many antibiotic-resistant strains. For instance, Pseudomonas aeruginosa is one of many evolving multidrug-resistant microorganisms that have been collectively coined the “ESKAPE” pathogens (Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, P aeruginosa, Enterobacter species) to emphasize the fact that they “escape” the effects of many antibacterial agents.

All of the above does not take into account the environmental factors that play a role in this resistance. The close quarters, mass/public transportation, and stressful pace of life of urban living not only bring these organisms together to share resistance genes but also increase our susceptibility.

What’s the issue?

We can all do our part in the fight against microbial resistance and join the antimicrobial stewardship. Here are a couple tips for dermatologists:

1. Stop using over-the-counter antibiotic ointment for every biopsy or minor procedure, which is one of the recommendations of the American Academy of Dermatology based on the ABIM Foundation’s Choosing Wisely campaign.
2. Oral and topical antibiotics for inflammatory skin diseases such as acne, rosacea, and hidradenitis suppurativa should only be used temporarily or at subantimicrobial dosing. Always combine a benzoyl peroxide–containing wash with a topical or oral antibiotic to hit the bacteria with multiple mechanisms of antibacterial activity to limit resistance. Don’t use benzoyl peroxide stronger than 2.5% for the face; make sure to wash it off completely to avoid staining your towels, sheets, and clothing.

We can all play our part in the fight against antimicrobial resistance. How do you fight the resistance?

We want to know your views! Tell us what you think.

In recent years, resistance to antimicrobial drugs has become increasingly widespread, resulting in a health threat of epidemic proportions. The long list of drug-resistant bacteria continues to expand at an accelerated pace. What does this mean in the dermatology world? We are not the only problem but are certainly part of the problem, representing 5% of all antibiotic prescriptions annually even though we represent only 1% of all physicians in the United States. These prescriptions certainly do not just include skin and soft tissue functions, as a survey-based study by Chouake et al (J Drugs Dermatol. 2014;13:119-124.) showed that dermatologists are overusing antibiotics in the treatment of simple skin abscesses such as acne vulgaris, one of the most common inflammatory skin diseases.

Although the inappropriate utilization of antibiotics for acne has been a subject of great discourse for years, it recently reentered the limelight in a study by Nagler et al published online in October 2015 in the Journal of the American Academy of Dermatology. They showed that patients who ultimately were treated with isotretinoin had been receiving antibiotics for months without any sign of therapeutic life or course end in sight. This retrospective chart review evaluated the duration of systemic antibiotic use prior to starting isotretinoin in 137 patients with inflammatory/nodulocystic acne. Antibiotic use continued for a mean of 331.3 days (median, 238 days). Duration of antibiotic use was divided into categories: 3 months or less (15.3%), 6 months or more (64.2%), or 1 year or more (33.6%).

Let’s take a broad look at antimicrobial resistance. Bacterial drug resistance has numerous negative effects on medicine and society. Drug-resistant bacterial infections result in higher doses of drugs, the addition of treatments with higher toxicity, longer hospital stays, and increased mortality. In the United States, infections due to antibiotic-resistant bacteria add $20 billion to total health care costs plus $35 billion in costs to society.

Unfortunately, it is relatively easy for bacterium to develop drug resistance through 3 simple steps: acquisition by microbes of resistance genes, expression of those resistance genes, and selection for pathogens expressing those resistance genes. The selective pressure in favor of resistance occurs whenever microbes are exposed to a drug but not eradicated, either by the killing effects of the drug itself or by inhibitory effects of the drug followed by killing by the host’s immune system. In any setting that creates this selective pressure in favor of drug resistance, such as poor patient compliance (ie, infrequent dosing, taking an antibiotic for too long as we see with the use of antibiotics for the treatment of inflammatory skin diseases such as acne), the likelihood of that resistance actually developing is increased. In addition, drugs that inhibit but do not kill microbes are more likely to allow some microbial cells to live and therefore develop resistance when exposed to a drug, which accounts for the majority of antibiotics in our armament. Lastly, abuse of broad-spectrum antibiotics has further spurred the emergence of many antibiotic-resistant strains. For instance, Pseudomonas aeruginosa is one of many evolving multidrug-resistant microorganisms that have been collectively coined the “ESKAPE” pathogens (Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, P aeruginosa, Enterobacter species) to emphasize the fact that they “escape” the effects of many antibacterial agents.

All of the above does not take into account the environmental factors that play a role in this resistance. The close quarters, mass/public transportation, and stressful pace of life of urban living not only bring these organisms together to share resistance genes but also increase our susceptibility.

What’s the issue?

We can all do our part in the fight against microbial resistance and join the antimicrobial stewardship. Here are a couple tips for dermatologists:

1. Stop using over-the-counter antibiotic ointment for every biopsy or minor procedure, which is one of the recommendations of the American Academy of Dermatology based on the ABIM Foundation’s Choosing Wisely campaign.
2. Oral and topical antibiotics for inflammatory skin diseases such as acne, rosacea, and hidradenitis suppurativa should only be used temporarily or at subantimicrobial dosing. Always combine a benzoyl peroxide–containing wash with a topical or oral antibiotic to hit the bacteria with multiple mechanisms of antibacterial activity to limit resistance. Don’t use benzoyl peroxide stronger than 2.5% for the face; make sure to wash it off completely to avoid staining your towels, sheets, and clothing.

We can all play our part in the fight against antimicrobial resistance. How do you fight the resistance?

We want to know your views! Tell us what you think.

From the Department of Pediatrics, Section of Endocrinology & Diabetes, Medical College of Wisconsin, Milwaukee, WI.

Abstract

• Objective: To review the diagnosis and management of polycystic ovary syndrome (PCOS) in adolescent patients.
• Methods: Review of the literature.
• Results: PCOS is a complex, heterogeneous disorder that frequently manifests during puberty. The symptoms of PCOS (ie, menstrual irregularities, hirsutism, and acne) tend to overlap with normal pubertal changes. Diagnostic criteria for PCOS in the adolescent age-group is still lacking. Current practice is to utilize adult diagnostic criteria, which raises the concern for misdiagnosis. The underlying etiology for the disorder is still unclear, but insulin resistance is present in both obese and non-obese PCOS patients. Although recognizing adolescents with PCOS is challenging, evaluating and managing patients for hyperandrogenemia and metabolic syndrome is imperative to prevent long-term reproductive and metabolic complications.
• Conclusion: PCOS is increasingly encountered during adolescence. Recognizing adolescent girls with PCOS is a challenge but important for preventing long-term adverse health outcomes.

Polycystic ovary syndrome (PCOS) is a complex disorder most commonly characterized by chronic anovulation and clinical and biochemical features of hyperandrogenemia. It affects 4% to 12% of reproductive-aged women [1,2]. In adolescents, the exact prevalence is unknown, but in a recent study the prevalence of a confirmed diagnosis of PCOS in adolescents aged 15 to 19 years was 0.56%, which increased to 1.14% when undiagnosed cases with documented symptoms qualifying for PCOS according to NIH criteria were included [3]. The primary underlying defect in PCOS remains unknown, but key features include insulin resistance, impaired gonadotropin dynamics, and androgen excess.

Profound functional variations in the hypothalamic-pituitary-ovarian axis commonly seen during normal puberty may result in clinical and biochemical changes that mimic some of the features of PCOS. During the early stages of puberty, adolescent girls tend to have anovulatory menstrual cycles, higher androgen levels, and polycystic ovaries [4,5]. Thus, the clinical signs of hyperandrogenemia commonly seen in adults are less reliable in the adolescent age-group. Diagnostic criteria have been developed for adults and are based upon the various combinations of oligomenorrhea, unexplained hyperandrogenemia, and polycystic ovaries on imaging (Table 1) [6–8]. Applying these adult criteria in adolescent patients with suspected PCOS has always raised the concern of misdiagnosis as some of the changes seen in this age-group may likely be due to normal pubertal development. However, due to the paucity of data, the current practice is to utilize the adult diagnostic criteria. Because of the heterogeneous nature of the disorder, recognizing adolescents with PCOS may be challenging. However, early recognition and management is important to prevent some of the long-term reproductive and metabolic complications associated with this syndrome.

Case Study

Initial Presentation

A 16-year-old female patient presents to the PCOS clinic for evaluation of obesity and amenorrhea.

History

The patient, who is otherwise healthy, began gaining weight at age 7. During this period, her weight increased from the 15th to (currently) the 90th percentile; her height remained constant (75th percentile). Menarche was at 12 years of age. Menstrual periods have been irregular since the onset of menarche and she has had no periods for the past 5 months. She noticed excessive hair growth on her face, chin, and neck soon after the onset of menarche. She has been shaving her facial hair once every 2–3 days.

The patient’s detailed diet history included eating 3 meals daily and snacks in-between meals. The patient was consuming sweet beverages regularly. There was minimal intake fruits and vegetables. The portion sizes for each meal were large. The patient had minimal physical activity and screen time was more than 2 hours daily.

Family history is significant for obesity and type 2 diabetes in her mother and maternal grandmother and is negative for PCOS.

Physical Examination

Vital signs were within normal limits. She was 5 ft 6 in tall and weighed 242 lb, with a body mass index (BMI) of 40 (99th percentile; Z-score 2.41). Physical examination showed coarse hair extending from the sideburns to the chin as well as from pubis symphysis to navel with evidence of hair removal. She had acanthosis nigricans on her neck, mild acne, and evidence of central obesity with pink striae marks on the abdomen. She was Tanner stage 5 for breast and pubic hair and there was no evidence of virilization (clitoral hypertrophy, deepening of the voice, severe hirsutism, male pattern baldness, and masculine habitus). Other physical examination findings were within normal limits.

• What physical findings in this patient are suggestive of clinical hyperandrogenemia?

Physiologic irregular menstruation is a well known phenomenon in adolescent girls and is generally due to anovulatory cycles [9–12]. Menstrual cycles shorter than 19 days or longer than 90 days at any stage after menarche are considered abnormal. The menstrual irregularity that is commonly seen within the first 2–3 years after the first menarche can last up to 5 years [5]. However, the majority of girls establish 20- to 45-day cycles within the first 2 years [13].

Androgen excess, defined by the presence of clinical and/or biochemical hyperandrogenemia, should be considered in any adolescent girl who is 2 to 3 years’ post-menarche and presenting with irregular menstrual periods, coarse terminal hair in a male distribution pattern (hirsutism), or moderate to severe inflammatory acne. Hirsutism is androgen dependent [14–16] and must be distinguished from hypertrichosis, which is generalized excessive vellus hair growth present all over the body. Clinical hyperandrogenemia, which includes hirsutism, acne vulgaris, as well as androgenetic alopecia, is well correlated with elevated androgen levels; however, the severity of hirsutism does not correlate well with circulating androgen levels [17,18]. Mild hirsutism is often not associated with hyperandrogenemia in otherwise asymptomatic individuals,but it may be a sign of hyperandrogenemia in adolescents when associated with other features of PCOS, ie, menstrual irregularity [14–16, 19–22]. Defining hirsutism in early adolescence may be difficult since the sexual hair may still be developing, and laboratory evaluation should be considered (see below), especially in an overweight/obese adolescent girl presenting with oligomenorrhea. Ethnic variation due to decreased skin sensitivity to androgens can result in minimal hirsutism despite elevated plasma androgen levels and must be considered among certain Asian women. Women with PCOS from China, Japan, Thailand, and East and Southeast Asian countries tend to have low scores on hirsutism rating scales even with elevated plasma androgens levels [16,23].

Although having acne during puberty is not considered as a marker for hyperandrogenemia, patients with moderate to severe inflammatory acne that is poorly responsive to topical treatment should be evaluated for underlying hyperandrogenemia [19,24,25].

• What laboratory tests should be obtained to when there is clinical suspicion of hyperandrogenemia?

Case Continued

The patient underwent laboratory assessment that included total and free testosterone levels, lipid panel, thyroid studies, prolactin level, comprehensive metabolic panel (CMP) and hemoglobin A1c (HbA1c). Due to lack of virilization, she was not tested for PCOS-like syndromes. Her total and free testosterone were 90 ng/dL (normal, < 41) and 24.7 pg/mL (normal, 0.5–3.9) respectively. Thyroid-stimulating hormone and prolactin levels were normal. She had normal lipid levels and CMP but HbA1c was 5.9% (pre-diabetic range). The results of a 2-hour oral glucose tolerance test revealed a level of 160 mg/dL, indicative of impaired glucose tolerance.

• What is the pathophysiology and diagnostic criteria for PCOS in adolescents?

PCOS has diverse etiology and has been linked to both genetic and environmental factors affecting ovarian steroidogenesis [13,30]. While the familial clustering strongly supports the role of genetic factors, variability in phenotypic features within the same or different families indicates the importance of environmental contribution [31–34].

The exact underlying mechanism leading to disruption of ovulation is still unclear; however, hyperinsulinemia augmenting ovarian androgen production has been well recognized [35–37]. Insulin resistance is a characteristic finding in PCOS and occurs both in obese and lean patients [38,39]. Obesity further exacerbates the insulin resistance state in PCOS patients. Therefore, obese patients with PCOS have more severe hyperandrogenemia and consequences from it (hirsutism, menstrual abnormalities, and metabolic derangements) than normal-weight PCOS patients [40,41]. Similar to LH, insulin can stimulate ovarian theca cells directly and cause increased production of androgens [42]. Elevated androgen levels cause the irregular menstrual periods as well as clinical signs of hyperandrogenemia, such as hirsutism and acne.

Altered gonadotropin dynamics is another possible etiological factor that is linked with PCOS. Hyperinsulinemia affects the regulation of gonadotropin-releasing hormone (GnRH) pulse generator, causing hypersecretion of LH [43]. Obese peripubertal girls have been identified having altered LH secretion [44,45]. This results in increased LH levels relative to FSH. Normal FSH is required to stimulate ovarian folliculognensis; insufficient FSH levels cause anovulation and menstrual irregularities. Abnormal LH secretion and fasting insulin levels have been identified the independent predictors for hyperandrogenemia in some peripubertal obese girls [46].

In 2010 Carmina et al published new criteria to diagnose PCOS in adolescents [27].They recommended that in diagnosing PCOS in adolescents, all 3 previously mentioned criteria should be present: hyperandrogenemia, chronic anovulation, and polycystic ovaries. With the exception of worsening hirsutism, the new recommendations greatly emphasized biochemical hyperandrogenemia (elevated free testosterone levels using sensitive assays). Chronic anovulation was defined as persistence of menstrual irregularities 2 years post-menarche and pelvic ultrasound (USG) showing increased ovarian size (> 10 cm³). Normal physiological variations unrelated to hyperandrogenemia are common in adolescent ovaries and limits the usefulness of pelvic USG as a diagnostic criterion for PCOS [13,47,48]^. Also, the prevalence of increased ovarian size in hyperandrogenemic adolescent patients was reported to be low, and its utility as a criterion for diagnosis needs to be further explored [49]. In our current practice we do not rely on pelvic USG findings to make a PCOS diagnosis.

Due to longstanding controversies and lack of consensus surrounding the accurate diagnostic criteria, a recent guideline was developed by experts in pediatric endocrinology and adolescent medicine invited by the Pediatric Endocrine Society to address these issues [13].The guideline committee assessed the literature in order to define which criteria have sufficient evidence to be used for diagnosis of PCOS in adolescents. They recommend that PCOS should be considered in an adolescent girl presenting with unexplained menstrual irregularities, moderate to severe hirsutism or acne, and elevated levels of serum androgens (total and free testosterone) using reliable assay with well-defined ranges. Although intrinsic insulin resistance unique to PCOS is well known, none of the current guidelines either for adolescent and adult women include it as part of the diagnostic criteria. Since longitudinal studies focusing on the natural history of PCOS in this age-group are lacking, the current recommendations focus on timely screening and treatment in symptomatic adolescent girls suspected of having PCOS.

When there are PCOS features but menstrual irregularity has not been present for at least 2 years, one can defer the diagnostic label and instead use the term at-risk for PCOS. Such patients should have frequent longitudinal re-evaluations and should be offered treatment for their symptoms [13].

• How should adolescents with PCOS be managed?

The treatment of PCOS is symptom-directed and should be tailored according to the complaints of the individual patient. However, it also must focus on the core dysfunctions: anovulation, hyperandrogenemia, obesity, and insulin resistance. It also requires bridging patient expectations of regulating menses, lessening the troublesome clinical signs of hyperandrogenemia (hirsutism, acne), and obesity management with the health care provider’s goals of preventing endometrial hyperplasia and cancer, diabetes mellitus, and cardiovascular disease.

Regulating menstruation and reducing cutaneous manifestations of hyperandrogenemia is the priority for any adolescent with PCOS. Combined oral contraceptive pills (COCs) are the first line of medical treatment for most adolescents. COCs restore endometrial cycling and suppress androgen levels, and are therefore optimal in treating abnormal uterine bleeding, protecting against endometrial carcinoma, and alleviating cutaneous manifestations of hyperandrogenemia (hirsutism and acne). Progestin monotherapy is considered an alternative therapy in individuals with contraindications to COCs (ie, thromboembolic risk). Although it is not effective in lowering androgen levels thus does not help reduce hair growth and acne, progestin monotherapy protects the endometrium and reduces the risk of endometrial cancer [50].

The majority of patients with PCOS are overweight or obese. Regardless of BMI, patients with PCOS have profound intrinsic insulin resistance that gets worse with overweight or obesity. Weight reduction by restricting caloric intake and increasing physical exercise is vital and has shown to be effective in regulating menstrual cycles, but is difficult to achieve [51–53]. Metformin can regulate menstrual cycles and decrease androgen levels by improving insulin sensitivity [54,55]. The use of metformin in PCOS patients is still controversial and abnormal glucose tolerance is the only approved indication [61]. However, combing metformin with COCs and lifestyle modification in obese PCOS patients has been shown to be used more frequently in pediatric endocrine clinics [56]. COCs are the only agents that can lower testosterone levels and improve ovulation and hirsutism; these effects are seen less frequently with lifestyle modification or metformin, either used alone or in combination.

COC monotherapy is first-line therapy to treat hirsutism. Consider anti-androgen treatment for hirsutism if there is no improvement after 6–9 months of hormonal treatment [57]. Antiandrogens reduce hirsutism by decreasing androgen production and binding the androgen receptors in target tissue. Spironolactone is the most commonly used antiandrogen therapy in adolescent girls with PCOS. Given the risk of teratogenicity with antiandrogens if pregnancy occurs, it is recommended to use it in combination with COCs [57]. Cosmetic measures including direct hair removal and electrolysis should be discussed with patients as other options for treatment of hirsutism.

Obese patients with PCOS are at higher risk for metabolic syndrome, a constellation of features including glucose intolerance, central obesity, hypertension, and dyslipidemia. Hyperandrogenemia and insulin resistance are linked with metabolic syndrome in PCOS. Reducing hyperandrogenemia and insulin resistance could reverse metabolic derangements and further reduce the risk of cardiovascular disease [58].

Worsening insulin resistance with COCs in PCOS has raised the concern of long-term metabolic derangements and cardiovascular adverse effects. COCs tend to increase total cholesterol, triglyceride, and high-sensitivity C-reactive protein levels [59]. However, the long-term implications of these findings are not well understood, attributable to the lack of longitudinal studies, especially in women with PCOS receiving COCs. Newer COCs containing less androgenic progestin may have less deleterious effect on insulin resistance and lipid profile. Due to insufficient use in adolescent patients, a definitive conclusion about their long-term safety cannot be drawn. Thus, there remains a theoretical risk of COCs exacerbating the underlying metabolic derangements in PCOS that can lead to subsequent adverse cardiovascular events.

Adolescent girls with PCOS are also at an increased risk for depression and anxiety disorders. The 2013 Endocrine Society clinical practice guideline suggests that adolescent girls with PCOS should be screened for depression and anxiety by history [51].If symptoms are present, patients should receive appropriate psychological referral and treatment.

Case Continued

As she had no contraindications to COCs, the patient was started on COC therapy to regulate her menstrual periods and alleviate the symptoms of hirsutism. Due to impaired glucose tolerance test results and increased risk for type 2 diabetes, treatment with metformin was also initiated. The patient met with a dietician, who offered recommendations for adopting a healthy lifestyle and introduced her to the “3,2,1,0, blast off” model: 3 consistent meals, 2 hours or less of screen time, 1 hour or more of physical activity, and 0 sweetened beverages a day. The patient was also advised to increase daily consumption of fruits and vegetables. Results of the 2-item Patient Health Questionnaire (PHQ-2) for depression were negative.

At a follow-up visit 6 months later, the patient reported that her menstrual periods were regular. There was some improvement in hirsutism, requiring less shaving, and there was no increase in weight. Repeat laboratory evaluations showed normal free testosterone level, decreased HbA1c (5.2%), and improved random blood glucose (130 mg/dL). The patient was seen regularly and treatment results monitored. No side effects were seen over a 4.5-year period. As PCOS is a lifelong condition, at the age of 21 the patient was referred to an adult endocrine clinic for further management.

Corresponding author: Alvina R. Kansra, MD, Medical College of Wisconsin, 8701 Watertown Plank Rd., Wauwatosa, WI 53226, [email protected].

Financial disclosures: None.

From the Department of Pediatrics, Section of Endocrinology & Diabetes, Medical College of Wisconsin, Milwaukee, WI.

Abstract

• Objective: To review the diagnosis and management of polycystic ovary syndrome (PCOS) in adolescent patients.
• Methods: Review of the literature.
• Results: PCOS is a complex, heterogeneous disorder that frequently manifests during puberty. The symptoms of PCOS (ie, menstrual irregularities, hirsutism, and acne) tend to overlap with normal pubertal changes. Diagnostic criteria for PCOS in the adolescent age-group is still lacking. Current practice is to utilize adult diagnostic criteria, which raises the concern for misdiagnosis. The underlying etiology for the disorder is still unclear, but insulin resistance is present in both obese and non-obese PCOS patients. Although recognizing adolescents with PCOS is challenging, evaluating and managing patients for hyperandrogenemia and metabolic syndrome is imperative to prevent long-term reproductive and metabolic complications.
• Conclusion: PCOS is increasingly encountered during adolescence. Recognizing adolescent girls with PCOS is a challenge but important for preventing long-term adverse health outcomes.

Polycystic ovary syndrome (PCOS) is a complex disorder most commonly characterized by chronic anovulation and clinical and biochemical features of hyperandrogenemia. It affects 4% to 12% of reproductive-aged women [1,2]. In adolescents, the exact prevalence is unknown, but in a recent study the prevalence of a confirmed diagnosis of PCOS in adolescents aged 15 to 19 years was 0.56%, which increased to 1.14% when undiagnosed cases with documented symptoms qualifying for PCOS according to NIH criteria were included [3]. The primary underlying defect in PCOS remains unknown, but key features include insulin resistance, impaired gonadotropin dynamics, and androgen excess.

Profound functional variations in the hypothalamic-pituitary-ovarian axis commonly seen during normal puberty may result in clinical and biochemical changes that mimic some of the features of PCOS. During the early stages of puberty, adolescent girls tend to have anovulatory menstrual cycles, higher androgen levels, and polycystic ovaries [4,5]. Thus, the clinical signs of hyperandrogenemia commonly seen in adults are less reliable in the adolescent age-group. Diagnostic criteria have been developed for adults and are based upon the various combinations of oligomenorrhea, unexplained hyperandrogenemia, and polycystic ovaries on imaging (Table 1) [6–8]. Applying these adult criteria in adolescent patients with suspected PCOS has always raised the concern of misdiagnosis as some of the changes seen in this age-group may likely be due to normal pubertal development. However, due to the paucity of data, the current practice is to utilize the adult diagnostic criteria. Because of the heterogeneous nature of the disorder, recognizing adolescents with PCOS may be challenging. However, early recognition and management is important to prevent some of the long-term reproductive and metabolic complications associated with this syndrome.

Case Study

Initial Presentation

A 16-year-old female patient presents to the PCOS clinic for evaluation of obesity and amenorrhea.

History

The patient, who is otherwise healthy, began gaining weight at age 7. During this period, her weight increased from the 15th to (currently) the 90th percentile; her height remained constant (75th percentile). Menarche was at 12 years of age. Menstrual periods have been irregular since the onset of menarche and she has had no periods for the past 5 months. She noticed excessive hair growth on her face, chin, and neck soon after the onset of menarche. She has been shaving her facial hair once every 2–3 days.

The patient’s detailed diet history included eating 3 meals daily and snacks in-between meals. The patient was consuming sweet beverages regularly. There was minimal intake fruits and vegetables. The portion sizes for each meal were large. The patient had minimal physical activity and screen time was more than 2 hours daily.

Family history is significant for obesity and type 2 diabetes in her mother and maternal grandmother and is negative for PCOS.

Physical Examination

Vital signs were within normal limits. She was 5 ft 6 in tall and weighed 242 lb, with a body mass index (BMI) of 40 (99th percentile; Z-score 2.41). Physical examination showed coarse hair extending from the sideburns to the chin as well as from pubis symphysis to navel with evidence of hair removal. She had acanthosis nigricans on her neck, mild acne, and evidence of central obesity with pink striae marks on the abdomen. She was Tanner stage 5 for breast and pubic hair and there was no evidence of virilization (clitoral hypertrophy, deepening of the voice, severe hirsutism, male pattern baldness, and masculine habitus). Other physical examination findings were within normal limits.

• What physical findings in this patient are suggestive of clinical hyperandrogenemia?

Physiologic irregular menstruation is a well known phenomenon in adolescent girls and is generally due to anovulatory cycles [9–12]. Menstrual cycles shorter than 19 days or longer than 90 days at any stage after menarche are considered abnormal. The menstrual irregularity that is commonly seen within the first 2–3 years after the first menarche can last up to 5 years [5]. However, the majority of girls establish 20- to 45-day cycles within the first 2 years [13].

Androgen excess, defined by the presence of clinical and/or biochemical hyperandrogenemia, should be considered in any adolescent girl who is 2 to 3 years’ post-menarche and presenting with irregular menstrual periods, coarse terminal hair in a male distribution pattern (hirsutism), or moderate to severe inflammatory acne. Hirsutism is androgen dependent [14–16] and must be distinguished from hypertrichosis, which is generalized excessive vellus hair growth present all over the body. Clinical hyperandrogenemia, which includes hirsutism, acne vulgaris, as well as androgenetic alopecia, is well correlated with elevated androgen levels; however, the severity of hirsutism does not correlate well with circulating androgen levels [17,18]. Mild hirsutism is often not associated with hyperandrogenemia in otherwise asymptomatic individuals,but it may be a sign of hyperandrogenemia in adolescents when associated with other features of PCOS, ie, menstrual irregularity [14–16, 19–22]. Defining hirsutism in early adolescence may be difficult since the sexual hair may still be developing, and laboratory evaluation should be considered (see below), especially in an overweight/obese adolescent girl presenting with oligomenorrhea. Ethnic variation due to decreased skin sensitivity to androgens can result in minimal hirsutism despite elevated plasma androgen levels and must be considered among certain Asian women. Women with PCOS from China, Japan, Thailand, and East and Southeast Asian countries tend to have low scores on hirsutism rating scales even with elevated plasma androgens levels [16,23].

Although having acne during puberty is not considered as a marker for hyperandrogenemia, patients with moderate to severe inflammatory acne that is poorly responsive to topical treatment should be evaluated for underlying hyperandrogenemia [19,24,25].

• What laboratory tests should be obtained to when there is clinical suspicion of hyperandrogenemia?

Case Continued

The patient underwent laboratory assessment that included total and free testosterone levels, lipid panel, thyroid studies, prolactin level, comprehensive metabolic panel (CMP) and hemoglobin A1c (HbA1c). Due to lack of virilization, she was not tested for PCOS-like syndromes. Her total and free testosterone were 90 ng/dL (normal, < 41) and 24.7 pg/mL (normal, 0.5–3.9) respectively. Thyroid-stimulating hormone and prolactin levels were normal. She had normal lipid levels and CMP but HbA1c was 5.9% (pre-diabetic range). The results of a 2-hour oral glucose tolerance test revealed a level of 160 mg/dL, indicative of impaired glucose tolerance.

• What is the pathophysiology and diagnostic criteria for PCOS in adolescents?

PCOS has diverse etiology and has been linked to both genetic and environmental factors affecting ovarian steroidogenesis [13,30]. While the familial clustering strongly supports the role of genetic factors, variability in phenotypic features within the same or different families indicates the importance of environmental contribution [31–34].

The exact underlying mechanism leading to disruption of ovulation is still unclear; however, hyperinsulinemia augmenting ovarian androgen production has been well recognized [35–37]. Insulin resistance is a characteristic finding in PCOS and occurs both in obese and lean patients [38,39]. Obesity further exacerbates the insulin resistance state in PCOS patients. Therefore, obese patients with PCOS have more severe hyperandrogenemia and consequences from it (hirsutism, menstrual abnormalities, and metabolic derangements) than normal-weight PCOS patients [40,41]. Similar to LH, insulin can stimulate ovarian theca cells directly and cause increased production of androgens [42]. Elevated androgen levels cause the irregular menstrual periods as well as clinical signs of hyperandrogenemia, such as hirsutism and acne.

Altered gonadotropin dynamics is another possible etiological factor that is linked with PCOS. Hyperinsulinemia affects the regulation of gonadotropin-releasing hormone (GnRH) pulse generator, causing hypersecretion of LH [43]. Obese peripubertal girls have been identified having altered LH secretion [44,45]. This results in increased LH levels relative to FSH. Normal FSH is required to stimulate ovarian folliculognensis; insufficient FSH levels cause anovulation and menstrual irregularities. Abnormal LH secretion and fasting insulin levels have been identified the independent predictors for hyperandrogenemia in some peripubertal obese girls [46].

In 2010 Carmina et al published new criteria to diagnose PCOS in adolescents [27].They recommended that in diagnosing PCOS in adolescents, all 3 previously mentioned criteria should be present: hyperandrogenemia, chronic anovulation, and polycystic ovaries. With the exception of worsening hirsutism, the new recommendations greatly emphasized biochemical hyperandrogenemia (elevated free testosterone levels using sensitive assays). Chronic anovulation was defined as persistence of menstrual irregularities 2 years post-menarche and pelvic ultrasound (USG) showing increased ovarian size (> 10 cm³). Normal physiological variations unrelated to hyperandrogenemia are common in adolescent ovaries and limits the usefulness of pelvic USG as a diagnostic criterion for PCOS [13,47,48]^. Also, the prevalence of increased ovarian size in hyperandrogenemic adolescent patients was reported to be low, and its utility as a criterion for diagnosis needs to be further explored [49]. In our current practice we do not rely on pelvic USG findings to make a PCOS diagnosis.

Due to longstanding controversies and lack of consensus surrounding the accurate diagnostic criteria, a recent guideline was developed by experts in pediatric endocrinology and adolescent medicine invited by the Pediatric Endocrine Society to address these issues [13].The guideline committee assessed the literature in order to define which criteria have sufficient evidence to be used for diagnosis of PCOS in adolescents. They recommend that PCOS should be considered in an adolescent girl presenting with unexplained menstrual irregularities, moderate to severe hirsutism or acne, and elevated levels of serum androgens (total and free testosterone) using reliable assay with well-defined ranges. Although intrinsic insulin resistance unique to PCOS is well known, none of the current guidelines either for adolescent and adult women include it as part of the diagnostic criteria. Since longitudinal studies focusing on the natural history of PCOS in this age-group are lacking, the current recommendations focus on timely screening and treatment in symptomatic adolescent girls suspected of having PCOS.

When there are PCOS features but menstrual irregularity has not been present for at least 2 years, one can defer the diagnostic label and instead use the term at-risk for PCOS. Such patients should have frequent longitudinal re-evaluations and should be offered treatment for their symptoms [13].

• How should adolescents with PCOS be managed?

The treatment of PCOS is symptom-directed and should be tailored according to the complaints of the individual patient. However, it also must focus on the core dysfunctions: anovulation, hyperandrogenemia, obesity, and insulin resistance. It also requires bridging patient expectations of regulating menses, lessening the troublesome clinical signs of hyperandrogenemia (hirsutism, acne), and obesity management with the health care provider’s goals of preventing endometrial hyperplasia and cancer, diabetes mellitus, and cardiovascular disease.

Regulating menstruation and reducing cutaneous manifestations of hyperandrogenemia is the priority for any adolescent with PCOS. Combined oral contraceptive pills (COCs) are the first line of medical treatment for most adolescents. COCs restore endometrial cycling and suppress androgen levels, and are therefore optimal in treating abnormal uterine bleeding, protecting against endometrial carcinoma, and alleviating cutaneous manifestations of hyperandrogenemia (hirsutism and acne). Progestin monotherapy is considered an alternative therapy in individuals with contraindications to COCs (ie, thromboembolic risk). Although it is not effective in lowering androgen levels thus does not help reduce hair growth and acne, progestin monotherapy protects the endometrium and reduces the risk of endometrial cancer [50].

The majority of patients with PCOS are overweight or obese. Regardless of BMI, patients with PCOS have profound intrinsic insulin resistance that gets worse with overweight or obesity. Weight reduction by restricting caloric intake and increasing physical exercise is vital and has shown to be effective in regulating menstrual cycles, but is difficult to achieve [51–53]. Metformin can regulate menstrual cycles and decrease androgen levels by improving insulin sensitivity [54,55]. The use of metformin in PCOS patients is still controversial and abnormal glucose tolerance is the only approved indication [61]. However, combing metformin with COCs and lifestyle modification in obese PCOS patients has been shown to be used more frequently in pediatric endocrine clinics [56]. COCs are the only agents that can lower testosterone levels and improve ovulation and hirsutism; these effects are seen less frequently with lifestyle modification or metformin, either used alone or in combination.

COC monotherapy is first-line therapy to treat hirsutism. Consider anti-androgen treatment for hirsutism if there is no improvement after 6–9 months of hormonal treatment [57]. Antiandrogens reduce hirsutism by decreasing androgen production and binding the androgen receptors in target tissue. Spironolactone is the most commonly used antiandrogen therapy in adolescent girls with PCOS. Given the risk of teratogenicity with antiandrogens if pregnancy occurs, it is recommended to use it in combination with COCs [57]. Cosmetic measures including direct hair removal and electrolysis should be discussed with patients as other options for treatment of hirsutism.

Obese patients with PCOS are at higher risk for metabolic syndrome, a constellation of features including glucose intolerance, central obesity, hypertension, and dyslipidemia. Hyperandrogenemia and insulin resistance are linked with metabolic syndrome in PCOS. Reducing hyperandrogenemia and insulin resistance could reverse metabolic derangements and further reduce the risk of cardiovascular disease [58].

Worsening insulin resistance with COCs in PCOS has raised the concern of long-term metabolic derangements and cardiovascular adverse effects. COCs tend to increase total cholesterol, triglyceride, and high-sensitivity C-reactive protein levels [59]. However, the long-term implications of these findings are not well understood, attributable to the lack of longitudinal studies, especially in women with PCOS receiving COCs. Newer COCs containing less androgenic progestin may have less deleterious effect on insulin resistance and lipid profile. Due to insufficient use in adolescent patients, a definitive conclusion about their long-term safety cannot be drawn. Thus, there remains a theoretical risk of COCs exacerbating the underlying metabolic derangements in PCOS that can lead to subsequent adverse cardiovascular events.

Adolescent girls with PCOS are also at an increased risk for depression and anxiety disorders. The 2013 Endocrine Society clinical practice guideline suggests that adolescent girls with PCOS should be screened for depression and anxiety by history [51].If symptoms are present, patients should receive appropriate psychological referral and treatment.

Case Continued

As she had no contraindications to COCs, the patient was started on COC therapy to regulate her menstrual periods and alleviate the symptoms of hirsutism. Due to impaired glucose tolerance test results and increased risk for type 2 diabetes, treatment with metformin was also initiated. The patient met with a dietician, who offered recommendations for adopting a healthy lifestyle and introduced her to the “3,2,1,0, blast off” model: 3 consistent meals, 2 hours or less of screen time, 1 hour or more of physical activity, and 0 sweetened beverages a day. The patient was also advised to increase daily consumption of fruits and vegetables. Results of the 2-item Patient Health Questionnaire (PHQ-2) for depression were negative.

At a follow-up visit 6 months later, the patient reported that her menstrual periods were regular. There was some improvement in hirsutism, requiring less shaving, and there was no increase in weight. Repeat laboratory evaluations showed normal free testosterone level, decreased HbA1c (5.2%), and improved random blood glucose (130 mg/dL). The patient was seen regularly and treatment results monitored. No side effects were seen over a 4.5-year period. As PCOS is a lifelong condition, at the age of 21 the patient was referred to an adult endocrine clinic for further management.

Corresponding author: Alvina R. Kansra, MD, Medical College of Wisconsin, 8701 Watertown Plank Rd., Wauwatosa, WI 53226, [email protected].

Financial disclosures: None.

From the Department of Pediatrics, Section of Endocrinology & Diabetes, Medical College of Wisconsin, Milwaukee, WI.

Abstract

• Objective: To review the diagnosis and management of polycystic ovary syndrome (PCOS) in adolescent patients.
• Methods: Review of the literature.
• Results: PCOS is a complex, heterogeneous disorder that frequently manifests during puberty. The symptoms of PCOS (ie, menstrual irregularities, hirsutism, and acne) tend to overlap with normal pubertal changes. Diagnostic criteria for PCOS in the adolescent age-group is still lacking. Current practice is to utilize adult diagnostic criteria, which raises the concern for misdiagnosis. The underlying etiology for the disorder is still unclear, but insulin resistance is present in both obese and non-obese PCOS patients. Although recognizing adolescents with PCOS is challenging, evaluating and managing patients for hyperandrogenemia and metabolic syndrome is imperative to prevent long-term reproductive and metabolic complications.
• Conclusion: PCOS is increasingly encountered during adolescence. Recognizing adolescent girls with PCOS is a challenge but important for preventing long-term adverse health outcomes.

Polycystic ovary syndrome (PCOS) is a complex disorder most commonly characterized by chronic anovulation and clinical and biochemical features of hyperandrogenemia. It affects 4% to 12% of reproductive-aged women [1,2]. In adolescents, the exact prevalence is unknown, but in a recent study the prevalence of a confirmed diagnosis of PCOS in adolescents aged 15 to 19 years was 0.56%, which increased to 1.14% when undiagnosed cases with documented symptoms qualifying for PCOS according to NIH criteria were included [3]. The primary underlying defect in PCOS remains unknown, but key features include insulin resistance, impaired gonadotropin dynamics, and androgen excess.

Profound functional variations in the hypothalamic-pituitary-ovarian axis commonly seen during normal puberty may result in clinical and biochemical changes that mimic some of the features of PCOS. During the early stages of puberty, adolescent girls tend to have anovulatory menstrual cycles, higher androgen levels, and polycystic ovaries [4,5]. Thus, the clinical signs of hyperandrogenemia commonly seen in adults are less reliable in the adolescent age-group. Diagnostic criteria have been developed for adults and are based upon the various combinations of oligomenorrhea, unexplained hyperandrogenemia, and polycystic ovaries on imaging (Table 1) [6–8]. Applying these adult criteria in adolescent patients with suspected PCOS has always raised the concern of misdiagnosis as some of the changes seen in this age-group may likely be due to normal pubertal development. However, due to the paucity of data, the current practice is to utilize the adult diagnostic criteria. Because of the heterogeneous nature of the disorder, recognizing adolescents with PCOS may be challenging. However, early recognition and management is important to prevent some of the long-term reproductive and metabolic complications associated with this syndrome.

Case Study

Initial Presentation

A 16-year-old female patient presents to the PCOS clinic for evaluation of obesity and amenorrhea.

History

The patient, who is otherwise healthy, began gaining weight at age 7. During this period, her weight increased from the 15th to (currently) the 90th percentile; her height remained constant (75th percentile). Menarche was at 12 years of age. Menstrual periods have been irregular since the onset of menarche and she has had no periods for the past 5 months. She noticed excessive hair growth on her face, chin, and neck soon after the onset of menarche. She has been shaving her facial hair once every 2–3 days.

The patient’s detailed diet history included eating 3 meals daily and snacks in-between meals. The patient was consuming sweet beverages regularly. There was minimal intake fruits and vegetables. The portion sizes for each meal were large. The patient had minimal physical activity and screen time was more than 2 hours daily.

Family history is significant for obesity and type 2 diabetes in her mother and maternal grandmother and is negative for PCOS.

Physical Examination

Vital signs were within normal limits. She was 5 ft 6 in tall and weighed 242 lb, with a body mass index (BMI) of 40 (99th percentile; Z-score 2.41). Physical examination showed coarse hair extending from the sideburns to the chin as well as from pubis symphysis to navel with evidence of hair removal. She had acanthosis nigricans on her neck, mild acne, and evidence of central obesity with pink striae marks on the abdomen. She was Tanner stage 5 for breast and pubic hair and there was no evidence of virilization (clitoral hypertrophy, deepening of the voice, severe hirsutism, male pattern baldness, and masculine habitus). Other physical examination findings were within normal limits.

• What physical findings in this patient are suggestive of clinical hyperandrogenemia?

Physiologic irregular menstruation is a well known phenomenon in adolescent girls and is generally due to anovulatory cycles [9–12]. Menstrual cycles shorter than 19 days or longer than 90 days at any stage after menarche are considered abnormal. The menstrual irregularity that is commonly seen within the first 2–3 years after the first menarche can last up to 5 years [5]. However, the majority of girls establish 20- to 45-day cycles within the first 2 years [13].

Androgen excess, defined by the presence of clinical and/or biochemical hyperandrogenemia, should be considered in any adolescent girl who is 2 to 3 years’ post-menarche and presenting with irregular menstrual periods, coarse terminal hair in a male distribution pattern (hirsutism), or moderate to severe inflammatory acne. Hirsutism is androgen dependent [14–16] and must be distinguished from hypertrichosis, which is generalized excessive vellus hair growth present all over the body. Clinical hyperandrogenemia, which includes hirsutism, acne vulgaris, as well as androgenetic alopecia, is well correlated with elevated androgen levels; however, the severity of hirsutism does not correlate well with circulating androgen levels [17,18]. Mild hirsutism is often not associated with hyperandrogenemia in otherwise asymptomatic individuals,but it may be a sign of hyperandrogenemia in adolescents when associated with other features of PCOS, ie, menstrual irregularity [14–16, 19–22]. Defining hirsutism in early adolescence may be difficult since the sexual hair may still be developing, and laboratory evaluation should be considered (see below), especially in an overweight/obese adolescent girl presenting with oligomenorrhea. Ethnic variation due to decreased skin sensitivity to androgens can result in minimal hirsutism despite elevated plasma androgen levels and must be considered among certain Asian women. Women with PCOS from China, Japan, Thailand, and East and Southeast Asian countries tend to have low scores on hirsutism rating scales even with elevated plasma androgens levels [16,23].

Although having acne during puberty is not considered as a marker for hyperandrogenemia, patients with moderate to severe inflammatory acne that is poorly responsive to topical treatment should be evaluated for underlying hyperandrogenemia [19,24,25].

• What laboratory tests should be obtained to when there is clinical suspicion of hyperandrogenemia?

Case Continued

The patient underwent laboratory assessment that included total and free testosterone levels, lipid panel, thyroid studies, prolactin level, comprehensive metabolic panel (CMP) and hemoglobin A1c (HbA1c). Due to lack of virilization, she was not tested for PCOS-like syndromes. Her total and free testosterone were 90 ng/dL (normal, < 41) and 24.7 pg/mL (normal, 0.5–3.9) respectively. Thyroid-stimulating hormone and prolactin levels were normal. She had normal lipid levels and CMP but HbA1c was 5.9% (pre-diabetic range). The results of a 2-hour oral glucose tolerance test revealed a level of 160 mg/dL, indicative of impaired glucose tolerance.

• What is the pathophysiology and diagnostic criteria for PCOS in adolescents?

PCOS has diverse etiology and has been linked to both genetic and environmental factors affecting ovarian steroidogenesis [13,30]. While the familial clustering strongly supports the role of genetic factors, variability in phenotypic features within the same or different families indicates the importance of environmental contribution [31–34].

The exact underlying mechanism leading to disruption of ovulation is still unclear; however, hyperinsulinemia augmenting ovarian androgen production has been well recognized [35–37]. Insulin resistance is a characteristic finding in PCOS and occurs both in obese and lean patients [38,39]. Obesity further exacerbates the insulin resistance state in PCOS patients. Therefore, obese patients with PCOS have more severe hyperandrogenemia and consequences from it (hirsutism, menstrual abnormalities, and metabolic derangements) than normal-weight PCOS patients [40,41]. Similar to LH, insulin can stimulate ovarian theca cells directly and cause increased production of androgens [42]. Elevated androgen levels cause the irregular menstrual periods as well as clinical signs of hyperandrogenemia, such as hirsutism and acne.

Altered gonadotropin dynamics is another possible etiological factor that is linked with PCOS. Hyperinsulinemia affects the regulation of gonadotropin-releasing hormone (GnRH) pulse generator, causing hypersecretion of LH [43]. Obese peripubertal girls have been identified having altered LH secretion [44,45]. This results in increased LH levels relative to FSH. Normal FSH is required to stimulate ovarian folliculognensis; insufficient FSH levels cause anovulation and menstrual irregularities. Abnormal LH secretion and fasting insulin levels have been identified the independent predictors for hyperandrogenemia in some peripubertal obese girls [46].

In 2010 Carmina et al published new criteria to diagnose PCOS in adolescents [27].They recommended that in diagnosing PCOS in adolescents, all 3 previously mentioned criteria should be present: hyperandrogenemia, chronic anovulation, and polycystic ovaries. With the exception of worsening hirsutism, the new recommendations greatly emphasized biochemical hyperandrogenemia (elevated free testosterone levels using sensitive assays). Chronic anovulation was defined as persistence of menstrual irregularities 2 years post-menarche and pelvic ultrasound (USG) showing increased ovarian size (> 10 cm³). Normal physiological variations unrelated to hyperandrogenemia are common in adolescent ovaries and limits the usefulness of pelvic USG as a diagnostic criterion for PCOS [13,47,48]^. Also, the prevalence of increased ovarian size in hyperandrogenemic adolescent patients was reported to be low, and its utility as a criterion for diagnosis needs to be further explored [49]. In our current practice we do not rely on pelvic USG findings to make a PCOS diagnosis.

Due to longstanding controversies and lack of consensus surrounding the accurate diagnostic criteria, a recent guideline was developed by experts in pediatric endocrinology and adolescent medicine invited by the Pediatric Endocrine Society to address these issues [13].The guideline committee assessed the literature in order to define which criteria have sufficient evidence to be used for diagnosis of PCOS in adolescents. They recommend that PCOS should be considered in an adolescent girl presenting with unexplained menstrual irregularities, moderate to severe hirsutism or acne, and elevated levels of serum androgens (total and free testosterone) using reliable assay with well-defined ranges. Although intrinsic insulin resistance unique to PCOS is well known, none of the current guidelines either for adolescent and adult women include it as part of the diagnostic criteria. Since longitudinal studies focusing on the natural history of PCOS in this age-group are lacking, the current recommendations focus on timely screening and treatment in symptomatic adolescent girls suspected of having PCOS.

When there are PCOS features but menstrual irregularity has not been present for at least 2 years, one can defer the diagnostic label and instead use the term at-risk for PCOS. Such patients should have frequent longitudinal re-evaluations and should be offered treatment for their symptoms [13].

• How should adolescents with PCOS be managed?

The treatment of PCOS is symptom-directed and should be tailored according to the complaints of the individual patient. However, it also must focus on the core dysfunctions: anovulation, hyperandrogenemia, obesity, and insulin resistance. It also requires bridging patient expectations of regulating menses, lessening the troublesome clinical signs of hyperandrogenemia (hirsutism, acne), and obesity management with the health care provider’s goals of preventing endometrial hyperplasia and cancer, diabetes mellitus, and cardiovascular disease.

Regulating menstruation and reducing cutaneous manifestations of hyperandrogenemia is the priority for any adolescent with PCOS. Combined oral contraceptive pills (COCs) are the first line of medical treatment for most adolescents. COCs restore endometrial cycling and suppress androgen levels, and are therefore optimal in treating abnormal uterine bleeding, protecting against endometrial carcinoma, and alleviating cutaneous manifestations of hyperandrogenemia (hirsutism and acne). Progestin monotherapy is considered an alternative therapy in individuals with contraindications to COCs (ie, thromboembolic risk). Although it is not effective in lowering androgen levels thus does not help reduce hair growth and acne, progestin monotherapy protects the endometrium and reduces the risk of endometrial cancer [50].

The majority of patients with PCOS are overweight or obese. Regardless of BMI, patients with PCOS have profound intrinsic insulin resistance that gets worse with overweight or obesity. Weight reduction by restricting caloric intake and increasing physical exercise is vital and has shown to be effective in regulating menstrual cycles, but is difficult to achieve [51–53]. Metformin can regulate menstrual cycles and decrease androgen levels by improving insulin sensitivity [54,55]. The use of metformin in PCOS patients is still controversial and abnormal glucose tolerance is the only approved indication [61]. However, combing metformin with COCs and lifestyle modification in obese PCOS patients has been shown to be used more frequently in pediatric endocrine clinics [56]. COCs are the only agents that can lower testosterone levels and improve ovulation and hirsutism; these effects are seen less frequently with lifestyle modification or metformin, either used alone or in combination.

COC monotherapy is first-line therapy to treat hirsutism. Consider anti-androgen treatment for hirsutism if there is no improvement after 6–9 months of hormonal treatment [57]. Antiandrogens reduce hirsutism by decreasing androgen production and binding the androgen receptors in target tissue. Spironolactone is the most commonly used antiandrogen therapy in adolescent girls with PCOS. Given the risk of teratogenicity with antiandrogens if pregnancy occurs, it is recommended to use it in combination with COCs [57]. Cosmetic measures including direct hair removal and electrolysis should be discussed with patients as other options for treatment of hirsutism.

Obese patients with PCOS are at higher risk for metabolic syndrome, a constellation of features including glucose intolerance, central obesity, hypertension, and dyslipidemia. Hyperandrogenemia and insulin resistance are linked with metabolic syndrome in PCOS. Reducing hyperandrogenemia and insulin resistance could reverse metabolic derangements and further reduce the risk of cardiovascular disease [58].

Worsening insulin resistance with COCs in PCOS has raised the concern of long-term metabolic derangements and cardiovascular adverse effects. COCs tend to increase total cholesterol, triglyceride, and high-sensitivity C-reactive protein levels [59]. However, the long-term implications of these findings are not well understood, attributable to the lack of longitudinal studies, especially in women with PCOS receiving COCs. Newer COCs containing less androgenic progestin may have less deleterious effect on insulin resistance and lipid profile. Due to insufficient use in adolescent patients, a definitive conclusion about their long-term safety cannot be drawn. Thus, there remains a theoretical risk of COCs exacerbating the underlying metabolic derangements in PCOS that can lead to subsequent adverse cardiovascular events.

Adolescent girls with PCOS are also at an increased risk for depression and anxiety disorders. The 2013 Endocrine Society clinical practice guideline suggests that adolescent girls with PCOS should be screened for depression and anxiety by history [51].If symptoms are present, patients should receive appropriate psychological referral and treatment.

Case Continued

As she had no contraindications to COCs, the patient was started on COC therapy to regulate her menstrual periods and alleviate the symptoms of hirsutism. Due to impaired glucose tolerance test results and increased risk for type 2 diabetes, treatment with metformin was also initiated. The patient met with a dietician, who offered recommendations for adopting a healthy lifestyle and introduced her to the “3,2,1,0, blast off” model: 3 consistent meals, 2 hours or less of screen time, 1 hour or more of physical activity, and 0 sweetened beverages a day. The patient was also advised to increase daily consumption of fruits and vegetables. Results of the 2-item Patient Health Questionnaire (PHQ-2) for depression were negative.

At a follow-up visit 6 months later, the patient reported that her menstrual periods were regular. There was some improvement in hirsutism, requiring less shaving, and there was no increase in weight. Repeat laboratory evaluations showed normal free testosterone level, decreased HbA1c (5.2%), and improved random blood glucose (130 mg/dL). The patient was seen regularly and treatment results monitored. No side effects were seen over a 4.5-year period. As PCOS is a lifelong condition, at the age of 21 the patient was referred to an adult endocrine clinic for further management.

Corresponding author: Alvina R. Kansra, MD, Medical College of Wisconsin, 8701 Watertown Plank Rd., Wauwatosa, WI 53226, [email protected].

Financial disclosures: None.

The Society of Hospital Medicine (SHM) proudly names Robert E. Burke, MD, MS, assistant chief of hospital medicine at Denver VA Medical Center, as the recipient of the 2016 Junior Investigator Award. He will receive the award at HM16 in San Diego.

Dr. Burke’s research focuses on improving transitional care outcomes for older adults. An academic hospitalist and health services researcher, Dr. Burke is working toward becoming a nationally recognized outcomes researcher and implementation scientist working in hospitals and post-acute-care (PAC) facilities.

In addition to this award, Dr. Burke also received the 2015 Career Development Award from SHM, the Alliance for Academic Internal Medicine, and the Association of Specialty Professors in support of the Grants for Early Medical/Surgical Subspecialists’ Transition to Aging Research Program (GEMSSTAR).

The Junior Investigator Award recognizes talented early-stage investigators in the first five years of a faculty position. Criteria for selection include the impact the research may have on hospital medicine, career achievements and milestones (e.g., abstracts, peer-reviewed publications, intra- and extramural grant funding), and engagement with SHM. TH

Brett Radler is SHM’s communications coordinator.

The Society of Hospital Medicine (SHM) proudly names Robert E. Burke, MD, MS, assistant chief of hospital medicine at Denver VA Medical Center, as the recipient of the 2016 Junior Investigator Award. He will receive the award at HM16 in San Diego.

Dr. Burke’s research focuses on improving transitional care outcomes for older adults. An academic hospitalist and health services researcher, Dr. Burke is working toward becoming a nationally recognized outcomes researcher and implementation scientist working in hospitals and post-acute-care (PAC) facilities.

In addition to this award, Dr. Burke also received the 2015 Career Development Award from SHM, the Alliance for Academic Internal Medicine, and the Association of Specialty Professors in support of the Grants for Early Medical/Surgical Subspecialists’ Transition to Aging Research Program (GEMSSTAR).

The Junior Investigator Award recognizes talented early-stage investigators in the first five years of a faculty position. Criteria for selection include the impact the research may have on hospital medicine, career achievements and milestones (e.g., abstracts, peer-reviewed publications, intra- and extramural grant funding), and engagement with SHM. TH

Brett Radler is SHM’s communications coordinator.

The Society of Hospital Medicine (SHM) proudly names Robert E. Burke, MD, MS, assistant chief of hospital medicine at Denver VA Medical Center, as the recipient of the 2016 Junior Investigator Award. He will receive the award at HM16 in San Diego.

Dr. Burke’s research focuses on improving transitional care outcomes for older adults. An academic hospitalist and health services researcher, Dr. Burke is working toward becoming a nationally recognized outcomes researcher and implementation scientist working in hospitals and post-acute-care (PAC) facilities.

In addition to this award, Dr. Burke also received the 2015 Career Development Award from SHM, the Alliance for Academic Internal Medicine, and the Association of Specialty Professors in support of the Grants for Early Medical/Surgical Subspecialists’ Transition to Aging Research Program (GEMSSTAR).

The Junior Investigator Award recognizes talented early-stage investigators in the first five years of a faculty position. Criteria for selection include the impact the research may have on hospital medicine, career achievements and milestones (e.g., abstracts, peer-reviewed publications, intra- and extramural grant funding), and engagement with SHM. TH

Brett Radler is SHM’s communications coordinator.

Prescription medications

Photo courtesy of the CDC

New research has revealed inherited genetic variations that may predispose patients to severe toxicity from thiopurines, a class of medications used as anticancer and immunosuppressive drugs.

Investigators identified 4 variations in the NUDT15 gene that alter thiopurine metabolism, leaving patients particularly sensitive to the drugs and at risk for toxicity.

One in 3 Japanese patients in this study carried the variations.

And evidence suggests the variations are common in other populations across Asia and in individuals of Hispanic ethnicity.

Jun J. Yang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these findings in Nature Genetics.

In 2015, Dr Yang and his colleagues published evidence linking a NUDT15 variant to reduced tolerance of mercaptopurine and reported the variant was more common in patients of East Asian ancestry.

With the current study, the investigators identified 3 additional NUDT15 variants and found that all 4 variants—p.Arg139Cys, p.Arg139His, p.Val18Ile, and p.Val18_Val19insGlyVal—were associated with lower levels of enzymatic activity and imbalance of thiopurine metabolism.

In a group of 270 children with acute lymphoblastic leukemia (ALL), the variants caused a 74.4% to 100% loss of NUDT15 function. They also predicted enzyme activity and mercaptopurine tolerance. In Singapore and Japan, for example, patients with the 2 highest risk variants had the lowest level of enzyme activity.

“These patients had excessive levels of the active drug metabolites per mercaptopurine dose, which suggests we may reduce the drug dose to achieve the level necessary to kill leukemia cells without causing toxicity,” Dr Yang said, adding that the NUDT15 variants have no other known health consequences.

The investigators also checked leukemic cells from 285 children newly diagnosed with ALL and found that patients with NUDT15 variants were more sensitive to thiopurines.

“That suggests we can screen for NUDT15 variants and potentially plan mercaptopurine doses according to each patient’s genotype before the therapy starts,” Dr Yang said. “This way, we hope to avoid toxicity without compromising treatment effectiveness.”

The investigators noted that future studies are needed to determine optimal thiopurine doses for patients with different NUDT15 variants.

Meanwhile, the search continues for variants in NUDT15 or other genes that influence chemotherapy effectiveness and safety. The NUDT15 variants and previously identified TPMT variants could not fully explain why Guatemalan patients in this study tolerated the lowest doses of mercaptopurine.

Prescription medications

Photo courtesy of the CDC

New research has revealed inherited genetic variations that may predispose patients to severe toxicity from thiopurines, a class of medications used as anticancer and immunosuppressive drugs.

Investigators identified 4 variations in the NUDT15 gene that alter thiopurine metabolism, leaving patients particularly sensitive to the drugs and at risk for toxicity.

One in 3 Japanese patients in this study carried the variations.

And evidence suggests the variations are common in other populations across Asia and in individuals of Hispanic ethnicity.

Jun J. Yang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these findings in Nature Genetics.

In 2015, Dr Yang and his colleagues published evidence linking a NUDT15 variant to reduced tolerance of mercaptopurine and reported the variant was more common in patients of East Asian ancestry.

With the current study, the investigators identified 3 additional NUDT15 variants and found that all 4 variants—p.Arg139Cys, p.Arg139His, p.Val18Ile, and p.Val18_Val19insGlyVal—were associated with lower levels of enzymatic activity and imbalance of thiopurine metabolism.

In a group of 270 children with acute lymphoblastic leukemia (ALL), the variants caused a 74.4% to 100% loss of NUDT15 function. They also predicted enzyme activity and mercaptopurine tolerance. In Singapore and Japan, for example, patients with the 2 highest risk variants had the lowest level of enzyme activity.

“These patients had excessive levels of the active drug metabolites per mercaptopurine dose, which suggests we may reduce the drug dose to achieve the level necessary to kill leukemia cells without causing toxicity,” Dr Yang said, adding that the NUDT15 variants have no other known health consequences.

The investigators also checked leukemic cells from 285 children newly diagnosed with ALL and found that patients with NUDT15 variants were more sensitive to thiopurines.

“That suggests we can screen for NUDT15 variants and potentially plan mercaptopurine doses according to each patient’s genotype before the therapy starts,” Dr Yang said. “This way, we hope to avoid toxicity without compromising treatment effectiveness.”

The investigators noted that future studies are needed to determine optimal thiopurine doses for patients with different NUDT15 variants.

Meanwhile, the search continues for variants in NUDT15 or other genes that influence chemotherapy effectiveness and safety. The NUDT15 variants and previously identified TPMT variants could not fully explain why Guatemalan patients in this study tolerated the lowest doses of mercaptopurine.

Prescription medications

Photo courtesy of the CDC

New research has revealed inherited genetic variations that may predispose patients to severe toxicity from thiopurines, a class of medications used as anticancer and immunosuppressive drugs.

Investigators identified 4 variations in the NUDT15 gene that alter thiopurine metabolism, leaving patients particularly sensitive to the drugs and at risk for toxicity.

One in 3 Japanese patients in this study carried the variations.

And evidence suggests the variations are common in other populations across Asia and in individuals of Hispanic ethnicity.

Jun J. Yang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these findings in Nature Genetics.

In 2015, Dr Yang and his colleagues published evidence linking a NUDT15 variant to reduced tolerance of mercaptopurine and reported the variant was more common in patients of East Asian ancestry.

With the current study, the investigators identified 3 additional NUDT15 variants and found that all 4 variants—p.Arg139Cys, p.Arg139His, p.Val18Ile, and p.Val18_Val19insGlyVal—were associated with lower levels of enzymatic activity and imbalance of thiopurine metabolism.

In a group of 270 children with acute lymphoblastic leukemia (ALL), the variants caused a 74.4% to 100% loss of NUDT15 function. They also predicted enzyme activity and mercaptopurine tolerance. In Singapore and Japan, for example, patients with the 2 highest risk variants had the lowest level of enzyme activity.

“These patients had excessive levels of the active drug metabolites per mercaptopurine dose, which suggests we may reduce the drug dose to achieve the level necessary to kill leukemia cells without causing toxicity,” Dr Yang said, adding that the NUDT15 variants have no other known health consequences.

The investigators also checked leukemic cells from 285 children newly diagnosed with ALL and found that patients with NUDT15 variants were more sensitive to thiopurines.

“That suggests we can screen for NUDT15 variants and potentially plan mercaptopurine doses according to each patient’s genotype before the therapy starts,” Dr Yang said. “This way, we hope to avoid toxicity without compromising treatment effectiveness.”

The investigators noted that future studies are needed to determine optimal thiopurine doses for patients with different NUDT15 variants.

Meanwhile, the search continues for variants in NUDT15 or other genes that influence chemotherapy effectiveness and safety. The NUDT15 variants and previously identified TPMT variants could not fully explain why Guatemalan patients in this study tolerated the lowest doses of mercaptopurine.

As part of its Next Accreditation System, the Accreditation Council for Graduate Medical Education (ACGME) has introduced the Clinical Learning Environment Review (CLER) program, designed to assess the learning environment of institutions that have ACGME residency and fellowship programs.¹ The CLER program emphasizes the responsibility of these hospitals, multispecialty groups, and other organizations to focus on quality and safety in the health care environment of resident learning and patient care. The expectation is that emphasis on quality of care in a residency training program will influence these physicians’ approach to quality of care after graduation.^2,3 The Department of Dermatology at the University of Mississippi Medical Center (UMMC)(Jackson, Mississippi) saw CLER as an opportunity to demonstrate leadership in the patient safety movement.

CLER Program at UMMC

As a model CLER program at our institution, our project at the outset concentrated resident efforts on the focus areas specified by the ACGME (Table 1). We also were aware that our ACGME committee would need to answer questions during CLER site visits (Table 2). Because the data generated would not be used for accreditation decisions, there was no concern that exposing errors would jeopardize our postgraduate training certification.

The first 15 minutes of monthly faculty meetings were devoted to the presentation of a resident project, called a QA/QI (quality assurance/quality improvement) moment, that addressed ACGME focus areas 1, 2, 3, or 6 (Table 1). (Transitions in care [focus area 4] and work hours and fatigue [focus area 5] generally are less important issues in a predominantly outpatient specialty such as dermatology.) The residents were encouraged to identify areas where patient harm could occur due to poorly designed systems and to report situations in which patients actually were harmed.

Each project had to be approved by the department chairperson based on the following 4 requirements: First, the initiative must have the potential to notably impact patient safety and reduce harm. Second, residents with faculty support had to design methods to assess the identified problem. Third, participants had to design (to the best of their abilities) cost-effective and achievable interventions in a manner that would not produce unintended consequences. Fourth, residents were asked to devise a system to close the loop, ensuring that the effort put into the process was not wasted.

Findings From the CLER Program

The CLER program generates data on program and institutional attributes that have a salutatory effect on quality and safety, specifically involving 6 focus areas highlighted in Table 1. Putting residents at the center of efforts to improve the quality of care in our department proved critical to improving patient safety.

Involving residents in a series of QA/QI initiatives was logical because they rotate with faculty members. They also are in a position to view inconsistencies and to work to establish consistent patterns of patient care. In addition, our busy faculty members are charged with a variety of other clinical, educational, and administrative duties complicated by requirements in the design of a new residency training program. Faculty and residents working together were able to find problem areas in our department and devise solutions to improve those problems.

The CLER program involved a series of steps. Residents were charged with identifying errors (QA) and then devising a system to prevent similar errors from being repeated (QI)(Table 3). Efforts focused on preventing needless harm in our department. Initiatives developed by residents, who are closest to patients, have advantages over safety programs developed by the hospital’s administration. Residents became passionate about error prevention when they determined that their efforts could make a difference to patients.

Forward Thinking for Dermatology Practices

Perhaps there are lessons here that could apply to safety promotion in the practicing dermatologist’s office. The American Board of Dermatology, within the framework established by the American Board of Medical Specialties, requires physicians seeking recertification to participate in preapproved practice assessment QI exercises twice every 10 years.¹⁷ Six programs sponsored by the American Academy of Dermatology have now been approved in the areas of melanoma, biopsy follow-up measure, psoriasis, chronic urticaria, venous insufficiency, and laser- and light-based therapy for rejuvenation.¹⁸ An additional program has been approved for dermatopathologists through the American Society of Dermatopathology.¹⁹ None of these programs match the topics chosen by our residents in consultation with faculty to meet safety gaps identified in clinics at UMMC. Perhaps the next generation of performance improvement continuing medical education programs could include a pilot program for part 4 of Maintenance of Certification credit that is nonpunitive, patient focused, and allows dermatologists to design specific error-prevention solutions tailored to their individual practice in the same way residency programs are taking up this task.

As part of its Next Accreditation System, the Accreditation Council for Graduate Medical Education (ACGME) has introduced the Clinical Learning Environment Review (CLER) program, designed to assess the learning environment of institutions that have ACGME residency and fellowship programs.¹ The CLER program emphasizes the responsibility of these hospitals, multispecialty groups, and other organizations to focus on quality and safety in the health care environment of resident learning and patient care. The expectation is that emphasis on quality of care in a residency training program will influence these physicians’ approach to quality of care after graduation.^2,3 The Department of Dermatology at the University of Mississippi Medical Center (UMMC)(Jackson, Mississippi) saw CLER as an opportunity to demonstrate leadership in the patient safety movement.

CLER Program at UMMC

As a model CLER program at our institution, our project at the outset concentrated resident efforts on the focus areas specified by the ACGME (Table 1). We also were aware that our ACGME committee would need to answer questions during CLER site visits (Table 2). Because the data generated would not be used for accreditation decisions, there was no concern that exposing errors would jeopardize our postgraduate training certification.

The first 15 minutes of monthly faculty meetings were devoted to the presentation of a resident project, called a QA/QI (quality assurance/quality improvement) moment, that addressed ACGME focus areas 1, 2, 3, or 6 (Table 1). (Transitions in care [focus area 4] and work hours and fatigue [focus area 5] generally are less important issues in a predominantly outpatient specialty such as dermatology.) The residents were encouraged to identify areas where patient harm could occur due to poorly designed systems and to report situations in which patients actually were harmed.

Each project had to be approved by the department chairperson based on the following 4 requirements: First, the initiative must have the potential to notably impact patient safety and reduce harm. Second, residents with faculty support had to design methods to assess the identified problem. Third, participants had to design (to the best of their abilities) cost-effective and achievable interventions in a manner that would not produce unintended consequences. Fourth, residents were asked to devise a system to close the loop, ensuring that the effort put into the process was not wasted.

Findings From the CLER Program

The CLER program generates data on program and institutional attributes that have a salutatory effect on quality and safety, specifically involving 6 focus areas highlighted in Table 1. Putting residents at the center of efforts to improve the quality of care in our department proved critical to improving patient safety.

Involving residents in a series of QA/QI initiatives was logical because they rotate with faculty members. They also are in a position to view inconsistencies and to work to establish consistent patterns of patient care. In addition, our busy faculty members are charged with a variety of other clinical, educational, and administrative duties complicated by requirements in the design of a new residency training program. Faculty and residents working together were able to find problem areas in our department and devise solutions to improve those problems.

The CLER program involved a series of steps. Residents were charged with identifying errors (QA) and then devising a system to prevent similar errors from being repeated (QI)(Table 3). Efforts focused on preventing needless harm in our department. Initiatives developed by residents, who are closest to patients, have advantages over safety programs developed by the hospital’s administration. Residents became passionate about error prevention when they determined that their efforts could make a difference to patients.

Forward Thinking for Dermatology Practices

Perhaps there are lessons here that could apply to safety promotion in the practicing dermatologist’s office. The American Board of Dermatology, within the framework established by the American Board of Medical Specialties, requires physicians seeking recertification to participate in preapproved practice assessment QI exercises twice every 10 years.¹⁷ Six programs sponsored by the American Academy of Dermatology have now been approved in the areas of melanoma, biopsy follow-up measure, psoriasis, chronic urticaria, venous insufficiency, and laser- and light-based therapy for rejuvenation.¹⁸ An additional program has been approved for dermatopathologists through the American Society of Dermatopathology.¹⁹ None of these programs match the topics chosen by our residents in consultation with faculty to meet safety gaps identified in clinics at UMMC. Perhaps the next generation of performance improvement continuing medical education programs could include a pilot program for part 4 of Maintenance of Certification credit that is nonpunitive, patient focused, and allows dermatologists to design specific error-prevention solutions tailored to their individual practice in the same way residency programs are taking up this task.

As part of its Next Accreditation System, the Accreditation Council for Graduate Medical Education (ACGME) has introduced the Clinical Learning Environment Review (CLER) program, designed to assess the learning environment of institutions that have ACGME residency and fellowship programs.¹ The CLER program emphasizes the responsibility of these hospitals, multispecialty groups, and other organizations to focus on quality and safety in the health care environment of resident learning and patient care. The expectation is that emphasis on quality of care in a residency training program will influence these physicians’ approach to quality of care after graduation.^2,3 The Department of Dermatology at the University of Mississippi Medical Center (UMMC)(Jackson, Mississippi) saw CLER as an opportunity to demonstrate leadership in the patient safety movement.

CLER Program at UMMC

As a model CLER program at our institution, our project at the outset concentrated resident efforts on the focus areas specified by the ACGME (Table 1). We also were aware that our ACGME committee would need to answer questions during CLER site visits (Table 2). Because the data generated would not be used for accreditation decisions, there was no concern that exposing errors would jeopardize our postgraduate training certification.

The first 15 minutes of monthly faculty meetings were devoted to the presentation of a resident project, called a QA/QI (quality assurance/quality improvement) moment, that addressed ACGME focus areas 1, 2, 3, or 6 (Table 1). (Transitions in care [focus area 4] and work hours and fatigue [focus area 5] generally are less important issues in a predominantly outpatient specialty such as dermatology.) The residents were encouraged to identify areas where patient harm could occur due to poorly designed systems and to report situations in which patients actually were harmed.

Each project had to be approved by the department chairperson based on the following 4 requirements: First, the initiative must have the potential to notably impact patient safety and reduce harm. Second, residents with faculty support had to design methods to assess the identified problem. Third, participants had to design (to the best of their abilities) cost-effective and achievable interventions in a manner that would not produce unintended consequences. Fourth, residents were asked to devise a system to close the loop, ensuring that the effort put into the process was not wasted.

Findings From the CLER Program

The CLER program generates data on program and institutional attributes that have a salutatory effect on quality and safety, specifically involving 6 focus areas highlighted in Table 1. Putting residents at the center of efforts to improve the quality of care in our department proved critical to improving patient safety.

Involving residents in a series of QA/QI initiatives was logical because they rotate with faculty members. They also are in a position to view inconsistencies and to work to establish consistent patterns of patient care. In addition, our busy faculty members are charged with a variety of other clinical, educational, and administrative duties complicated by requirements in the design of a new residency training program. Faculty and residents working together were able to find problem areas in our department and devise solutions to improve those problems.

The CLER program involved a series of steps. Residents were charged with identifying errors (QA) and then devising a system to prevent similar errors from being repeated (QI)(Table 3). Efforts focused on preventing needless harm in our department. Initiatives developed by residents, who are closest to patients, have advantages over safety programs developed by the hospital’s administration. Residents became passionate about error prevention when they determined that their efforts could make a difference to patients.

Forward Thinking for Dermatology Practices

Perhaps there are lessons here that could apply to safety promotion in the practicing dermatologist’s office. The American Board of Dermatology, within the framework established by the American Board of Medical Specialties, requires physicians seeking recertification to participate in preapproved practice assessment QI exercises twice every 10 years.¹⁷ Six programs sponsored by the American Academy of Dermatology have now been approved in the areas of melanoma, biopsy follow-up measure, psoriasis, chronic urticaria, venous insufficiency, and laser- and light-based therapy for rejuvenation.¹⁸ An additional program has been approved for dermatopathologists through the American Society of Dermatopathology.¹⁹ None of these programs match the topics chosen by our residents in consultation with faculty to meet safety gaps identified in clinics at UMMC. Perhaps the next generation of performance improvement continuing medical education programs could include a pilot program for part 4 of Maintenance of Certification credit that is nonpunitive, patient focused, and allows dermatologists to design specific error-prevention solutions tailored to their individual practice in the same way residency programs are taking up this task.

A convenient, once-daily fixed combination of 0.3% adapalene plus 2.5% benzoyl peroxide gel significantly improved lesion counts over the course of 12 weeks in patients aged 12 years and older with moderate or severe acne.

Investigators enrolled just over 500 patients from 31 sites in the United States and Canada. About half of patients were rated as having severe acne and half as having moderate acne on the investigator’s global assessment (IGA) scale, Dr. Linda F. Stein Gold said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

Patients were randomized to three treatment groups: adapalene 0.3%/benzoyl peroxide 2.5% gel (A-BPO-0.3%), adapalene 0.1%/benzoyl peroxide 2.5% (A-BPO-0.1%), or vehicle. Patients in each group had approximately the same total lesion count, and about half in each group had truncal acne lesions, said Dr. Stein Gold, director of clinical research in the department of dermatology at Henry Ford Hospital, Detroit.

Patients were instructed to use their study medications once daily at night after washing with a provided cleanser. They were provided with a standardized moisturizer and cleaners.

Treatment with A-BPO-0.3% was judged as successful (IGA of 1 or almost clear) at 12 weeks in 31% of patients with severe acne. By contrast, 13.3% of patients with severe acne were judged as almost clear. In patients with severe acne, A-BPO-1% was not statistically superior to vehicle (J Drugs Dermatol. 2015 Dec 1;14[12]:1427-35).

“Topical treatment is still the cornerstone of acne therapy, and it is great to have additional options, especially for our more severe acne patients,” Dr. Stein Gold said.

Patients noted dryness, scaling, erythema, and stinging/burning with A-BPO-0.3%, especially between weeks 1 and 2.

Dr. Stein Gold disclosed that she serves as a consultant and scientific advisory board member to Galderma, which markets A-BPO-0.3% as Epiduo Forte.

SDEF and this news organization are owned by the same parent company.

[email protected]

On Twitter @denisefulton

A convenient, once-daily fixed combination of 0.3% adapalene plus 2.5% benzoyl peroxide gel significantly improved lesion counts over the course of 12 weeks in patients aged 12 years and older with moderate or severe acne.

Investigators enrolled just over 500 patients from 31 sites in the United States and Canada. About half of patients were rated as having severe acne and half as having moderate acne on the investigator’s global assessment (IGA) scale, Dr. Linda F. Stein Gold said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

Patients were randomized to three treatment groups: adapalene 0.3%/benzoyl peroxide 2.5% gel (A-BPO-0.3%), adapalene 0.1%/benzoyl peroxide 2.5% (A-BPO-0.1%), or vehicle. Patients in each group had approximately the same total lesion count, and about half in each group had truncal acne lesions, said Dr. Stein Gold, director of clinical research in the department of dermatology at Henry Ford Hospital, Detroit.

Patients were instructed to use their study medications once daily at night after washing with a provided cleanser. They were provided with a standardized moisturizer and cleaners.

Treatment with A-BPO-0.3% was judged as successful (IGA of 1 or almost clear) at 12 weeks in 31% of patients with severe acne. By contrast, 13.3% of patients with severe acne were judged as almost clear. In patients with severe acne, A-BPO-1% was not statistically superior to vehicle (J Drugs Dermatol. 2015 Dec 1;14[12]:1427-35).

“Topical treatment is still the cornerstone of acne therapy, and it is great to have additional options, especially for our more severe acne patients,” Dr. Stein Gold said.

Patients noted dryness, scaling, erythema, and stinging/burning with A-BPO-0.3%, especially between weeks 1 and 2.

Dr. Stein Gold disclosed that she serves as a consultant and scientific advisory board member to Galderma, which markets A-BPO-0.3% as Epiduo Forte.

SDEF and this news organization are owned by the same parent company.

[email protected]

On Twitter @denisefulton

A convenient, once-daily fixed combination of 0.3% adapalene plus 2.5% benzoyl peroxide gel significantly improved lesion counts over the course of 12 weeks in patients aged 12 years and older with moderate or severe acne.

Investigators enrolled just over 500 patients from 31 sites in the United States and Canada. About half of patients were rated as having severe acne and half as having moderate acne on the investigator’s global assessment (IGA) scale, Dr. Linda F. Stein Gold said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

Patients were randomized to three treatment groups: adapalene 0.3%/benzoyl peroxide 2.5% gel (A-BPO-0.3%), adapalene 0.1%/benzoyl peroxide 2.5% (A-BPO-0.1%), or vehicle. Patients in each group had approximately the same total lesion count, and about half in each group had truncal acne lesions, said Dr. Stein Gold, director of clinical research in the department of dermatology at Henry Ford Hospital, Detroit.

Patients were instructed to use their study medications once daily at night after washing with a provided cleanser. They were provided with a standardized moisturizer and cleaners.

Treatment with A-BPO-0.3% was judged as successful (IGA of 1 or almost clear) at 12 weeks in 31% of patients with severe acne. By contrast, 13.3% of patients with severe acne were judged as almost clear. In patients with severe acne, A-BPO-1% was not statistically superior to vehicle (J Drugs Dermatol. 2015 Dec 1;14[12]:1427-35).

“Topical treatment is still the cornerstone of acne therapy, and it is great to have additional options, especially for our more severe acne patients,” Dr. Stein Gold said.

Patients noted dryness, scaling, erythema, and stinging/burning with A-BPO-0.3%, especially between weeks 1 and 2.

Dr. Stein Gold disclosed that she serves as a consultant and scientific advisory board member to Galderma, which markets A-BPO-0.3% as Epiduo Forte.

SDEF and this news organization are owned by the same parent company.

[email protected]

On Twitter @denisefulton