Correspondence
ChristopherM. Jones, Pharm.D., M.P.H.
Department of Health and Human Services
Washington, DC
christopher.jones@hhs.gov
GrantT. Baldwin, Ph.D., M.P.H.
Centers for Disease Control and Prevention
Atlanta, GA
Lemeneh Tefera, M.D.
Centers for Medicare and Medicaid Services
Baltimore, MD
No potential conflict of interest relevant to this letter was re-
ported.
1. Meara E, Horwitz JR, Powell W, et al. State legal restrictions
and prescription-opioid use among disabled adults. N Engl J
Med 2016;375:44-53.
2. Prescription Drug Monitoring Program Center of Excellence
at Brandeis University. PDMP prescriber use mandates: charac-
teristics, current status, and outcomes in selected states. May
2016 (http://www.pdmpexcellence.org/sites/all/pdfs/COE%20
briefing%20on%20mandates%203rd%20revision.pdf).
3. Patrick SW, Fry CE, Jones TF, Buntin MB. Implementation of
prescription drug monitoring programs associated with reduc-
tions in opioid-related death rates. Health Aff (Millwood) 2016;
35:1324-32.
4. Bao Y, Pan Y, Taylor A, et al. Prescription drug monitoring
programs are associated with sustained reductions in opioid
prescribing by physicians. Health Aff (Millwood) 2016;35:1045-
51.
DOI: 10.1056/NEJMc1610108
The authors reply: Like Jones et al., we encour-
age further investigation of policy responses to
the opioid epidemic. However, our study comple-
ments and is in no way less robust than the stud-
ies by Bao et al.1 and Patrick et al.2 Recognizing
that laws do not operate in isolation, we consider
both the products of individual laws, including
PDMPs, and the effects of the interaction of those
laws. We consider the behaviors that the laws are
meant to target, including prescribing by multiple
Polycystic Ovary Syndrome
To the Editor: In their review article on the
polycystic ovary syndrome, McCartney and Mar-
shall (July 7 issue)1 did not address the topic of
nonalcoholic fatty liver disease. Several studies
have recently shown that the prevalence of non-
alcoholic fatty liver disease is markedly increased
among women with the polycystic ovary syn-
drome, independent of overweight or obesity and
other coexisting components of the metabolic syn-
drome, and that these women are more likely to
have the more severe forms (nonalcoholic steato-
n engl j med 375;14nejm.org October 6, 2016
The New England Journal of Medicine
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Copyright 2016 Massachusetts Medical Society. All rights reserved.
practitioners, high-dose prescribing, and prescrib-
ing that leads to nonfatal overdose. Our patient-
level data cover every state for a period of 7 years.
Differences in results may be explained by dif-
ferences in the populations examined. We studied
disabled Medicare beneficiaries, who account for
3% of the U.S. population and nearly one quarter
of the deaths from prescription-opioid overdose.
The null findings from our study of this vulner-
able population do not necessarily reflect the ways
in which other groups have responded to laws de-
signed to address the problem of opioid overdose.
However, if we are to address the critical issues
related to opioid misuse, abuse, and overdose, we
cannot ignore the ways in which disappointing
findings, such as those we have presented, fit
into the broad picture that should inform policy.
Ellen Meara, Ph.D.
Dartmouth College
Hanover, NH
ellen.r.meara@dartmouth.edu
JillR. Horwitz, Ph.D., J.D.
University of California, Los Angeles
Los Angeles, CA
NancyE. Morden, M.D., M.P.H.
Dartmouth College
Hanover, NH
Since publication of their article, the authors report no fur-
ther potential conflict of interest.
1. Bao Y, Pan Y, Taylor A, et al. Prescription drug monitoring
programs are associated with sustained reductions in opioid
prescribing by physicians. Health Aff (Millwood) 2016;35:1045-
51.
2. Patrick SW, Fry CE, Jones TF, Buntin MB. Implementation of
prescription drug monitoring programs associated with reduc-
tions in opioid-related death rates. Health Aff (Millwood) 2016;
35:1324-32.
DOI: 10.1056/NEJMc1610108
hepatitis, advanced fibrosis, and cirrhosis).2 Ac-
cumulating evidence also suggests that nonalco-
holic fatty liver disease exacerbates hepatic and
peripheral insulin resistance, confers a predispo-
sition to atherogenic dyslipidemia, and causes the
release of several proinflammatory, procoagulant,
and profibrogenic mediators that may play im-
portant roles in the pathophysiology of the poly-
cystic ovary syndrome and its related complications
(principally cardiovascular disease and diabetes).3-5
These findings call for a more active and system-
1397
 The n e w e ng l a n d j o u r na l
atic search for nonalcoholic fatty liver disease in
patients with the polycystic ovary syndrome.
Giovanni Targher, M.D.
University of Verona
Verona, Italy
giovanni.targher@univr.it
No potential conflict of interest relevant to this letter was re-
ported.
1. McCartney CR, Marshall JC. Polycystic ovary syndrome.
N Engl J Med 2016;375:54-64.
2. Targher G, Rossini M, Lonardo A. Evidence that non-alco-
holic fatty liver disease and polycystic ovary syndrome are asso-
ciated by necessity rather than chance: a novel hepato-ovarian
axis? Endocrine 2016;51:211-21.
3. Targher G, Zoppini G, Bonora E, Moghetti P. Hemostatic
and fibrinolytic abnormalities in polycystic ovary syndrome. Se-
min Thromb Hemost 2014;40:600-18.
4. Targher G, Day CP, Bonora E. Risk of cardiovascular disease
in patients with nonalcoholic fatty liver disease. N Engl J Med
2010;363:1341-50.
5. Targher G, Marchesini G, Byrne CD. Risk of type 2 diabetes
in patients with non-alcoholic fatty liver disease: causal associa-
tion or epiphenomenon? Diabetes Metab 2016;42:142-56.
DOI: 10.1056/NEJMc1610000
To the Editor: McCartney and Marshall cite a
meta-analysis of randomized, controlled trials in-
volving women with the polycystic ovary syndrome
that showed a significant difference in the clini-
cal pregnancy rate between those who received
metformin and those who received placebo (pooled
odds ratio, 2.31; 95% confidence interval, 1.52 to
3.51) but no significant difference in the live birth
rate.1 It is important to note that the meta-analy-
sis of the pregnancy rate included eight trials in-
volving 707 women, whereas the meta-analysis of
the live birth rate yielded a pooled odds ratio of
1.80 but was underpowered and included only
three trials involving 115 women.
Because the polycystic ovary syndrome is a
common reason to use ovulation-induction agents,
multiparity is a major issue. When pregnancy is
achieved with the use of metformin, a singleton
pregnancy typically ensues. In contrast, ovulation-
induction agents are the primary cause of mul-
tiple births in the United States.2 Finally, a 2012
multicenter, randomized trial (not included in
the meta-analysis mentioned above) showed a
45% higher rate of live births when women with
the polycystic ovary syndrome received metfor-
min, rather than placebo, before and during treat-
ment with various ovulation-induction agents.3
JohnE. Nestler, M.D.
Virginia Commonwealth University
Richmond, VA
john.nestler@vcuhealth.org either alone or in combination with additional
1398 n engl j med 375;14nejm.org October 6, 2016
The New England Journal of Medicine
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Copyright 2016 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
No potential conflict of interest relevant to this letter was re-
ported.
1. Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH. Insulin-
sensitising drugs (metformin, rosiglitazone, pioglitazone, D-
chiro-inositol) for women with polycystic ovary syndrome, oligo
amenorrhoea and subfertility. Cochrane Database Syst Rev 2012;
5:CD003053.
2. Kulkarni AD, Jamieson DJ, Jones HW Jr, et al. Fertility treat-
ments and multiple births in the United States. N Engl J Med
2013;369:2218-25.
3. Morin-Papunen L, Rantala AS, Unkila-Kallio L, et al. Metfor-
min improves pregnancy and live-birth rates in women with
polycystic ovary syndrome (PCOS): a multicenter, double-blind,
placebo-controlled randomized trial. J Clin Endocrinol Metab
2012;97:1492-500.
DOI: 10.1056/NEJMc1610000
The authors reply: In response to Targher: the
polycystic ovary syndrome is associated with a
number of risk factors for nonalcoholic fatty liver
disease (e.g., obesity and the metabolic syndrome),
and observational studies suggest an increased
prevalence of this condition among women with
the polycystic ovary syndrome. Although preven-
tion of the severe forms of nonalcoholic fatty liver
disease is highly desirable, the best approaches to
identification and management are unclear. A 2012
guideline for the diagnosis and management of
nonalcoholic fatty liver disease recommended
against routine screening in high-risk groups
(e.g., patients with type 2 diabetes or obesity)
due to uncertainties surrounding diagnostic tests
and treatment options, along with lack of knowl-
edge related to the long-term benefits and cost-
effectiveness of screening.1 Similar considerations
informed the Endocrine Society guideline for the
diagnosis and treatment of the polycystic ovary
syndrome, which recommended against routine
screening.2 Although the guideline jointly pub-
lished by the American Association of Clinical En-
docrinologists, American College of Endocrinolo-
gy, and the Androgen Excess and PCOS Society
recommended routine screening for nonalcohol-
ic fatty liver disease, procedural guidance was
not provided.3
We believe that it would be reasonable to mea-
sure serum aminotransferase levels in patients
with the polycystic ovary syndrome with obesity,
acanthosis nigricans, or any component of the
metabolic syndrome an approach consistent
with the Endocrine Society guideline.2 However,
serum aminotransferase levels have limited di-
agnostic sensitivity for nonalcoholic fatty liver
disease, and the overall benefit of such screening,
 Correspondence

testing (e.g., liver ultrasonography), remains un- ChristopherR. McCartney, M.D.

defined. JohnC. Marshall, M.B., Ch.B., M.D.
We agree with Nestlers comments: the meta- University of Virginia School of Medicine
analysis that we cited may have lacked sufficient Charlottesville, VA
jcm9h@virginia.edu
statistical power to confirm a benefit of metfor-
min alone on the live birth rate, and the risk of Since publication of their article, the authors report no fur-
ther potential conflict of interest.
multiparity is an essential component of coun-
seling regarding fertility treatment options. Nes- 1. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and
tler also highlights the study by Morin-Papunen management of non-alcoholic fatty liver disease: practice guide-
et al., which suggested that metformin increased line by the American Gastroenterological Association, American
Association for the Study of Liver Diseases, and American Col-
live birth rates in a cohort of patients with the lege of Gastroenterology. Gastroenterology 2012;142:1592-609.
polycystic ovary syndrome and anovulatory infer- 2. Legro RS, Arslanian SA, Ehrmann DA, et al. Diagnosis and
tility, some of whom also underwent various stan- treatment of polycystic ovary syndrome: an Endocrine Society
clinical practice guideline. J Clin Endocrinol Metab 2013;98:
dard ovulation-induction procedures (e.g., 44% of 4565-92.
the participants received metformin or placebo 3. Goodman NF, Cobin RH, Futterweit W, Glueck JS, Legro RS,
only; 38% also received clomiphene). Although Carmina E. American Association of Clinical Endocrinologists,
American College of Endocrinology, and Androgen Excess and
other randomized, placebo-controlled trials have PCOS Society disease state clinical review: guide to the best
not supported the notion that metformin enhances practices in the evaluation and treatment of polycystic ovary syn-
live birth rates with clomiphene,4,5 we recognize drome part 2. Endocr Pract 2015;21:1415-26.
4. Legro RS, Barnhart HX, Schlaff WD, et al. Clomiphene, met-
that this apparent discordance could partly re- formin, or both for infertility in the polycystic ovary syndrome.
flect differences in trial methods (e.g., duration N Engl J Med 2007;356:551-66.
of metformin pretreatment and timing of metfor- 5. Moll E, Bossuyt PM, Korevaar JC, Lambalk CB, van der Veen
F. Effect of clomifene citrate plus metformin and clomifene ci-
min discontinuation during pregnancy) and trial trate plus placebo on induction of ovulation in women with
population (e.g., apparent differences in hyper- newly diagnosed polycystic ovary syndrome: randomised double
androgenism or adiposity). We believe that de- blind clinical trial. BMJ 2006;332:1485.
lineation of the proper role of metformin in fertil- DOI: 10.1056/NEJMc1610000
ity treatment for women with the polycystic ovary
syndrome deserves further study.

State of Telehealth
To the Editor: Dorsey and Topol (July 14 issue)1
describe many limitations of telehealth. Since 1998,
pediatric hematologists and oncologists at Mich-
igan State University have been implementing a
combination of physical outreach and telemedicine
clinics for children in the Upper Peninsula of Mich-
igan who have chronic hematologic disorders,2 and
these efforts have overcome many of the limitations
raised by the authors.
During a telehealth visit, the remote compre-
hensive care team (pediatric hematologists and
oncologists, a nurse, and a social worker, all of
whom are employees at Michigan State University)
obtains a detailed history and provides nursing,
psychosocial support, and assistance with insur-
ance coverage and procurement of clotting-factor
concentrates. The team observes the physical ex-
amination conducted by the patients on-site pri-
mary care provider in the Upper Peninsula.
With funding from the National Hemophilia
Program Coordinating Center,3 we conducted an
evaluation and determined that the cost for pa-
tients to attend clinics locally and receive spe-
cialty care remotely through telemedicine is ap-
proximately $40, as compared with $1,275 for
patients who drive from the Upper Peninsula to
Michigan State University and $1,877 for patients
who travel this distance by air to receive care.
Specialty care is provided in the patients medi-
cal home. The primary care provider is involved
in the decision making and has been able to suc-
cessfully implement a desmopressin challenge test
in patients with hemophilia or von Willebrands
disease. Barriers to care have included an inabil-

n engl j med 375;14nejm.org October 6, 2016 1399

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