The

n e w e ng l a n d j o u r na l

increased requirements for transfusion of packed

red cells in the first 2 days after randomization in
the main SAFE study and on the second day in the
SAFETBI study.
Ultimately, the selection of resuscitation fluid
for patients with traumatic brain injury will depend on the attending clinicians preference and
experience, the cost and availability of specific
fluids, and the interpretation of published evidence, to which our study adds new data.

of

m e dic i n e

John A. Myburgh, M.D., Ph.D.

D. James Cooper, M.D.
Simon Finfer, M.D.
Australian and New Zealand Intensive Care Society
Melbourne 3000, Australia
j.myburgh@unsw.edu.au

for the SAFE Study Investigators

1. The SAFE Study Investigators. A comparison of albumin and

saline for fluid resuscitation in the intensive care unit. N Engl J

Med 2004;350:2247-56.

Gynecomastia
To the Editor: In his review of gynecomastia,
Dr. Braunstein (Sept. 20 issue)1 includes numerous medications that may be associated with gynecomastia but does not mention a potential link
of statins to gynecomastia. The only medication
used by the patient described in the clinical vignette
was a statin, and case reports have suggested that
statins might induce gynecomastia.2,3 In one case
report, the gynecomastia was reversed after a
change in statin medication.2 A possible mechanism for this relationship is a reduction in adrenal or gonadal steroid production through the effects of statins on the cholesterol pathway.2
Isabela Romao, M.D.
Evan Klass, M.D.
North ShoreLong Island Jewish Health System
Lake Success, NY 11042

Laboratory for Pathology

3317 DA Dordrecht, the Netherlands
pwestenend@paldordt.nl

Remmert Storm, M.D.

Rob J. Oostenbroek, M.D.
Albert Schweitzer Hospital
3300 AK Dordrecht, the Netherlands
1. Westenend PJ, Jobse C. Evaluation of fine-needle aspiration

2. Hammons KB, Edwards RF, Rice WY. Golf-inhibiting gyne-

cytology of breast masses in males. Cancer 2002;96:101-4.

2. Westenend PJ. Core needle biopsy in male breast lesions.
J Clin Pathol 2003;56:863-5.
3. Giordano SH. A review of the diagnosis and management of
male breast cancer. Oncologist 2005;10:471-9.

To the Editor: Braunstein stresses the importance of physical examination in the diagnosis of
a breast mass in men and the addition of mammography in selected cases but does not discuss
the role of fine-needle aspiration cytology and core
biopsy in the diagnostic workup. In our hospital,
fine-needle aspiration cytology or core biopsy is
used in the evaluation of lesions that are equivocal or suggestive of cancer on physical examination, mammography, or both. In our experience
and in the experience of others, fine-needle aspiration cytology has a negative predictive value that
is close to 100% and, in almost all studies, a posi-

The author replies: Romao and Klass raise the

possibility that the patient in the case vignette had
drug-induced gynecomastia from a statin. The only
evidence of a relationship between the statin and
the gynecomastia in the two patients in the case
reports they referenced was the appearance of gynecomastia after treatment with pravastatin was
started in one patient and after a switch was made
from simvastatin to atorvastatin in the other; the
breast enlargement resolved after withdrawal of
the drug in the first patient and after a switch
back to simvastatin in the second patient. Neither
patient was rechallenged with the presumed culprit, and both patients were taking other medications that have been implicated in other case
reports of gynecomastia. This illustrates the dif-

1. Braunstein GD. Gynecomastia. N Engl J Med 2007;357:1229-

37.

comastia associated with atorvastatin therapy. Pharmacotherapy

2006;26:1165-8.
3. Aerts J, Karmochkine M, Raguin G. Gynecomastia due to pravastatin. Presse Med 1999;28:787. (In French.)

2636

tive predictive value of 100%.1 In a small study of

core biopsy, no false positive or false negative results were found.2 With the use of this strategy,
diagnostic operations for gynecomastia may be
avoided, and for men in whom breast cancer is
diagnosed, appropriate treatment may be facilitated.3
Pieter J. Westenend, M.D.

n engl j med 357;25 www.nejm.org december 20, 2007

The New England Journal of Medicine

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Copyright 2007 Massachusetts Medical Society. All rights reserved.

correspondence

ficulty of evaluating most of these types of case

reports, since they show only a temporal relationship. As to the postulated statin-induced reduction
in adrenal or gonadal steroid production, multiple
studies have shown no significant differences between basal or stimulated hormone levels in men
before and after statin use or in men using statins
versus those not using the drugs.1,2 In addition,
double-blind, placebo-controlled trials of statin
use in children and adolescents have not shown
differences in adrenal or gonadal steroid levels
or alterations in pubertal development between
patients receiving statins and those receiving
placebo.3,4
Westenend and colleagues advocate the use of
fine-needle aspiration and core biopsy in the evaluation of breast masses. In most cases, one should
be able to discriminate between gynecomastia and
other breast lesions on physical examination. If
not, the next step should be diagnostic (not
screening) mammography, ultrasonography, or
both. If the diagnosis is still uncertain, then fineneedle aspiration is reasonable as long as the
pathologists have sufficient experience in interpreting the results of breast fine-needle aspiration.
Unfortunately, there is a high rate of unsatisfac-

tory specimens, and florid gynecomastia may be

mistaken for breast cancer with this technique.5
Finally, Westenends report on core biopsy in men
with breast lesions demonstrates the potential
usefulness of this technique. However, there is
insufficient information from other centers to advocate widespread use at this time.
Glenn D. Braunstein, M.D.
CedarsSinai Medical Center
Los Angeles, CA 90048
braunstein@cshs.org
1. Travia D, Tosi F, Negri C, Faccini G, Moghetti P, Muggeo M.

Sustained therapy with 3-hydroxy-3-methylglutaryl-coenzyme-A

reductase inhibitors does not impair steroidogenesis by adrenals
and gonads. J Clin Endocrinol Metab 1995;80:836-40.
2. Hall SA, Page ST, Travison TG, Montgomery RB, Link CL,
McKinlay JB. Do statins affect androgen levels in men? Results
from the Boston area community health survey. Cancer Epidemiol Biomarkers Prev 2007;16:1587-84.
3. de Jongh S, Ose L, Szamosi T, et al. Efficacy and safety of
statin therapy in children with familial hypercholesterolemia:
a randomized, double-blind, placebo-controlled trial with simvastatin. Circulation 2002;106:2231-7.
4. Stein EA, Illingworth DR, Kwiterovich PO Jr, et al. Efficacy
and safety of lovastatin in adolescent males with heterozygous
familial hypercholesterolemia: a randomized controlled trial.
JAMA 1999;281:137-44.
5. Siddiqui MT, Zakowski MF, Ashfaq R, Ali SZ. Breast masses
in males: multi-institutional experience on fine-needle aspiration.
Diagn Cytopathol 2002;26:87-91.

Reversal of Pacing-Induced Heart Failure

by Left Ventricular Apical Pacing
To the Editor: Children with congenital complete atrioventricular block often require lifelong
pacemaker therapy. Although such therapy restores
a normal heart rate, it also results in dyssynchronous left ventricular activation and contraction and
compromises left ventricular function.1-3 These effects are most pronounced during right ventricular pacing, the predominant pacing site in children and adults. Eventually, heart failure develops
in 6 to 7% of children who undergo long-term
right ventricular pacing.2
The harmful effects of right ventricular pacing
initiated the search for pacing modes that would
maintain or restore synchronous activation in
other words, biventricular pacing and alternative
single-site ventricular pacing. In previous studies,3,4 we showed that the physiologic apex-tobase sequence of electrical activation during left
ventricular apical pacing resulted in a hemody-

namic response that was as good as the response

with multisite pacing in dogs; we also showed that
such activation had favorable acute hemodynamic
effects in children.4
On the basis of these findings, we used left
ventricular apical pacing to treat a 2-year-old girl
with congenital complete atrioventricular block
and heart failure induced by right ventricular pacing. In this patient, single-chamber right ventricular epicardial pacing had been started 1 day after
birth to treat symptomatic bradycardia. During
right ventricular pacing, echocardiography showed
dyssynchronous left ventricular contraction, which
was associated with progressive left ventricular
dilatation (Fig. 1). After 2 years of right ventricular pacing, rapid deterioration occurred, with the
development of congestive heart failure (afterload
reduction with lisinopril had been started): the
shortening fraction decreased to approximately

n engl j med 357;25 www.nejm.org december 20, 2007

The New England Journal of Medicine

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Copyright 2007 Massachusetts Medical Society. All rights reserved.

2637