new england journal
n engl j med
Alastair G. Sutcliffe, M.D., Ph.D.
University College London
London, United Kingdom
Since publication of their article, the authors report no fur-
ther potential conflict of interest.
Petridou ET, Sergentanis TN, Panagopoulou P, et al. In vitro
fertilization and risk of childhood leukemia in Greece and Swe-
den. Pediatr Blood Cancer 2012;58:930-6.
Hargreave M, Jensen A, Toender A, Andersen KK, Kjaer SK.
Fertility treatment and childhood cancer risk: a systematic meta-
analysis. Fertil Steril 2013;100:150-61.
Källén B, Finnström O, Lindam A, Nilsson E, Nygren KG,
Olausson PO. Cancer risk in children and young adults con-
ceived by in vitro fertilization. Pediatrics 2010;126:270-6.
DOI: 10.1056/NEJMc1315232
Mutant Prolactin Receptor and Familial Hyperprolactinemia
To the Editor:
Newey et al. (Nov. 21 issue)
compare the mutant prolactin receptor with other
mutant endocrine receptors (parathyroid hor-
mone and growth hormone) characterized by
loss of function (hypocalcemia and short stature,
respectively). The authors attempt to explain the
reproductive abnormalities in their pedigree as
being the result of hyperprolactinemia and ex-
cessive signaling by the prolactin receptor. They
point out the persistent postpartum galactorrhea
of the proband is indicative of excess prolactin
signaling. However, they report a loss of function
in relation to this mutation in heterologous sys-
tems. Hyperprolactinemia in the presence of a
loss-of-function mutation would not lead to in-
creased signaling. One possibility is that the
reproductive abnormalities are mediated by a
second receptor, as is the case in syndromes of
resistance to other hormones (thyroid hormone
and glucocorticoids). Alternatively, the reproduc-
tive abnormalities seen could be due to loss of
function. One way to resolve this question would
be to determine the patients’ clinical response to
cabergoline: if oligomenorrhea and infertility
were due to excess prolactin signaling, one would
expect these conditions to resolve with the nor-
malization of prolactin levels after treatment
with a dopamine agonist, and if these condition
were due to a loss of function in prolactin-recep-
tor signaling, then dopamine agonist treatment
would have no effect, despite the normalization
of prolactin levels.
Charles Harris, M.D., Ph.D.
Washington University School of Medicine
St. Louis, MO
No potential conflict of interest relevant to this letter was re-
Newey PJ, Gorvin CM, Cleland SJ, et al. Mutant prolactin
receptor and familial hyperprolactinemia. N Engl J Med 2013;
DOI: 10.1056/NEJMc1315848
To the Editor:
Newey at al. identified a germ-
line loss-of-function mutation affecting the pro-
lactin receptor as a cause of familial hyperprolac-
tinemia in three sisters, two of whom presented
with oligomenorrhea and one with infertility.
Aside from its essential role in lactation, prolac-
tin has no established role in reproductive func-
tion in humans.
Therefore, it is unclear whether
the inactivating mutation in the gene encoding the
prolactin receptor (
) explains the reproduc-
tive phenotypes in the three sisters. Newey et al.
speculate that the hyperprolactinemia observed
in the three sisters may have induced hypogo-
nadism owing to the loss of hypothalamic pulsa-
tile secretion of the gonadotropin-releasing hor-
mone. However, this explanation does not seem
logical to me because inhibition of the secretion
of the gonadotropin-releasing hormone by means
of increased circulating levels of prolactin pre-
sumes the presence of a functioning prolactin
Therefore, an alternative explanation
may be that the increased prolactin levels in the
sisters represent merely a compensation for re-
duced signaling by the prolactin receptor and that
the reproductive abnormalities are coincidental.
Mathis Grossmann, M.D., Ph.D.
University of Melbourne
Heidelberg, VIC, Australia
No potential conflict of interest relevant to this letter was re-
Ben-Jonathan N, LaPensee CR, LaPensee EW. What can we
learn from rodents about prolactin in humans? Endocr Rev
Milenković L, D’Angelo G, Kelly PA, Weiner RI. Inhibition of
gonadotropin hormone-releasing hormone release by prolactin
The New England Journal of Medicine
Downloaded from at SAN FRANCISCO (UCSF) on February 12, 2016. For personal use only. No other uses without permission.
Copyright © 2014 Massachusetts Medical Society. All rights reserved.