The

new england journal

medicine

n engl j med

370;10

nejm.org

march

2014

976

Alastair G. Sutcliffe, M.D., Ph.D.

University College London

London, United Kingdom

a.sutcliffe@ucl.ac.uk

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

caharris@dom.wustl.edu

No potential conflict of interest relevant to this letter was re-

ported.

Newey PJ, Gorvin CM, Cleland SJ, et al. Mutant prolactin

receptor and familial hyperprolactinemia. N Engl J Med 2013;

369:2012-20.

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 (

PRLR

) 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

receptor.

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

mathisg@unimelb.edu.au

No potential conflict of interest relevant to this letter was re-

ported.

Ben-Jonathan N, LaPensee CR, LaPensee EW. What can we

learn from rodents about prolactin in humans? Endocr Rev

2008;29:1-41.

Milenković L, D’Angelo G, Kelly PA, Weiner RI. Inhibition of

gonadotropin hormone-releasing hormone release by prolactin

The New England Journal of Medicine

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