and Stock #JR0624), from the Bar Harbor laboratory in
Maine, transmit this phenotype as a Mendelian autosomal
recessive disorder. Homozygotes are characterized by
marked reduction in body weight, emaciated appearance,
and abnormal behavior, including head weaving and body
tremors, hyperactivity, and poor appetite. These data sug-
gest that the mice are anorexic and fail to ingest sufficient
food to sustain life. The fatal anorexia of these animals is
thought to be due to excessive serotonergic innervation.
This animal model might have provided an easier starting
point to isolate the leptin gene family by using areas of the
genome shared in common by these anorexic mice. This
technique comes under the broad rubric of quantitative trait
analysis (QTL), or genomic mismatch scanning (GMS). The
mutation in these mice has not been identified to date, but it
is an obvious experiment to see if the administration of leptin
might rescue the lethal phenotype and even restore repro-
ductive function.
Jeff Flier and his group at Beth Israel in Boston have
performed just such an experiment on starved or fasting
mice. Preventing the starvation-induced fall in leptin by
giving exogenous leptin blunts or attenuates the neuroendo-
crine changes that we ordinarily see in starvation and an-
orexia nervosa. Regulating the neuroendocrine axis during
food restriction may be a very important role for leptin in
human physiology (4).
The leptin story is just beginning. Leptin appears to be a
critical link between energy stores and hypothalamic pitu-
itary function in mice and humans. The continued investiga-
tion of this hormone will ultimately help to provide new
insights and therapies for polycystic ovary and insulin re-
sistant patients. For rational drug design, it will require a
firmer knowledge of the signalling pathways that are in-
volved downstream from the leptin receptor so that unique,
specific, tailored, drug targets can be identified. The pitfalls
in this approach are redundant signalling pathways and the
likelihood that deficiency in certain receptors can be par-
tially overcome by mobilizing more and more receptors with
an excess of ligand.
I don’t mean to spill the beans, but many of our readers
have noted that leptin will only be a landmark discovery for
ovulation induction if pheromones fail. It is hard to be any
simpler than collecting the body odor (arm pit or underarm)
of an ovulating human female and keeping it under your
nose for 6 hours. The medical short hand or sobriquet for
this new approach is referred to as using an “axillary
compound” for ovulation induction (5). It may not be en-
tirely aesthetic, but you can’t beat it for cost.
Paul G. McDonough, M.D., Editor, Letters
Referrences
1. Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD. A leptin missense
mutation associated with hypogonadism and morbid obesity. Nat Genet
1998;18:213–5.
2. Clement K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, et al.
A mutation in the human leptin receptor gene causes obesity andpituitary
dysfunction. Nature 1998;392:398–401.
3. Maltais LJ, Lane PW, Beamer WG. Anorexia, a recessive mutation
causing starvation in preweanling mice. J Hered 1984;75:468 –72.
4. Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier
E, et al. Role of leptin in the neuroendocrine response to fasting. Nature
1996;382:250–2.
5. Stern K, McClintock MK. Regulation of ovulation by human phero-
mones. Nature 1998;392:177–9.
PII S0015-0282(98)00238-6
A Negative Study With Power?
To the Editor:
The Letter-to-the-Editor section in the January issue of
Fertility and Sterility demonstrated the strong differences of
opinion that exist among different researchers about the
significance of antiphospholipid antibodies and IVF outcome
(1). The possibility exists however that aspirin and/or hepa-
rin may improve pregnancy rates irrespective of presence or
absence of antiphospholipid antibodies through some other
mechanism, e.g., improvement of endometrial blood flow
reported by Wada et al. (2). The recently published article by
Wechstein et al. (3) reporting on donor-oocyte recipients (a
group known to be characteristically devoid of antiphospho-
lipid antibodies (4) found a significantly improved implan-
tation rate in aspirin-treated patients. However, their ran-
domized prospective study failed to demonstrate any
differences in endometrial thickness despite improved im-
plantation rates in aspirin-treated recipients (3).
We also performed a randomized prospective study eval-
uating the efficacy of low-dose aspirin in improving endo-
metrial thickness, echo patterns, and endometrial blood flow
as measured by color Doppler in patients receiving frozen
embryo transfers. Furthermore, we compared pregnancy and
implantation rates. Similar to Weckstein et al., we did not
find any differences in endometrial thickness or echo pat-
terns and, in contrast to Wada et al. (2), we found no
difference in blood flow—at least with aspirin alone. We
also found significant differences in pregnancy rates between
the two groups in our study. However, the controls had a
significantly higher pregnancy rate per transfer then those
treated with aspirin (33.3% vs. 11.1%).
We submitted this data in a manuscript to Fertility and
Sterility on May 20, 1997, but it was rejected. There is
always going to be a greater tendency for reviewers to accept
an article with positive rather than negative results. There is
also a tendency for authors not to be as perseverant in
submitting a negative study (we have not submitted to an-
other journal since the rejection). This is one of the flaws in
performing meta-analyses because there may be just as many
negative studies performed as positive ones, but there is a
greater tendency for the positive ones to be published. Hope-
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