CORRESPONDENCE
addition, a structured clinical interview
for the revised DSM III criteria was
done to prevent confounding of CFS
and psychiatric diagnoses. The findings
in CFS about subtle changes in the
hypothalamus-pituitary-adrenal axis (of
which pathogenetically the importance
is unknown), have led to two
randomised controlled trials, from
which we and the investigators of these
trials do not derive Baschetti’s
conclusion that steroids are treatment of
choice.5
*J B Prins, G Bleijenberg, Th M deBoo,
J W M van der Meer
Departments of *Medical Psychology,
Epidemiology and Biostatistics, and Internal
Medicine, University Medical Centre, PO Box
9101, 6500 HB Nijmegen, Netherlands
1 Swanink CMA, Vercoulen JHMM,
Bleijenberg G, Fennis JFM, Galama JMD,
van der Meer JWM. Chronic fatigue
syndrome: a clinical and laboratory study
with a well-matched control group. J Int Med
1995; 237: 499–506.
2 Deale A, Husain K, Chalder T, Wessely S.
Cognitive behaviour therapy versus
relaxation for chronic fatigue syndrome:
outcome at five year follow-up: final report
for South Thames Research and
Development Project Grant Scheme
(London Region).
3 Powell P, Bentall RP, Nye Fi, Edwards
RHT. Randomised controlled trial of patient
education to encourage graded exercise in
chronic fatigue syndrome. BMJ 2001; 322:
1–5.
4 Reid S, Chalder T, Cleare A, Hotopf M,
Wessely S. Extracts from “Clinical
Evidence”: chronic fatigue syndrome. BMJ
2000; 320: 292–96.
5 Cleare AJ, Heap E, Malhi GS, Wessely S,
O’Keane V, Miell J. Low-dose
hydrocortisone in chronic fatigue syndrome:
a randomised crossover trial. Lancet 1999;
353: 455–58.
Genetic testing and
paternity
Sir—The conclusions of Anneke
Lucassen and Michael Parker (March
31, p 1033)1 about the ethical issue of
revealing non-paternity should be
supported. Patients should be
informed in advance that genetic
testing might have this outcome.
This situation is, however, by no
means unique for genetic testing. I had
a consultation with a male refugee
from Kosovo aged 45 years who sought
medical advice for atrial fibrillation. He
told me he had been married for
5 years and had a daughter aged 1 year
with his wife. During physical
examination I noted small testicles and
later a diagnosis of Klinefelter’s
syndome was established. Non-
paternity is very probable.
Should I have drawn attention to the
fact that non-paternity could be
THE LANCET • Vol 358 • July 21, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.
revealed before I started the physical
examination?
Medical examinations, not only
genetic testing, might reveal facts that
are uncomfortable for patients. Such
situations cannot always be anticipated,
and, thus, the attending doctors have to
treat them with the necessary
sensibility.
I did not inform the patient about
his questionable paternity since I
discovered it without previously
discussing the issue with him. Maybe I
am wrong, but I judge this decision to
be in his best interest.
Michael M Ritter
Medical Department, Von-Bodelschwingh
Hospital, 49477 Ibbenbueren, Germany
1 Lucassen A, Parker M. Revealing false
paternity: some ethical considerations.
Lancet 2001; 357: 1033–05.
Fetal toxic effects and
angiotensin-II-receptor
antagonists
Sir—Haruya Saji and colleagues (Feb
3, p 363)1 report on fetal toxic effects
related to losartan. In the past 4
months, we have recorded similar
adverse outcome in three fetuses
exposed in utero to angiotensin-II-
receptor type 1 (AT1) antagonists of
the sartan family.
The first pregnant woman, aged 41
years, had been treated for essential
hypertension and type 2 diabetes for
3 years with valsartan 80 mg and
hydrochlorothiazide 12·5 mg daily,
metformin, and potassium chloride.
She presented initally at 24 weeks’
gestation, at which time severe
oligohydramnios was seen on
ultrasonography. Amnio-infusion was
diagnosed. We substituted methyldopa
and nicardipine for valsartan and
hydrochlorothiazide. 2 weeks later,
anamnios was complete. Termination
of pregnancy was done at 27 weeks
(figure).
The second case was a hypertensive
mother, aged 39 years, who had been
taking valsartan and hydrochloro-
thiazide for 4 years. At 28 weeks’
gestation, complete absence of amni-
otic fluid was seen on ultrasonography.
2 weeks after substitution of these
drugs by trandate, amniotic fluid
volume was normal, but there were
fetal abnormalities, including renal
hyperechogenicity, dilatation of
cerebral ventricles, and narrow chest.
With the parents’ consent, a termin-
ation was done at 32 weeks.
The third mother, aged 35 years, had
been treated with losartan (50 mg
daily) for 4 years. At 22 weeks’
Renin expression in kidney from fetus
one
Immunoperoxydase labelling. Strong expression
of renin in juxtaglomerular apparatus, arteriolar
smooth-muscle cells and glomerular mesangial
cells. Original magnification 40.
gestation, the ultrasonogram was
normal. She was followed up in
another department and losartan was
continued. On the scan at 34 weeks,
severe oligohydramnios was noted and
losartan was substituted. After amnio-
infusion, the woman developed fever
with fetal tachycardia. Delivery of a
hypotonic male (Agpar 1/4/4) was
done by cesarean section at 34 weeks.
Non-reactive and persistent hypo-
tension, multivisceral failure, and
persistent anuria did not respond to
treatment and he died at day 4.
Two fetuses had foot and face
deformities of the oligohydramnios
sequence at necropsy. Strikingly, no
fetus had pulmonary hypoplasia. Skull
bones were hypoplastic with widely
open sutures. The kidneys had a
normal gross appearance, without
abnormalities of the urinary tract, but
were large, compared with age-
matched controls. Microscopic
examination showed tubular
dysgenesis characterised by absence or
poor differentiation of proximal
tubules, retraction of glomerular tufts,
and striking thickening of arterial and
arteriolar walls. Vascular changes were
confined to the kidneys. Medullary ray
glomerular counting2 showed an
increased number of generations of
nephrons in all three fetuses. Immuno-
histochemical staining showed strong
and diffuse expression of renin in
juxtaglomerular apparatus extending to
arteriolar smooth-muscle cells, and
focally to glomerular mesangial cells;
this finding confirmed the toxic role of
the blockage of the AT1 receptor.
The abnormalities were similar to
those seen after fetal exposure to
angiotensin-converting-enzyme (ACE)
inhibitors.3 However, the absence of
pulmonary hypoplasia in the presence
of severe oligohydramnios, the
enlarged kidneys, and the severity of
renal arterial changes were unexpected.
In animal studies, the toxic effects of
AT1 receptor antagonists are mostly
linked to drug exposure during the last
241
CORRESPONDENCE
part of gestation.4,5 We recommend that
AT1-receptor antagonists be avoided
throughout pregnancy.
Jelena Martinovic, Alexandra Benachi,
Nicole Laurent, Farida Daïkha-Dahmane,
*Marie Claire Gubler
Departments of Histoembryology and
Obstetrics, and *Institut National de la Santé et
de la Recherche Médicale, Unité 423, Hospital
Necker Enfants Malades, Université René,
Descartes, 75743 Paris, France; Departments
of Pathology and of Obstetrics, Hospital
Bocage, Dijon; Department of Histoembryology,
Hospital Robert Debré, Paris; and Department
of Biochemistry, Hôpital Ambroise Paré, Paris
1 Saji H, Yamanaka M, Hagiwara A, Ijiri R.
Losartan and fetal toxic effects. Lancet 2001;
357: 363.
2 Hinchliffe SA, Sargent PH, Howard CV,
Chan YF, Hutton JL, Van Velzen D.
“Medullary ray glomerular counting” as a
method of assessment of human
nephrogenesis. Pathol Res Pract 1992; 188:
775–82.
3 Pryde PG, Sedman AB, Nugent CE,
Barr M. Angiotensin-converting enzyme
inhibitor fetopathy. J Am Soc Nephrol 1993,
3: 1575–82.
4 Spence SG, Allen HL, Cukierski MA,
Manson JM, Robertson RT, Eydelloth RS.
Defining the susceptible period of
developmental toxicity for the AT1-selective
angiotensin II receptor antagonist losartan in
rats. Teratology 1995, 51: 367–82.
5 Sorensen AM, Christensen S, Jonassen TE,
Andersen D, Petersen JS. Teratogenic
effects of ACE inhibitors and angiotensin II
receptor antagonists. Ugeskr Laeger 1998,
160: 1460–64.
Testicular cancer and
syndrome X
Sir—Jourik A Gietema and colleagues
(Jan 20, p 228)1 report an interesting
finding that long-term survivors of
metastatic testicular cancer can develop
an unfavourable profile of cardio-
vascular risk factors resembling
syndrome X. They conclude that
administration of cisplatin-based
combination chemotherapy as well as
subclinical hypogonadism seem to be
important factors in pathogenesis.
Plasma concentrations of testosterone
in the chemotherapy group were
significantly lower than those in the
stage 1 group. Moreover, in their
chemotherapy-treated patients, insulin
concentrations and insulin-to-glucose
ratios correlated negatively with serum
testosterone concentrations.
We agree that decreased circulating
testosterone can cause insulin resistance.
We have reported a small series in
which we showed that decreased
concentrations of testosterone after
castration contributed to insulin
resistance. We analysed events in six
patients whose diabetic control was
notably worsened by orchidectomy or
administration of a gonadotropin-
releasing hormone analogue to treat
advanced prostate cancer, used in
242
For personal use. Only reproduce with permission from The Lancet Publishing Group.
addition to antiandrogenic drugs.
Plasma concentrations of testosterone
became undetectable in all patients, and
all but one patient had increased insulin
secretion. HbA1c before and after
castration was 6·3% (SD 0·6) and
10·2% (1·7), respectively.
Bilateral tumours are rare at
diagnosis, but in 2% of patients with
testicular germ-cell tumour, a meta-
chronous new primary tumour will
develop in the remaining testis. Even
patients with testicular cancer in stage 1,
whose concentrations of testosterone
would decrease after bilateral orchid-
ectomy, might result in insulin
resistance.
The effect of cisplatin in the
pathogenesis of insulin resistance
remains to be elucidated, although
plasma concentrations of testosterone in
Gietema and colleagues’ chemotherapy
group were lower than in the stage 1
group. This difference probably reflects
direct damage to the testis by cisplatin,
which could be investigated in non-
testicular cancer patients receiving
cisplatin, such as those with lung cancer.
Other effects of cancer upon
development of insulin resistance, such
as induction of various cytokines
including interleukin 6, tumour necrosis
factor , and counter-regulatory
hormone, might also be important.
However, hypogonadism should not be
overlooked as an important cause of
insulin resistance in survivors of
testicular cancer.
Michiaki Fukui
Department of Endocrinology and Haematology,
Osaka General Hospital of West Japan Railway
Company, 1-2-22 Matsuzaki-cho, Abeno-ku,
Osaka 545-0053, Japan
1 Gietema JA, Meinardi MT,
van der Graaf WTA, Sleijfer DT. Syndrome
X in testicular cancer survivors. Lancet 2001;
357: 228–29.
CD36 deficiency and
insulin resistance
Sir—Koji Miyaoka and colleagues
(March 3, p 686)1 report phenotypic
data on carbohydrate metabolism
from their cohort of 26 Japanese
patients with genetic mutations
causing CD36 deficiency.
As Timothy Aitman points out in
his March 3 commentary,2 the
question of whether or not insulin
resistance is present in these patients
is important, since data from one
rodent model, the spontaneously
hypertensive rat (SHR), has
implicated a causal role for deficiency
of the rodent homologue (Cd36) in
impairment of insulin action.3
However, some uncertainty remains.
We have reported that Cd36 sequence
and expression were normal in
another rodent model of hypertension
with insulin resistance (the stroke-
prone spontaneously hypertensive rat,
SHRSP), which suggests the existence
of other gene mutations leading to a
similar phenotype.4
Unfortunately, Miyaoka and
colleagues’ data from patients with
CD36 deficiency are inconclusive.
First, few details are given of the
matching procedures used and, in
particular, whether participants with
CD36 deficiency were individually
matched with controls. The 26 cases
were on average 4 years older than
controls: since age is an important
determinant of insulin sensitivity5 and
serum lipids, inappropriate matching
could have contributed to the
apparent differences between the
groups. Conversely, differences
between the sexes (42% of cases vs
29% of controls were female) might
have diminished the potential of the
study to find differences in these
variables.
Second, only five of 26 CD36-
deficient participants underwent
measurement of fasting insulin, oral
glucose tolerance test, and
hyperinsulinaemic clamp study.
Fasting plasma insulin concentrations
were all within the reference range
derived from normal controls. As
expected from a study with a small
number of participants with a wide
distribution of weight (body-mass
index 17–33 kg/m2), the individual
insulin profiles across the glucose
tolerance tests were heterogeneous;
results were equally compatible with a
defect in insulin secretion as with the
presence of insulin resistance.
Finally, the limited data reported
from the clamp studies is difficult to
compare with other published data
without some indication of the rate of
insulin infusion used. The argument
seems to rest on the observation that
all five cases individually had lower
values for whole-body glucose uptake
than the mean value for nine controls.
Although this finding is in keeping
with the hypothesis that insulin
resistance was present, the separation
between means (mean 5·1 [SD 1·59,
five cases] vs 8·6 mg kg21 min21 [0·50
nine controls]) was not clear and may
be too small to allow abandonment of
the normal statistical requirement for
formal rejection of the null
hypothesis.
We agree with Miyaoka and co-
workers that a case-control study with
a larger number of people with CD36
deficiency is necessary. However,
until such a study is done, putative
direct or indirect effects of
THE LANCET • Vol 358 • July 21, 2001