Brief Communication

Ischemic Cerebral Infarction in an
Infant Following Gonadotropin Treatment
for Undescended Testes

Journal of Child Neurology
Volume 23 Number 11
November 2008 1324-1327
© 2008 Sage Publications
10.1177/0883073808318057
http://jcn.sagepub.com
hosted at
http://online.sagepub.com

Nihal Olgac Dundar, MD, Ozgur Duman, MD, Ayse Aralasmak, MD, and Senay Haspolat, MD

Cerebrovascular disorders are increasingly recognized as
important causes of mortality and morbidity in the pediatric
population. Risk factors for stroke in childhood are different
from those in adults. Human chorionic gonadotropin is a
polypeptide hormone produced by the human placenta and
is composed of an α-subunit and a β-subunit. Pregnyl (human
chorionic gonadotropin for injection) is a highly purified
pyrogen-free preparation obtained from the urine of pregnant

females. Ischemic cerebral infarction is seen in the young
infertile male and female patients after gonadotropin treatment. The authors describe the case of a boy with right-sided
hemiparesis following Pregnyl injection and discuss its possible pathogenetic mechanisms.

Introduction

of 4 and 9 or at early ages because of gonadal cancers
and, thus, may help predict whether or not orchiopexy
will be needed in the future.5 We present a case of
ischemic stroke in a 1-year-old boy with undescended
testes following gonadotropin therapy, which is the first
and only case reported in the literature.

Incidence of cerebrovascular disorders, including pediatric stroke, have increased and, depending on definitions
and inclusion criteria, range from 2 to 13 per 100 000
children under age 18 per year in North America and
Europe.1,2 Cerebrovascular disorders are among the top
10 causes of death in children, especially in the first year
of life.3 Among survivors, more than half of the childhood
stroke cases present with cognitive or motor disabilities.4
Unfortunately, ischemic strokes are still underdiagnosed
in infancy and childhood because of a lack of clinical suspicion and appropriate diagnostic testing. Variability of
potential risk factors for stroke is the main difference
between children and adults.
The action mechanism of human chorionic gonadotropin
is virtually identical to that of pituitary luteinizing hormone. It stimulates production of gonadal steroid hormones by stimulating the interstitial cells of testis to
produce androgens and the corpus luteum of the ovary to
produce progesterone.5 In general, human chorionic
gonadotropin is used to induce testicular descent.
Therapy is usually instituted in children between the ages
From the Departments of Child Neurology (NOD, OD, SH) and
Radiology (AA), Faculty of Medicine, Akdeniz University, Antalya, Turkey.
This study was supported by the Akdeniz University Scientific Committee.
Address correspondence to: Senay Haspolat, MD, Department of Child
Neurology, Faculty of Medicine, Akdeniz University, 07070 Antalya, Turkey;
e-mail: shaspolat@akdeniz.edu.tr.
Dundar NO, Duman O, Aralasmak A, Haspolat S. Ischemic cerebral infarction in an infant following gonadotropin treatment for undescended testes. J
Child Neurol. 2008;23:1324-1327.

Keywords: cerebral
scended testes

infarction;

gonadotropin;

unde-

Case Report
A 1-year-old male patient was admitted for sudden-onset
right-sided hemiparesis and restlessness. He had a history of
Pregnyl (human chorionic gonadotropin) 1500 U, 12 ampoule,
injection intramuscularly 3 times per week for undescended
testes 2 weeks earlier. Physical examination revealed weakness in the right arm and leg. On laboratory examination, the
following results were obtained: hematocrit 32.3%, hemoglobin 11 g/dL, white blood cell count 5600/μL, platelet
count 244 000/μL, and normal prothrombin time, activated
partial thromboplastin time, international normalized ratio,
biochemical analyses, and blood gases. Cerebral magnetic
resonance imaging revealed an acute infarct in the territory
of the left middle cerebral artery, and magnetic resonance
angiography showed occlusion of the left middle cerebral
artery (Figures 1 and 2). Other investigations for the etiology
of stroke were as follows: transthoracic echocardiography
revealed small secundum atrial septal defect, but bubble
study showed no intracardiac shunt that would be seen
with patent foramen ovale; Doppler ultrasound of the
carotid artery; hemoglobin electrophoresis, lupus anticoagulant assay, protein C, protein S, antithrombin III, factor V Leiden, activated protein C resistance, prothrombin
1324

Downloaded from jcn.sagepub.com at The University of Iowa Libraries on June 6, 2015

Ischemic Cerebral Infarction in an Infant / Dundar et al

Figure 1.

Axial diffusion weighted images show acute infarction in the left middle cerebral artery territory (black arrows).

Figure 2.

Magnetic resonance angiography shows occlusion of the left middle cerebral artery at its proximal segment (white arrows).

G20210A assessment, anticardiolipin, antinuclear antibody, homocysteine, and factor VIII, IX, and XII levels all
were normal. Methylenetetrahydrofolate reductase was
found heterozygote.
For initial treatment, a bolus of 75 U/kg heparin was
started and then followed by a daily dose of 25 U/kg/h.
After 2 days, warfarin was given at a dose of 0.13
mg/kg/day. Heparin was discontinued on day 5. Physical
therapy was also applied. At 2 months of warfarin therapy,
control cerebral magnetic resonance imaging and magnetic resonance angiography were performed. Cystic
encephalomalacia was now demonstrated in the previously
infarcted area in addition to recanalization of the left middle cerebral artery (Figures 3 and 4). Hemiparesis of the

1325

patient started to resolve. Warfarin therapy was continued
for 6 months. The patient is still on aspirin therapy.

Discussion
Childhood arterial ischemic stroke is not rare. In an earlier study the incidence was 2.6 per 100 000 children per
year, with the clinical presentation including hemiparesis
51%, speech disorder 17%, and seizures 48%.6 Strokes in
the pediatric population have many risk factors. At initial
presentation, half of childhood stroke cases have a known
predisposing cause, such as sickle cell disease, congenital
heart disease, or infection.7 For the remaining, a careful

Downloaded from jcn.sagepub.com at The University of Iowa Libraries on June 6, 2015

1326

Journal of Child Neurology / Vol. 23, No. 11, November 2008

Figure 3.

Follow-up axial diffusion weighted images show resolution of acute infarction to volume loss and cystic encephalomalacia (white arrows).

Figure 4.

Follow-up magnetic resonance angiography shows recanalized left middle cerebral artery (white arrows).

evaluation is needed. Variability of risk factors and multifactorial potential in childhood stroke are the main differences from adult stroke. Cardiac disease, including
congenital and acquired heart disease, is the most common
cause of stroke in childhood.8 Our patient had no cardiac
disease. Hematologic or metabolic disorders can cause
stroke, such as elevations in homocysteine and lipoprotein (a); deficiency of protein C, protein S, and
antithrombin III; the presence of the factor V Leiden
G1691A mutation or prothrombin mutation G20210A9-12;
iron deficiency anemia6,7; Fabry disease13; mitochondrial
myopathy encephalopathy; and strokelike syndrome.
None of them was present in our patient. Other factors
causing stroke include vascular disorders such as arterial
dissection,7 Moyamoya syndrome,14 and transient cerebral arteriopathy.15 In a recent prospective cohort of
patients with arterial ischemic stroke in the United
Kingdom, vascular abnormality was found in 79% of
patients on cerebral arterial imaging.6,7 The most common
abnormalities in this study were occlusion or narrowing

of the proximal large arteries. However, risk factors were
identifiable in only 72% of the cases.6 In another study,
association with infection was shown in at least one third
of the childhood stroke cases.7 In our patient, there were
no signs and symptoms of infection.
Known side effects of human chorionic gonadotropin
are headache, irritability, restlessness, depression,
fatigue, edema, precocious puberty, gynecomastia, and
pain at the site of injection.5 A serious adverse reaction
during infertility treatment is arterial thromboembolism.16 A hypercoagulable state with secondary supraphysiological hyperestrogenemia and hemoconcentration
after ovarian hyperstimulation may induce attacks of
thromboembolism. In the literature, there are many
reports about cerebral infarction during gonadotropin
treatment of infertility.17-21 In those cases, thrombosis was
described especially in the left internal carotid artery,
right middle cerebral artery, or intracranial venous system
and was thought to be because of the activation of the
coagulation cascade system after human chorionic

Downloaded from jcn.sagepub.com at The University of Iowa Libraries on June 6, 2015

Ischemic Cerebral Infarction in an Infant / Dundar et al

gonadotropin administration. Pregnyl (human chorionic
gonadotropin) was given to our patient for the treatment
of undescended testes and might have affected the coagulation cascade system. Additionally, heterogeneity of
methylenetetrahydrofolate reductase as in adults might
be a predisposing factor to hypercoagulability.
No randomized controlled treatment trial is conducted
in childhood stroke, except in the sickle cell disease, to
establish safety and efficacy of acute interventions or secondary preventative strategies. Studies about antiplatelet
(aspirin, clopidogrel) and anticoagulant (low-molecularweight heparin, warfarin) treatments are ongoing. Most
experts agree that aspirin use is beneficial in secondary
stroke prevention in the pediatric population despite the
aspirin failure rate being 17%.6,7,22 Majority of the failure
group is composed of patients with dissection, cardiac
embolism, and prothrombotic disorders. Of more than
50% of patients receiving antithrombotic therapy, outcomes were normal in 34%, neurologic abnormality in
56%, and death in 10%. In our patient, anticoagulant and
then antiplatelet treatments were applied, followed by
improvements in clinical exam findings such as resolution
of hemiparesis and imaging studies.
We, thus, describe the case of ischemic stroke in a 1year-old boy with undescended testes following Pregnyl
therapy, which is the first and only case reported in the
literature to our knowledge.

References
1. Lynch JK, Hirtz DG, DeVeber G, Nelson KB. Report of the
National Institute of Neurological Disorders and Stroke workshop on perinatal and childhood stroke. Pediatrics. 2002;109:
116-123.
2. Giroud M, Lemesle M, Gouyon JB, Nivelon JL, Milan C, Dumas R.
Cerebrovascular disease in children under 16 years of age in the
city of Dijon, France: a study of incidence and clinical features
from 1985 to 1993. J Clin Epidemiol. 1995;48:1343-1348.
3. Kerr LM, Anderson DM, Thompson JA, Lyver SM, Call GK.
Ischemic stroke in the young: evaluation and age comparison of
patients six months to thirty-nine years. J Child Neurol.
1993;8:266-270.
4. Steinlin J, Roellin K, Schroth G. Long-term follow-up after
stroke in childhood. Eur J Pediatr. 2004;163:245-250.
5. Ascoli M, Segaloff DL. Adenohypophyseal hormones and their
hypothalamic releasing factors. In Hardman JG, Limbird LE, eds.
Goodman & Gilman’s The Pharmacological Basis of Therapeutics.
9th ed. New York, NY: McGraw-Hill; 1996:1363-1382.
6. Sofronas M, Ichord RN, Fullerton HJ, et al. Pediatric stroke
initiatives and preliminary studies: what is known and what is

1327

needed? Pediatr Neurol. 2006;34:439-445.
7. Ganesan V, Prengler M, McShane MA, Wade AM, Kirkham FJ.
Investigation of risk factors in children with arterial ischemic
stroke. Ann Neurol. 2003;53:167-173.
8. Lanska MJ, Lanska DJ, Horwitz SJ, Aram DM. Presentation,
clinical course, and outcome of childhood stroke. Pediatr
Neurol. 1991;7:333-341.
9. Ganesan V, Kelsey H, Cookson J, Osborn A, Krikham FJ.
Activated protein C resistance in childhood stroke. Lancet.
1996;347:260.
10. Kenet G, Sadetzki S, Murad H, et al. Factor V Leiden and
antiphospholipid antibodies are significant risk factors for
ischemic stroke in children. Stroke. 2000;31:1283-1288.
11. Zenz W, Bodo Z, Plotho J, et al. Factor V Leiden and prothrombin gene G 20210 A variant in children with ischemic
stroke. Thromb Haemost. 1998;80:763-766.
12. Nowak-Gottl U, Strater R, Heinecke A, et al. Lipoprotein (a) and
genetic polymorphisms of clotting factor V, prothrombin, and
methylenetetrahydrofolate reductase are risk factors of spontaneous ischemic stroke in childhood. Blood. 1999;94:3678-3682.
13. Moore DF, Ye F, Schiffmann R, Butman JA. Increased signal
intensity in the pulvinar on T1-weighted images: a pathognomonic MR imaging sign of Fabry’s disease. AJNR Am J
Neuroradiol. 2003;24:1096-1101.
14. Yilmaz EY, Pritz MB, Bruno A, Lopez-Yunez A, Biller J.
Moyamoya: Indiana University Medical Center experience.
Arch Neurol. 2001;58:1274-1278.
15. Chabrier S, Rodesch G, Lasjaunias P, Tardieu M, Landrieu P,
Sebire G. Transient cerebral arteriopathy: a disorder recognized
by serial angiograms in children with stroke. J Child Neurol.
1998;13:27-32.
16. Kodama H, Fukuda J, Karube H, Matsui T, Shimizu Y, Tanaka T.
Status of the coagulation and fibrinolytic systems in ovarian
hyperstimulation syndrome. Fertil Steril. 1996;66:417-424.
17. Ou YC, Kao YL, Lai SL, et al. Thromboembolism after ovarian
stimulation: successful management of a woman with superior
sagittal sinus thrombosis after IVF and embryo transfer: case
report. Hum Reprod. 2003;18:2375-2381.
18. Espensen MK, Baggesen KL. Ischemic cerebral infarction in a
young woman undergoing gonadotropin treatment for infertility. Ugeskr Laeger. 2005;167:2901-2903.
19. El Sadek MM, Amer MK, Fahmy M. Acute cerebrovascular
accidents with severe ovarian hyperstimulation syndrome. Hum
Reprod. 1998;13:1793-1795.
20. Yoshii F, Ooki N, Shinohara Y, Uehara K, Mochimaru F.
Multiple cerebral infarctions associated with ovarian hyperstimulation syndrome. Neurology. 1999;53:225-227.
21. Silvestrini M, De Simone R, Santone GC, Tagliati M. A case of
stroke associated with gonadotropin treatment in a young
patient. Funct Neurol. 1992;7:43-45.
22. Ichord RN. Stroke in childhood. In: Singer HS, Kossoff EK,
Hartman AL, Crawford TO, eds. Treatment of Pediatric
Neurologic Disorders. New York, NY: Taylor & Francis; 2005.

Downloaded from jcn.sagepub.com at The University of Iowa Libraries on June 6, 2015