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Hypospadias:
does the usage of Clomiphene citrate influence
the incidence?
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Al-Quraan
Ghassan MD, Al-Nusirat
Bassam MD
Department of Obstetric and Gynecology,
Royal Medical Services
Al-Salaita
Ghazi MD
Department
of Pediatrics, Royal Medical Services
AL-Maaita
Eqab MD
Department of Family Medicine, Royal
Medical Services
Al-Quraan
Elena MD
Department of Family Medicine, Ministry
of health, Jordan
Dr.
Ghassan Al-Quraan
E-mail: Quraangh
@yahoo.com
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ABSTRACT
Objectives: To
evaluate the link between ovulation
induction drug (clomiphene citrate)
in pregnancy and the prevalence of
hypospadias.
Materials and Methods:
A retrospective survey of all
cases of hypospadias in the period
between the 1st of January 1999 until
31 of December 2003. These cases were
collected from the Obstetric-Gynecological
Department and the Neonatal Care Unit
in the Royal Medical Services Hospitals
in the south of Jordan. Odds ratios
were calculated for the probability
of a genital anomaly (hypospadias)
after exposure to clomiphene citrate
using conditional logistic regression
analysis (95% confidence intervals).
Results: We found
a total of 104 cases of hypospdias
in all hospitals, 19 ( 0.37% ) of
them were those who conceived after
ovulation induction by clomiphene
citrate, while the remaining 85 (
0.38% ) were the result of spontaneous
ovulation .Cases (19/5119 ) and controls
(85/22210) were matched , and odds
ratios adjusted for maternal age and
birth order were calculated and it
was 0.0 for hypospadias associated
with clomiphene citrate.
Conclusion: There
was no association between clomiphene
citrate and external genital malformation
specifically Hypospadias .Thus, women
exposed to clomiphene citrate after
conception, may be assured there is
no increased risk of urogenital anomalies
(Hypospadias).
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Key Words:
clomiphene citrate, Hypospadias, ovulation
induction.
In this year (2006), nearly
45 years will have passed after the first
description of a 'chemically' induced ovulation
with clomiphene citrate[1]. Over this period
it has maintained a solid footing in reproductive
medicine .Worldwide, clomiphene citrate
is used for inducing ovulation[2], as it
is the first-line therapy for physicians
practicing general gynecology when initiating
treatment of infertility due to ovulatory
dysfunction[3,4].
Clomiphene Citrate is a synthetic,
non-steroidal estrogen receptor agonist/antagonist.
This anti-estrogenic activity is the mechanism
of its action in inducing ovulation. Structurally
clomiphene citrate is related to diethylstilbestrol.
It has a racemic mixture of two 'isomers',
zuclomiphene and enclomiphene. The active
isomer is enclomiphene, (trans-isomer with
only anti-oestrogenic activity), and has
a short half life. On the opposite side,
the relatively inactive one (zuclomiphene),
has a very long half life. As a result,
the half life of clomiphene citrate is about
5 - 7 days, but its metabolites have been
found in blood samples on day 22 of the
menstrual cycle, and in the faeces up to
6 weeks after administration[5]. In addition,
clomiphene citrate displays a tendency for
prolonged nuclear receptor occupancy[6]
upon repetitive administration ,and this
has given rise to speculations about its
toxicity and possible teratogenic effects[7].
The extensive experience,
gained over a long period of prescribing
clomiphene citrate, makes it safe to use
,however , this conclusion is empirical
rather than a result of properly designed
studies[8], especially in view of the teratogenic
and toxic effects that have been described
in animals. The aim of our study was to
assess the risk of hypospadias among males
conceived following the use of clomiphene
citrate as an ovulation induction drug.
A retrospective survey
of all cases of hypospadias in the period
between the 1st of January 1999 until 31
of December 2003. These cases were collected
from the Obstetric-Gynecological Department
and the Neonatal Care Unit in the Royal
Medical Services Hospitals in south of Jordan.
All data was collected from three sources:
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- Birth registry in
each hospital which contains information
on the mother, date and time of delivery
, assurance number, the mode of delivery,
delivery outcome (male, female and any
congenital abnormalities ), midwife name
and any comments.
- Neonatal care unit
registry also contains information about
the newborn taken by the pediatrician
and staff nurse.
- Pharmacy registries
in selected hospitals which contain data
on all prescriptions for clomiphene citrate
(Clomid ). All mothers with epilepsy,
diabetes and those diagnosed with pre-eclampsia
were excluded from this study, as it has
been associated with increased risk for
hypospadias. Also mothers other than Jordanians
(immigrant ) were excluded from this study
as some countries of origin (e.g. Turkish)
have an increased risk for hypospadias.
In
this population based case-control study
, odds ratios were calculated for the probability
of a genital anomaly (hypospadias) after
exposure to clomiphene citrate using conditional
logistic regression analysis adjusted for
maternal age and birth order (95% confidence
intervals).
Of the 27,329 male newborns
that were enrolled in this population based
case - control study, we found a total of
104 cases of hypospdias in all hospitals.
Cases were distributed into two groups;
those who conceived after ovulation induction
by clomiphene citrate 0.37% (19/5119), and
those, control groups, who conceived spontaneously
0.38% (85/22210).
Odds ratios were calculated
for the probability of a genital anomaly
(hypospadias) after exposure to clomiphene
citrate using conditional logistic regression
analysis adjusted for maternal age and birth
order, and it was 0.0 for hypospadias associated
with clomiphene citrate. ( see Table I).
The analysis of these results
revealed that, there was no significant
differences between the two groups in the
incidence of hypospadias (0.37%) compared
with (0.38%) in the control one.
Thus fear of hypospadias in
women conceived after clomiphene citrate,
or who used it incidentally during early
pregnancy can be reduced towards the null,
as seen in figure -1
Embryologic formation of the
penile urethra takes place between 9 and
12 weeks after ovulation and depends on
the secretion of testosterone by the fetal
testes[9], and by 12-14 weeks gestation,
differentiation of internal genital ducts
and external genitalia along either male
or female is complete[10], therefore, we
considered exposure during the 1st trimester
to be most important.
Hypospadias is a developmental
anomaly considered one of the most prevalent
urogenital malformations, the etiology of
which, is still not clearly understood11,and
affects 1 in 250 male newborns[12].
In 2002, an increased risk
of hypospadias was reported for sons of
women exposed to diethyl-stilbestrol (DES)
in utero, which is a non-steroidal estrogen,
and nowadays it is no longer used in obstetric
patients of childbearing age. Because of
the fact that clomiphene citrate and DES
are related structurally, the latter was
reported to be responsible for the appearance
of clear cell adenocarcinoma of the vagina
of female offsprings[13], and the development
of benign epididymal cysts in DES-exposed
men [14-19] , fear about clomiphene citrate
teratogenicity and concern has been raised
over a possible increase in disorders of
the male reproductive tract, specifically
hypospadias.
Fortunately, clomiphene citrate
is a well tolerated drug (in 1997 only one
of 113 patients dropped out because of drug
side-effects in a study by Kousta et al
[20]). According to our knowledge of current
literature, the potential effects of clomiphene
on the fetus have been investigated in animal
studies, while others (human studies) investigate
the effect of sex hormones exposure to the
urogenital system as shown in Table II.
The overall clinical experience
up till now indicates that the use of clomiphene
citrate is associated with an incidence
of birth defects similar to that observed
in the general population[20,21]. Similar
observation was reported in our study in
which there was no significant differences
between the two groups in the incidence
of hypospadias (0.37%) compared with (0.38%)
in the control one.
At the present time, despite
the fact that all collected data was based
on routine daily records, and while the
comparison must be interpreted cautiously
in light of possible selection bias, it
may be concluded that clomiphene citrate
is not associated with any increased risk
of hypospadias.
In this study, we found that,
there was no association between clomiphene
citrate and external genital malformation
specifically Hypospadias. Thus, women exposed
to clomiphene citrate after conception,
may be assured there is no increased risk
of urogenital anomalies (Hypospadias).
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Table
1. Characteristics of 104
boys with hypospadias and 22210
control population.
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Without
Hypospadias |
With
Hypospadias |
Total
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Crude
Odds Ratio |
Adjusted
Odds Ratio |
Risk
Ratio |
With Clomiphene |
5100 |
19 |
5119 |
0.9697 |
- |
0.9698 |
Without Clomiphene
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22125 |
85 |
22210 |
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Total
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27225
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104
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27329
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0.9697
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0 |
0.9698 |
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Table
2. Effects of sex hormones
on genitalia, case-control and
cohort studies.
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Reference
No. |
Authors
|
Genital
changes investigated |
Sex
hormonesexposure |
22 |
Sweet et al, 1974
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Hypospadias |
Estrogen, hydroxyprogesteronecaproate
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23 |
Harlap et al, 1975
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Hypospadias Hydrocele
cryptorchidism |
Estrogen, progesterone,
abortifients |
24 |
Mau,
1981 |
Hypospadias
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Progestin
/ (pregnancy test) |
25 |
Monteleone
et al , 1981 |
Hypospadias
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Sex
hormones (not specified) |
26 |
Polednak
and Janerich, 1983 |
Hypospadias
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Hormonal
pregnancy tests, supportive hormones,
oral contraceptive pills |
27 |
Kallen,
1988 |
Hypospadias
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Oral
contraceptive pills |
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Figure
1. Effects of sex hormones
on genitalia, case-control
and cohort studies.
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1. |
Greenblat , R.B. (1961)
Chemical induction of ovulation.Fertil.
Steril., 12,402- 404. |
2. |
Furr BJ ,Woodburn JR.
Luteinizing hormone-releasing hormone
and its analogues : a review of biological
properties and clinical uses.J Endocrinol
Invest 1988 ;11 :535-57 . |
3. |
Gysler M, March CM, Mishell
Jr DR, et al.A decade's experience with
an individualized clomiphene treatment
regimen including its effect on the
postcoital test.Fertil Steril 1982;37:161-7. |
4. |
ACOG Practice Bulletin.
Management of Infertility Caused By
Ovulatory Dysfunction.2002;34. |
5. |
Geier A , Lunenfeld B
, Pariente C , Kotev - Emeth S , Cadmic
A , Kokia E , et al. Estrogen receptor
binding material in blood of patients
after clomiphene citrate administration
:determination by radioreceptor assay
. Fertil Steril 1987;47:778-84 |
6. |
Clark, J.H. and Markaverich,
B.M. (1982) The agonistic-antagonistic
properties of clomiphene :a review.
Pharmacol.Therapeut.,15 467-519. |
7. |
Adashi, E.Y. (1993) Clomiphene
citrate :the case for monoisomeric preparation.Baillieres
Clin. Obstet. Gynaecol.,7,331-347. |
8. |
Greenland, S. and Ackerman,
D.L. (1995) Clomiphene citrate and neural
tube defects: a pooled analysis of controlled
epidemiologic studies and recommendations
for future studies.Fertil. Steril. ,
64, 936-941. |
9. |
O´Rahilly R , Muller
F. Human Embryology and Teratology.
New York, NY:John Wiley and Sons ;1992. |
10. |
Fanaroff AA, Martin RJ
,eds.Neonatal-perinatal medicine: Disease
of the fetus and infants.4th ed. St.Louis:CV
Mosby , 1987. |
11. |
Manson JM, Carr MC 2003
Molecular epidemiology of hypospadias
:review of genetic and environmental
risk factor. Birth defects Res A Teratol
67 :825 - 83. |
12. |
Nelson , Textbook of
Pediatrics 17th edition , Behrman R.E.
,Kliegman R.M. , Jenson H.B. ,2004 ;1812. |
13. |
Herbst AL, Ulfelder H,
Poskanzer DC .Adenocarcinoma of the
vagina .Association of maternal stilbestrol
therapy with tumor appearance in young
women.N Engl J Med 1971 ; 284:878-81. |
14. |
Bibbo M , Gill WB ,Azizi
F , Blough R , Fang VS , Rosenfield
RL , et al. Follow-up study of male
and female offspring of DES-exposed
mothers. Obstet. Gynecol. 1977; 49 :1-8
. |
|
|
15. |
Leary FJ , Resseguie
LJ , Kurland LT , O'Brien PC , Emslander
RF , Noller KL . Male exposed in utero
to diethylstilbestrol .JAMA 1984 ; 252:2984-9.
|
16. |
Gill WB , Schumacher GF
, Bibbo M , Straus FH , Schoenberg HW
,. Association of diethylstilbestrol
exposure in utero with cryptorchidism,
testicular hypoplasia and semen abnormalities
. J Urol 1979 ;122 :36-9. |
17. |
Wilcox AJ , Baird DD
, Weinberg CR , Hornsby PP , Herbst
AL. Fertility in men exposed prenatally
to diethylstilbestrol. N Engl J Med
1995; 332 :1411-6. |
18. |
Niculescu A. Effect of
in utero exposure to DES on male progeny.
J Obstet Gynecol Neonatal Nurs 1985;14:
468-70. |
19. |
Conley GR , Sant GR ,
Ucci AA Mitcheson HD . Seminoma and
epididymal cysts in a young man with
known diethylstilbestrol exposure in
utero. JAMA 1983; 249 :1325-6. |
20. |
Kousta , E., White, D.M.
and Franks , S.(1997) Modern use of
clomiphene citrate in induction of ovulation.
Hum. Reprod. Update, 3, 359-365. |
21. |
Adashi , E.Y. (1996)
Ovulation induction :clomiphene citrate
. In Adashi, E.Y., Rock, J.A. and Rosenwaks,
Z.(EDS), Reproductive Surgery and Technology.
Lipincott-Raven , Philadelphia, USA,
pp .1182-1206. |
22. |
Sweet RA, Schrott HG,
Kurland R, Culp OS. Study of the incidence
of hypospadias in Rochester, Minnesota,
1940-1970, and a case control comparison
of possible etiologic factors. Mayo
Clin Proc 1974;49:52-8. |
23. |
Harlap S , Prywes R,Davies
AM . Birth defects and estrogens and
progesterones in pregnancy. Lancet 1975;
i:682-3. |
24. |
Mau G . Progestins during
pregnancy and hypospadias. Teratology
1981; 24 :285-7. |
25. |
Monteleone RN, Castilla
EE , Paz JE. Hypospadias : An epidemiological
study in Latin America. Am J Med Genet
1981 ;10:5-19. |
26. |
Polednak AP , Janerich
DT . Maternal characteristics and hypospadias
:A case control study. Teratology 1983
; 28 :67-73. |
27. |
Kallen B. Case- control
study of hypospadias on registry information.
Teratology 1988 ; 38 :45-50. |
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