C

Congenital hypogonadotropic hypogonadism and

micropenis: Effect of testosterone treatment on adult
penile size—Why sex reversal is not indicated
Bassam Bin-Abbas, MD, Felix A. Conte, MD, Melvin M. Grumbach, MD, and Selna L. Kaplan, MD, PhD
Micropenis is defined as a morphologi-
Micropenis is commonly due to fetal testosterone deficiency. The clinical man- cally normal penis, with a penile ure-
agement of this form of micropenis has been contentious, with disagreement thra, the stretched length of which,
about the capacity of testosterone treatment to induce a functionally adequate measured along the dorsal surface from
adult penis. As a consequence, some clinicians recommend sex reversal of af- the pubis to the tip of the glans, is more
fected male infants. We studied 8 male subjects with micropenis secondary to than –2.5 SD below the mean value for
congenital pituitary gonadotropin deficiency from infancy or childhood to ma- age.1,2 Stretched penile lengths vary
turity (ages 18 to 27 years). Four patients were treated with testosterone before
See editorial, p. 537.
2 years of age (group I) and four between age 6 and 13 years (group II). At
presentation, the mean penile length in group I was 1.1 cm (–4 SD; range, 0.5
from a mean of 3.5 ± 0.4 cm at birth1,2
to 1.5 cm) and in group II it was 2.7 cm (–3.4 SD; range, 1.5 to 3.5 cm). All pa- to 12.4 ± 2.7 cm in adults3,4 (Table I). A
tients received one or more courses of 3 intramuscular injections of testosterone stretched penile length of <2.5 cm in
enanthate (25 or 50 mg) at 4-week intervals in infancy or childhood. At the age term infants is by definition a micrope-
of puberty the dose was gradually increased to 200 mg monthly and later to an nis. This arbitrary definition is useful in
adult replacement regimen. As adults, both group I and II had attained a mean identifying male infants in need of eval-
final penile length of 10.3 cm ± 2.7 cm with a range of 8 to 14 cm (mean adult uation; it does not take into account the
stretched penile length for Caucasians is 12.4 ± 2.7 cm). Six of 8 men were sex- possibility that ethnic differences noted
ually active, and all reported normal male gender identity and psychosocial be- in adults3,5 may be present in new-
havior. We conclude that 1 or 2 short courses of testosterone therapy in infancy borns. The variation in penile length in
and childhood augment penile size into the normal range for age in boys with individuals, as well as in ethnic groups,
micropenis secondary to fetal testosterone deficiency; replacement therapy at suggests that penile length is genetical-
ly determined by undefined mecha-
the age of puberty results in an adult size penis within 2 SD of the mean. We
nisms. Similarly, the mean testicular
found no clinical, psychologic, or physiologic indications to support conversion
size of adult Asian male subjects is
of affected male infants to girls. Further, the results of this study do not support
smaller than that of Caucasian male
the notion, derived from data in the rat, that testosterone treatment in infancy subjects6,7; body size contributes little
or childhood impairs penile growth in adolescence and compromises adult pe- to this difference.
nile length. (J Pediatr 1999;134:579-83)
DHT Dihydrotestosterone
From the Department of Pediatrics, School of Medicine, University of California San Francisco. MPHD Multiple pituitary hormone deficiencies
Supported in part by a National Institutes of Health grant from the National Institute of Diabetes
and Digestive and Kidney Diseases (5T32-DK-07161), the National Institute of Child Health and
Human Development (R01-HD-02335), and the National Institutes of Health–sponsored Pediatric Male sex differentiation occurs be-
Clinical Research Center (M01 RR01271). Bassam S. Bin-Abbas is a Fellow in Pediatric En- tween 8 and 14 weeks of gestation as a
docrinology under a program sponsored by King Faisal Specialist Hospital and Research Centre, consequence of the action of anti-mül-
Riyadh, Saudi Arabia.
Presented at the Annual Meeting of the Pediatric Academic Societies, New Orleans, Louisiana,
lerian hormone on the primitive müller-
May 1-5, 1998. ian ducts and of human chorionic go-
Submitted for publication Nov 12, 1998; revision received Jan 14, 1999; accepted Jan 28, 1999. nadotropin–induced stimulation of
Reprint requests: Melvin M. Grumbach, MD, Department of Pediatrics, University of Califor- fetal Leydig’s cells, and subsequently
nia San Francisco, San Francisco, CA 94143-0434. the secretion of testosterone and its
Copyright © 1999 by Mosby, Inc. conversion to dihydrotestosterone.8
0022-3476/99/$8.00 + 0 9/21/97495 After midgestation, fetal testosterone

579
 BIN-ABBAS ET AL
Table I. Stretched penile length (in cen-
timeters)
Age Mean ± SD
Newborn (30 wk)* 2.5 ± 0.4
Newborn (term)* 3.5 ± 0.4
0 to 5 mo† 3.9 ± 0.8
6 to 12 mo 4.3 ± 0.8
1 to 2 y 4.7 ± 0.8
2 to 3 y 5.1 ± 0.9
3 to 4 y 5.5 ± 0.9
5 to 6 y 6.0 ± 0.9
10 to 11 y 6.4 ± 1.1
Adult‡ 12.4 ± 2.7
*Feldman and Smith2; see Tuladhar etal4
for the normal range of penile length in
preterm infants between 24 and 36
weeks’ gestational age.
†Schonfeld and Beebe1 (data from ages 0 to
5 months to 10 to 11 years).
‡Wessells et al.3
levels are sustained primarily by fetal
pituitary luteinizing hormone,8 result-
ing in a continued penile growth (4
cm/y) from 20 weeks to birth.2 Except
for a transient rise in testosterone levels
in the first 4 to 6 months of life, testos-
terone levels are <25 ng/dL during in-
fancy and childhood; penile growth
from birth to 11 years of age is about 3
cm.1 With the onset of puberty, reacti-
vation of the hypothalamic-pituitary-
testicular axis occurs,9 resulting in a
rise in testosterone and DHT levels ac-
companied by an increase in androgen
receptor activity10 and a marked in-
crease in penile growth.8,9 By the end
of puberty, penile growth ceases de-
spite elevated levels of testosterone and
DHT, whereas androgen-induced pro-
static growth continues. The etiology of
micropenis is heterogeneous. It can re-
sult from deficient fetal testosterone se-
cretion caused by a primary testicular
disorder or as a consequence of fetal
luteinizing hormone deficiency owing
to a hypothalamic-pituitary abnormali-
ty, a defect in testosterone and DHT
action, or anomalous development of
the penis.8,11-14
In 1979 we reported that infants and
children with micropenis secondary to
580
Table II. Results
Treated patients
Age at start of testosterone therapy
Penile length
Mean
Range
Penile length after 3 mo of testosterone therapy
Mean
Range
Age at initiation of replacement testosterone
Final adult penile length
Mean
Range
*Noncompliant.
inadequate fetal testosterone secretion
respond to one or more short courses of
a long-acting repository form of testos-
terone in infancy or childhood with pe-
nile growth into the normal range for
age.13 This is an age when the concen-
tration of androgen receptors in fore-
skin is 2-fold to 3-fold greater than that
in the adult.10 We recommended that
all male infants with micropenis be
given a trial of testosterone therapy be-
fore a decision on management and sex
reversal is made. This recommendation
was counter to that of some experts in
the field who recommended the conver-
sion of boys with micropenis caused
by fetal testosterone deficiency to
girls.15-19 Their approach is largely
based on the gender socialization hy-
pothesis of Money and Ehrhardt18 and
the stated but unproven belief that a
“functionally adequate” adult penis
could not be induced with testosterone
therapy in a high proportion of male in-
fants and children with micropenis
caused by deficient secretion of testos-
terone by the fetal testis.15,16,19,20 It be-
came common practice in some clinics
to recommend a female gender assign-
ment for male infants with micrope-
nis,19,20 an extreme example of the clin-
ical application of the “sexually neutral
at birth and infancy” hypothesis. The
management of micropenis has contin-
THE JOURNAL OF PEDIATRICS
MAY 1999
Before 2 y In childhood
(n = 4) (n = 4)
4 mo-2 y 6-13 y
1.1 cm (–4 SD) 2.7 cm (–3.4 SD)
0.5-1.5 cm 1.5-3.5 cm
3.3 cm (–1.6 SD) 4.8 cm (–1.4 SD)
2.5–4 cm 2.5-7.5 cm
13-15 y 13-15 y
10.3 cm (–0.8 SD) 10.3 cm (–0.8 SD)
8*-12 cm 8.5–14
ued to be a contentious matter. We now
present long-term data on adult penile
size and sexual function in 8 patients
with micropenis caused by both fetal
and postnatal pituitary gonadotropic
hormone deficiency. The patients were
treated with a short course of a reposi-
tory preparation of intramuscular
testosterone in infancy and/or child-
hood and, beginning at the age of pu-
berty with a testosterone replacement
regimen.
SUBJECTS
Four of the 8 patients with micrope-
nis (ages 18 to 27 years) were first seen
before 2 years of age (group I), and 4
were first seen between the ages of 6
and 13 years (group II). No patients in
this age group were excluded (Table
II). All had fetal and postnatal go-
nadotropin deficiency as a result of
multiple pituitary hormone deficien-
cies (5 of 8)21 or isolated gonadotropin
deficiency (Kallmann’s syndrome, 3 of
8).22 All had a normally formed scro-
tum and descended small testes. Other
causes of congenital micropenis were
ruled out (Table III). The patients
were followed up in the Pediatric En-
docrine Clinic at the University of Cal-
ifornia San Francisco.
THE JOURNAL OF PEDIATRICS
VOLUME 134, NUMBER 5
METHODS
Penile length was measured by the
method of Schonfeld.1 The penis is
stretched to resistance, and length is
measured along the dorsal aspect from
the pubis to the tip of the glans. All pa-
tients had serial follow-up evaluations
documenting bone age, height, weight,
penile length, mid-shaft circumference,
and testicular size. Replacement thera-
py with growth hormone, L-thyroxine,
and hydrocortisone was administered
to the patients with MPHD.21 All pa-
tients received either one or two cours-
es of 25 to 50 mg of testosterone enan-
thate in oil, monthly × 3 doses in
infancy or childhood, to induce phallic
growth into the normal range for age.13
At the age of puberty, testosterone re-
placement therapy (administered in-
tramuscularly) was initiated at 50 mg
monthly and gradually increased to
200 to 400 mg every 4 weeks to induce
phallic growth, normal secondary sex-
ual characteristics, and maximum
growth potential22; finally, an adult
testosterone replacement regimen was
initiated. The data are expressed as
means ± 1 SD, unless otherwise stated.
Group comparisons were carried out
by using the Student t test with P ≤ .05
considered significant.
RESULTS
The 8 patients were divided into 2
groups based on age at initiation of
short-term testosterone treatment.
Four patients (3 with MPHD and 1
with Kallmann’s syndrome [group I])
began receiving testosterone treatment
before 2 years of age, and 4 patients (2
with MPHD and 2 with Kallmann’s
syndrome [group II]) were treated be-
tween 6 and 13 years of age.
At presentation, the mean penile
length in patients in group I was 1.1
cm (–4 SD). The mean penile length
was 2.7 cm (–3.4 SD) in patients in
group II (Table II). A 3-month course
of testosterone increased penile length
BIN-ABBAS ET AL
Table III. Etiology of micropenis
I. Deficient testosterone secretion
A. Hypogonadotropic hypogonadism
1. Isolated, including Kallmann’s syndrome
2. Associated with other pituitary hormone deficiencies
3. Prader-Willi syndrome
4. Laurence-Moon syndrome
5. Bardet-Biedl syndrome
6. Rud’s syndrome
B. Primary hypogonadism
1. Anorchia
2. Klinefelter’s and Poly X syndromes
3. Gonadal dysgenesis (incomplete form)
4. Luteinizing hormone receptor defects (incomplete forms)
5. Genetic defects in testosterone steroidogenesis (incomplete forms)
6. Noonan’s syndrome
7. Trisomy 21
8. Robinow’s syndrome
9. Bardet-Biedl syndrome
10. Laurence-Moon syndrome
II. Defects in testosterone action
A. Growth hormone/insulin-like growth factor-I deficiency
B. Androgen receptor defects (incomplete forms)
C. 5 α-reductase deficiency (incomplete forms)
D. Fetal hydantoin syndrome
III. Developmental anomalies
A. Aphallia
B. Cloacal exstrophy
IV. Idiopathic
V. Associated with other congenital malformations
from a mean value of 1.1 cm (–4 SD) age at initiation of therapy and final
to 3.3 cm (–1.6 SD) in group I patients penile length. In childhood, testos-
and from 2.7 cm (–3.4 SD) to 4.8 cm terone therapy increased penile size
(–1.4 cm) in group II patients. A sec- without causing other signs of viriliza-
ond course of testosterone was given to tion, a significant increase in height ve-
3 patients in group I to maintain the locity, or advancement in skeletal mat-
penile size in the normal range for age. uration. As adults, the patients had
All patients began receiving monthly final penile lengths within 2 SD of the
testosterone therapy to induce sec- normal mean value and normal erec-
ondary sexual characteristics at 13 to tion, ejaculation, and male gender
15 years of age.8 Mean final penile identity. Six of the patients were sexu-
length for the 8 patients was 10.3 cm ± ally active and reported satisfactory
2 cm (–0.8 SD) with a range of 8 to 14 heterosexual relationships and orgasm.
cm and a median length of 9.75 cm. In the 2 patients with both growth
This represents a mean increase in pe- hormone and gonadotropin deficiency
nile size of +3 SD. The mean adult pe- in whom human growth hormone ther-
nile lengths in group I and group II apy was initiated months before a
were the same (Table II). There was course of intramuscular testosterone
no statistical correlation in this limited therapy, growth hormone replacement
sample between initial penile length or alone had no or a minimal effect on pe-
581
 BIN-ABBAS ET AL
nile length. Elsewhere, we described
the long-term growth in height of rep-
resentative male subjects with congeni-
tal MPHD receiving replacement ther-
apy with human growth hormone21
and of boys with Kallmann’s syndrome
receiving testosterone therapy.22
DISCUSSION
This long-term study of 8 male sub-
jects with micropenis caused by hypo-
gonadotropic hypogonadism, who were
followed up in one clinic, strongly sug-
gests that fetal deficiency of go-
nadotropins and testosterone does not
prevent the penis from responding to
testosterone in infancy or at the age of
puberty. Final penile lengths were in
the normal range in all patients, al-
though their inherent genetic potential
may not have been attained in all pa-
tients.23 We did not detect a statistical-
ly significant difference in adult penile
length between the patients treated be-
fore 2 years of age and those first treat-
ed later in childhood, but the numbers
in each group were relatively small. In
our experience with over 30 male in-
fants and children with micropenis
(some measured as little as 0.5 cm in
stretched length) caused by fetal testos-
terone deficiency, all have responded to
testosterone treatment with growth of
the micropenis into the normal range
for age (unpublished data).13,24 Fur-
thermore, 6 of 8 men were sexually ac-
tive, and all reported normal male gen-
der identity and psychosocial behavior.
These data support our earlier recom-
mendations and suggest that there is no
clinical,25 physiologic, or psycholog-
ic26,27 basis for considering gender re-
versal in infants with micropenis
caused by testosterone deficiency. Fur-
ther, the patients with congenital go-
nadotropin deficiency, either isolated or
as a component of MPHD, can poten-
tially achieve adequate spermatogene-
sis later in life with either gonadotropin
or pulsatile gonadotropin-releasing hor-
mone treatment.28,29
582
Experiments in the rat suggested that
premature or early postnatal treatment
with androgen compromised the attain-
ment of normal adult penile size.30,31
Despite striking differences in the
structure of the rodent (including an os
penis [baculum]) and the human
penis,32 the authors suggested that an-
drogen therapy in childhood might
compromise adult penile length.30,31
The data in this report do not support
this notion and are consistent with a
previous study from our group,5 indi-
cating that neither true precocious pu-
berty nor congenital virilizing adrenal
hyperplasia (clinical examples of pre-
pubertal exposure to androgens) re-
duced adult penile length below the
normal range even though adult stature
was reduced.
Although penile length may be re-
duced in infancy and early childhood
in boys with isolated growth hormone
deficiency or growth hormone resis-
tance,33,34 the prevalence of congenital
micropenis is rare and usually limited
to the familial forms with null muta-
tions in the growth hormone, growth
hormone receptor, or insulin-like
growth factor-I gene. Levy and Hus-
mann35 have proposed that growth
hormone alone can augment phallic
size into the normal range in patients
with micropenis and isolated growth
hormone deficiency. Seven of 8 of their
patients had an adult stretched penile
length in the normal range with a pe-
nile length of –1.73 SD (range, –0.91
to –2.66) below the mean value. Most
of their patients had a relatively small
penis in adulthood. In our group, in
contrast, the mean adult penile length
of the 5 patients with MPHD treated
with both human growth hormone and
testosterone was –0.56 SD (mean 10.9
cm ± 2.3 cm).
In sum, testosterone therapy in pa-
tients with a micropenis caused by fetal
testosterone deficiency results in nor-
mal or near normal adult penile length
and a penis that has erectile function.
In this long-term follow-up study, we
found no clinical, physiologic, or psy-
THE JOURNAL OF PEDIATRICS
MAY 1999
chologic grounds to support the gen-
der reversal of male infants with an-
drogen-responsive micropenis.
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