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Copyright © 1999 by Mosby, Inc.
Micropenis is commonly due to fetal testosterone deficiency. The clinical management of this form of micropenis has been contentious, with disagreement about the capacity of testosterone treatment to induce a functionally adequate adult penis. As a consequence, some clinicians recommend sex reversal of affected male infants. We studied 8 male subjects with micropenis secondary to congenital pituitary gonadotropin deficiency from infancy or childhood to maturity (ages 18 to 27 years). Four patients were treated with testosterone before 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 to 1.5 cm) and in group II it was 2.7 cm (-3.4 SD; range, 1.5 to 3.5 cm). All patients received one or more courses of 3 intramuscular injections of testosterone enanthate (25 or 50 mg) at 4-week intervals in infancy or childhood. At the age of puberty the dose was gradually increased to 200 mg monthly and later to an adult replacement regimen. As adults, both group I and II had attained a mean final penile length of 10.3 cm ± 2.7 cm with a range of 8 to 14 cm (mean adult stretched penile length for Caucasians is 12.4 ± 2.7 cm). Six of 8 men were sexually active, and all reported normal male gender identity and psychosocial behavior. We conclude that 1 or 2 short courses of testosterone therapy in infancy and childhood augment penile size into the normal range for age in boys with micropenis secondary to fetal testosterone deficiency; replacement therapy at the age of puberty results in an adult size penis within 2 SD of the mean. We found no clinical, psychologic, or physiologic indications to support conversion of affected male infants to girls. Further, the results of this study do not support the notion, derived from data in the rat, that testosterone treatment in infancy or childhood impairs penile growth in adolescence and compromises adult penile length. (J Pediatr 1999;134:579-83)
See editorial, p. 537.
Micropenis is defined as a morphologically normal penis,
with a penile urethra, the stretched length of which, measured along the dorsal surface
from the pubis to the tip of the glans, is more than -2.5 SD below the mean
value for age.[1]
[2]
Stretched penile lengths vary from a mean of 3.5 ± 0.4 cm at birth[1]
[2]
to 12.4 ± 2.7 cm in adults
[3]
[4]
(Table
I).
Male sex differentiation occurs between 8 and 14 weeks of gestation as a consequence of the action of anti-mullerian hormone on the primitive mullerian ducts and of human chorionic gonadotropin-induced stimulation of fetal Leydig's cells, and subsequently the secretion of testosterone and its conversion to dihydrotestosterone. [8] After midgestation, fetal testosterone levels are sustained primarily by fetal pituitary luteinizing hormone,[8] resulting 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, testosterone levels are <25 ng/dL during infancy and childhood; penile growth from birth to 11 years of age is about 3 cm.[1] With the onset of puberty, reactivation of the hypothalamic-pituitary-testicular axis occurs,[9] resulting in a rise in testosterone and DHT levels accompanied by an increase in androgen receptor activity [10] and a marked increase in penile growth.[8] [9] By the end of puberty, penile growth ceases despite elevated levels of testosterone and DHT, whereas androgen-induced prostatic growth continues. The etiology of micropenis is heterogeneous. It can result from deficient fetal testosterone secretion caused by a primary testicular disorder or as a consequence of fetal luteinizing hormone deficiency owing to a hypothalamic-pituitary abnormality, 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 inadequate fetal testosterone secretion respond to one or more short courses of a long-acting repository form of testosterone in infancy or childhood with penile growth into the normal range for age.[13] This is an age when the concentration of androgen receptors in foreskin 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 before a decision on management and sex reversal is made. This recommendation was counter to that of some experts in the field who recommended the conversion of boys with micropenis causedby fetal testosterone deficiency to girls.[15] [19] Their approach is largely based on the gender socialization hypothesis of Money and Ehrhardt[18] 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 infants and children with micropenis caused by deficient secretion of testosterone by the fetal testis.[15] [16] [19] [20] It became common practice in some clinics to recommend a female gender assignment for male infants with micropenis,[19] [20] an extreme example of the clinical application of the "sexually neutral at birth and infancy" hypothesis. The management of micropenis has continued 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 repository preparation of intramuscular testosterone in infancy and/or childhood and, beginning at the age of puberty with a testosterone replacement regimen.
Four of the 8 patients with micropenis (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).
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 patients had serial follow-up evaluations
documenting bone age, height, weight, penile length, mid-shaft circumference, and
testicular size. Replacement therapy with growth hormone, L-thyroxine, and hydrocortisone
was administered to the patients with MPHD.[21]
All patients received either one or two courses of 25 to 50 mg of testosterone enanthate
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 replacement therapy (administered intramuscularly)
was initiated at 50 mg monthly and gradually increased to 200 to 400 mg every 4 weeks
to induce phallic growth, normal secondary sexual characteristics, and maximum growth
potential[22]
; 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.
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 between 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 from a mean value of 1.1 cm (-4 SD) to 3.3 cm (-1.6 SD) in group I patients and from 2.7 cm (-3.4 SD) to 4.8 cm (-1.4 cm) in group II patients. A second course of testosterone was given to 3 patients in group I to maintain the penile size in the normal range for age. All patients began receiving monthly testosterone therapy to induce secondary sexual characteristics at 13 to 15 years of age.[8] Mean final penile length for the 8 patients was 10.3 cm ± 2 cm (-0.8 SD) with a range of 8 to 14 cm and a median length of 9.75 cm. This represents a mean increase in penile size of +3 SD. The mean adult penile lengths in group I and group II were the same (Table II). There was no statistical correlation in this limited sample between initial penile length or age at initiation of therapy and final penile length. In childhood, testosterone therapy increased penile size without causing other signs of virilization, a significant increase in height velocity, or advancement in skeletal maturation. As adults, the patients had final penile lengths within 2 SD of the normal mean value and normal erection, ejaculation, and male gender identity. Six of the patients were sexually active and reported satisfactory heterosexual relationships and orgasm.
In the 2 patients with both growth hormone and gonadotropin deficiency in whom human growth hormone therapy was initiated months before a course of intramuscular testosterone therapy, growth hormone replacement alone had no or a minimal effect on penile length. Elsewhere, we described the long-term growth in height of representative male subjects with congenital MPHD receiving replacement therapy with human growth hormone[21] and of boys with Kallmann's syndrome receiving testosterone therapy.[22]
This long-term study of 8 male subjects with micropenis caused by hypogonadotropic hypogonadism, who were followed up in one clinic, strongly suggests that fetal deficiency of gonadotropins 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, although their inherent genetic potential may not have been attained in all patients.[23] We did not detect a statistically significant difference in adult penile length between the patients treated before 2 years of age and those first treated later in childhood, but the numbers in each group were relatively small. In our experience with over 30 male infants and children with micropenis (some measured as little as 0.5 cm in stretched length) caused by fetal testosterone deficiency, all have responded to testosterone treatment with growth of the micropenis into the normal range for age (unpublished data).[13] [24] Furthermore, 6 of 8 men were sexually active, and all reported normal male gender identity and psychosocial behavior. These data support our earlier recommendations and suggest that there is no clinical,[25] physiologic, or psychologic[26] [27] basis for considering gender reversal in infants with micropenis caused by testosterone deficiency. Further, the patients with congenital gonadotropin deficiency, either isolated or as a component of MPHD, can potentially achieve adequate spermatogenesis later in life with either gonadotropin or pulsatile gonadotropin-releasing hormone treatment.[28] [29]
Experiments in the rat suggested that premature or early postnatal treatment with androgen compromised the attainment 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 androgen 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] indicating that neither true precocious puberty nor congenital virilizing adrenal hyperplasia (clinical examples of prepubertal exposure to androgens) reduced adult penile length below the normal range even though adult stature was reduced.
Although penile length may be reduced in infancy and early childhood in boys with isolated growth hormone deficiency or growth hormone resistance,[33] [34] the prevalence of congenital micropenis is rare and usually limited to the familial forms with null mutations in the growth hormone, growth hormone receptor, or insulin-like growth factor-I gene. Levy and Husmann[35] 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 penile 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 patients with a micropenis caused by fetal testosterone deficiency results in normal 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 psychologic grounds to support the gender reversal of male infants with androgen-responsive micropenis.
