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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
8 i G' @+ c* ~) V- PGONADOTROPIN0 C( c+ Y$ G" U: p) ^
RICHARD C. KLUGO* AND JOSEPH C. CERNY
2 X% k n/ M0 e2 UFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
* x1 @7 G: B9 |* Q7 q0 W) NABSTRACT0 ~ x S5 N2 |$ J' K
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
0 k3 t, G) D: f6 K" Pwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-1 O% }/ ~5 i; } @: O
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
0 D9 `7 {# R7 ~1 Rcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
$ L* I. k* P7 r+ f+ y r4 Gfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
8 T1 f8 R0 J4 a9 nincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average' K' T/ _& Z" ~4 z4 h- [
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
8 j( K; j3 Q9 ?; T4 H; koccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This# v; x$ |4 `8 B5 H9 A
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
) U; z1 C# J# |% U" e2 Dgrowth. The response appears to be greater in younger children, which is consistent with previ-% U8 D8 o4 F1 ^0 i
ously published studies of age-related 5 reductase activity.- }4 J& Z5 Q. K8 b0 N/ \- B- P
Children with microphallus regardless of its etiology will
8 w; g9 M: U+ f2 D. |! mrequire augmentation or consideration for alteration of exter-7 ]0 d2 I" {+ I C# }0 u
nal genitalia. In many instances urethroplasty for hypo-
) O; s9 k! i! z3 d; y% Ispadias is easier with previous stimulation of phallic growth.
# G* G& r9 c) [The use of testosterone administered parenterally or topically
3 s( o2 Q. S% bhas produced effective phallic growth. 1- 3 The mechanism of
; t1 Y: J' V' u& K5 Q3 jresponse has been considered as local or systemic. With this
9 T5 X- ]- g3 Z) c( |9 }. v$ Xin mind we studied 5 children with microphallus for response* B; l9 A" H7 l8 u$ \
to gonadotropin and to topical testosterone independently.- C# S: P4 q& O6 t9 d
MATERIALS AND METHODS
" `4 U# |( t9 R% {; HFive 46 XY male subjects between 3 and 17 years old were/ w( Q+ g) d4 o6 P
evaluated for serum testosterone levels and hypothalamic
4 s* W$ ?0 C Z# } J- Xfunction. Of these 5 boys 2 were considered to have Kallmann's5 s _ Z& Z2 u6 x0 G1 V
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-0 H ]0 E- s. F; g
lamic deficiency. After evaluation of response to luteinizing8 L8 N0 G! [8 `4 C& I
hormone-releasing hormone these patients were treated with
3 s1 X0 G) w+ E; u1,000 units of gonadotropin weekly for 3 weeks. Six weeks4 B/ u4 ?% J' {( I1 E. r2 c8 }
after completion of gonadotropin therapy 10 per cent topical
3 Y! }$ @! N8 A! l8 w6 c, atestosterone was applied to the phallus twice daily for 3 weeks.
! x7 H+ S, z2 ^7 m b" aSerum testosterone, luteinizing hormone and follicle-stimulat-5 `1 X. `3 m* X. [- E% L: R8 [9 K
ing hormone were monitored before, during and after comple-
7 p$ O% o# i( o+ E9 \9 r1 mtion of each phase of therapy. Penile stretch length was4 b2 }- }8 z2 w* G: g
obtained by measuring from the symphysis pubis to the tip of
% ^+ Q+ F9 i. p/ f/ v+ b6 T5 m# ]the glans. Penile circumferential (girth) measurements were
6 _8 r5 Q8 G, L5 Q# u/ ^3 Jobtained using an orthopedic digital measuring device (see6 }# {, S2 g9 ^3 W% _) O2 R
figure).
, h6 ^0 M+ `, Y& I X7 uRESULTS
9 E- i2 V* f2 i- y# w' L2 c: y! DSerum testosterone increased moderately to levels between
9 ^' T# q" X+ L2 K2 e* h2 L50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
1 i7 l% O. x% B! Wterone levels with topical testosterone remained near pre-
- [ V# W c* K4 Itreatment levels (35 ng./dl.) or were elevated to similar levels% H" [ X3 v9 |% a
developed after gonadotropin therapy (96 ng./dl.). Higher
& a' l4 m7 [; e, K, l1 z2 }* lserum levels were noted in older patients (12 and 17 years old),$ w: o/ }3 L; n8 V S4 V
while lower levels persisted in younger patients (4, 8, and 10) x. j! j4 l. m I! e6 `! C# [
years old) (see table). Despite absence of profound alterations
' O( n) j' V) k& I4 cof serum testosterone the topical therapy provided a greater
, S. T( s# k* T! SAccepted for publication July 1, 1977. ·
% C! ?+ a, U8 S3 e: e U: e" Z* ARead at annual meeting of American Urological Association,
* ]4 B! }7 G ]% Q+ mChicago, Illinois, April 24-28, 1977.$ X8 u/ [" b: w
* Requests for reprints: Division of Urology, Henry Ford Hospital,9 x1 S% ^6 Y, e2 s/ b6 A. I7 x" B
2799 W. Grand Blvd., Detroit, Michigan 48202.4 f0 w; P3 U4 I4 E" P+ c" `* e
improvement in phallic growth compared to gonadotropin.8 n4 g6 T& c# b+ i' y' ?- ~" O7 i) G
Average phallic growth with gonadotropin was 14.3 per cent
$ A( T% g P6 U5 X; T# `increase in length and 5.0 per cent increase of girth. Topical
; p% C* {1 K' n/ L( c* ?4 v' s5 |testosterone produced a 60.0 per cent increase of phallic length
; w5 j. g' B6 z0 b# ]6 x1 qand 52.9 per cent increase of girth (circumference). The
6 u5 E, @* r+ |% a, Q2 nresponse to topical testosterone was greatest in children be-
, A( z! o" b8 Z. R. m+ vtween 4 and 8 years old, with a gradual decrease to age 17. Y1 v1 A8 r% j$ q
years (see table).4 ]* d5 _! Z' R+ v( ~
DISCUSSION
5 @: k1 T6 I e$ a+ H5 f9 e) b3 [5 VTopical testosterone has been used effectively by other
* m" t3 S0 J, n: a' v2 A. M5 M1 K( xclinicians but its mode of action remains controversial. Im-
]- [) O) R! }$ D9 Pmergut and associates reported an excellent growth response) O5 R7 w2 d# R& I' E
to topical testosterone with low levels of serum testosterone,2 P6 [- s Z X8 y# ^! D4 B
suggesting a local effect.1 Others have obtained growth re-
4 D# y& l3 I% z+ Nsponse with high. levels of serum testosterone after topical
$ Y$ z9 a6 ~8 @0 Kadministration, suggesting a systemic response. 3 The use of
. e) U, T; l* d# k* [6 wgonadotropin to obtain levels of serum testosterone compara-
7 @/ e" ] i0 R, Dble to levels obtained with topical testosterone would seem to7 n Y. W" \- J% N
provide a means to compare the relative effectiveness of
" o! ?6 K9 j! V2 l0 y* k5 i6 |topical testosterone to systemic testosterone effect. It cer-
' w* _3 J' b' k! ~; atainly has been established that gonadotropin as well as par-
7 M4 g9 R* f2 F+ y- n" jenteral testosterone administration will produce genital
& Y( [( _$ q" h$ C4 T$ a! Agrowth. Our report shows that the growth of the phallus was: |8 A" Y- u( E9 c2 K J3 \
significantly greater with topical applications than with go-
; C# w9 f; A$ S* mnadotropin, particularly in children less than 10 years old.+ J9 g0 Q4 i/ F8 ?! t6 U
The levels of serum testosterone remained similar or lower
3 h& W/ a6 k+ O8 B8 ^than with gonadotropin during therapy, suggesting that topi-
- o& J2 \. ~: y8 W- y4 ccal application produces genital growth by its local effect as
( h* W/ G0 j8 b/ Z8 A, B/ vwell as its systemic effect.
3 a# q$ B! o Y% RReview of our patients and their growth response related to' y2 s9 {0 s U' ` f
age shows a greater growth response at an earlier age. This is
1 ]* E9 c8 ^( X" aconsistent with the findings of Wilson and Walker, who( C( J. w* ?: {5 f: L
reported an increased conversion of testosterone to dihydrotes-, P4 p$ d5 x% x$ r) h1 Q$ g
tosterone in the foreskin of neonates and infants.4 This activ-
, Y) `. C3 {0 T$ `/ A; A- Gity gradually decreases with age until puberty when it ap-
$ e" L/ B! q9 h) D8 J/ rproaches the same level of activity as peripheral skin. It may
7 c" Q5 {& w2 h# Y# n% f6 g0 @well be that absorption of testosterone is less when applied at
+ G, e$ l) h* t; g2 P8 Fan earlier age as suggested by lower serum levels in children
% N4 z8 N. H& y# ^less than 10 years old. This fact may be explained by the
' | |" K& F) f4 X( X1 P% e' @; s& agreater ability of phallic skin to convert testosterone to dihy-
- L- v* u# G- ]: R5 sdrotestosterone at this age. Conversely, serum levels in older1 B- ?# f0 I! _1 [
patients were higher, possibly because of decreased local: ]' e1 J% a2 H# g/ G
667$ W& V" Z$ _: s- P
668 KLUGO AND CERNY
- Q8 g1 @0 A p0 ^7 TPt. Age; U( H$ [& w" R) I1 ^1 c7 Q
(yrs.)
" }3 e# V4 R, NSerum Testosterone Phallus (cm.) Change Length
* ]. e0 p, a8 _- T" R: q(ng./dl.) Girth x Length (%)1 F5 K3 V$ L5 C* o
4
2 T6 M4 p/ [1 ?+ j/ r: W5 D2 U8. C. A. D9 @ u# a
10* Y3 Y0 `$ v0 n' [
12
* v9 T% [4 h' `* z17
5 w6 @: t" v0 j% oGonadotropin& G% R8 E8 |; q9 ?
71.6 2.0 X 3 16.6
6 ?$ c7 {: N( K' \/ o50.4 4.0 X 5.0 20.0
8 a+ h% ~4 M/ j- K22.0 4.5 X 4.0 25.0
2 j: S h) C) B7 [84.6 4.0 X 4.5 11.1+ ?9 L8 }3 K6 J
85.9 4.5 X 5.5 9.0
7 x, L3 N1 }8 _1 A+ _Av. 14.3
" w! L* T5 T1 y7 a43 x& @- V) L& G3 T
8$ j2 K5 C9 D1 C
100 b! t* |$ M! l% j, c
12; W! k$ D; S0 a+ m7 R
17* v' Y! Q% h: X8 o5 t
Topical testosterone
" s: }( I( }8 g" ]7 ^34.6 4.5 X 6.5 85( F+ Z: P3 x& `% [. b) ?2 f5 L
38.8 6.0 X 8.5 700 w$ i& T8 n- y6 C S
40.0 6.0 X 6.5 62.5! ?! X" w: m2 g/ h& O* M6 ?. c
93.6 6.0 X 7.0 55.5
' e4 X6 l+ Y) Z# U0 d95.0 6.5 X 7.0 27.2
m- M1 i% g6 ZAv. 60.0* S* @/ V8 M `$ Z. p2 y4 W+ H
available testosterone. Again, emphasis should be placed on- d( V7 o d% E$ X- s6 z1 E
early therapy when lower levels of testosterone appear to! j3 Y% H$ W/ o0 C! d1 ]
provide the best responses. The earlier therapy is instituted4 ~) X2 z' q E0 P
the more likely there will be an excellent response with low& I- U) q, x" i3 C% b# r
serum levels. Response occurs throughout adolescence as$ k! Q! C' V6 U ~
noted in nomograms of phallic growth. 7 The actual response
5 C2 x |5 q \5 vto a given serum level of testosterone is much greater at birth
9 N" H! m5 k& b2 T+ G. u5 F; \. |and gradually decreases as boys reach puberty. This is most
1 D0 O' b9 p7 `4 V8 \0 H Zlikely related to the conversion of testosterone to dihydrotes-% C: f) R3 `+ v$ b8 t* h
tosterone and correlates well with the studies of testosterone9 }! `1 \9 P" h: d& r! _
conversion in foreskin at various ages.* n. w3 Y) V/ i% A7 S" A
The question arises regarding early treatment as to whether5 T5 r6 t8 n; M& W
one might sacrifice ultimate potential growth as with acceler-
$ P% \6 |* n) Q6 X9 pated bone growth. The situation appears quite the reverse! l; ?9 f) q5 ?# v9 _. o* Y' W, T
with phallic response. If the early growth period is not used
- G/ Q- v; y- Z8 ewhen 5a reductase activity is greatest then potential growth; k. h6 l; |" W
may be lost. We have not observed any regression of growth
" z! g+ I, }" c' j6 \/ j; j+ \attained with topical or gonadotropin therapy. It may well
4 ]* v# x! ]! R1 O6 ]; Lbe that some patients will show little or no response to any: f) E% m, c5 q7 I( d/ s( i% s
form of therapy. This would suggest a defect in the ability to' y7 M/ @3 X: p3 u! X
convert testosterone to dihydrotestosterone and indicate that8 d) E; I; p6 ^# B- y! V9 B
phallic and peripheral skin, and subcutaneous tissue should
0 v- X5 u- A0 Obe compared for 5a reductase activity.
% v$ }% j. s# `& OA, loop enlarges to measure penile girth in millimeters. B,
8 C, Q+ ^: I. X S0 t& `- H$ Iexample of penile girth computed easily and accurately.* j* e- J5 E7 B$ P$ C7 J' t, z1 I( H
conversion of testosterone to dihydrotestosterone. It is in this$ C3 o5 s G) v( u: X
older group that others have noted high levels of serum, s& r3 s( L7 V$ s8 B* Y1 Y* ~
testosterone with topical application. It would also appear
: o6 L- M; I' \7 D$ V7 t1 x$ Qthat phallic response during puberty is related directly to the
) Z2 h. z. s$ ~serum testosterone level. There also is other evidence of local) r/ D0 `2 o- u- }- }3 {
response to testosterone with hair growth and with spermato-) h$ o' f- R$ O/ l6 l
genesis. 5• 6
, ~1 o$ l8 R2 k- CAdministration of larger doses of gonadotropin or systemic' f4 g- u' ~7 ^
testosterone, as well as topical applications that produce% w& ]& u2 p, Z
higher levels of serum testosterone (150 to 900 ng./dl.), will
; a3 e% j7 s$ S% k5 Kalso produce phallic growth but risks accelerated skeletal
P; Z) f: j2 r+ x" k; }maturation even after stopping treatment. It would appear
, x3 }) N% i5 l$ w: L; wthat this may be avoided by topical applications of testosterone
7 }$ G: U& d+ T. pand monitoring of serum testosterone. Even with this control, B0 j% v3 M; ]! g' k% w" D
the duration of our therapy did not exceed 3 weeks at any
- \- S" j/ _( a. L0 }7 otime. It is apparent that the prepuberal male subject may. n6 u. T$ M' `! z/ T6 t0 e3 M
suffer accelerated bone growth with testosterone levels near$ W4 \# d. X8 B+ K# ~. N1 @3 S7 {; {
200 ng./dl. When skeletal maturation is complete the level of
3 t* [$ _" K* P9 l# }7 B0 fserum testosterone can be maintained in the 700 to 1,300 ng./
- A$ \ B5 d5 X" kdl. range to stimulate phallic growth and secondary sexual5 H% p2 h/ S: I7 W& m2 G2 y8 G
changes. Therefore, after skeletal maturation parenteral tes-
0 E1 D+ v7 I# ~5 Ytosterone may be used to advantage. Before skeletal matura-. H6 T: R) T# N5 }" L D& v
tion care must be taken to avoid maintaining levels of serum
+ f! \2 _' b" vtestosterone more than 100 ng./dl. Low-dose gonadotropin
& X$ C) y! o$ d6 d0 i8 gdepends upon intrinsic testicular activity and may require! c" ] ]& ^: Q1 e! Y
prolonged administration for any response.
6 p; |& q, H, [& A+ ], p* VAlternately, topical testosterone does not depend upon tes-- O4 M* b+ H* U' y% G! ]* g
ticular function and may provide a more constant level of
8 f3 N. [& g9 ]REFERENCES
1 L O0 p- |* |( J: w9 A) I) S r+ `1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
: i& v0 O+ q+ h7 ?& ^R.: The local application of testosterone cream to the prepub-+ X# \; y/ H. V
ertal phallus. J. Urol., 105: 905, 1971.
i9 b* _8 f6 g3 D5 t S: y) W3 Z2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone8 w: b2 B# l1 q+ I: S
treatment for micropenis during early childhood. J. Pediat.,
5 |$ z+ H. |) Z& F! \6 [* d4 J83: 247, 1973.
' D8 _" ] c* B5 B3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
7 Z/ C4 X$ L5 P1 l4 fone therapy for penile growth. Urology, 6: 708, 1975.$ T }9 n y4 c$ a7 [5 f! v
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone1 V; ]2 c- T1 E/ A2 G
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by: h! H6 z& x* p/ o
skin slices of man. J. Clin. Invest., 48: 371, 1969.
& R$ o* y6 i. l$ _0 [/ S5 }! z. k5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
' f* I" g9 X9 I& d& m: P3 j* F3 Nby topical application of androgens. J.A.M.A., 191: 521, 1965.
4 G9 X9 \3 a2 L5 E6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
' L" F6 L3 U! D& r! ?6 \androgenic effect of interstitial cell tumor of the testis. J./ a: L; r' n5 g0 ^! y( L
Urol., 104: 774, 1970.( S; u$ \' |' i8 b" v$ ^+ X
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
: Y3 O N' ` ation in the male genitalia from birth to maturity. J. Urol., 48: |
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