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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
- ^. \! W- _5 VGONADOTROPIN, C8 Y- X! d% z( \
RICHARD C. KLUGO* AND JOSEPH C. CERNY
' p7 O9 z3 h& c1 X; o" G8 \From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
& B% r5 R2 p M* ~3 p$ TABSTRACT$ O0 i. B& P& o" [
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
5 T6 k e& w4 M. G- D- x# ]8 g' Rwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-+ ^$ W( E+ x2 I4 n
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone) x0 O5 T1 Z4 f
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent8 L# A$ S1 ]( j' s, V f9 c
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
* l5 p( p, F' W. ^5 F, E5 _( xincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
8 p. v5 g6 B4 Wincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
4 g8 \+ O5 g+ Ioccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
6 ^" ~# Z+ o8 E, dstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile- r8 Z2 E/ b* l( X
growth. The response appears to be greater in younger children, which is consistent with previ-
' O) T2 @* G% o M! u) W3 ^ously published studies of age-related 5 reductase activity.4 H/ h) p/ j6 Y3 G
Children with microphallus regardless of its etiology will! K1 Q/ f+ A q2 U8 f; B
require augmentation or consideration for alteration of exter-2 t& n& E, v+ X+ [" x
nal genitalia. In many instances urethroplasty for hypo-
0 |$ E9 h, N# z7 e$ |: {7 X9 |$ @spadias is easier with previous stimulation of phallic growth.
- g, s8 h) l' N |The use of testosterone administered parenterally or topically
2 p6 Y6 t$ r+ E% B5 ]has produced effective phallic growth. 1- 3 The mechanism of1 e1 S! s9 @$ u! |. g2 G2 q
response has been considered as local or systemic. With this6 `( s, }8 J& T* k5 q' @/ h
in mind we studied 5 children with microphallus for response/ a, b2 P$ _8 |* O$ j, L
to gonadotropin and to topical testosterone independently.1 N# p5 x. G1 f I- g' p$ P
MATERIALS AND METHODS( t; p& { f, t0 R* F
Five 46 XY male subjects between 3 and 17 years old were
4 Z! u* l. m0 D. ?' ~6 Q* Tevaluated for serum testosterone levels and hypothalamic
- s0 n J6 {' c) p+ L( \- A% ofunction. Of these 5 boys 2 were considered to have Kallmann's
5 a$ Y+ u8 R, Z8 s) S% xsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
$ W! g- H- i2 `- ?5 p8 Ulamic deficiency. After evaluation of response to luteinizing
2 J3 y8 A9 m& R z5 ]hormone-releasing hormone these patients were treated with
" y n+ D& H& G+ W2 r# a1,000 units of gonadotropin weekly for 3 weeks. Six weeks
/ b- k# k0 S* ?9 E( {* p5 \ lafter completion of gonadotropin therapy 10 per cent topical
" W$ [- D8 Q5 g5 i0 ^5 _1 Vtestosterone was applied to the phallus twice daily for 3 weeks.( C, D* ?; o0 X( _* k1 ^- W
Serum testosterone, luteinizing hormone and follicle-stimulat-6 O3 m j0 K# \9 O$ y4 R0 O7 u
ing hormone were monitored before, during and after comple-
$ q( f j) P0 ^8 D" q( ution of each phase of therapy. Penile stretch length was
5 Q; M2 }3 s! n/ u5 zobtained by measuring from the symphysis pubis to the tip of! W' E: Y4 @4 X. P
the glans. Penile circumferential (girth) measurements were. E# @5 j. G$ Z: w, M
obtained using an orthopedic digital measuring device (see ~- v6 q2 k* I! B
figure).+ H) G2 h; }$ f( O, ~3 l' y9 T( @
RESULTS8 o* T/ }( ]$ g/ X4 v% [* f, [
Serum testosterone increased moderately to levels between
- V( c8 u5 w! F50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
- C5 R [% a/ }! V* }1 Qterone levels with topical testosterone remained near pre-0 {& @( H/ ]. E, ~( X
treatment levels (35 ng./dl.) or were elevated to similar levels
. {9 y5 k7 A4 m1 Q2 i# ^developed after gonadotropin therapy (96 ng./dl.). Higher/ o& |( z7 \7 m+ C) A, ]4 B0 \9 n
serum levels were noted in older patients (12 and 17 years old),
3 x4 ^4 z2 F' L! Ewhile lower levels persisted in younger patients (4, 8, and 100 \4 f& [7 @1 p
years old) (see table). Despite absence of profound alterations
6 R6 A- g+ \% m. d2 @& f7 Y8 a+ vof serum testosterone the topical therapy provided a greater; z; q; \0 R! F* B4 J/ [" J5 \
Accepted for publication July 1, 1977. ·$ v. H$ ?2 A/ v; }
Read at annual meeting of American Urological Association,4 i. ?% D. ^2 {" N4 o: P
Chicago, Illinois, April 24-28, 1977.# v. t5 c& b2 L, W
* Requests for reprints: Division of Urology, Henry Ford Hospital,
+ u& p) L M4 w2 I4 o2799 W. Grand Blvd., Detroit, Michigan 48202.+ v$ P6 D! I) I, E1 e# I
improvement in phallic growth compared to gonadotropin.4 C) Z; |: |# R
Average phallic growth with gonadotropin was 14.3 per cent! N$ i, S1 Q! j s1 \- F
increase in length and 5.0 per cent increase of girth. Topical
( v2 N/ g: Q% T2 z3 ttestosterone produced a 60.0 per cent increase of phallic length
' W1 m% i6 O4 T9 fand 52.9 per cent increase of girth (circumference). The7 z. Z7 o8 s; b, r: V2 U; \
response to topical testosterone was greatest in children be-
! K- b/ X1 H3 d, }& v$ h" @tween 4 and 8 years old, with a gradual decrease to age 17' B4 f3 F3 N) t8 ~
years (see table).
( `. ]* `3 C; i9 n, F2 [DISCUSSION
* \" b/ h9 K, ^& H M$ Y0 TTopical testosterone has been used effectively by other# y; Q! @# x! Y) v
clinicians but its mode of action remains controversial. Im-3 z$ f# k3 c# ^
mergut and associates reported an excellent growth response: t8 M# A4 N1 l: {- X d
to topical testosterone with low levels of serum testosterone,
* w" h- C. c! r- dsuggesting a local effect.1 Others have obtained growth re-
; n+ Y" n" {6 Q) x {* qsponse with high. levels of serum testosterone after topical
# i" b# N4 e$ ~' T/ @) c2 sadministration, suggesting a systemic response. 3 The use of0 o6 y- S2 c) m7 q3 G
gonadotropin to obtain levels of serum testosterone compara-
* m9 Z' ]9 L1 H7 N/ T) R n1 b& L! Able to levels obtained with topical testosterone would seem to( @8 E. o$ e1 b$ w3 {7 A' F j
provide a means to compare the relative effectiveness of$ F; x. f( p' o0 u- s
topical testosterone to systemic testosterone effect. It cer-2 L3 w; N- T3 R5 a* E3 [
tainly has been established that gonadotropin as well as par-
3 V, Y0 n9 `3 W/ ^3 l& M& fenteral testosterone administration will produce genital, ]; D% M2 t9 C. L
growth. Our report shows that the growth of the phallus was
# }3 s ?2 X" M, y/ k" c9 H/ osignificantly greater with topical applications than with go-. [6 F. U1 m0 p) x
nadotropin, particularly in children less than 10 years old.
) H* s! M a2 [0 _$ @! YThe levels of serum testosterone remained similar or lower
0 Q! M2 V, V9 H; n( |6 l8 Uthan with gonadotropin during therapy, suggesting that topi-
' G; Z+ z. r1 |, _3 xcal application produces genital growth by its local effect as
, m) Y3 M) h* z( Dwell as its systemic effect.
( ?7 P; b! E$ E' S, U' bReview of our patients and their growth response related to
# e' ?9 r/ f( Bage shows a greater growth response at an earlier age. This is
- o2 t0 {/ |0 xconsistent with the findings of Wilson and Walker, who' I' e- z% ~& _3 R2 I7 x L; G
reported an increased conversion of testosterone to dihydrotes-/ s: ]+ }4 O, {5 K& E
tosterone in the foreskin of neonates and infants.4 This activ-) T2 D1 C- E. K" f
ity gradually decreases with age until puberty when it ap-
/ {4 B! t1 `" r8 a9 x9 i0 R3 nproaches the same level of activity as peripheral skin. It may3 u' b; {! O r7 g. K7 f- y2 |
well be that absorption of testosterone is less when applied at
, p! `- r, ?6 I7 |% H* Yan earlier age as suggested by lower serum levels in children: n+ S+ J5 I( l
less than 10 years old. This fact may be explained by the8 v8 @2 i9 {" f5 t1 R5 O/ Q
greater ability of phallic skin to convert testosterone to dihy-+ Z `& P& K" [$ m2 N/ N
drotestosterone at this age. Conversely, serum levels in older: f4 M( {4 S; u3 i& S
patients were higher, possibly because of decreased local
9 W: u7 G2 R4 M" Q6 p7 U, k1 X667; V1 a) ~+ @0 d: l: [- o% y: r
668 KLUGO AND CERNY1 R6 L6 n. q, M' J' L! u
Pt. Age
* t9 W# v' T* P5 w( a; R( T" W(yrs.); m6 l' u1 a z; L1 Q$ h F- L
Serum Testosterone Phallus (cm.) Change Length2 ^/ {1 M2 k' Y# S- l
(ng./dl.) Girth x Length (%)/ j9 E; d% ~* x: t7 U+ F ]6 ^
44 F' A, `. e1 {" j4 x4 g' W
8
' p! G4 h0 f+ B$ f# S% W10
5 ]1 a! C& n- |4 U9 _6 H( n12; K. p5 D1 Q+ K+ n
17+ T: ]4 k) N9 e2 c8 r9 J
Gonadotropin$ N& ~" B% |( w0 }; Z
71.6 2.0 X 3 16.6
( G2 m7 S$ H* q2 ^0 T& _$ M) e50.4 4.0 X 5.0 20.0
! @6 N8 S# ^3 \3 M( C22.0 4.5 X 4.0 25.0
3 r1 ?/ W1 ~$ C9 Z, o7 X5 W84.6 4.0 X 4.5 11.1) h8 q Y3 D9 N+ ^7 H) W" h
85.9 4.5 X 5.5 9.0% P% X7 W1 q5 r6 \0 i; s# R
Av. 14.38 w3 }. ]7 E% h1 k% d) W* T, i: z
4
1 V. A+ P4 l! a2 e8 G5 f8
2 s( G, x0 ~! x4 e10+ ?3 T: k, y6 u- i+ {0 R
12: }" |) f# P- q/ k
17
1 [$ |: Y& U7 Z) `* |Topical testosterone
3 h+ h. Q' ?0 ]. v( K34.6 4.5 X 6.5 85
# c* J. j3 ~! ]/ W5 R( q38.8 6.0 X 8.5 70: E1 j/ [! K5 V. _$ z
40.0 6.0 X 6.5 62.58 ^5 P) Z# V1 \- @( {
93.6 6.0 X 7.0 55.5) u& S( B, w' `. C9 S% ~' _
95.0 6.5 X 7.0 27.2
/ F s C# x7 uAv. 60.00 p1 d7 Q! N3 C3 y E
available testosterone. Again, emphasis should be placed on) g: O% q2 t" s* ^9 J, n
early therapy when lower levels of testosterone appear to7 }! a: u! T* J+ f, y0 n
provide the best responses. The earlier therapy is instituted- F( Q; r' J$ A# o1 I1 G" [
the more likely there will be an excellent response with low! W9 c: J0 _/ F* E1 l5 O( B* A1 F
serum levels. Response occurs throughout adolescence as4 q' b7 K; L n/ \3 L
noted in nomograms of phallic growth. 7 The actual response8 V! b6 l; }# D# m5 w
to a given serum level of testosterone is much greater at birth
2 E- C5 y% {" V% H- A& a m2 Land gradually decreases as boys reach puberty. This is most
T5 O: V% A, ^+ \3 I2 nlikely related to the conversion of testosterone to dihydrotes-- z9 d. q b# n! v# |
tosterone and correlates well with the studies of testosterone
6 s( g$ [' V' N& u' u1 e5 \, rconversion in foreskin at various ages.* ^& p% e' d# e% C
The question arises regarding early treatment as to whether& D. ]8 G# |* N1 p- Q% i. S
one might sacrifice ultimate potential growth as with acceler-1 g- [7 l8 ], K5 {& H
ated bone growth. The situation appears quite the reverse; W5 l' G8 W, i( r- u
with phallic response. If the early growth period is not used
+ V& f* p% f1 t* \+ P& K- h# \7 `) Lwhen 5a reductase activity is greatest then potential growth" ~, Z1 D% G- x) y2 V, L
may be lost. We have not observed any regression of growth% C n0 }$ `2 ~
attained with topical or gonadotropin therapy. It may well# ~1 }% ] I9 K- \
be that some patients will show little or no response to any
2 r' ^, L0 c, m x) G) R8 K% b( _form of therapy. This would suggest a defect in the ability to
& J& o1 @+ R8 Y4 Xconvert testosterone to dihydrotestosterone and indicate that
+ \8 N! [' H% Y# W: Ephallic and peripheral skin, and subcutaneous tissue should
" q+ N7 L' H. ]& F0 Z& Nbe compared for 5a reductase activity.
2 b+ ?: r; H: J0 o) BA, loop enlarges to measure penile girth in millimeters. B,
5 l1 N) u9 _2 O' n4 wexample of penile girth computed easily and accurately.
& u) a/ \4 ~0 A% P# l9 i6 @- {. Lconversion of testosterone to dihydrotestosterone. It is in this" V& T0 I, @8 T. @
older group that others have noted high levels of serum% J9 v5 L* W4 E, d% G
testosterone with topical application. It would also appear; A/ H' I3 H! F! K
that phallic response during puberty is related directly to the- g4 W" W6 f4 H2 o
serum testosterone level. There also is other evidence of local x% V. ]6 M# Y' @+ U
response to testosterone with hair growth and with spermato-
4 N& h q1 N& K( e jgenesis. 5• 6
+ J1 ?, d' Z; d. `3 j XAdministration of larger doses of gonadotropin or systemic
* q: H0 {6 r7 Y) K7 r* Ttestosterone, as well as topical applications that produce
- f# Q; S$ L+ P' jhigher levels of serum testosterone (150 to 900 ng./dl.), will
0 I) M. h2 Z$ ~also produce phallic growth but risks accelerated skeletal
& N2 U" `9 f8 R* |maturation even after stopping treatment. It would appear# }( ^$ B+ j+ C/ J
that this may be avoided by topical applications of testosterone
% e0 y' o0 B9 Qand monitoring of serum testosterone. Even with this control, B% _1 N3 q6 K2 e) N
the duration of our therapy did not exceed 3 weeks at any, N) W9 _) c' }" t5 r; t: B
time. It is apparent that the prepuberal male subject may: ?5 X7 t/ j5 w# l
suffer accelerated bone growth with testosterone levels near
]( W5 T4 [: b200 ng./dl. When skeletal maturation is complete the level of9 W8 u: i" ]& q: ?( R/ G
serum testosterone can be maintained in the 700 to 1,300 ng./
2 F; Y0 N0 @' y5 Qdl. range to stimulate phallic growth and secondary sexual
3 S8 B; Z6 b- K+ Vchanges. Therefore, after skeletal maturation parenteral tes-# P8 l& m! F8 \$ s) o( D; V
tosterone may be used to advantage. Before skeletal matura-
8 g5 q& ]5 M6 l ^# \( V4 Gtion care must be taken to avoid maintaining levels of serum
; n1 f/ B$ y7 D- ~$ Stestosterone more than 100 ng./dl. Low-dose gonadotropin1 r0 O6 h Q' d; M
depends upon intrinsic testicular activity and may require
: ~$ O9 W- y. pprolonged administration for any response.7 s' V( i. r7 a! t- m" S; ~. O9 B
Alternately, topical testosterone does not depend upon tes-8 [6 y2 v0 {4 d V: ]
ticular function and may provide a more constant level of
5 E! i9 M X; L7 QREFERENCES" v( J$ j. S* _$ F. u
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,6 k9 B5 m1 m' g. J* D8 k9 ^1 [
R.: The local application of testosterone cream to the prepub-* w: c$ D, p: X" g. J2 H5 V
ertal phallus. J. Urol., 105: 905, 1971.' X& ~" b( C% K$ ]. S
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone2 m! A- J! y! z. R; P# Z. K
treatment for micropenis during early childhood. J. Pediat.,
2 L! o0 u( O0 Z4 i- W1 A83: 247, 1973." [* P1 O# A# e
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
z2 l5 n1 @2 N! |: Oone therapy for penile growth. Urology, 6: 708, 1975.
. u% C# K" |/ b7 ^: i: K; @8 e9 y' R4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
, |% P0 \' S8 s, X( y3 B+ H+ Eto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
8 ~3 h, _! m R1 tskin slices of man. J. Clin. Invest., 48: 371, 1969.3 q- e7 m3 F; J/ I/ ~
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth& j* b# U' `% S% J, d, A: u
by topical application of androgens. J.A.M.A., 191: 521, 1965.
2 [0 J1 g" I6 f: J3 {. ?6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local$ E; l& T9 m% E3 N2 x9 o+ X6 T
androgenic effect of interstitial cell tumor of the testis. J.* G1 e" H8 e1 z" K' A
Urol., 104: 774, 1970.
! U) l* A2 p" o; u8 s0 q7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
. T9 r8 e% l' l" ?& s4 D1 @tion in the male genitalia from birth to maturity. J. Urol., 48: |
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