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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
6 G" O# U$ t' n* G: q* x! xGONADOTROPIN! \  W( M$ l1 M: S2 L: ]
RICHARD C. KLUGO* AND JOSEPH C. CERNY
, i' D" U2 I3 m; mFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan# m2 ?, ]* _2 V* J& c& v6 A) J$ K
ABSTRACT1 r/ F7 e! ^+ y1 f3 m+ L. ~
Five patients were treated with gonadotropin and topical testosterone for micropenis associated! f" ^4 W2 A7 o. C( Y) ]
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-3 g( {/ V" a. I* f+ t  p; R. O# {& o
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone$ i4 Q  d& I) m' V! C
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent1 l8 v& P0 T4 |
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent/ P" G, W' O0 R* [8 z# O
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
& W( K9 x8 E( k: z: R+ T; }increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response" Z9 ]! ~( _% F
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This) m1 |# z7 ]9 l( l7 o
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
/ i1 Q$ F% O7 C: X8 c4 Wgrowth. The response appears to be greater in younger children, which is consistent with previ-
4 I" W$ F3 w5 n$ Z, f, T  G) sously published studies of age-related 5 reductase activity.5 F/ a' n+ ^' Y: H! p6 v+ u0 W0 R
Children with microphallus regardless of its etiology will
% S$ r4 B, }6 v2 j' yrequire augmentation or consideration for alteration of exter-
9 o5 t% Y% E; n0 e7 _* R/ inal genitalia. In many instances urethroplasty for hypo-
8 ?3 o9 r0 r" N9 M5 c2 ~spadias is easier with previous stimulation of phallic growth.
. w% E0 [3 J0 r1 [! u& v: \The use of testosterone administered parenterally or topically' s5 ?2 {9 `( j( _6 \: a* e0 Y
has produced effective phallic growth. 1- 3 The mechanism of, k9 }. N4 k6 M. X( O3 \$ U$ X: n7 B
response has been considered as local or systemic. With this
5 G  i) x5 H/ t+ `in mind we studied 5 children with microphallus for response) H6 r) S+ W1 C4 j
to gonadotropin and to topical testosterone independently.
. L+ m, v8 ?6 E4 V5 TMATERIALS AND METHODS, j2 z* q' I( X/ x6 E
Five 46 XY male subjects between 3 and 17 years old were: S9 g: |' @4 u
evaluated for serum testosterone levels and hypothalamic6 N% o* B; x4 }4 s
function. Of these 5 boys 2 were considered to have Kallmann's
6 [5 F8 b8 g6 usyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-" }, f; E' O6 F
lamic deficiency. After evaluation of response to luteinizing
* K& z3 j( \0 o$ e* Y2 Whormone-releasing hormone these patients were treated with3 S( u9 G- H3 E# e
1,000 units of gonadotropin weekly for 3 weeks. Six weeks- _- w  A, L8 }3 H$ g2 t* w
after completion of gonadotropin therapy 10 per cent topical, a0 Y1 U) t; F$ N( g0 G0 m) o) v
testosterone was applied to the phallus twice daily for 3 weeks.4 \( K0 u' J5 Z0 _+ S0 ~' C; F1 ^
Serum testosterone, luteinizing hormone and follicle-stimulat-; r( K+ |# f( Z/ |
ing hormone were monitored before, during and after comple-1 M% X" P0 K5 c: F- a0 _# W9 t
tion of each phase of therapy. Penile stretch length was
; k" x4 b, |4 Q! qobtained by measuring from the symphysis pubis to the tip of- s: w* v" f# K! |
the glans. Penile circumferential (girth) measurements were
, Z9 a2 N0 ^" l- vobtained using an orthopedic digital measuring device (see+ m1 {& Z$ `9 A6 D: O
figure).+ Q- ^1 l" x" i* }7 _$ K1 X
RESULTS$ R# k( W4 ~, ?! R
Serum testosterone increased moderately to levels between. V+ d+ G) h5 \' b5 G
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-  K8 k1 F4 N' q! c% b2 u
terone levels with topical testosterone remained near pre-
5 D; I, R: q& S3 u/ }, [+ Wtreatment levels (35 ng./dl.) or were elevated to similar levels& R6 t: Z+ R$ I  Q6 N  T4 g. {
developed after gonadotropin therapy (96 ng./dl.). Higher
$ T8 O, m& V1 ^6 E- p" `serum levels were noted in older patients (12 and 17 years old),
. f8 |/ y8 u; f1 v. B  b9 }5 ]while lower levels persisted in younger patients (4, 8, and 10/ h3 [% j; @1 B
years old) (see table). Despite absence of profound alterations
, F5 |& s* S- @2 U( Pof serum testosterone the topical therapy provided a greater
1 E* [% F* ?/ u. Q/ yAccepted for publication July 1, 1977. ·
+ a; T* w, E* o$ j$ O3 x7 k( ARead at annual meeting of American Urological Association,
& C4 E0 t6 t% N' B1 z/ RChicago, Illinois, April 24-28, 1977.
; m/ a% g3 R: E( T  D* Requests for reprints: Division of Urology, Henry Ford Hospital,
8 q( {; M9 H, S# `" w2799 W. Grand Blvd., Detroit, Michigan 48202.
- p$ E& Z9 h: z  Cimprovement in phallic growth compared to gonadotropin.
# {' E& P6 L* i; I' G# o- r/ Q$ R/ Z  wAverage phallic growth with gonadotropin was 14.3 per cent
$ ~. O. P+ m  n4 H) d6 y  h6 uincrease in length and 5.0 per cent increase of girth. Topical$ i+ K/ m) G; G; b4 ^# M
testosterone produced a 60.0 per cent increase of phallic length
# a$ c1 V9 p; N& L: p  hand 52.9 per cent increase of girth (circumference). The) v! M7 T$ r; a/ c8 j6 \; c
response to topical testosterone was greatest in children be-
! r* A$ K, E3 m  v5 V  x% Wtween 4 and 8 years old, with a gradual decrease to age 17
- D% }! p0 o6 n. q: n4 y( wyears (see table).
  n$ q4 _+ R) U# HDISCUSSION
- I5 I3 M7 m. j9 g; STopical testosterone has been used effectively by other3 K! }; X; j0 ~" O: U# |: w* h
clinicians but its mode of action remains controversial. Im-
; }  {7 T3 t" W6 D1 Emergut and associates reported an excellent growth response' D" x: F: l2 U4 x% g: Q1 i! h
to topical testosterone with low levels of serum testosterone,
. p6 x6 R+ g: e( Zsuggesting a local effect.1 Others have obtained growth re-
5 z. N- C( ?9 E* U; @$ Bsponse with high. levels of serum testosterone after topical
$ i# V- s* k5 Zadministration, suggesting a systemic response. 3 The use of
) x0 X, `/ N- X) ~- t" D# H8 E1 Ygonadotropin to obtain levels of serum testosterone compara-
! D6 i+ f- T# F* `ble to levels obtained with topical testosterone would seem to  k2 Q3 m" [8 Q8 i) N
provide a means to compare the relative effectiveness of. F/ \  u/ u& g/ K7 M% z; A
topical testosterone to systemic testosterone effect. It cer-
2 m2 l) E0 s% u( {7 q* B8 Stainly has been established that gonadotropin as well as par-
% [7 z- M/ K! v1 Wenteral testosterone administration will produce genital
; t: F8 P- D' [/ I1 Fgrowth. Our report shows that the growth of the phallus was, M* J% b: u6 L
significantly greater with topical applications than with go-  _, s( L$ d- E* O
nadotropin, particularly in children less than 10 years old.
. ]4 e5 ?" o0 [* y. f7 q# nThe levels of serum testosterone remained similar or lower
' I8 A! f7 I; ]7 ^6 F# bthan with gonadotropin during therapy, suggesting that topi-, \" {' R. I7 v, h& u
cal application produces genital growth by its local effect as( P- H0 f! e2 a6 j5 @- d" L, {
well as its systemic effect.4 {' U" R9 A" o8 O" Q/ n! P
Review of our patients and their growth response related to& V3 V+ ?2 b8 _& n% k: J6 R
age shows a greater growth response at an earlier age. This is
( o* g8 i+ X& D6 Rconsistent with the findings of Wilson and Walker, who
% H) P! L/ D  U+ p9 e, G, \reported an increased conversion of testosterone to dihydrotes-
/ o1 D) I. P% b1 v3 Htosterone in the foreskin of neonates and infants.4 This activ-
/ r5 d8 P8 ?* `+ }$ w7 Iity gradually decreases with age until puberty when it ap-
* I: X$ h# x2 i( Zproaches the same level of activity as peripheral skin. It may
" \8 w1 d" J$ E+ k* Lwell be that absorption of testosterone is less when applied at, _5 v; n3 r7 a: L. R: H+ I" p
an earlier age as suggested by lower serum levels in children! S1 Q3 {2 g1 a7 |
less than 10 years old. This fact may be explained by the
/ N$ p( j5 V- V6 {! dgreater ability of phallic skin to convert testosterone to dihy-
8 }3 r" H, I# E2 }! Mdrotestosterone at this age. Conversely, serum levels in older
# W. j& ^& R9 |patients were higher, possibly because of decreased local
; B- _8 v. f. ]667
2 Z4 P* _" N# h+ ?- d  `4 s668 KLUGO AND CERNY
6 d) a, N0 V4 d9 W  J1 LPt. Age6 m$ i, Z( s& O+ n. @; H: N
(yrs.)
( B, N: p  P, @1 Y2 @Serum Testosterone Phallus (cm.) Change Length
/ e7 e  @+ c& X. w  j(ng./dl.) Girth x Length (%). R4 ?' Y9 _9 w
4
- T; S: C) a, V- ]4 \2 Z87 l$ c0 v/ b# u* E4 Y" x1 x  U
10
7 c' l' E1 B7 {; {0 M: \4 V12
" |& U* {2 z* l17$ `  B6 h) I# F1 M
Gonadotropin# F' ^6 n. `$ @. ^# D7 P" _
71.6 2.0 X 3 16.6( i+ |5 b0 U3 ~7 H. n$ P# D
50.4 4.0 X 5.0 20.0
# i' G! I' M/ E22.0 4.5 X 4.0 25.0% c4 D7 z1 L* n! u6 J6 P/ k# y1 h  q
84.6 4.0 X 4.5 11.1
+ [2 I& E9 W4 W5 S' a' l85.9 4.5 X 5.5 9.00 N! c" W* J+ q" q% `9 t
Av. 14.3
+ K  e8 }  y+ U) u6 }47 |; Y0 o1 }& ]% X/ k9 B* k
8# _+ P: S0 O: f! b& U9 J
10% W- o" q5 \8 I. i% _, D
12
; Q& U+ Y# R/ x  i- X4 Y2 f17
% w# ~9 A! G- CTopical testosterone- S: w8 l1 D# b: S7 O
34.6 4.5 X 6.5 85
8 `8 |+ _' t' ]  A38.8 6.0 X 8.5 705 j* p2 l( c, L1 v" L2 F2 `
40.0 6.0 X 6.5 62.5
2 C- {/ ]3 b+ p, R+ I$ c/ u( ^93.6 6.0 X 7.0 55.57 b' A. \' }* ]- Z, @  t4 [
95.0 6.5 X 7.0 27.2
2 O8 c  u: A7 u2 o: H+ I; W5 ~Av. 60.0
7 U7 K  w- U$ S0 `1 Oavailable testosterone. Again, emphasis should be placed on' G  A- v: E' Q* M5 n5 Z+ r
early therapy when lower levels of testosterone appear to0 C% J9 Z9 l# u, k% u4 v
provide the best responses. The earlier therapy is instituted
& O2 T& w1 ?$ s6 R# U+ Ethe more likely there will be an excellent response with low5 [/ j4 G  O! c
serum levels. Response occurs throughout adolescence as: A. H3 B9 K; C3 Z4 h3 [( ?( M
noted in nomograms of phallic growth. 7 The actual response
. O4 h! t! b/ K8 n0 G7 G4 a; wto a given serum level of testosterone is much greater at birth
1 e/ i6 a, U8 f% I% Eand gradually decreases as boys reach puberty. This is most
* g1 G- s. v  Tlikely related to the conversion of testosterone to dihydrotes-$ ^( T8 S$ D5 Q5 Y; {) {
tosterone and correlates well with the studies of testosterone) y2 e( e9 v" w. j' }  |' F  `
conversion in foreskin at various ages.) M( u; ^1 ~, K
The question arises regarding early treatment as to whether* \! s7 G, G0 E0 u/ q
one might sacrifice ultimate potential growth as with acceler-" T: T' n5 J7 j( j
ated bone growth. The situation appears quite the reverse
) d- h+ P7 Z# n/ w; ?. Dwith phallic response. If the early growth period is not used
" t* W6 E/ u9 b$ Gwhen 5a reductase activity is greatest then potential growth
# O& h5 I, u6 S6 E) _may be lost. We have not observed any regression of growth2 f& ]3 V6 @! ?
attained with topical or gonadotropin therapy. It may well
9 k% |4 b5 y/ o# S- Q  Ybe that some patients will show little or no response to any6 p7 h& o) D/ W* h  v1 D2 [2 f
form of therapy. This would suggest a defect in the ability to: e# R3 ]) m+ c- P
convert testosterone to dihydrotestosterone and indicate that
7 b1 T1 l0 j( |5 m) t& Bphallic and peripheral skin, and subcutaneous tissue should& O5 y; j( T! A8 _
be compared for 5a reductase activity.6 r' H" ^, |/ v4 [# h
A, loop enlarges to measure penile girth in millimeters. B,1 s8 s, K( l( L5 Q3 J$ K
example of penile girth computed easily and accurately.. u1 `2 c9 R, H* |) Z) c0 B
conversion of testosterone to dihydrotestosterone. It is in this% j1 R, C" h  J& R2 M
older group that others have noted high levels of serum' S+ `+ g# D% g2 m: Z9 b
testosterone with topical application. It would also appear
# O" `# [- o/ E( L* Q1 G! bthat phallic response during puberty is related directly to the$ l8 v2 d$ L: Z: n* L, h# n9 v+ T$ ^
serum testosterone level. There also is other evidence of local' t$ C- J1 `# n6 n
response to testosterone with hair growth and with spermato-, A8 k+ v, q+ ?5 E* N2 ]1 B
genesis. 5• 6
9 y3 q5 X: J1 v: Z8 VAdministration of larger doses of gonadotropin or systemic7 P& r$ y! q, u. G- K- p- s! O: P
testosterone, as well as topical applications that produce
% p: ^  E3 X8 L" _* U- Lhigher levels of serum testosterone (150 to 900 ng./dl.), will) G  m* d' I+ f- o8 H% e- o, x( {" ]$ }
also produce phallic growth but risks accelerated skeletal
0 w0 e+ c& c0 o% {, I3 k6 Z2 ?3 \4 Vmaturation even after stopping treatment. It would appear$ X. R* d5 E2 q, g3 q6 M
that this may be avoided by topical applications of testosterone, K3 _, `- w- m, E% @- A
and monitoring of serum testosterone. Even with this control/ s- H' M& m9 h9 m9 e
the duration of our therapy did not exceed 3 weeks at any
7 ]3 m& z3 n- r- e1 `! |; L3 Gtime. It is apparent that the prepuberal male subject may7 k1 X, e( N+ B" G) h& i9 e
suffer accelerated bone growth with testosterone levels near8 I$ g" v2 d# C+ \) g5 P4 e$ B+ j: N
200 ng./dl. When skeletal maturation is complete the level of/ L5 c1 o- b: r: v2 v
serum testosterone can be maintained in the 700 to 1,300 ng./0 C/ I8 d% |0 c
dl. range to stimulate phallic growth and secondary sexual
& J' h4 s  N1 \% l1 Kchanges. Therefore, after skeletal maturation parenteral tes-
7 I. x" f/ j& mtosterone may be used to advantage. Before skeletal matura-; P( Z$ a; Q7 n
tion care must be taken to avoid maintaining levels of serum3 d' T4 T' A$ k2 U# I6 o/ D1 i
testosterone more than 100 ng./dl. Low-dose gonadotropin5 T' I' N: A# t1 B) q" I
depends upon intrinsic testicular activity and may require
- [6 O2 Q, E5 x" _7 _prolonged administration for any response.
+ {: r9 Y5 _1 f7 [  VAlternately, topical testosterone does not depend upon tes-
2 s3 e5 j3 v8 ]; `ticular function and may provide a more constant level of1 n. d2 b" z4 t. z
REFERENCES
6 \) D* _- v! F+ [1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
2 r5 {7 X( {; F* _& G4 bR.: The local application of testosterone cream to the prepub-
1 _3 B) a3 [* X, c  X( N1 b; c* ]) {ertal phallus. J. Urol., 105: 905, 1971.
* E3 V# H, N8 ^2 K2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
6 P' v& i- s" y$ f' Z7 q: T$ f7 ~( Ctreatment for micropenis during early childhood. J. Pediat.,5 g% }: l1 Q1 K" k
83: 247, 1973.
" r0 f0 u! p6 D& `9 |0 I3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-& Q3 u# z) v+ b0 h8 }8 ^
one therapy for penile growth. Urology, 6: 708, 1975.3 |" v- k) q* q
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
1 l4 K! a* \! T" ?& A% t- xto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by6 h. n# w, W- k& \6 K% @
skin slices of man. J. Clin. Invest., 48: 371, 1969.  Y& M/ B% P+ k! L5 D0 ~) Q
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
# v. ~) U( w4 \0 R7 bby topical application of androgens. J.A.M.A., 191: 521, 1965.
3 c# x) m+ }0 p8 l: O6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
$ z# T) [2 [: _& `androgenic effect of interstitial cell tumor of the testis. J.- `) M  T# d9 ~
Urol., 104: 774, 1970.
, j# }( q3 B* }  l4 l2 ~7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
$ }  _% |5 J; C4 l* I. M( C+ H) Rtion in the male genitalia from birth to maturity. J. Urol., 48:
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