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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND. z- J8 y6 |/ h6 x) c! ^  \
GONADOTROPIN6 G8 p1 ?/ b7 D4 P9 R. t
RICHARD C. KLUGO* AND JOSEPH C. CERNY
0 {/ M1 b: ?& `; ^! O0 }From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
" Q2 S' a& N5 N9 D5 R; w! w8 pABSTRACT$ n5 Y7 z0 L; }& W7 o6 n$ w
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
- ^& q* \4 x8 P/ Jwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-3 @6 q6 \" t( i$ H
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone! S) h  I9 Z  a8 g
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent+ d* C, n+ m7 w
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
5 Z2 S. Z. [2 H1 {- |increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
3 j* o8 _5 b' X& N& _$ N" qincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response9 y4 E. |$ F# x2 Z5 m) v* ], z$ {
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
+ Z9 Z2 }1 e8 Y) t1 rstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
" w" V9 G! w# p2 |growth. The response appears to be greater in younger children, which is consistent with previ-5 n  {* E  X( @! a# W$ _3 E
ously published studies of age-related 5 reductase activity.6 d! Q$ ~, v1 D$ E
Children with microphallus regardless of its etiology will
( H5 A' z/ j! V9 k. t1 {require augmentation or consideration for alteration of exter-0 z4 O& A9 h* a6 `$ ]! T7 R$ Q
nal genitalia. In many instances urethroplasty for hypo-
4 T  J. B$ i% ~2 Q" lspadias is easier with previous stimulation of phallic growth.- ]  I& `' C  p# r% u# n
The use of testosterone administered parenterally or topically& t9 O4 ~% H5 y2 D
has produced effective phallic growth. 1- 3 The mechanism of; {5 c2 z! ^, S* R3 n
response has been considered as local or systemic. With this
0 d* F9 U  d# _% t0 @5 yin mind we studied 5 children with microphallus for response
$ ^) V- ^3 f) N' Y0 Oto gonadotropin and to topical testosterone independently.5 O: q/ F" C9 o: n
MATERIALS AND METHODS0 O3 e5 Z- [; j3 V+ Y% v4 \
Five 46 XY male subjects between 3 and 17 years old were
6 q) E* C  i+ qevaluated for serum testosterone levels and hypothalamic" Z5 f$ f& _! d6 w( r
function. Of these 5 boys 2 were considered to have Kallmann's
! X: a& ~7 r2 z; [- D: Dsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-; R9 `3 Z- U5 D* |( H8 a
lamic deficiency. After evaluation of response to luteinizing' m: R7 D: v9 {" }
hormone-releasing hormone these patients were treated with
5 L# g& j9 w; _7 d8 i/ L  G1,000 units of gonadotropin weekly for 3 weeks. Six weeks
% V0 B; o0 m. ]% h7 N. aafter completion of gonadotropin therapy 10 per cent topical
# o# V# N" q. O; |' dtestosterone was applied to the phallus twice daily for 3 weeks.6 ]3 R3 H) R$ ?: b) Z4 M) J
Serum testosterone, luteinizing hormone and follicle-stimulat-
0 `1 X8 j* F; u& @ing hormone were monitored before, during and after comple-; e9 i$ d2 S% @& C  T; s
tion of each phase of therapy. Penile stretch length was
& O- ~, Y6 j+ h2 g- a- cobtained by measuring from the symphysis pubis to the tip of+ A8 G5 \1 z  m. n
the glans. Penile circumferential (girth) measurements were
1 ^0 w0 I" ?4 N% J! E$ Z  O% }obtained using an orthopedic digital measuring device (see- F$ H0 n) g0 B4 G
figure).' ~2 p( _! z  K7 H4 I; w
RESULTS9 r' k" ]3 W( ?4 z+ S9 l
Serum testosterone increased moderately to levels between6 G6 x9 t' K' e2 \/ \! d! f; o6 {
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
( L" b9 s; U" O' b! V9 g$ d4 w' |terone levels with topical testosterone remained near pre-. @9 S% L' q  Y  L: E
treatment levels (35 ng./dl.) or were elevated to similar levels+ K5 w7 P4 b# V- l+ J& S. S7 e$ _
developed after gonadotropin therapy (96 ng./dl.). Higher
/ p2 H0 S" R+ k% k6 T3 x: K6 Z' ?serum levels were noted in older patients (12 and 17 years old),
& ]& L1 ?5 }- o* W  ^2 h6 xwhile lower levels persisted in younger patients (4, 8, and 10
& w1 P6 u1 t! j. M: `years old) (see table). Despite absence of profound alterations
, D" N. ^& b+ l, h; D7 \of serum testosterone the topical therapy provided a greater
* r! _2 F: ^3 g% C" m; HAccepted for publication July 1, 1977. ·
9 P! m% z! ]( W- T- c+ e; iRead at annual meeting of American Urological Association,. I8 ^9 }$ s% _' l& _3 K. J4 C
Chicago, Illinois, April 24-28, 1977.' h9 x1 a: x: H: G4 @# i
* Requests for reprints: Division of Urology, Henry Ford Hospital,
1 M3 z) v$ y$ x# S* k2799 W. Grand Blvd., Detroit, Michigan 48202.' {/ V; Q) T( R, U. j* E
improvement in phallic growth compared to gonadotropin.
2 L0 H% L8 v" H! U6 vAverage phallic growth with gonadotropin was 14.3 per cent% l$ {% O: K* M
increase in length and 5.0 per cent increase of girth. Topical' Q% {& i6 C* O, p+ w
testosterone produced a 60.0 per cent increase of phallic length7 s3 |4 Y7 D' n  `; c: e
and 52.9 per cent increase of girth (circumference). The. O% q# F% \5 k3 B+ L, ^% @
response to topical testosterone was greatest in children be-
# Q8 G% P! G- i( Ltween 4 and 8 years old, with a gradual decrease to age 17
# H. s/ s- a, Y& I1 e0 U9 oyears (see table)., F& X; r+ l4 Q/ s/ F$ R* n# g
DISCUSSION2 e  a0 C. P7 k) x! X9 W6 w
Topical testosterone has been used effectively by other& ]# d; d1 a" G  i5 ?7 n+ t8 ^
clinicians but its mode of action remains controversial. Im-/ X2 Y3 B0 s7 ]0 `% ]
mergut and associates reported an excellent growth response
" z+ Q2 H7 g# Q/ e  n3 Ato topical testosterone with low levels of serum testosterone,
/ n7 m, \1 y1 z: e* Z  L% csuggesting a local effect.1 Others have obtained growth re-
; a. Q' q9 k3 e3 y- A# r, {sponse with high. levels of serum testosterone after topical
% d1 h8 n  z  l+ A: }administration, suggesting a systemic response. 3 The use of0 C! C+ O) v1 z! v8 a
gonadotropin to obtain levels of serum testosterone compara-0 e7 [4 b! X9 M; e5 G) J  Q
ble to levels obtained with topical testosterone would seem to1 h' U5 ?7 J6 M! A$ H$ y
provide a means to compare the relative effectiveness of" s4 q% k8 c+ E& {" T, k4 C, |
topical testosterone to systemic testosterone effect. It cer-( t* o  C1 P6 J
tainly has been established that gonadotropin as well as par-
" V9 m$ u! k8 F& b1 Y) a' Penteral testosterone administration will produce genital% z5 o- E: U' T4 ]4 J% j
growth. Our report shows that the growth of the phallus was8 l) V& m  i6 o2 d( A3 b, l
significantly greater with topical applications than with go-
, v7 X9 c1 t8 H4 Z2 ?  r( Jnadotropin, particularly in children less than 10 years old.8 \$ C" `0 D9 n, w" Y6 Y. q+ A7 I
The levels of serum testosterone remained similar or lower7 y( W( @2 A! q; A
than with gonadotropin during therapy, suggesting that topi-
6 ~: Z; D7 H7 d( q$ @: {cal application produces genital growth by its local effect as; O( x8 T# K; A9 _0 e+ I% p6 l
well as its systemic effect.. f, {1 `$ K/ j9 y, z% p, k
Review of our patients and their growth response related to
* X4 F" R2 u: l& Hage shows a greater growth response at an earlier age. This is
7 a$ E7 H( J0 E3 ~consistent with the findings of Wilson and Walker, who- H& W* Q& s, k# z# i4 @) \
reported an increased conversion of testosterone to dihydrotes-
( x7 a/ a1 E+ N" Ttosterone in the foreskin of neonates and infants.4 This activ-) _# Z. H( O& F: W6 V* n5 y7 ^, M
ity gradually decreases with age until puberty when it ap-
& _0 g% M: Y8 u; ^. g' eproaches the same level of activity as peripheral skin. It may1 P8 r& G1 Y2 h/ e2 L5 }3 K
well be that absorption of testosterone is less when applied at# V4 H* c* k0 Z5 ]! H
an earlier age as suggested by lower serum levels in children( S# |- G3 ~( J# d8 K
less than 10 years old. This fact may be explained by the! k* T+ E4 F, ^$ V- w
greater ability of phallic skin to convert testosterone to dihy-# B' a5 ^6 B1 t5 h- t
drotestosterone at this age. Conversely, serum levels in older, P) T  i2 h0 Q) k1 S7 d
patients were higher, possibly because of decreased local9 H6 d# t+ M, c4 m' H2 j+ J* A7 N
667, g* b2 m; w% @" k6 p; [1 g1 ^
668 KLUGO AND CERNY& @' `( u5 }" z0 o2 v
Pt. Age
2 ~1 h# i( U  ^/ C$ w8 N( X(yrs.)2 m- E8 V; w8 b2 b3 h) \( m
Serum Testosterone Phallus (cm.) Change Length% A- {3 D% H) @6 A% k6 E$ \! t
(ng./dl.) Girth x Length (%)5 U$ Y# `# m. Y& W- V) a! {5 x) Z, E
4% B/ a$ l6 p, R
82 p2 b5 z; ]# `; c
10, h7 u+ q. {4 `8 z* T8 b- P+ A
12
0 E/ G9 E/ T' L, K17
* U1 t  J9 y" z- B! |3 W4 A9 L" }Gonadotropin" X4 P, _$ t6 B2 y
71.6 2.0 X 3 16.6( `# t  X7 ^0 d# U$ H( P' T$ D
50.4 4.0 X 5.0 20.0
4 h5 P- ]+ I. z9 A# _22.0 4.5 X 4.0 25.0& n. h) K& n% Y( p4 ~; @
84.6 4.0 X 4.5 11.1
1 d9 ^: j' c, `0 {4 o2 k2 [85.9 4.5 X 5.5 9.0
; f6 ^8 c% R" sAv. 14.3/ t; o: G* r* q6 j! s) O/ U' [' q" m
4% x2 W" g$ b  M3 E/ T
8! R. a; F# d0 @4 ]% @- {  H
10& R' f- \6 C7 D
12
% e9 t$ ~- n* a" M4 K* e- [8 c17
5 d: O, E- [' k+ j! A7 ~Topical testosterone
: a# y$ l. [5 B. h+ D7 u34.6 4.5 X 6.5 85
/ f6 v4 A. U9 M% {38.8 6.0 X 8.5 703 z. r) }- M# m! X6 F6 ~" T7 V* S
40.0 6.0 X 6.5 62.5
, E8 \- g4 }5 E+ ~/ M$ `93.6 6.0 X 7.0 55.5$ w+ W8 T5 `  G3 B7 @0 }
95.0 6.5 X 7.0 27.2
' L1 q4 {7 t# O# bAv. 60.08 m6 l( R0 ?- J) l7 f
available testosterone. Again, emphasis should be placed on
$ x8 S! E" O3 Q) P) ?0 Cearly therapy when lower levels of testosterone appear to
  |+ _6 W. F0 Jprovide the best responses. The earlier therapy is instituted. s- x( H- x" o( G; h8 j
the more likely there will be an excellent response with low
! p& G) H1 c' p% rserum levels. Response occurs throughout adolescence as3 T/ d* z; l' A3 w
noted in nomograms of phallic growth. 7 The actual response
2 k+ p0 ~# p( D5 `' Wto a given serum level of testosterone is much greater at birth
, x* T; s; r9 u# D8 `% R8 land gradually decreases as boys reach puberty. This is most8 o* ?6 T9 h; j9 |: S
likely related to the conversion of testosterone to dihydrotes-+ i. |: r* R$ \7 M8 A9 \
tosterone and correlates well with the studies of testosterone  e: f, ?# h) i- M6 \
conversion in foreskin at various ages.9 w' b; Q6 B7 i
The question arises regarding early treatment as to whether
5 A/ N, @/ Q, Bone might sacrifice ultimate potential growth as with acceler-1 n$ r: G4 M2 o8 |. |, |
ated bone growth. The situation appears quite the reverse% i: g0 @) d! z& H/ [- w2 t$ J
with phallic response. If the early growth period is not used
  P0 d0 G* \# o* V" Cwhen 5a reductase activity is greatest then potential growth
! O) h7 e2 v$ {: tmay be lost. We have not observed any regression of growth. o/ |  |+ P, y* c+ |8 L) Z+ t/ C
attained with topical or gonadotropin therapy. It may well
( }2 W- n6 M+ kbe that some patients will show little or no response to any
" O! D/ d4 x% S+ z2 m& Fform of therapy. This would suggest a defect in the ability to2 O: `. A7 g! ?+ G2 _+ I0 r4 ]
convert testosterone to dihydrotestosterone and indicate that
( d/ `7 L5 f# C' S. _2 |phallic and peripheral skin, and subcutaneous tissue should
. p+ U( g0 [3 s" j+ o# _be compared for 5a reductase activity.
6 Y. q5 }3 H0 O" i8 UA, loop enlarges to measure penile girth in millimeters. B,1 y7 z  T1 a8 }
example of penile girth computed easily and accurately.
  }) |6 i8 L6 Aconversion of testosterone to dihydrotestosterone. It is in this
2 b0 Q; ^7 F; a3 g, T1 \: Bolder group that others have noted high levels of serum
% V9 {3 w$ c7 m2 N) W: Ctestosterone with topical application. It would also appear9 H; F+ Z( s( H# ]" w+ {9 s# }
that phallic response during puberty is related directly to the3 f4 U9 D9 Z6 u9 v1 h  ]. b9 P+ o
serum testosterone level. There also is other evidence of local
' r* J0 T4 F3 Y! `8 v: Uresponse to testosterone with hair growth and with spermato-
% B) x5 {8 V. C& U# i8 m: Vgenesis. 5• 6
% T) P: T, G& ^3 b5 n1 X5 gAdministration of larger doses of gonadotropin or systemic
1 l! b: ?5 f8 d( }% ]9 G+ t! V! h) Q. D5 ttestosterone, as well as topical applications that produce
0 I" R- {8 C8 H/ ]# vhigher levels of serum testosterone (150 to 900 ng./dl.), will
& E" \" C' T, Aalso produce phallic growth but risks accelerated skeletal
2 w+ a; ^1 p4 M( _maturation even after stopping treatment. It would appear
1 b5 S4 C0 D* S1 n2 y+ pthat this may be avoided by topical applications of testosterone
4 F6 `* Z' {) @, \0 h' m- {$ Band monitoring of serum testosterone. Even with this control
) H) x+ @: M' k5 M) y9 nthe duration of our therapy did not exceed 3 weeks at any- i8 }1 x) M4 v
time. It is apparent that the prepuberal male subject may0 K0 X8 ]9 ?3 c0 j1 Y- ^
suffer accelerated bone growth with testosterone levels near& H% Q0 u; F3 u# ~& X0 d* I$ v" e
200 ng./dl. When skeletal maturation is complete the level of7 M& h. P3 K* |% |
serum testosterone can be maintained in the 700 to 1,300 ng./0 X# Z& L6 z% Z* P2 m
dl. range to stimulate phallic growth and secondary sexual; q. `3 v0 O+ A) Q+ f
changes. Therefore, after skeletal maturation parenteral tes-+ @- a! c% M' h# L
tosterone may be used to advantage. Before skeletal matura-; h" w6 F( w; z
tion care must be taken to avoid maintaining levels of serum
$ v# Q$ F7 r; J( [& d# h/ T) Ktestosterone more than 100 ng./dl. Low-dose gonadotropin
% R7 E! I& `) {: xdepends upon intrinsic testicular activity and may require/ P0 d! U% `% X6 M
prolonged administration for any response.
# i% Q$ B. i" e% i8 O/ m, _* p% N+ QAlternately, topical testosterone does not depend upon tes-
* Q+ ?% ~9 M% y. ~4 U, Q/ H- Wticular function and may provide a more constant level of
" \& y" V4 z6 l3 Z6 l# I# v6 dREFERENCES
, W" f& j4 ^- K, Y# A- i% ]1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,  B7 C( G! I! V0 S/ h2 g
R.: The local application of testosterone cream to the prepub-; M6 f6 v; W0 l8 T& b
ertal phallus. J. Urol., 105: 905, 1971.
2 |4 s7 |7 F! V8 O9 A' s) Q2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
( ?& ~. B' [$ B5 Y8 Ktreatment for micropenis during early childhood. J. Pediat.,2 @& N0 m* u8 q3 e0 C+ e  `3 r
83: 247, 1973.
' y# `% z, u6 k# ]" A& L' r3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
- [% m3 ~+ i* F6 f& ?one therapy for penile growth. Urology, 6: 708, 1975.
1 P% h" k: l4 j  D* I" w4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone' W# E- n( `, v+ o1 X
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by: o5 v& k5 }) ?7 P! h- {1 R  {0 b9 e
skin slices of man. J. Clin. Invest., 48: 371, 1969.$ W5 p( O" e3 P0 J( n; H( ?
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth3 k7 N- I: Y: z3 ]+ ?, `6 A
by topical application of androgens. J.A.M.A., 191: 521, 1965.) s% w* ?: w9 ^2 S; s
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
, g" S0 j7 k" g+ @+ D" _9 Nandrogenic effect of interstitial cell tumor of the testis. J.
2 l1 g0 g. U* z4 {; I* `' rUrol., 104: 774, 1970.
1 f8 @* i6 {: g& c+ p, Z% C3 ~+ L7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-6 _& `- ^7 |! F4 N" ?
tion in the male genitalia from birth to maturity. J. Urol., 48:
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