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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
: A2 n. R; v; b7 f  ZGONADOTROPIN7 W9 t& g- i" J( {
RICHARD C. KLUGO* AND JOSEPH C. CERNY* [9 h+ B1 `7 B  g) G  S5 H; h) F
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan; q# ?) v# t+ J8 W8 ]( a
ABSTRACT
/ g( C3 }! L! x9 p7 xFive patients were treated with gonadotropin and topical testosterone for micropenis associated4 L9 K) T* a) ?" n
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
8 R) ~8 _3 l% [$ a2 ?0 Ptropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone7 y5 E  c4 G2 A2 _1 I1 {+ m
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent" }# u' I8 c- O1 |
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent, K% x  b# P! z3 k# \# h
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average& M+ Q* b- d# c, {# U1 }1 H
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
( o  u- L7 Z& n6 z4 Hoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This* P0 }1 m8 v" I. c, M+ }
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile* T  i' L; x. g5 d6 D
growth. The response appears to be greater in younger children, which is consistent with previ-
0 W$ y# t7 M+ Qously published studies of age-related 5 reductase activity.
, J8 D% ~' W0 N! E. Q+ qChildren with microphallus regardless of its etiology will
, t: |* M7 O4 _. k; Lrequire augmentation or consideration for alteration of exter-; O8 L* m/ G# p) z! X' O
nal genitalia. In many instances urethroplasty for hypo-
% {7 Z* U4 H( w+ Q. Jspadias is easier with previous stimulation of phallic growth.
6 B: l, t  @, i! ^% I8 sThe use of testosterone administered parenterally or topically' Z. e9 J6 W+ e0 `
has produced effective phallic growth. 1- 3 The mechanism of
( b, Q; z7 F, P( l- \  F7 Presponse has been considered as local or systemic. With this( ~( ?2 z1 q2 S" g& |% f- @! e
in mind we studied 5 children with microphallus for response
% f- B. V0 o/ o  ^to gonadotropin and to topical testosterone independently.! r3 Q2 {) S6 u3 ~: ?% D" O
MATERIALS AND METHODS
& |5 D9 ~: ~9 L; m9 [( `3 ?) `6 EFive 46 XY male subjects between 3 and 17 years old were$ `) `2 S! d8 M" _
evaluated for serum testosterone levels and hypothalamic3 ]( L- I9 o# w2 m  h' c6 Y  a7 t# s
function. Of these 5 boys 2 were considered to have Kallmann's
- ]* `# n9 i  ^: n' A  h9 Wsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
) w# X7 ?- Q" D2 N( e- Flamic deficiency. After evaluation of response to luteinizing! j, a8 Q1 n: @3 ?& W
hormone-releasing hormone these patients were treated with& I4 a" x( r5 F- S! c; \
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
  ~6 B. a1 B) b+ U; hafter completion of gonadotropin therapy 10 per cent topical/ x/ C' V: K* H. U8 O
testosterone was applied to the phallus twice daily for 3 weeks.1 i  x' [; E; V' D/ i
Serum testosterone, luteinizing hormone and follicle-stimulat-# X7 N) t- d. R! n3 N8 J* l/ N
ing hormone were monitored before, during and after comple-& S7 b3 r) S+ m: o7 J
tion of each phase of therapy. Penile stretch length was. n; z+ z! ]; A; k9 [+ \% ^! A% h7 @
obtained by measuring from the symphysis pubis to the tip of
1 x, ]" w/ E$ z, \' A. O# j* Rthe glans. Penile circumferential (girth) measurements were
# |6 J0 M4 c7 {6 Hobtained using an orthopedic digital measuring device (see
: I. v2 W0 l9 ^6 D. Q  ^figure).
- [9 e  Q/ L+ L5 MRESULTS3 o* N: D- s) ?% f7 j  I" X
Serum testosterone increased moderately to levels between) S, @5 k  q: [. D" E
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
+ ]+ g/ b: d: E& Y0 k: Zterone levels with topical testosterone remained near pre-" x8 b! J  l6 _( x$ b1 o
treatment levels (35 ng./dl.) or were elevated to similar levels+ \# j8 u7 s2 t0 h% L
developed after gonadotropin therapy (96 ng./dl.). Higher
7 R$ _0 ^. W4 N- ?serum levels were noted in older patients (12 and 17 years old),
5 X5 F3 Y# f& B  gwhile lower levels persisted in younger patients (4, 8, and 10
2 @" g2 z( t" x( r6 H2 O8 ryears old) (see table). Despite absence of profound alterations) N4 Z- q- ]$ m8 X# r
of serum testosterone the topical therapy provided a greater
8 ]* y% ^8 h) Q% X: z6 v, lAccepted for publication July 1, 1977. ·- q, s1 h( x( y6 |4 h
Read at annual meeting of American Urological Association,
/ D- Z1 M3 z2 x2 N* zChicago, Illinois, April 24-28, 1977.0 G/ F' |. h" c; T! z4 y0 m0 x
* Requests for reprints: Division of Urology, Henry Ford Hospital,. A2 Q+ n- h8 ~# g. d
2799 W. Grand Blvd., Detroit, Michigan 48202.
, }7 K$ R9 o& B, j4 U0 timprovement in phallic growth compared to gonadotropin.
* M$ i. s" N: Q, XAverage phallic growth with gonadotropin was 14.3 per cent$ v$ |0 k2 o! U+ V
increase in length and 5.0 per cent increase of girth. Topical! y& j4 R* m$ Q: D3 F, T
testosterone produced a 60.0 per cent increase of phallic length5 v; g. M1 P+ l4 _
and 52.9 per cent increase of girth (circumference). The
1 M' G7 j& ~3 l& f$ [1 cresponse to topical testosterone was greatest in children be-
0 C5 p2 o2 i% |# E3 u0 k  i9 ^4 Htween 4 and 8 years old, with a gradual decrease to age 17
+ D) c3 r9 ^0 u6 [" q: fyears (see table).5 g: g9 I! O' P) V, ~
DISCUSSION
0 B/ w+ u& r' \& |Topical testosterone has been used effectively by other" t. m' G! K( B
clinicians but its mode of action remains controversial. Im-
) h/ j" ~# n' H: }5 G9 n% wmergut and associates reported an excellent growth response
+ f+ \# `! ?: S. {# k# {to topical testosterone with low levels of serum testosterone,% ^- M- P; j8 @! {! g) I
suggesting a local effect.1 Others have obtained growth re-0 F" h+ }) J9 O3 R
sponse with high. levels of serum testosterone after topical
4 H' f$ O0 d# Y1 P0 m$ X3 sadministration, suggesting a systemic response. 3 The use of
7 u) T+ L  e6 s7 m4 m7 W9 T# `gonadotropin to obtain levels of serum testosterone compara-
& I8 x( ]7 _0 [6 a3 T# Kble to levels obtained with topical testosterone would seem to
! _0 ~# p+ n) N, L3 ~  v  p) k5 zprovide a means to compare the relative effectiveness of
+ H" Z! o$ z$ i& P9 d0 Jtopical testosterone to systemic testosterone effect. It cer-5 f6 d( ~) |+ u& a+ p
tainly has been established that gonadotropin as well as par-
, @; u' \: B" c# G; x+ q; `enteral testosterone administration will produce genital+ ?; \- u; {; p8 i' t
growth. Our report shows that the growth of the phallus was5 {) Y0 g& X* F: @
significantly greater with topical applications than with go-) `) ^% R0 z# P, g8 W8 \
nadotropin, particularly in children less than 10 years old.
4 I; |8 p* X5 \# O% k7 ?The levels of serum testosterone remained similar or lower
8 Q5 N9 Z; j( r4 m; {than with gonadotropin during therapy, suggesting that topi-
* E7 Y4 ]- Q; T1 z6 ~$ X, m2 Lcal application produces genital growth by its local effect as9 G, G1 ^, J7 {5 W# v- Y2 t) A
well as its systemic effect.
8 Z6 d( `+ ]7 c/ v4 v: o! Q' ~Review of our patients and their growth response related to
2 r2 m7 f. J( f6 c0 l. C: T& `age shows a greater growth response at an earlier age. This is0 E  U4 O+ |: f% E( d0 m
consistent with the findings of Wilson and Walker, who
8 L" `, o* u  G; [reported an increased conversion of testosterone to dihydrotes-
2 |5 G$ S( f8 W& U" ]1 |0 n, T" itosterone in the foreskin of neonates and infants.4 This activ-, [5 Z4 H+ F" h& {) }; X
ity gradually decreases with age until puberty when it ap-, y) P  x3 }% ?9 R9 V0 n2 r. ]
proaches the same level of activity as peripheral skin. It may1 X9 O! z2 S) m& M+ J; X3 W% f
well be that absorption of testosterone is less when applied at
7 W2 Z* b) {+ {0 ~' Zan earlier age as suggested by lower serum levels in children' U) k# [! Z' n" ~- N: z0 e
less than 10 years old. This fact may be explained by the
4 v1 Y! T+ i4 a9 j, P9 S; m4 a! Dgreater ability of phallic skin to convert testosterone to dihy-
, n( H; j/ |. D7 ]$ b8 a* sdrotestosterone at this age. Conversely, serum levels in older
2 e) j2 N; i2 V/ lpatients were higher, possibly because of decreased local7 i- |7 k' L8 |  @- R) D. |* T
667$ F* Q* t) e- p+ C, I
668 KLUGO AND CERNY
8 W1 ?7 }7 [, M: Y; E1 |Pt. Age
* H1 |" `" d( P+ b. M(yrs.)
2 ?. l; N2 S: \+ O) n' ^Serum Testosterone Phallus (cm.) Change Length
; Q1 ]( _6 H& e) u- S(ng./dl.) Girth x Length (%)% b, w/ ~& u% X2 \7 F* m  |
4
# h* W( B; r- ]" U) ?' `8
4 H3 Q. @" K1 f/ e10) a$ F% K5 r0 X7 M
12& g/ _  B$ B( K7 w4 W
17
" m# Q4 [5 @( O. Y9 I9 I& W- M! oGonadotropin
' m, [: n* I1 m5 q71.6 2.0 X 3 16.6
0 r3 ]: R2 X+ W& N. }* N6 \2 |) {4 {50.4 4.0 X 5.0 20.0
5 Z5 ^) W9 Q2 S, X3 j0 w* r22.0 4.5 X 4.0 25.0: R" r) ^# U. L& @( v* X# ], l
84.6 4.0 X 4.5 11.1
- B. z1 m, ]) A, A- G7 R3 Q85.9 4.5 X 5.5 9.0
0 X4 U; y6 ]- J& fAv. 14.3* x$ @# c9 V3 \9 L7 N) }
4) n1 ?6 x; |# u5 X8 s
8& A( [) _7 H- g3 G5 J! p
102 Q) o  g3 k, {% E
12
1 {/ p) a6 g0 h8 t  R& k2 f17
5 f9 [: K4 [* G7 w$ Z* ~1 wTopical testosterone
/ E3 `( B& m% B3 f34.6 4.5 X 6.5 854 a: A. ~4 D& Q% ~
38.8 6.0 X 8.5 70( e5 J& U# l; R0 x1 L6 p6 k. |/ p
40.0 6.0 X 6.5 62.5# B6 R; T' z3 x9 P
93.6 6.0 X 7.0 55.5
: M9 u" p" j! {/ ~6 G$ W' [9 R95.0 6.5 X 7.0 27.20 a) J2 H& e8 j3 i$ n/ h% S
Av. 60.0* X) n; e+ z1 [% ^0 h4 Q
available testosterone. Again, emphasis should be placed on8 |9 I1 s% r, A6 g7 ~% M& L# Z& c
early therapy when lower levels of testosterone appear to
4 O# K6 u! x# E$ b  }4 |5 p  D6 Zprovide the best responses. The earlier therapy is instituted
% J5 A- m5 R$ B. k2 m9 l, s0 ythe more likely there will be an excellent response with low
$ c8 N, n- l5 h3 Z8 p7 Bserum levels. Response occurs throughout adolescence as
# l% \( {8 z+ ^: k+ bnoted in nomograms of phallic growth. 7 The actual response1 Q; s/ z5 b9 f. a) X' B1 O: C
to a given serum level of testosterone is much greater at birth
5 _+ x0 d* }, c4 Yand gradually decreases as boys reach puberty. This is most
; Z2 \! q0 f" H- Hlikely related to the conversion of testosterone to dihydrotes-" t7 @1 c+ d) N! N  Z+ r, o
tosterone and correlates well with the studies of testosterone
' k. u7 d: f; C  aconversion in foreskin at various ages./ O+ Y9 |6 @( D% T# G, U
The question arises regarding early treatment as to whether5 B9 U1 @3 ]" e. W3 f
one might sacrifice ultimate potential growth as with acceler-
- n& r) o( P& H& k' H$ C4 k/ Hated bone growth. The situation appears quite the reverse
( H/ v  ?7 ~2 c$ w# Jwith phallic response. If the early growth period is not used
! ?5 E( o( h6 f! f8 V6 Z# d' X/ Dwhen 5a reductase activity is greatest then potential growth( B) K7 }' O' G7 c4 o  s; y
may be lost. We have not observed any regression of growth. g( p* o2 G+ N+ u$ U4 O; z, d
attained with topical or gonadotropin therapy. It may well
" w$ U  J: O% Y9 [+ j  N$ Q" C! `6 bbe that some patients will show little or no response to any
2 m% M6 x8 J! Hform of therapy. This would suggest a defect in the ability to$ [( J. E0 ^, I8 x+ ^% B
convert testosterone to dihydrotestosterone and indicate that
& Y4 }% V. u4 c& C4 K8 ~/ Uphallic and peripheral skin, and subcutaneous tissue should) d5 G$ r( i6 K4 ]0 b. R) n4 L
be compared for 5a reductase activity.8 |1 E  @% Y0 i- @; m' ^  B
A, loop enlarges to measure penile girth in millimeters. B,1 j/ ]# C/ p: C) I, D6 T$ O
example of penile girth computed easily and accurately.4 y% w6 e$ I2 c4 P0 y- g
conversion of testosterone to dihydrotestosterone. It is in this; P6 h  B* ^4 Y6 l- Y; b' _+ L
older group that others have noted high levels of serum4 ^* x' y3 i6 O% O
testosterone with topical application. It would also appear/ S: A( ]' e$ R( u0 a" H2 v
that phallic response during puberty is related directly to the  X" T* D5 W" w, D5 p% G
serum testosterone level. There also is other evidence of local" w  [" _  N3 O! k# q
response to testosterone with hair growth and with spermato-. i1 F% ^" |  k
genesis. 5• 6& L6 y2 s2 l2 y* I1 S: T
Administration of larger doses of gonadotropin or systemic
# u2 r/ F" T# ~# R1 u, ptestosterone, as well as topical applications that produce% `! J4 c* I  c2 P+ S6 q
higher levels of serum testosterone (150 to 900 ng./dl.), will
1 Y- W! C' P! R! Y: L# S% zalso produce phallic growth but risks accelerated skeletal
" L) {/ T7 f  A3 v/ m* v- U6 s8 l" Pmaturation even after stopping treatment. It would appear
" F  x7 g/ M* I6 U6 O' V0 sthat this may be avoided by topical applications of testosterone$ P9 Y) ]8 i* V& t
and monitoring of serum testosterone. Even with this control
! H6 d- V2 V! E: Z, Q# Zthe duration of our therapy did not exceed 3 weeks at any) S  V8 d7 ^  n+ a
time. It is apparent that the prepuberal male subject may
. K8 j- U- K% [suffer accelerated bone growth with testosterone levels near' H4 T9 z, {  f1 W1 e
200 ng./dl. When skeletal maturation is complete the level of
! Q4 n( d5 A9 a7 \$ W) ]serum testosterone can be maintained in the 700 to 1,300 ng./
: s2 H1 J( m' s6 z& `dl. range to stimulate phallic growth and secondary sexual
6 c$ }4 f. ]' B7 p. _" \changes. Therefore, after skeletal maturation parenteral tes-
. X- @* ]; |* B: otosterone may be used to advantage. Before skeletal matura-
7 [1 ~0 K- o4 S9 n8 R; h* o0 R" W: Wtion care must be taken to avoid maintaining levels of serum7 P. V$ `4 o* M  t
testosterone more than 100 ng./dl. Low-dose gonadotropin
5 _$ d- v9 u3 @$ _5 k$ Q) Ydepends upon intrinsic testicular activity and may require9 J  [' g$ @# I$ i
prolonged administration for any response.
) A$ e, F+ {0 _  U+ \+ OAlternately, topical testosterone does not depend upon tes-! ~+ h: ^" d% r. b6 I# d
ticular function and may provide a more constant level of
$ u% d2 j3 v' y$ m) q9 ]REFERENCES
* H, ?' R) @7 b2 ]) H7 {. Z+ {1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
# `" {% C" I2 X( y+ fR.: The local application of testosterone cream to the prepub-
4 {, B& k, G  a2 _ertal phallus. J. Urol., 105: 905, 1971.
. B' y* T: u, w8 T* m2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone- f- i% i0 M: w
treatment for micropenis during early childhood. J. Pediat.,  B) _! {7 N" A% L4 o
83: 247, 1973.
8 u  S  Z/ M# k1 o2 L2 n3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
0 l5 z/ |, `6 |0 q2 j3 lone therapy for penile growth. Urology, 6: 708, 1975.& `. S1 x3 h- N3 O- i( x
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone" P/ ?: l' c3 c# t
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
% ^5 l' w9 X7 h! T9 M# @skin slices of man. J. Clin. Invest., 48: 371, 1969.  c. W/ o* I; }2 Y/ G6 C# x
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth: r6 v; S5 C# |5 J
by topical application of androgens. J.A.M.A., 191: 521, 1965.# H3 @  o8 k2 c9 U% v, X4 W# T
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
; |1 `, M% f  O  O) x+ ~0 C5 fandrogenic effect of interstitial cell tumor of the testis. J.: Z" Q! _0 X# N  z$ c0 s5 s
Urol., 104: 774, 1970.
1 F5 ~2 |8 I4 U$ J1 ^4 r$ r7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-, z' r, E# f8 t
tion in the male genitalia from birth to maturity. J. Urol., 48:
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