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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
/ s; ^2 |! l0 e5 W  \GONADOTROPIN
3 L" _0 e) n( D. x6 F2 z6 t* G( eRICHARD C. KLUGO* AND JOSEPH C. CERNY2 D( H+ K6 o" U! W( H9 s
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
( R4 o3 @  \% `+ m7 OABSTRACT
0 a2 V$ E+ n9 X8 H' z+ t5 t( W/ q6 nFive patients were treated with gonadotropin and topical testosterone for micropenis associated9 J9 b+ u' s3 g% T0 U3 I
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
, I" F! X6 {# ^" |0 stropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
9 t4 L1 G( @% U1 |# M/ bcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
$ ~: ~: F) C; K- Zfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
& t1 I2 _0 S$ q2 tincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
3 i" v4 @+ J: O  E, ^0 K% {5 [8 o9 bincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response+ X- V0 G! c9 _* Y- M3 d4 _. i% _
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This6 d1 B1 I7 M- J5 R
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile" `  J  q& c4 o& ?' }
growth. The response appears to be greater in younger children, which is consistent with previ-
0 K, V8 Y& ^# X4 t/ ~! w' Vously published studies of age-related 5 reductase activity.
* O* s, B3 D3 O+ GChildren with microphallus regardless of its etiology will5 e  p9 |% |' w
require augmentation or consideration for alteration of exter-
" I+ Y2 p' [0 F; Tnal genitalia. In many instances urethroplasty for hypo-
3 e8 [: a. ^  ?/ a/ f) ^% n6 ]spadias is easier with previous stimulation of phallic growth.! ^. ?$ g6 H; ~6 P/ G8 n" Z# ^
The use of testosterone administered parenterally or topically$ y+ n3 Z/ _9 }/ c: ?, S
has produced effective phallic growth. 1- 3 The mechanism of
6 ]3 t, l, {2 @* G, S/ z" x1 z9 ~response has been considered as local or systemic. With this' u1 O- ]/ F0 h' Q& N1 n4 h
in mind we studied 5 children with microphallus for response, z* v8 Y3 {% s& T; D' J) n* I
to gonadotropin and to topical testosterone independently.
6 ^& D7 J# Q) ?! L5 XMATERIALS AND METHODS
; Y  Z, R$ T! M9 k0 K! g+ U% MFive 46 XY male subjects between 3 and 17 years old were3 U! n5 D  S8 z5 F8 ^
evaluated for serum testosterone levels and hypothalamic
. Q; |, j+ n9 Ffunction. Of these 5 boys 2 were considered to have Kallmann's" V' |1 F* F# h! A9 o3 e; C
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
8 C4 X( D0 z' b' F: D! V3 ulamic deficiency. After evaluation of response to luteinizing
6 P! k3 ?; I" Y! a0 Q2 u, Xhormone-releasing hormone these patients were treated with- l; `& l& X. X+ y
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
% r. n/ K4 n+ i+ G. c' Gafter completion of gonadotropin therapy 10 per cent topical
7 m( S5 X/ A% j0 P5 c: J4 u4 [testosterone was applied to the phallus twice daily for 3 weeks., n; w: t' A1 i3 t
Serum testosterone, luteinizing hormone and follicle-stimulat-+ z0 F; V3 }, Q0 W  {$ v4 @! J
ing hormone were monitored before, during and after comple-6 l0 f* e" d6 Y9 E& C, B6 T
tion of each phase of therapy. Penile stretch length was
) q+ ~. B! r! G' y8 Iobtained by measuring from the symphysis pubis to the tip of
1 i4 m% h4 [7 s/ k  O/ Nthe glans. Penile circumferential (girth) measurements were, S, N" c! T2 l; n8 V; q
obtained using an orthopedic digital measuring device (see
  R9 e3 R, ^9 g8 e6 p4 Zfigure).
# J; T0 q9 T& b: V9 CRESULTS
( ], C2 e# A7 qSerum testosterone increased moderately to levels between
; h+ l/ q" {  u& t50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
: q6 E8 O1 e& [9 K" Uterone levels with topical testosterone remained near pre-
3 z$ L, P1 ^* B2 a% D; n; ~treatment levels (35 ng./dl.) or were elevated to similar levels
; G8 `& l, A$ x+ {* Y) v& M: L7 Bdeveloped after gonadotropin therapy (96 ng./dl.). Higher: x- d  |( a9 j- Q
serum levels were noted in older patients (12 and 17 years old),- ^& `) Z  B; T# X3 }: I% [
while lower levels persisted in younger patients (4, 8, and 10
3 U- M6 }) {) C8 C6 V6 }/ G4 kyears old) (see table). Despite absence of profound alterations8 ]3 }$ C4 A$ F1 r8 t
of serum testosterone the topical therapy provided a greater
4 U% c) y* b' v6 O$ ^( `Accepted for publication July 1, 1977. ·" `! Q' O+ |7 P( f
Read at annual meeting of American Urological Association,. m0 |* H1 b( R6 h4 K, P
Chicago, Illinois, April 24-28, 1977./ q$ M' z" `4 y) k
* Requests for reprints: Division of Urology, Henry Ford Hospital,2 {" O- }/ Q* j. M$ X2 {: C
2799 W. Grand Blvd., Detroit, Michigan 48202.
; r' T0 w/ a# g2 r+ S' h# j3 ]improvement in phallic growth compared to gonadotropin.
' \6 u, m8 f/ S" rAverage phallic growth with gonadotropin was 14.3 per cent- J; `0 F: T0 i8 R
increase in length and 5.0 per cent increase of girth. Topical  V' F' p3 m2 p, s7 ?- n2 j  i# L
testosterone produced a 60.0 per cent increase of phallic length
$ M- j" g! w$ R7 |& g6 oand 52.9 per cent increase of girth (circumference). The
. Y! b8 ~! s, |; y) ^: ]response to topical testosterone was greatest in children be-
9 F% j- M( b( k6 G+ a: z+ u" @tween 4 and 8 years old, with a gradual decrease to age 17" X, f$ \# A9 n4 T& N& ]6 D- r
years (see table).5 q  ~$ Q* C) w  a6 u& h
DISCUSSION
- k" q! u, j* {# M% g' FTopical testosterone has been used effectively by other6 D8 V# F" B# Y4 U2 V
clinicians but its mode of action remains controversial. Im-3 [4 G1 A. E+ {, q
mergut and associates reported an excellent growth response
1 t4 W- U  j  e( m0 v& Z# s! p  Gto topical testosterone with low levels of serum testosterone,
. c; I9 ?9 r! |+ ~# csuggesting a local effect.1 Others have obtained growth re-0 n: V1 K# E3 e
sponse with high. levels of serum testosterone after topical
4 n: S0 ~3 G7 \; J# j- T8 Oadministration, suggesting a systemic response. 3 The use of
- I' j# s) g! t, x2 p  ggonadotropin to obtain levels of serum testosterone compara-6 U- A9 r0 m- `2 I4 i
ble to levels obtained with topical testosterone would seem to
; b  E; P7 O" {1 w2 o# Pprovide a means to compare the relative effectiveness of2 D/ y3 F- t$ k
topical testosterone to systemic testosterone effect. It cer-
# Q& m; i1 @! X4 X, S0 I6 Ftainly has been established that gonadotropin as well as par-
7 c  f+ D" Y( @; [enteral testosterone administration will produce genital
% {" Q, L1 I# v+ A! W) E, Ogrowth. Our report shows that the growth of the phallus was5 x: K+ p; P$ E- x
significantly greater with topical applications than with go-
, S7 T( W$ f( V# P- \nadotropin, particularly in children less than 10 years old.
! ]) p# n$ d! d' H5 K; EThe levels of serum testosterone remained similar or lower9 Q% [9 S9 Y6 b( G( }! f* R: c% D$ J4 x
than with gonadotropin during therapy, suggesting that topi-# w. \7 k. n) H( q
cal application produces genital growth by its local effect as
% H2 H7 h4 y$ Ewell as its systemic effect." R0 X1 X+ H$ B. G' v
Review of our patients and their growth response related to
; n; a. j! S$ k2 S3 n+ zage shows a greater growth response at an earlier age. This is8 K, `& U) Y7 [8 t! e- b
consistent with the findings of Wilson and Walker, who8 T2 c9 \1 i8 [  ~  ]7 M. O
reported an increased conversion of testosterone to dihydrotes-
% q. A; e2 v- a7 l$ n! M# Ytosterone in the foreskin of neonates and infants.4 This activ-
9 E0 v6 t8 t. r0 ]4 e( w' S: ^ity gradually decreases with age until puberty when it ap-
7 m' k1 k6 @" u) F7 |7 S$ Tproaches the same level of activity as peripheral skin. It may
' d& \1 `7 _2 c( K' D- J- e7 A3 Swell be that absorption of testosterone is less when applied at( ~" `$ K$ {8 f2 t: S" R
an earlier age as suggested by lower serum levels in children
: X$ T7 V0 z* v2 i. i6 ^  cless than 10 years old. This fact may be explained by the
6 Q$ @/ B( A  T; v5 Kgreater ability of phallic skin to convert testosterone to dihy-  w$ {# m( ]% J: R9 a
drotestosterone at this age. Conversely, serum levels in older  U* S8 a- k$ z$ n4 u  x
patients were higher, possibly because of decreased local
- \4 T7 q) I5 x. m9 b7 r8 Q6672 Q2 g+ C+ N" w; ]
668 KLUGO AND CERNY% c+ F/ u) n1 K1 R8 Z
Pt. Age
6 c! n+ Y8 s( I(yrs.)
- F4 D& `8 V/ `2 b2 ^0 a7 o* k% MSerum Testosterone Phallus (cm.) Change Length1 R$ a* ^$ w8 U
(ng./dl.) Girth x Length (%)$ f7 l0 N0 a- W: t, X7 `) S6 ^$ ]
4+ f1 r/ _1 x3 n# z8 f# t7 ]# ]1 N
8
) L& D& }! [/ Y) [$ M10
+ |" F6 M2 Y6 G' U! X9 g, Z6 _% m12
* S3 L2 j4 Y' \, d! ^- o3 a17
' X3 T. X2 h4 a) qGonadotropin& F& v6 r) I  R: E$ E
71.6 2.0 X 3 16.6
' ?3 m% K+ @! a! o( w50.4 4.0 X 5.0 20.0
6 P/ P, j+ W6 G. y) b22.0 4.5 X 4.0 25.0/ Z3 o7 M+ N1 N7 r
84.6 4.0 X 4.5 11.1
! B3 h+ |1 E. q, V7 t5 A9 F1 b, B85.9 4.5 X 5.5 9.03 B' o) K- T" Q  O$ B9 M7 u9 I( R
Av. 14.3
1 W( L3 X+ R% ~) z( l4  T6 S, G. n+ W
84 P5 G  Q" V1 K) F" W9 C
10
" F: A) K2 w7 p& @( E124 Z4 L7 v% Q. F& l6 K) e
179 O6 q7 s. M# b8 r; v# t& V5 F0 G
Topical testosterone, }% J' U" O7 [
34.6 4.5 X 6.5 855 e) L8 a7 O7 e
38.8 6.0 X 8.5 70
" ?5 h+ ^8 ?0 i40.0 6.0 X 6.5 62.5
7 u( J- a$ [( {1 a  M3 [93.6 6.0 X 7.0 55.5% u, k: a1 ?5 H" k7 L) b! H) o4 V' J
95.0 6.5 X 7.0 27.2- V- \1 H* q  M! @. V
Av. 60.0- O# k0 H' l5 f+ z$ [
available testosterone. Again, emphasis should be placed on% c, q# I$ V: x: |" V8 s
early therapy when lower levels of testosterone appear to' f' Q) H; h) M6 o( W% y; W
provide the best responses. The earlier therapy is instituted/ ^* ~/ `% N& B7 s
the more likely there will be an excellent response with low
* Z9 C9 @. G4 Y. {( f4 r3 ^serum levels. Response occurs throughout adolescence as
: V& _2 o) A: w! _noted in nomograms of phallic growth. 7 The actual response6 G5 ]$ O; P+ g0 `, P5 H
to a given serum level of testosterone is much greater at birth! U+ l: ]5 O2 C* _. ^: i
and gradually decreases as boys reach puberty. This is most
) ~2 v! Z/ u+ e+ \* P% }: R: J' ]. Tlikely related to the conversion of testosterone to dihydrotes-( z# c* ~# I- B+ g  @8 [$ u5 _8 ^
tosterone and correlates well with the studies of testosterone
1 k* h2 A5 _% E3 t% L# Q: W! k) R4 gconversion in foreskin at various ages.- s: J+ x  V+ a7 S/ [0 G
The question arises regarding early treatment as to whether
0 e* K  }4 P, ]- H2 i; @one might sacrifice ultimate potential growth as with acceler-. b& x/ {2 L! J8 z, @" G3 ?5 i
ated bone growth. The situation appears quite the reverse
5 C) q- n3 q; D$ M( T# g0 _with phallic response. If the early growth period is not used8 b2 G& h- u$ `! D. E3 L
when 5a reductase activity is greatest then potential growth
- d5 J3 {4 Y; Q  v3 fmay be lost. We have not observed any regression of growth/ a# z) f  w5 I& |0 a8 {# b
attained with topical or gonadotropin therapy. It may well
0 I3 t$ P; q- j/ |) [, Q; ibe that some patients will show little or no response to any
; E3 m: Q0 d/ ~  w  j& ]form of therapy. This would suggest a defect in the ability to
$ z! e3 B7 T2 e* kconvert testosterone to dihydrotestosterone and indicate that
) c9 B& |# B( v( M+ |phallic and peripheral skin, and subcutaneous tissue should
' j, f& L& }9 k2 j) v% Kbe compared for 5a reductase activity.' p, W: K% c! U
A, loop enlarges to measure penile girth in millimeters. B,
) F$ h$ m, Q4 f3 Xexample of penile girth computed easily and accurately.* i$ W' [- Z3 f, Y( B
conversion of testosterone to dihydrotestosterone. It is in this$ t+ \" e7 j9 z% E/ s) o; G
older group that others have noted high levels of serum# w  x8 P; ?4 d
testosterone with topical application. It would also appear
  Y, c* S$ N/ Y$ U' C7 _that phallic response during puberty is related directly to the
% M& U' s: h0 X/ y2 h( `serum testosterone level. There also is other evidence of local
9 B4 K) S& Y) O$ ~response to testosterone with hair growth and with spermato-
0 P5 j8 |& G8 }" ]3 Egenesis. 5• 65 t: x% S2 p7 V  u! S* ]7 f8 n1 e
Administration of larger doses of gonadotropin or systemic" ^: P7 f( J! ^
testosterone, as well as topical applications that produce$ C3 {( y+ B9 r% G( A) }3 e
higher levels of serum testosterone (150 to 900 ng./dl.), will
% x4 }: G# V% L8 ?also produce phallic growth but risks accelerated skeletal! a4 S7 {; h$ [* [# e0 L# P% u
maturation even after stopping treatment. It would appear9 y! }5 v$ e' Q7 I
that this may be avoided by topical applications of testosterone
, O3 U0 X$ H2 m& a& [and monitoring of serum testosterone. Even with this control
3 Z  {" Y& ~5 n, Sthe duration of our therapy did not exceed 3 weeks at any
5 w1 ?! B7 A# s: r# W) Ntime. It is apparent that the prepuberal male subject may
9 b) J' i% X$ s0 f; a4 Bsuffer accelerated bone growth with testosterone levels near- j8 c$ ?; m! k/ Z, n, J. O$ N
200 ng./dl. When skeletal maturation is complete the level of
' z8 K5 {% j/ W4 c- jserum testosterone can be maintained in the 700 to 1,300 ng./
; O, R" _' n; w* d2 F) b- jdl. range to stimulate phallic growth and secondary sexual
6 V8 t5 {- b' z$ J  c4 H9 lchanges. Therefore, after skeletal maturation parenteral tes-, g& V- u* m) R" {$ c, l
tosterone may be used to advantage. Before skeletal matura-
3 S+ N7 ^5 c6 X9 O" ^2 ption care must be taken to avoid maintaining levels of serum
0 t% V/ ^% t$ `" t; |  Wtestosterone more than 100 ng./dl. Low-dose gonadotropin
4 L9 w7 F( @9 Tdepends upon intrinsic testicular activity and may require1 t; e1 i" j8 \
prolonged administration for any response.
% ?1 A# r. T8 Z& H$ g3 WAlternately, topical testosterone does not depend upon tes-
% s* v1 ~% v* M! Rticular function and may provide a more constant level of( W. v- |* J6 c- q  g
REFERENCES5 D" \8 }. k. W! w2 ^+ x& K% r
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,( E+ p. o* ]- s( H4 w  H- c/ o
R.: The local application of testosterone cream to the prepub-4 `) e' ]7 X) a9 Y& b; ~9 l! M
ertal phallus. J. Urol., 105: 905, 1971.0 z7 C; `: k+ E, u/ g
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
+ ]0 S5 h" A: K& j% J; Wtreatment for micropenis during early childhood. J. Pediat.,
2 _, N/ V3 U5 \83: 247, 1973.
7 E# o% o% c5 s3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-$ K8 p% F" |% J/ E9 B) E
one therapy for penile growth. Urology, 6: 708, 1975.. c/ D: B3 M* x: p
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
6 w0 q' q3 \' h, yto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by, S9 B. A* J! B6 ]3 X3 X
skin slices of man. J. Clin. Invest., 48: 371, 1969., y! P$ z/ W" P7 L; I/ B
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth8 w+ h% ~& T" s5 K1 W8 z8 k$ e
by topical application of androgens. J.A.M.A., 191: 521, 1965.# u" X1 k/ `; l* T/ b; n
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
, x* @$ I) m; j  ]* kandrogenic effect of interstitial cell tumor of the testis. J.- a& s. g; e% D+ l* v; w
Urol., 104: 774, 1970.
6 X! p8 t. g3 k# V( W7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
* \! k% @& O  K) S$ z/ o% ?, ation in the male genitalia from birth to maturity. J. Urol., 48:
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