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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND/ }% F4 D# ?  F
GONADOTROPIN
7 B6 I7 p7 B  v' p  mRICHARD C. KLUGO* AND JOSEPH C. CERNY
3 a: j8 N" J! M* q2 jFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
2 C) U* z/ [' `+ s8 y$ d' {' XABSTRACT
# L& K% {! x' m; ?5 R5 O$ lFive patients were treated with gonadotropin and topical testosterone for micropenis associated- S8 q( V: h" M, }: n" A; O
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-+ _# B* a2 I! G9 _0 g' L1 k9 ^5 d
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone9 a3 b/ ^1 \0 l2 T) L
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent: P: \3 [- S$ ]2 e  h$ V$ u1 `
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent. h  i9 r6 ^% T0 }3 w# ^$ p
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average7 `4 e+ R0 c4 g- f7 |  _+ Q
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
0 X6 {% }) {) X, C1 \2 ^, Y8 doccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This0 Z' n" D: u: r  U
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
# ^! ]2 q; y8 X' ~growth. The response appears to be greater in younger children, which is consistent with previ-+ G# `' A4 P' O1 \
ously published studies of age-related 5 reductase activity.
* z. |+ k; T6 e, M0 E- ?( fChildren with microphallus regardless of its etiology will
+ D  F% }* f: krequire augmentation or consideration for alteration of exter-
3 l4 D  W' Z7 g2 [+ b9 k" ^8 Rnal genitalia. In many instances urethroplasty for hypo-
2 a/ H( Y1 I! t3 G- Q# cspadias is easier with previous stimulation of phallic growth.
' a* ~" m* ]+ f6 i" i" {2 c5 eThe use of testosterone administered parenterally or topically
8 L" S+ l8 ?2 I1 ]& e; `1 h, phas produced effective phallic growth. 1- 3 The mechanism of
7 @  O4 w, F- {# q" hresponse has been considered as local or systemic. With this; X6 B" a5 Z0 x9 ]/ N2 E: N% n: ^" _
in mind we studied 5 children with microphallus for response% f$ ~# H% n  j1 o3 W7 |
to gonadotropin and to topical testosterone independently.
: S& A! A! P2 \' ?5 d* c  P& IMATERIALS AND METHODS, U  B6 f0 m) o. |' x
Five 46 XY male subjects between 3 and 17 years old were
% G# D9 i) {, U0 yevaluated for serum testosterone levels and hypothalamic) g) U" M/ n) d, H7 v( e' Z' l& `
function. Of these 5 boys 2 were considered to have Kallmann's- B& r. f! V  f! ], v9 k0 ^: F
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-  j! a+ A3 t  O$ Z, R
lamic deficiency. After evaluation of response to luteinizing
2 T; F( U' {  yhormone-releasing hormone these patients were treated with9 y; {8 X' n; S. g( U7 n* G/ {
1,000 units of gonadotropin weekly for 3 weeks. Six weeks3 _5 g& h3 z8 \7 M
after completion of gonadotropin therapy 10 per cent topical
3 ]+ D' M3 r7 Dtestosterone was applied to the phallus twice daily for 3 weeks.
/ o' @0 [8 `" L& c' RSerum testosterone, luteinizing hormone and follicle-stimulat-" U0 `4 l( s* J6 Y1 k
ing hormone were monitored before, during and after comple-
3 e! P5 B. ?& q4 s. Z+ rtion of each phase of therapy. Penile stretch length was- x7 |& X' o4 C' c- H% ~% `
obtained by measuring from the symphysis pubis to the tip of
# b- e- ^' ]: V; m+ @+ d( o1 ethe glans. Penile circumferential (girth) measurements were
5 C" Y1 @# d. I7 W* m# T( robtained using an orthopedic digital measuring device (see
! W6 _. a/ ?/ yfigure).7 T  [4 x; h0 o, i4 u; `2 W# v
RESULTS
0 {$ V7 i8 }: W3 E! S9 C5 H. wSerum testosterone increased moderately to levels between
2 R# a' C% q9 r9 `5 ~50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-0 K$ V# \" q% W
terone levels with topical testosterone remained near pre-
7 K, D7 W1 O1 c8 Ktreatment levels (35 ng./dl.) or were elevated to similar levels% d  i3 b3 `. k% I
developed after gonadotropin therapy (96 ng./dl.). Higher
6 a1 c, e' Q; c3 F7 T8 d. A# s% N0 t2 iserum levels were noted in older patients (12 and 17 years old),7 U( C( Y/ i/ w2 a* q$ {
while lower levels persisted in younger patients (4, 8, and 10- _* H! ]5 Y  E. r; I% d4 W2 `* z2 l
years old) (see table). Despite absence of profound alterations
- D- `+ V2 y$ h/ f) bof serum testosterone the topical therapy provided a greater4 E- O, p7 K* _8 _( w
Accepted for publication July 1, 1977. ·
/ ]( n) O8 E5 t# ^/ gRead at annual meeting of American Urological Association,- h5 h" H8 U& j6 _! ]/ T+ h
Chicago, Illinois, April 24-28, 1977.
3 X9 N! N, {- P/ G2 U$ z) N1 {* Requests for reprints: Division of Urology, Henry Ford Hospital,$ o; D: s: c6 |  }& l
2799 W. Grand Blvd., Detroit, Michigan 48202.
5 \# y7 O- M2 j( c7 f; ^improvement in phallic growth compared to gonadotropin.
7 H; f, b8 J) b: s+ i1 uAverage phallic growth with gonadotropin was 14.3 per cent5 O& ?/ n% u& F! K! b" c! D! u# C1 o
increase in length and 5.0 per cent increase of girth. Topical/ S" ~+ ~. p; ^" ^7 W
testosterone produced a 60.0 per cent increase of phallic length2 c7 q3 ^$ H& f; q. [
and 52.9 per cent increase of girth (circumference). The  j* C2 c+ j5 m( @) ]. S1 _6 {  a
response to topical testosterone was greatest in children be-
! g) n, T; s7 v/ Q2 `& [3 {% Ptween 4 and 8 years old, with a gradual decrease to age 17  Y7 z" U; h2 e* `- R& I0 q
years (see table).: K4 e# s2 M+ ]* k8 Q' e; }
DISCUSSION1 M' T; `. A% q. Q) D& Q
Topical testosterone has been used effectively by other
( b4 V+ i" C4 u8 r7 _8 ^clinicians but its mode of action remains controversial. Im-
) Y" |( _3 S( s5 Pmergut and associates reported an excellent growth response
4 E; M5 S, t9 ~3 u8 `/ tto topical testosterone with low levels of serum testosterone,
6 k1 P9 O/ u! o! [% R1 osuggesting a local effect.1 Others have obtained growth re-
" s" R" N9 W% g' d  D1 s' [! D) v4 qsponse with high. levels of serum testosterone after topical
2 P* W; e9 x& ?; p' w0 e; q7 |administration, suggesting a systemic response. 3 The use of
/ o$ b" u9 ~' v+ d$ a- _! `4 Ygonadotropin to obtain levels of serum testosterone compara-
- F, w1 \# [: W, j8 |$ R$ Qble to levels obtained with topical testosterone would seem to* q, k& \8 k* L$ X9 @
provide a means to compare the relative effectiveness of
' {9 z) r' _+ Htopical testosterone to systemic testosterone effect. It cer-/ |: E9 W6 y* f: U/ a0 J. B" k. {6 |
tainly has been established that gonadotropin as well as par-! ~* {3 f7 f; Q; J" h
enteral testosterone administration will produce genital* H6 g. s$ o, b! i( {
growth. Our report shows that the growth of the phallus was
! |; ^' g+ u0 R& k( g1 }significantly greater with topical applications than with go-
2 Z/ ^* M* b7 A0 ~% h; tnadotropin, particularly in children less than 10 years old.
# B% d$ R9 e& RThe levels of serum testosterone remained similar or lower
" G+ S4 K! G5 l9 Ythan with gonadotropin during therapy, suggesting that topi-, b6 [7 A; X8 _8 Q3 x: Q8 L+ X2 J
cal application produces genital growth by its local effect as
; X# |* X- M) ?$ p/ Mwell as its systemic effect.
. u2 F% e3 X: Z6 ^( L' t" Q& ?Review of our patients and their growth response related to1 s- a$ R8 b* h' j9 a2 q2 P  A, z
age shows a greater growth response at an earlier age. This is; D  A9 f  D& D* f( _5 {* V
consistent with the findings of Wilson and Walker, who
& w# ]5 R0 X5 c; f( m' C9 Yreported an increased conversion of testosterone to dihydrotes-
8 P* k) T& {/ u% i5 q, Wtosterone in the foreskin of neonates and infants.4 This activ-
, H0 w9 m8 S; Q) D4 n7 Z8 N6 hity gradually decreases with age until puberty when it ap-6 y2 B4 C3 N5 ?/ W6 y; f
proaches the same level of activity as peripheral skin. It may. x/ K5 }% ~# f) a
well be that absorption of testosterone is less when applied at" J+ `: ?) Q: r% u
an earlier age as suggested by lower serum levels in children
9 j8 g9 U# R/ t  q0 U6 l/ }less than 10 years old. This fact may be explained by the" J' e4 t+ W2 E
greater ability of phallic skin to convert testosterone to dihy-0 T! g! ^! r2 R' B- _3 l- u
drotestosterone at this age. Conversely, serum levels in older
) Y9 ]$ n3 }7 \patients were higher, possibly because of decreased local
- _. i+ u+ P  z! P! i0 ]; x$ J667* h& j3 g* O$ e3 x& R
668 KLUGO AND CERNY& h: k0 o1 ^$ ]+ T7 R/ |# `8 B
Pt. Age
' o1 I- L; R8 B(yrs.)
* H1 w. B- F& K; |9 ISerum Testosterone Phallus (cm.) Change Length) Q# V+ L9 p& A$ [" u
(ng./dl.) Girth x Length (%)5 b/ L9 }+ z0 x# Y
4! \* [4 a) t2 {
8
% \- O1 f# C8 k* K: u10
' C" R1 ?0 ~; E1 Y12- X6 W2 W; A) m: x2 i
17
) T" Q4 _3 T5 P& x/ L! @. ]Gonadotropin
) A& ]7 c0 y  b71.6 2.0 X 3 16.6. y/ e5 ?0 h6 U) Q5 r% J
50.4 4.0 X 5.0 20.0" I, U# @, V' y2 T% f2 ^, _
22.0 4.5 X 4.0 25.0
& X; }# j# D+ x$ J7 y84.6 4.0 X 4.5 11.1
" {% w: r3 g' [$ Q0 ]; T3 V85.9 4.5 X 5.5 9.0
- b+ W# R+ o- Q2 YAv. 14.3
1 \% P, j: t) [1 w2 o7 w, N$ L4& |# T8 Z8 Y. f7 v6 z5 K6 W
8
6 O6 k5 z" |5 l0 S6 k109 E% g6 w2 M2 N  D  v
12( P9 F% ?6 N2 R) \7 ^5 x
17
( Z+ r$ [3 Q  M4 ^Topical testosterone! {- A: D' D! z$ u
34.6 4.5 X 6.5 857 D. Z( D* v; c& x; r! q0 Z
38.8 6.0 X 8.5 70/ U# T9 v/ P8 ^8 _. U; i( I
40.0 6.0 X 6.5 62.5
9 I1 ~5 G0 W+ m93.6 6.0 X 7.0 55.5
; c/ b* p$ Z$ C2 I95.0 6.5 X 7.0 27.2
% x9 ~' l$ j0 R" h1 o, ?Av. 60.0
, {/ m( D; I4 D% z6 vavailable testosterone. Again, emphasis should be placed on+ q$ ?3 Y4 C4 N4 H0 M+ ~8 C
early therapy when lower levels of testosterone appear to
. n  D1 a7 y1 S9 @provide the best responses. The earlier therapy is instituted) Q$ c! {, \1 ~  N6 I4 ?- E
the more likely there will be an excellent response with low+ D1 i' L2 ~8 X9 F
serum levels. Response occurs throughout adolescence as
% l' J  Y5 {; i! W* B$ N6 s5 r% tnoted in nomograms of phallic growth. 7 The actual response( S3 ?* i' M+ c! C' y
to a given serum level of testosterone is much greater at birth5 p( Q+ C5 j6 X% B5 d
and gradually decreases as boys reach puberty. This is most
4 X# c; ]6 `* rlikely related to the conversion of testosterone to dihydrotes-
. c9 y; u3 `  N' b  w8 Ptosterone and correlates well with the studies of testosterone
# A/ x( V3 h/ R4 B. c$ k  Aconversion in foreskin at various ages.
& ^* A, S9 I. Q9 e9 \. oThe question arises regarding early treatment as to whether3 V7 O0 ?% j: o3 S0 K2 ~+ _
one might sacrifice ultimate potential growth as with acceler-
3 S2 U7 T) B8 [4 q, z% s. Yated bone growth. The situation appears quite the reverse2 [+ Z0 _1 B. O9 V, p
with phallic response. If the early growth period is not used
/ C  H; U, R  F8 Rwhen 5a reductase activity is greatest then potential growth
9 C: W9 w5 D' `6 ?' {, zmay be lost. We have not observed any regression of growth
0 B: l! J0 I1 x7 ~  g& N. t1 cattained with topical or gonadotropin therapy. It may well
9 I7 R% Z2 y, R3 W2 W6 }! abe that some patients will show little or no response to any( H" k: k6 ?0 g. L- R1 y* y6 c
form of therapy. This would suggest a defect in the ability to
/ z, \' C- Z; ^0 Q' Econvert testosterone to dihydrotestosterone and indicate that* N0 l' \; n, y1 v1 y
phallic and peripheral skin, and subcutaneous tissue should3 s8 n& \! R. l# ]1 ~' j
be compared for 5a reductase activity.
; l+ E' _3 j5 g- w$ YA, loop enlarges to measure penile girth in millimeters. B,
' W% d. W4 N/ X3 Mexample of penile girth computed easily and accurately.
9 w! u8 B+ G- j/ m+ b$ Pconversion of testosterone to dihydrotestosterone. It is in this
: J+ K) {2 e: i% s; P" A9 Rolder group that others have noted high levels of serum; F6 r, ?8 G" u; C* i) }
testosterone with topical application. It would also appear9 w' E$ [, c' N7 i  O
that phallic response during puberty is related directly to the% ~5 n2 Y- N4 C- C0 U8 U: U1 Q
serum testosterone level. There also is other evidence of local0 A0 U& c3 O$ k8 {
response to testosterone with hair growth and with spermato-
$ _- \9 W7 w! o( \genesis. 5• 6
. h/ c4 a2 }. LAdministration of larger doses of gonadotropin or systemic
( |7 x* `. e  v. x9 Ntestosterone, as well as topical applications that produce7 B- E4 I9 p& O0 u6 t
higher levels of serum testosterone (150 to 900 ng./dl.), will
/ i7 m6 Z3 r7 u) M4 jalso produce phallic growth but risks accelerated skeletal9 d/ d6 x7 e. ^# u; U
maturation even after stopping treatment. It would appear
' Y9 u- u! M( V3 z7 {; z- ^6 r7 M3 Y! nthat this may be avoided by topical applications of testosterone" m% D8 b% k7 `7 ~1 y5 @: A$ V
and monitoring of serum testosterone. Even with this control
2 N. ^6 j6 U8 ethe duration of our therapy did not exceed 3 weeks at any
0 \- \- |+ d1 O' Otime. It is apparent that the prepuberal male subject may+ g) z* J" {* H3 ?* B
suffer accelerated bone growth with testosterone levels near- u  Z, ^$ @6 I: k8 z
200 ng./dl. When skeletal maturation is complete the level of5 O' s/ ?- q. a/ c' Z6 h  T) X
serum testosterone can be maintained in the 700 to 1,300 ng./
  w0 a' J  l9 u; R) I; ldl. range to stimulate phallic growth and secondary sexual8 e4 i, {" K/ K  x
changes. Therefore, after skeletal maturation parenteral tes-
9 S4 O' n6 [" w% D' N' m# ^+ ttosterone may be used to advantage. Before skeletal matura-) f" S+ j1 N5 |$ I9 c
tion care must be taken to avoid maintaining levels of serum
; c! d0 G+ k1 W8 q" Wtestosterone more than 100 ng./dl. Low-dose gonadotropin
" P; k+ S  z2 q$ Bdepends upon intrinsic testicular activity and may require
' d5 h+ L, X( E% Bprolonged administration for any response.
* c6 t, Z7 a" u' R& I) NAlternately, topical testosterone does not depend upon tes-
( W8 X- W5 z0 S) R; B" m  Sticular function and may provide a more constant level of
* M$ y) c. i! ?8 T- D$ S0 sREFERENCES
+ Z$ K7 W% d# v0 m( o, m1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
' O1 {* n) Z# ^1 h/ C3 IR.: The local application of testosterone cream to the prepub-
4 A( w# ~3 e. v3 uertal phallus. J. Urol., 105: 905, 1971.
% }' X7 a/ a* c2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
5 k4 g) D' F6 \& @  h7 K0 h6 z7 F3 Gtreatment for micropenis during early childhood. J. Pediat.," [6 X) B( n8 F8 l1 e
83: 247, 1973.
+ k& y2 Y; ~) j5 x6 |3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
# G- Y* V/ h. I, [( c! |! o2 d/ Fone therapy for penile growth. Urology, 6: 708, 1975.
' H0 H6 D( I% w3 S, u7 Z% ]5 M4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone& Y* ^6 K+ n  l1 L3 @8 t, O
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by8 c/ p1 ?0 q; U
skin slices of man. J. Clin. Invest., 48: 371, 1969.  o: c+ l  `( j: K
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth; K8 G/ c( |+ K
by topical application of androgens. J.A.M.A., 191: 521, 1965.' K/ u. l8 d& }, q/ _: d* s
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
$ D: M% ?, O, oandrogenic effect of interstitial cell tumor of the testis. J.
* n0 y3 N* R3 v( j1 uUrol., 104: 774, 1970.
( X& `8 q& W) X2 S8 z7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-2 T, A# L' e! G, C* ~
tion in the male genitalia from birth to maturity. J. Urol., 48:
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