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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND4 |6 \& d2 b7 i7 G
GONADOTROPIN4 u9 u7 N& _; i" m* I# c
RICHARD C. KLUGO* AND JOSEPH C. CERNY! Y# @, G- _5 h: y) j3 ~
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
0 o+ E" L$ a, W9 I3 NABSTRACT
. K# h5 p" M# F3 nFive patients were treated with gonadotropin and topical testosterone for micropenis associated8 G5 E+ ^# S0 [; O( G# Q1 v
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-" r2 x: J" v/ P% ?
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone. f- }) a8 x7 u. g
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
9 I% H. r; l; Xfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
; R7 w) o9 u/ ]8 }" v: t- B5 X: Tincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
. U+ b4 N4 W" o. L) lincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response5 k! }8 E4 [0 q
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This; r& A, V6 X9 ]% @
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile9 b3 U2 b% c. x6 J6 D
growth. The response appears to be greater in younger children, which is consistent with previ-5 N- K* h5 d3 u! [6 P7 W  U
ously published studies of age-related 5 reductase activity.3 \) T; h: T# W: a# I3 E
Children with microphallus regardless of its etiology will1 X: \% F, r1 k3 ]- n
require augmentation or consideration for alteration of exter-
% m5 r, k$ t1 q5 cnal genitalia. In many instances urethroplasty for hypo-
( J# r% s; K" @" I5 z: fspadias is easier with previous stimulation of phallic growth.
- i: T6 F7 B  x9 M& n: ]The use of testosterone administered parenterally or topically
" D2 V( m7 z7 d8 q1 B4 V( u& c  {has produced effective phallic growth. 1- 3 The mechanism of5 @2 u  ?( O7 g/ V- ~9 [# O
response has been considered as local or systemic. With this  s# I# K2 N0 k; H1 H0 K
in mind we studied 5 children with microphallus for response, i3 b+ o5 V6 Z+ I! G
to gonadotropin and to topical testosterone independently.
( I6 I- W; o" F7 K5 |& D3 a! DMATERIALS AND METHODS
* W7 x* _' j( j" _9 D( k/ X7 PFive 46 XY male subjects between 3 and 17 years old were; i( j- B' k! |- ^$ p0 Y7 s
evaluated for serum testosterone levels and hypothalamic: l1 ]8 Z* ~( P
function. Of these 5 boys 2 were considered to have Kallmann's" `( e) d4 t7 x
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-% y7 J0 k/ C( y' |/ u0 f
lamic deficiency. After evaluation of response to luteinizing
, z0 t0 O& l& V& nhormone-releasing hormone these patients were treated with
2 L3 E+ K( G. I; L( D+ \5 @1,000 units of gonadotropin weekly for 3 weeks. Six weeks
% S1 J, n# M7 m/ Wafter completion of gonadotropin therapy 10 per cent topical- Q  H, p/ X/ A3 T4 f
testosterone was applied to the phallus twice daily for 3 weeks.
" y" f% f) U/ ]: b8 jSerum testosterone, luteinizing hormone and follicle-stimulat-7 Y1 ], ?; r1 O2 f6 V: S
ing hormone were monitored before, during and after comple-
& l' t( ~3 |1 p: C3 h/ stion of each phase of therapy. Penile stretch length was
' Q4 {% k2 n" B2 Xobtained by measuring from the symphysis pubis to the tip of
0 K$ U" \2 u; y7 p" a& g# ithe glans. Penile circumferential (girth) measurements were
3 `. U9 L; c6 y/ _obtained using an orthopedic digital measuring device (see  }% X+ J; u- ]: E# [% t# T
figure).' a( Y3 B# S  h% H9 d# W
RESULTS8 L) T/ F8 j- ?1 d$ C3 O' l
Serum testosterone increased moderately to levels between
+ b( O3 p" u8 ~( k, b0 J+ r50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
0 z# X6 F/ Z1 C, g! {. Z! b+ yterone levels with topical testosterone remained near pre-$ S7 J  Z1 K# L' V4 h  ]6 O4 z
treatment levels (35 ng./dl.) or were elevated to similar levels% ~( s/ Q; |- L" A
developed after gonadotropin therapy (96 ng./dl.). Higher  z! p+ P4 O4 o( w( }! J6 e- k& e: h+ g
serum levels were noted in older patients (12 and 17 years old),
" Q# V& W7 x" h/ D$ X4 Pwhile lower levels persisted in younger patients (4, 8, and 109 M5 w- L3 [+ C5 o+ v
years old) (see table). Despite absence of profound alterations
$ ]$ L; q! E. m0 i5 n; M  dof serum testosterone the topical therapy provided a greater, p& Z# e9 G9 _: u" X6 C3 D
Accepted for publication July 1, 1977. ·
4 s' _( b" i7 F# b) e  uRead at annual meeting of American Urological Association,
3 z, G/ j+ M5 q' a! ?Chicago, Illinois, April 24-28, 1977.
8 S6 o$ p. I$ r3 t, g* Requests for reprints: Division of Urology, Henry Ford Hospital,
0 o2 y3 f+ `+ |0 c" Q4 T- V7 S2799 W. Grand Blvd., Detroit, Michigan 48202.
. U8 e, K0 A* ?: ?% ?improvement in phallic growth compared to gonadotropin.
- `! E5 |$ F, [1 n9 W' H2 B. iAverage phallic growth with gonadotropin was 14.3 per cent* ^' r' k& C0 X( b& H
increase in length and 5.0 per cent increase of girth. Topical5 |) R9 C5 H0 ]! k
testosterone produced a 60.0 per cent increase of phallic length
* d" @& H0 `4 [" l+ H$ W. tand 52.9 per cent increase of girth (circumference). The* n- i1 B, [  y8 j* j" X1 S/ \! L
response to topical testosterone was greatest in children be-
. \" \: M' l! {+ ^( K9 Vtween 4 and 8 years old, with a gradual decrease to age 17
3 z% Z; [. r  G0 a8 \$ C! [+ ayears (see table).
" s, T+ X# l6 @8 k# \8 R4 D$ ^DISCUSSION0 C! Q& Q( z  ~1 Z' F- i1 r
Topical testosterone has been used effectively by other# V2 c8 q& z) Z# n! u
clinicians but its mode of action remains controversial. Im-! F. Q' j/ v& w9 X5 R  n) u
mergut and associates reported an excellent growth response
' i1 F% c9 W$ ~* {) R; L) _to topical testosterone with low levels of serum testosterone,
. @1 J8 \+ O' O8 Isuggesting a local effect.1 Others have obtained growth re-
- F4 N# A9 o( Z' ysponse with high. levels of serum testosterone after topical0 ~2 m$ m  e1 c. P; _3 w
administration, suggesting a systemic response. 3 The use of
5 @% w9 Y/ m# P" fgonadotropin to obtain levels of serum testosterone compara-
& S$ _( J6 V, c+ U" T, Q* rble to levels obtained with topical testosterone would seem to
+ _$ |1 j1 e3 m! a. t! L/ t: Sprovide a means to compare the relative effectiveness of
# q5 R. q7 L4 E/ l9 Atopical testosterone to systemic testosterone effect. It cer-" `" @' I6 M5 D# Z" n/ X
tainly has been established that gonadotropin as well as par-
' h$ c* j3 b! L( oenteral testosterone administration will produce genital
4 s7 {8 k  P8 V/ W' jgrowth. Our report shows that the growth of the phallus was( B! W7 Y; I+ I3 z9 l/ `' M& ^. S
significantly greater with topical applications than with go-
# d# ~; l# A5 w# lnadotropin, particularly in children less than 10 years old.
! m( l3 x) M9 ~" r0 F  i* _The levels of serum testosterone remained similar or lower
  v8 W$ P8 Y7 o0 V& d: H1 Bthan with gonadotropin during therapy, suggesting that topi-
% D% |9 ^+ C  j1 X4 {4 a* d2 ~cal application produces genital growth by its local effect as) g7 r% {% ]' f1 `3 r5 d
well as its systemic effect.! Q; i5 Q( r. d$ B) Y! _
Review of our patients and their growth response related to
# f+ q& Y( T! x& c  Q- y% tage shows a greater growth response at an earlier age. This is
3 p+ y7 J, `8 W9 C- o5 f: Lconsistent with the findings of Wilson and Walker, who5 z! h8 d! h; F: X
reported an increased conversion of testosterone to dihydrotes-
( V" f& @( V+ S/ v* ~% Y  L% Wtosterone in the foreskin of neonates and infants.4 This activ-6 ^7 R( N* S0 p' H$ E
ity gradually decreases with age until puberty when it ap-" x9 B( e# G! W5 Z6 u* f/ X- Z
proaches the same level of activity as peripheral skin. It may
: n2 w) L1 R# Nwell be that absorption of testosterone is less when applied at$ }. _; V6 l& v+ T
an earlier age as suggested by lower serum levels in children5 N# m# ]+ a& W" a
less than 10 years old. This fact may be explained by the, M8 k4 w- _5 Q! l- x2 L1 @
greater ability of phallic skin to convert testosterone to dihy-
! d# r+ Z5 h+ edrotestosterone at this age. Conversely, serum levels in older) U( k% ?. ]# S
patients were higher, possibly because of decreased local0 S+ X. s! [9 @4 ^7 k5 ~
667! [% j+ Z  P6 o1 O. ]2 Y0 j- a
668 KLUGO AND CERNY/ L$ g6 F! E8 j+ o+ L9 }
Pt. Age# B1 j. j) ^3 A9 l9 E
(yrs.)
3 ~- B4 Y' @* F% iSerum Testosterone Phallus (cm.) Change Length
6 ?: F8 V% E1 u2 [+ V(ng./dl.) Girth x Length (%)
3 _1 M2 \3 Q8 i2 I4 N6 r& l4
1 Z6 Z0 N7 \5 a  e8( E6 a; L7 _7 W, C; e
10
! q2 R( c" [) X* n: Q( Z! u! _- y122 {- J, _3 l+ E0 B5 C6 Y) f
17% z- o9 F' n3 \5 T
Gonadotropin* v# ?, e: u( R: u+ i
71.6 2.0 X 3 16.68 E6 F/ ^$ E$ ^3 f
50.4 4.0 X 5.0 20.0. a5 b& F- ?4 l7 l2 p7 c8 v
22.0 4.5 X 4.0 25.0' Y$ b5 x7 P8 f; Z: ^
84.6 4.0 X 4.5 11.1: J, M6 [7 k2 [
85.9 4.5 X 5.5 9.0
: w( q" |4 A: h1 A  ^3 \! eAv. 14.3  [! d: e& k% j, o
40 N" b9 E3 ^& e, l
8
% |/ }: I* p( C$ G10
" S: A, ~( `  Z; h128 w. u+ K2 x4 h0 z: [2 ~0 q
17
" f$ q# R7 l/ U; P! a5 _, W' FTopical testosterone
' n, H7 ?; y3 M5 z34.6 4.5 X 6.5 85
+ d) Z. ^! X( ?$ w38.8 6.0 X 8.5 702 f0 o6 G( y5 \4 Z
40.0 6.0 X 6.5 62.5% ^4 {! `+ X- r/ F# y
93.6 6.0 X 7.0 55.5/ d; b& `  n& m: O( b; O
95.0 6.5 X 7.0 27.2
  T" \% Y/ D5 o# ?0 }Av. 60.0
9 A& |6 O- C; k) d$ c5 ]7 a: J0 ^available testosterone. Again, emphasis should be placed on
! y& f! T) l) mearly therapy when lower levels of testosterone appear to9 D% b+ I* R# h3 b( B
provide the best responses. The earlier therapy is instituted5 p9 c6 x5 ^0 c* D$ {+ k+ s
the more likely there will be an excellent response with low
& A) ^) ^! ~* n0 I5 Y/ D! ]serum levels. Response occurs throughout adolescence as
6 V: h4 U: r9 I8 ^: dnoted in nomograms of phallic growth. 7 The actual response
0 F3 U* X( o7 Cto a given serum level of testosterone is much greater at birth
7 N- G; }/ C+ qand gradually decreases as boys reach puberty. This is most
$ i% k4 x6 Z$ P) Q8 s' P9 F2 ]likely related to the conversion of testosterone to dihydrotes-8 I0 \# Z& f9 s/ d
tosterone and correlates well with the studies of testosterone5 c' A7 Q7 m" |# Q+ K) Z
conversion in foreskin at various ages.) u, C9 U0 P) _4 m
The question arises regarding early treatment as to whether
% X2 f6 M4 p" P- `/ Oone might sacrifice ultimate potential growth as with acceler-% D7 x$ i9 a0 _8 y
ated bone growth. The situation appears quite the reverse; I+ _: A2 e6 ?$ w, ~
with phallic response. If the early growth period is not used
1 x# K; k* ^: z' b6 dwhen 5a reductase activity is greatest then potential growth& c, o' k! n% z
may be lost. We have not observed any regression of growth) ^6 K7 O7 l, |. }* X$ y
attained with topical or gonadotropin therapy. It may well& f. K/ `& i6 B, P
be that some patients will show little or no response to any
. E$ K7 l3 ?4 @$ B+ k' zform of therapy. This would suggest a defect in the ability to
) s: O$ ~1 D, |$ Bconvert testosterone to dihydrotestosterone and indicate that' [: S# b* _) C1 X# [
phallic and peripheral skin, and subcutaneous tissue should
4 d7 ?' E/ a* {' A) Ebe compared for 5a reductase activity.
% J$ m+ e$ ]  T8 `& QA, loop enlarges to measure penile girth in millimeters. B,
' ?1 F- U1 l& Z4 Texample of penile girth computed easily and accurately.6 x  a/ x2 ~, l) Z7 V/ n" b
conversion of testosterone to dihydrotestosterone. It is in this" }; r) X7 F! S9 r$ \
older group that others have noted high levels of serum
: c$ D& i/ {- V: M, b. P) k: {testosterone with topical application. It would also appear
( \7 W0 w+ r! ^1 R, C# J5 mthat phallic response during puberty is related directly to the! z+ s3 v8 k4 ~
serum testosterone level. There also is other evidence of local
3 j6 S6 V8 {" d7 _# qresponse to testosterone with hair growth and with spermato-
5 t# j* s8 _; d9 M/ A. d; [genesis. 5• 6# {; C; Y6 d, S& W
Administration of larger doses of gonadotropin or systemic
& n, ]  V; |8 E# i7 v# Dtestosterone, as well as topical applications that produce
( |3 W1 A3 K$ `9 Y! Yhigher levels of serum testosterone (150 to 900 ng./dl.), will
( f1 c( [- w8 oalso produce phallic growth but risks accelerated skeletal6 U# E8 p! V: b7 V& v4 `: X+ G
maturation even after stopping treatment. It would appear" c6 t. i) x/ s/ d3 Y
that this may be avoided by topical applications of testosterone0 Q$ u- o, e& M8 Q5 }
and monitoring of serum testosterone. Even with this control
1 f% {; K7 j/ ?( v6 ~7 O/ t3 Hthe duration of our therapy did not exceed 3 weeks at any# i9 ~' L- [  T  X; R
time. It is apparent that the prepuberal male subject may# {. j" S9 |6 i
suffer accelerated bone growth with testosterone levels near+ S9 V: v* f4 S1 r7 Q/ H
200 ng./dl. When skeletal maturation is complete the level of$ j+ _( ?4 V) e
serum testosterone can be maintained in the 700 to 1,300 ng./
3 S7 u! i9 t' L0 x' mdl. range to stimulate phallic growth and secondary sexual
- e. A' ]/ @! {2 O8 ~changes. Therefore, after skeletal maturation parenteral tes-$ N6 m1 _: b& N$ }* ]) l* @2 B" s
tosterone may be used to advantage. Before skeletal matura-% h" }7 s4 Z1 {& b& C5 |* J
tion care must be taken to avoid maintaining levels of serum
6 Y2 O, s1 u- z) o9 itestosterone more than 100 ng./dl. Low-dose gonadotropin
7 F# ]3 z7 N% w2 D4 _/ F1 J0 Ddepends upon intrinsic testicular activity and may require9 G6 ]4 Y8 C8 g2 r3 @
prolonged administration for any response.
. A( B6 X6 u* B( S- N2 Z  i/ x% ^Alternately, topical testosterone does not depend upon tes-
7 {8 w, \8 ]+ h& Yticular function and may provide a more constant level of  y2 `5 @5 q* P! x
REFERENCES5 {. @" d- m/ z. ?! Y" |
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
7 }$ P$ w: G' F" v6 D% E1 xR.: The local application of testosterone cream to the prepub-
$ @: p' \3 x" [4 |ertal phallus. J. Urol., 105: 905, 1971.8 b/ i9 A* K, J+ r: e4 Z% y
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
, c! |# H- E7 x9 j# ^4 xtreatment for micropenis during early childhood. J. Pediat.,
+ F4 k* ~; {; a! n4 M83: 247, 1973.+ G4 c6 L+ t& }3 k# x& d
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
; K: D7 z# ?& y5 ^5 V; Q) lone therapy for penile growth. Urology, 6: 708, 1975.* }& G7 G+ }$ V8 R* t
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone3 [% j% n9 Z' g- R; q0 a
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
9 |5 N0 x% P% M' hskin slices of man. J. Clin. Invest., 48: 371, 1969.
5 O+ d& C& _' u* G* ]/ Z  R8 ~5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth3 \& q) F+ ?, ~2 \
by topical application of androgens. J.A.M.A., 191: 521, 1965.& y; u0 t* P- l$ Q
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
" E7 g  n3 }  N( M% handrogenic effect of interstitial cell tumor of the testis. J.$ i) R( M6 N7 E  L  O* M
Urol., 104: 774, 1970.
; d8 ], h. z6 k! k7 g0 i* }9 O$ x: E7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
/ @- s" `1 R0 V' A( Ation in the male genitalia from birth to maturity. J. Urol., 48:
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