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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
3 Y9 a! [. a$ ]! S7 d9 o4 tGONADOTROPIN2 l( `3 m8 a2 h; M. [% d& p
RICHARD C. KLUGO* AND JOSEPH C. CERNY
! v2 m1 F0 q/ j5 s$ E/ IFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
; u+ \- p* H" l9 eABSTRACT
, L( c4 n, V9 x& XFive patients were treated with gonadotropin and topical testosterone for micropenis associated
* _  u5 _2 a: Swith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-6 I  `0 X) t- |9 Z) a/ Z2 C6 m) R
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
# p/ k  Z9 S# [* k" V+ dcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent$ w; O, K; G  _  M/ A& \# A. K1 D
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent6 O) H: X" i' p! M1 H3 L9 k2 K  T
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
9 ]9 J4 z6 h2 h& [increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
' {2 p2 `6 n7 a' b8 goccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
+ G6 N* g% r* W. K  Gstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile% G; u& b! G4 G! D
growth. The response appears to be greater in younger children, which is consistent with previ-' S. D4 ~. Y1 _8 |4 T/ g
ously published studies of age-related 5 reductase activity.. x9 e. }' P6 w
Children with microphallus regardless of its etiology will
! V, S6 `2 D4 v% L' D# {require augmentation or consideration for alteration of exter-; Q1 i3 ?, {* Z( v! E/ _* l* W0 `
nal genitalia. In many instances urethroplasty for hypo-
9 _2 I" _& c7 M5 }& x. Sspadias is easier with previous stimulation of phallic growth.
0 H) K$ ]4 E7 k. n: WThe use of testosterone administered parenterally or topically4 G- i  ?/ m; c  X4 C# a
has produced effective phallic growth. 1- 3 The mechanism of) D0 S/ m  N  N9 V5 d) v- \/ ~: a+ X1 |
response has been considered as local or systemic. With this" j- i4 y5 g7 i8 @* j- X4 A
in mind we studied 5 children with microphallus for response
% f9 k3 m" n# uto gonadotropin and to topical testosterone independently.) J" u; `. V  D# Y" g! F4 `
MATERIALS AND METHODS+ [% b- \  f$ h
Five 46 XY male subjects between 3 and 17 years old were* c9 K$ F6 A4 e4 k* u, b8 Z0 l
evaluated for serum testosterone levels and hypothalamic( h; G7 K- R  r! \1 S# y" B. A  T
function. Of these 5 boys 2 were considered to have Kallmann's
& l# I* @" b8 h4 rsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
# H! x3 \$ x3 n7 alamic deficiency. After evaluation of response to luteinizing- y% k! \# g* Q8 j5 z" l
hormone-releasing hormone these patients were treated with
; ]# O! y# ~  G1,000 units of gonadotropin weekly for 3 weeks. Six weeks
! `) m# X  |: u5 qafter completion of gonadotropin therapy 10 per cent topical9 d1 c( E2 i& m+ U9 F
testosterone was applied to the phallus twice daily for 3 weeks.: h* Y+ c8 G* V* M: R( `' E
Serum testosterone, luteinizing hormone and follicle-stimulat-$ G8 S1 f- `: Y/ s4 l8 P8 V4 Y
ing hormone were monitored before, during and after comple-
- p4 \8 N  `" y# Ztion of each phase of therapy. Penile stretch length was6 A( Y$ }6 B/ {( ?, K5 L5 ?
obtained by measuring from the symphysis pubis to the tip of
/ P# D; u# Q+ ^" X1 ythe glans. Penile circumferential (girth) measurements were
; O. y( n, D2 i! _7 Vobtained using an orthopedic digital measuring device (see0 V3 n. S) i5 Z1 h% @
figure).4 A& |0 _8 ?$ L  o! J
RESULTS# ]; [7 w) K  J" Q, I
Serum testosterone increased moderately to levels between
( A1 {* z: q" C  L, l8 o3 O6 H50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-3 R& o' w4 q2 W
terone levels with topical testosterone remained near pre-. b6 U- }. y- T+ \1 D0 _6 R
treatment levels (35 ng./dl.) or were elevated to similar levels
- r3 p: f; \# T" Ideveloped after gonadotropin therapy (96 ng./dl.). Higher( U$ c$ a3 P0 P2 r9 k1 c- J/ I
serum levels were noted in older patients (12 and 17 years old),
' k' T# s9 g2 x0 K; rwhile lower levels persisted in younger patients (4, 8, and 10
/ p9 r3 F8 @7 U+ B. K0 Byears old) (see table). Despite absence of profound alterations: ^5 i& G5 T8 \* a+ P2 Z
of serum testosterone the topical therapy provided a greater# i( [, E' O  \3 {% G
Accepted for publication July 1, 1977. ·: m) @- R7 G; R' X8 f& Y
Read at annual meeting of American Urological Association,
6 h7 h/ P' r4 G; V+ m' U6 jChicago, Illinois, April 24-28, 1977.
3 x5 y. J, G* S$ p# L* Requests for reprints: Division of Urology, Henry Ford Hospital,, I( S" w& t6 y  D
2799 W. Grand Blvd., Detroit, Michigan 48202.
7 w/ N* R, I9 P0 u: J- aimprovement in phallic growth compared to gonadotropin.
# w& J5 }& ^+ S/ X$ }! |Average phallic growth with gonadotropin was 14.3 per cent
2 {$ w; K, j+ S# y# @( ^7 Eincrease in length and 5.0 per cent increase of girth. Topical
% G3 _% X, c3 k+ B3 Q7 ttestosterone produced a 60.0 per cent increase of phallic length( a9 Y  i0 s& m; J1 t( ?
and 52.9 per cent increase of girth (circumference). The$ u1 v# y" E/ g. Z9 e- X3 T
response to topical testosterone was greatest in children be-
" J4 ~- z3 s, l9 ]0 j' I! x. Dtween 4 and 8 years old, with a gradual decrease to age 17. [/ g0 b% P) M8 k- I. f
years (see table).5 e- d3 j) s5 x8 ?: X: z: |$ g- N
DISCUSSION: d- c% T( D# S/ t& Q1 ?% x7 @
Topical testosterone has been used effectively by other8 B% G9 f3 v+ r. a1 T& y: Z1 N
clinicians but its mode of action remains controversial. Im-# W6 y& E$ o2 d$ z2 b
mergut and associates reported an excellent growth response& l3 \) O$ y' Y& H, p2 x
to topical testosterone with low levels of serum testosterone,
6 p" t& k+ u8 y- ]suggesting a local effect.1 Others have obtained growth re-
0 _* b/ W) Q4 K8 g* O- _, ?sponse with high. levels of serum testosterone after topical
. z* c1 j2 U% P# Padministration, suggesting a systemic response. 3 The use of, a4 y2 m: W8 g8 I
gonadotropin to obtain levels of serum testosterone compara-
! d. K2 |* ]7 c8 Wble to levels obtained with topical testosterone would seem to" u# @; N# z$ [) W( O
provide a means to compare the relative effectiveness of2 Z) O% U3 E6 s% Q, f: w
topical testosterone to systemic testosterone effect. It cer-
9 Z1 B" [: ?% A) [, h* F) Itainly has been established that gonadotropin as well as par-
) ~9 u7 U3 U$ benteral testosterone administration will produce genital( B* j! u5 v' L
growth. Our report shows that the growth of the phallus was
; }, n5 i2 `' Z) H. j/ s5 Ssignificantly greater with topical applications than with go-
. ~, r5 G+ {. T% S" wnadotropin, particularly in children less than 10 years old.4 K2 O! ?5 _- n1 I2 ~
The levels of serum testosterone remained similar or lower: K7 h) R3 Z* o$ q4 P
than with gonadotropin during therapy, suggesting that topi-
3 C0 y+ f8 ^# K$ O. b2 f- [) V; Acal application produces genital growth by its local effect as
/ H( Y% ?' j: n" Y4 @well as its systemic effect.
# N0 j4 A# V0 U4 Y$ k& {Review of our patients and their growth response related to
$ _" B5 q5 g$ @$ I7 Xage shows a greater growth response at an earlier age. This is) |& r' A# @+ B% f- u, y/ e! l
consistent with the findings of Wilson and Walker, who
  O* N. {" U) o+ N, wreported an increased conversion of testosterone to dihydrotes-1 n& i+ a% Y% Q+ z7 D# T
tosterone in the foreskin of neonates and infants.4 This activ-5 p3 z  e5 ^# [" C, o! T
ity gradually decreases with age until puberty when it ap-. _- x% f5 A, M$ \3 |
proaches the same level of activity as peripheral skin. It may
8 A! W( Q% \& R) w: x, K. m8 }well be that absorption of testosterone is less when applied at
" T$ `8 P2 r2 y( Man earlier age as suggested by lower serum levels in children
9 N' q+ h# \9 E+ ]  [2 d3 \9 B2 Qless than 10 years old. This fact may be explained by the! @8 F7 g* b* ]) i. \
greater ability of phallic skin to convert testosterone to dihy-
! Z) D+ L2 e' K9 j/ k: q, adrotestosterone at this age. Conversely, serum levels in older5 h. T; ~8 ]9 C# p" j1 Q
patients were higher, possibly because of decreased local
/ x4 v7 v6 y, d  o, U+ F( L667- o+ T, J3 f5 ^6 [$ u; I4 O: e6 u
668 KLUGO AND CERNY6 l$ T2 p' ^" r2 i- Y* l
Pt. Age
: K) s6 S2 C( z& M  E. e4 R) G(yrs.)
6 s( e- K9 h% ]+ m4 pSerum Testosterone Phallus (cm.) Change Length, q& f. f7 \5 }8 x6 G
(ng./dl.) Girth x Length (%), `! X: ^2 j( E7 }" ^5 j& `
4/ L* @; {* t! o; V9 S
8
# g9 Q6 f: d+ b- B) V1 o10
  p; x! \- ]6 g# B8 A. l12
0 G5 F7 h& [. F% e% e, Q17& D+ k$ F5 o* X5 W
Gonadotropin' h' ~, z1 z* h8 ~
71.6 2.0 X 3 16.6
2 o) @5 P- P" f7 ]50.4 4.0 X 5.0 20.0
" e) Z/ x/ I' D# x5 Y22.0 4.5 X 4.0 25.05 M! C& J0 L! {0 j& x9 _$ y
84.6 4.0 X 4.5 11.1. }& q' v! L) |" D" u- P
85.9 4.5 X 5.5 9.0
8 W2 d8 H  z: {- O2 ~Av. 14.3
) B3 v6 G3 `5 x) }9 p41 i& i) P* ^  F
8
/ w" Y( }4 p. ~2 ?. A# j0 r10
0 l  m9 p# `$ J$ N12
% k6 n0 Z$ H0 a9 ]  {/ A) ?17
/ F5 L. ?: F5 ~/ B2 W/ y. y9 z6 sTopical testosterone! J  F. T. v& m+ H0 a" ^
34.6 4.5 X 6.5 85
# R  g: c& K' @38.8 6.0 X 8.5 70
$ n/ o8 j0 z" b# u1 {40.0 6.0 X 6.5 62.5; O" y; g( I; y! O
93.6 6.0 X 7.0 55.5
3 _) F+ b: |6 l9 Y  h. m/ W95.0 6.5 X 7.0 27.21 O% C% {+ V1 g3 v
Av. 60.0; g4 u* K9 f4 C# u' ~9 L6 E
available testosterone. Again, emphasis should be placed on2 u) a* q0 m! k0 s
early therapy when lower levels of testosterone appear to0 i- y. X4 P' l5 k$ o4 ~9 _8 I
provide the best responses. The earlier therapy is instituted
( Q( k; x. r  n, @the more likely there will be an excellent response with low
8 X6 x& H( B3 I$ G% S6 z+ Cserum levels. Response occurs throughout adolescence as
2 L" ?) \2 p! A( Fnoted in nomograms of phallic growth. 7 The actual response4 y1 \, f' a+ J4 S* F7 D
to a given serum level of testosterone is much greater at birth' W3 n. ], o: X* W, B, d$ _# `
and gradually decreases as boys reach puberty. This is most. {2 A1 [  f/ c9 x9 W8 [; D
likely related to the conversion of testosterone to dihydrotes-; }: n3 P  l( F( j5 z3 z
tosterone and correlates well with the studies of testosterone3 d/ G2 t! q3 _6 [- i7 G
conversion in foreskin at various ages., H* Z- G8 @) g8 w
The question arises regarding early treatment as to whether, D5 x6 i0 K8 V7 z; W$ h# p
one might sacrifice ultimate potential growth as with acceler-
. J2 v5 i: K( m9 [ated bone growth. The situation appears quite the reverse
8 g$ W9 W8 S+ ]1 ?7 ewith phallic response. If the early growth period is not used
% T% T. c: @) x9 K# iwhen 5a reductase activity is greatest then potential growth; R# n0 L! p+ E) |# t* g
may be lost. We have not observed any regression of growth
4 W- N; _2 o3 F! C  Q3 Qattained with topical or gonadotropin therapy. It may well8 ~/ m5 b( A5 d3 |- A: y( Y1 o
be that some patients will show little or no response to any
) l% H) N* z, Qform of therapy. This would suggest a defect in the ability to
+ q- |. ^: N3 b9 B; X+ g2 uconvert testosterone to dihydrotestosterone and indicate that
" r& D# B2 e+ I! j# c6 _phallic and peripheral skin, and subcutaneous tissue should
6 \% W( D7 K1 X) o: y2 D2 _be compared for 5a reductase activity.
. O0 ]! X  ^4 EA, loop enlarges to measure penile girth in millimeters. B,! C( Q& o) f( D$ s; `3 q1 {: Y
example of penile girth computed easily and accurately., |( R: n5 R& K" Y1 k. A
conversion of testosterone to dihydrotestosterone. It is in this- u, u" c6 p0 {' `5 {) \
older group that others have noted high levels of serum& v9 S: d6 g6 {( n! _0 X$ `$ n
testosterone with topical application. It would also appear  ^0 S1 c; Q1 ~" O1 n- \" U6 P# K: o
that phallic response during puberty is related directly to the- P7 H, k, p8 Q6 P9 U5 J
serum testosterone level. There also is other evidence of local
; ~# e$ l+ L7 }8 Presponse to testosterone with hair growth and with spermato-) q; O. |# \! b
genesis. 5• 6
. l6 Y' `' X# k2 u0 p& F. {8 DAdministration of larger doses of gonadotropin or systemic
* c) I# }, {6 j/ ^0 p3 L  Qtestosterone, as well as topical applications that produce
. n+ N+ U/ M. [, F5 l) uhigher levels of serum testosterone (150 to 900 ng./dl.), will1 ~" _' P6 J" J# d0 ]
also produce phallic growth but risks accelerated skeletal
- }1 n# V% Z. y  `  jmaturation even after stopping treatment. It would appear
8 [" s, b; v. G! [+ _that this may be avoided by topical applications of testosterone/ O* n5 b9 J+ B' B4 w2 n
and monitoring of serum testosterone. Even with this control- o8 Y8 A) P5 f4 H$ b
the duration of our therapy did not exceed 3 weeks at any
, ?" r3 D& _/ i, O9 Atime. It is apparent that the prepuberal male subject may9 A1 @- r+ H! F
suffer accelerated bone growth with testosterone levels near
  c( E" M5 B+ C200 ng./dl. When skeletal maturation is complete the level of
( L; z3 K$ t+ ?" Zserum testosterone can be maintained in the 700 to 1,300 ng./
+ ^( \! W+ b* e* [9 O& Fdl. range to stimulate phallic growth and secondary sexual8 S) P, L. K- d/ d6 u
changes. Therefore, after skeletal maturation parenteral tes-
: c3 K* Q$ u7 Y! qtosterone may be used to advantage. Before skeletal matura-
8 |# r/ |& c; }4 Ytion care must be taken to avoid maintaining levels of serum
* Q/ D$ s5 n6 N# R5 e. m( ktestosterone more than 100 ng./dl. Low-dose gonadotropin7 m( W- n1 X) z
depends upon intrinsic testicular activity and may require
/ k, l) m# W: F2 J1 T7 Q% j9 aprolonged administration for any response.: b2 {9 b: f4 [$ ~0 g
Alternately, topical testosterone does not depend upon tes-8 a6 Z' d# K, g2 Z
ticular function and may provide a more constant level of
; K2 i* y+ D" j# gREFERENCES
& d; Z. S% |+ J5 ?. q& n; p. C1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,/ m( b3 t0 {& D* _6 {
R.: The local application of testosterone cream to the prepub-
; m+ K# z7 X& @: n: O* q# V# {" A9 {% ?ertal phallus. J. Urol., 105: 905, 1971.
' m) m$ X5 X( h* j. n2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
6 V: _5 Z9 H' U' gtreatment for micropenis during early childhood. J. Pediat.,
+ D$ Y/ a; A0 y+ K- W4 B3 ^83: 247, 1973.
$ }/ S7 n$ F; j" C5 l+ c) F) [3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
6 S% l3 j* S; Sone therapy for penile growth. Urology, 6: 708, 1975.
* @) w$ D& [' _. ?# [( m1 b* y4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
& x2 [0 `4 Y% H1 g1 vto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by3 k* l/ p$ q& ?8 _
skin slices of man. J. Clin. Invest., 48: 371, 1969.
* |' n, n- e7 }5 d9 X5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth% c) M; N* A* E. f" K, N, }
by topical application of androgens. J.A.M.A., 191: 521, 1965.
' o* E1 \8 I$ z2 @$ e" j! ~6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local6 d; V1 u: A+ z- t- `' q+ R( B
androgenic effect of interstitial cell tumor of the testis. J.' N, R- }9 A" q
Urol., 104: 774, 1970.
" s) P2 t* |( J( f1 @7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-" Y( ?5 v0 j$ n) i4 G
tion in the male genitalia from birth to maturity. J. Urol., 48:
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