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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
- b: j1 c1 }6 N2 h, vGONADOTROPIN
  ]+ o/ e$ ?9 M8 v# P$ ARICHARD C. KLUGO* AND JOSEPH C. CERNY3 ^1 K4 P/ X3 I# u2 [* W
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
9 B+ A% V/ E* Z# ~ABSTRACT
$ U- C/ C1 O) D  B' w. _1 T( HFive patients were treated with gonadotropin and topical testosterone for micropenis associated
& Y! |, k3 W- v2 ?- `, N2 Owith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
- {5 M& H$ R# p/ Mtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
. b% D1 r- I0 V  l* U0 u8 H- ?+ ?cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent) x6 E) h2 _5 n
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
8 {! b0 R0 w8 p2 q" f" D! r) ]increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average* B8 I$ w+ I; l1 K# Q% ?# [" P
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
$ u4 W, g$ t# |( @) B& {( eoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This  _' s1 `; i% m$ E( E4 _8 A. J
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile6 g  t/ F8 |/ ?! Y- ]; p1 ]. F
growth. The response appears to be greater in younger children, which is consistent with previ-
9 ?* @- D# \  h7 e- }ously published studies of age-related 5 reductase activity.2 L" x( \. v/ Y
Children with microphallus regardless of its etiology will
6 S0 L) ]; v+ f) H0 ~7 Erequire augmentation or consideration for alteration of exter-1 }0 Q( f9 \2 x- c- ~
nal genitalia. In many instances urethroplasty for hypo-
. e+ ^( r7 c8 P( g! n, Z  W! |spadias is easier with previous stimulation of phallic growth.( A& v3 F" k# a* H- Y
The use of testosterone administered parenterally or topically) o8 B$ V4 [9 a6 ^3 e" ?9 f% r
has produced effective phallic growth. 1- 3 The mechanism of5 C* r6 d. E& u/ F% l
response has been considered as local or systemic. With this
9 D# z$ R! c* }$ K3 Z! Zin mind we studied 5 children with microphallus for response  z, L, e7 H# K. y
to gonadotropin and to topical testosterone independently.
( @9 X! `/ X0 L% j8 jMATERIALS AND METHODS
# e) {) a5 P1 V4 rFive 46 XY male subjects between 3 and 17 years old were
2 D3 D! Z) q# m! H4 d+ n5 x" x! Gevaluated for serum testosterone levels and hypothalamic8 s+ x4 ^" h: E& h! p9 U+ ?
function. Of these 5 boys 2 were considered to have Kallmann's/ M7 J& f: {& e: r6 u, l0 C5 [
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
+ h; L6 T( ^# y& @lamic deficiency. After evaluation of response to luteinizing9 k7 J& I8 {' y* }; I( S2 h
hormone-releasing hormone these patients were treated with
  f6 c/ Y( y9 n) R8 T, M1,000 units of gonadotropin weekly for 3 weeks. Six weeks3 c* \5 d+ L3 ^$ Y! r
after completion of gonadotropin therapy 10 per cent topical
* x9 S3 V8 G: W; |- v! {% jtestosterone was applied to the phallus twice daily for 3 weeks.
( R2 n- h, n  T. v0 \Serum testosterone, luteinizing hormone and follicle-stimulat-2 i/ w$ n! ?3 E" G. A3 ~
ing hormone were monitored before, during and after comple-
: q) \  {+ u/ x6 y4 R& c3 htion of each phase of therapy. Penile stretch length was4 @3 ?! @- O& k! i0 G3 e
obtained by measuring from the symphysis pubis to the tip of) Z" w( H2 W" l/ P/ M3 ?
the glans. Penile circumferential (girth) measurements were, N3 M9 E3 f- ~
obtained using an orthopedic digital measuring device (see4 w) F3 r- L  u2 {( T
figure).
3 W& c0 f% M) F' G* w6 qRESULTS) n3 M( @/ Y$ c% |
Serum testosterone increased moderately to levels between/ w+ Q4 J# c7 h& B& t+ ]
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
2 t/ q/ O7 ~4 x5 ^! Xterone levels with topical testosterone remained near pre-" H2 F0 _* I4 u. ^' ~( r, L# e
treatment levels (35 ng./dl.) or were elevated to similar levels
! m/ t+ L7 j0 E0 @4 ^2 Zdeveloped after gonadotropin therapy (96 ng./dl.). Higher
; [) }: Z$ A3 s$ D  ^serum levels were noted in older patients (12 and 17 years old),
; q; O) ^8 B* J, o: F5 }while lower levels persisted in younger patients (4, 8, and 10
5 n4 z+ _) K' s+ M% }: wyears old) (see table). Despite absence of profound alterations3 q. T  a) m, n* A
of serum testosterone the topical therapy provided a greater: t) N; @1 F( M# U
Accepted for publication July 1, 1977. ·7 O( s# z0 ?7 Z9 e/ g
Read at annual meeting of American Urological Association,
% ]3 G; z6 l# k0 s# UChicago, Illinois, April 24-28, 1977.4 L* ?2 ~; D0 C! Q. k
* Requests for reprints: Division of Urology, Henry Ford Hospital,  _* F+ [  y4 a
2799 W. Grand Blvd., Detroit, Michigan 48202.
3 w3 k. g% H/ L+ @$ R  eimprovement in phallic growth compared to gonadotropin.
8 [5 F- U- i+ H$ VAverage phallic growth with gonadotropin was 14.3 per cent
4 _! \7 s: _7 C/ l! c; k) |increase in length and 5.0 per cent increase of girth. Topical
- H7 |3 e. \9 Q* W4 C3 [6 Vtestosterone produced a 60.0 per cent increase of phallic length
, S3 f/ S* Z0 f) S4 Mand 52.9 per cent increase of girth (circumference). The  @! U) W) s: U' X
response to topical testosterone was greatest in children be-. k2 j* v" M9 u  }% j3 V7 R% r
tween 4 and 8 years old, with a gradual decrease to age 177 [0 d3 F" D) T# C# j7 n0 C% Z
years (see table).
, o! v/ u  ?+ q0 c6 Q5 |DISCUSSION4 Y1 M/ c) T$ s* u0 K3 C7 x
Topical testosterone has been used effectively by other& Z3 ~: K% I- x% ]! y
clinicians but its mode of action remains controversial. Im-8 w6 a! |1 T) C! l/ Y2 |5 y9 t
mergut and associates reported an excellent growth response0 [* S8 Y( }! ^
to topical testosterone with low levels of serum testosterone,( w7 X* ?7 v& X9 }
suggesting a local effect.1 Others have obtained growth re-. ?; R7 G. c5 ?
sponse with high. levels of serum testosterone after topical6 b) w* e/ b8 @+ @* G" A2 }! R
administration, suggesting a systemic response. 3 The use of
. w$ a0 u  d) T( jgonadotropin to obtain levels of serum testosterone compara-$ B5 s6 N- D- _$ J1 }- d' z2 A
ble to levels obtained with topical testosterone would seem to
# O, ~( T2 p. k. fprovide a means to compare the relative effectiveness of( `& H9 Q8 r! e( G
topical testosterone to systemic testosterone effect. It cer-
( k$ N" _' v% X0 m" gtainly has been established that gonadotropin as well as par-; n) Q$ j# _) ~/ z& m0 I  ~' f
enteral testosterone administration will produce genital
% X$ g# I& S) x9 S1 Kgrowth. Our report shows that the growth of the phallus was, ^8 H# k5 G# b. v4 Q" F1 Q7 i
significantly greater with topical applications than with go-
4 N: u# X) s6 f/ i5 \' G; _$ snadotropin, particularly in children less than 10 years old.% s7 H" x+ W# c6 @7 i! h/ K
The levels of serum testosterone remained similar or lower
5 b7 S. b# G, e0 q. m' Xthan with gonadotropin during therapy, suggesting that topi-. C/ P. g8 G" f& B- k4 K- t
cal application produces genital growth by its local effect as. L) B1 J! P% _) C6 p
well as its systemic effect.) z  I' |2 V& B- d$ b
Review of our patients and their growth response related to2 B5 Q( L+ P3 z" z, H5 H- ?3 ^$ [
age shows a greater growth response at an earlier age. This is
' c. y1 r. m+ X: o# k# Sconsistent with the findings of Wilson and Walker, who
) F9 L8 X; Z2 ^5 Yreported an increased conversion of testosterone to dihydrotes-. W% {) v/ Z! n( G; C0 t% C2 Y
tosterone in the foreskin of neonates and infants.4 This activ-( B) ]" ]4 D/ d" R
ity gradually decreases with age until puberty when it ap-4 k; Y5 r6 ]" ^) R4 h
proaches the same level of activity as peripheral skin. It may, I' t" S, S  T3 K% [
well be that absorption of testosterone is less when applied at. F' ]: u+ ?0 R4 `3 N2 U
an earlier age as suggested by lower serum levels in children
: z2 l7 t; n- s- I5 W2 s8 Nless than 10 years old. This fact may be explained by the
4 o4 }- V$ `3 a, ~# {$ A, Jgreater ability of phallic skin to convert testosterone to dihy-
' [9 E  \0 u" J- V2 V9 E6 fdrotestosterone at this age. Conversely, serum levels in older
" B( I1 c+ X, R" `% y5 J8 Z# \patients were higher, possibly because of decreased local
/ q2 s7 W- M# @667
5 O: ]5 p! D7 v3 V% ^9 C! V668 KLUGO AND CERNY) Q' |# M! |7 n5 N, @1 u" t6 c
Pt. Age
+ M% H, R0 e* R* \6 U2 e3 F(yrs.)/ @+ y9 M% r' C% m4 z4 ]
Serum Testosterone Phallus (cm.) Change Length$ C+ M5 G: Y. p& n+ t% d! C
(ng./dl.) Girth x Length (%)" J! _% ~  [' E2 p# f* P
48 ^, i' ]) L4 U5 a& J. T
8$ ]( s7 K$ z, I9 G5 G% h2 E2 s
107 u9 |- w4 b  r/ D0 {
12/ R. M; W5 h. I+ N( r
17
. s4 q4 n6 B6 {' s/ O# GGonadotropin& e' Y, A9 y4 [, Q5 p5 \' l
71.6 2.0 X 3 16.6
- ^8 v4 l' q! M2 _2 N50.4 4.0 X 5.0 20.0
7 z! o" u  O7 l# l' p22.0 4.5 X 4.0 25.00 h+ c  n, N6 @) H
84.6 4.0 X 4.5 11.1
( v/ e$ C& P$ e5 T6 w9 S1 h" U% e85.9 4.5 X 5.5 9.0
. ]5 T' f. Z: h- OAv. 14.3
2 y( v8 p  R8 X+ e0 G: ^& k4
" a9 A. j; w6 e0 r* _; s2 A7 W8
4 h; O/ j4 x/ b) c" x: w# G10) j- \" }) Y( i  a7 Y7 A! E' h6 ?
12
- s9 |2 C; D0 D. B* F17
/ N4 Y+ q! q/ Z' O- [Topical testosterone! s4 T' d* t: x3 J* Z. V4 I
34.6 4.5 X 6.5 85
* \. Z: q$ j9 V9 L+ N" g* U38.8 6.0 X 8.5 70; Z- I3 s; e4 f, x! a* R
40.0 6.0 X 6.5 62.5
: c# ~( Q& n0 r! W3 P% T- g93.6 6.0 X 7.0 55.5
, a: R/ F& m& [3 j. S' h95.0 6.5 X 7.0 27.2
0 m# ~  V, P/ X: |9 kAv. 60.0! J7 `0 c' S" {  w- i
available testosterone. Again, emphasis should be placed on
( [7 t3 E% M( ]% Gearly therapy when lower levels of testosterone appear to6 x' E2 l+ `# d4 f* N' M
provide the best responses. The earlier therapy is instituted+ K2 }0 v4 Y2 u9 D) W4 D
the more likely there will be an excellent response with low. V7 x8 t6 y3 l1 z2 y: ?
serum levels. Response occurs throughout adolescence as
# N3 M, \, p' l  Snoted in nomograms of phallic growth. 7 The actual response
2 V. l& }+ n8 ~  E( w) oto a given serum level of testosterone is much greater at birth" r9 x2 V, M% w
and gradually decreases as boys reach puberty. This is most
2 R8 g$ R' [( a, k" |! c4 k9 [0 \likely related to the conversion of testosterone to dihydrotes-, b" a, r" k: B" p0 K6 {4 W
tosterone and correlates well with the studies of testosterone
( k* ^/ S6 A/ E8 V& tconversion in foreskin at various ages.
3 u! ~9 U3 e' r" }# PThe question arises regarding early treatment as to whether
% E; I- d2 D. M/ z+ None might sacrifice ultimate potential growth as with acceler-
; _8 D, M0 [. P" j# \& v# Z7 l, s. }1 bated bone growth. The situation appears quite the reverse
$ M0 V" w% d0 e$ ywith phallic response. If the early growth period is not used( |( X. p# r6 g# p5 m
when 5a reductase activity is greatest then potential growth
. P1 i& e+ s6 b6 q5 \may be lost. We have not observed any regression of growth. P& i2 m8 K6 X( h
attained with topical or gonadotropin therapy. It may well
1 l, I3 n- G) i# ~be that some patients will show little or no response to any! D; w3 b7 A; U" J
form of therapy. This would suggest a defect in the ability to6 Z! N! a/ _* v: z2 |) b5 a* Z
convert testosterone to dihydrotestosterone and indicate that
3 C& I8 \4 f; ^3 a7 ]: S: ?; q1 q" Ephallic and peripheral skin, and subcutaneous tissue should# }( ^6 ^  G9 F  l
be compared for 5a reductase activity.
3 b& B& w! c  `% Q  UA, loop enlarges to measure penile girth in millimeters. B,# l5 F: C& o' m
example of penile girth computed easily and accurately.) C" L1 k: u2 b9 d* V$ @3 q% Q. l
conversion of testosterone to dihydrotestosterone. It is in this
) ^" _+ A# {. r/ |7 U: |& `' J: @older group that others have noted high levels of serum
# i3 y8 f2 c! S0 xtestosterone with topical application. It would also appear
2 Q3 V, m0 S$ Zthat phallic response during puberty is related directly to the
* x3 B2 W$ f# c. x: wserum testosterone level. There also is other evidence of local( w( v  ?6 W0 O1 M' e
response to testosterone with hair growth and with spermato-" W: Q! [+ K/ P2 e. J2 G8 m
genesis. 5• 63 p" Q2 ]7 v$ `8 m7 U
Administration of larger doses of gonadotropin or systemic
" e5 s! l# k8 etestosterone, as well as topical applications that produce" m* `  C# r: Q4 _% e' Z" Y
higher levels of serum testosterone (150 to 900 ng./dl.), will1 Y2 K0 y4 f, h* r
also produce phallic growth but risks accelerated skeletal; N+ u$ b0 F* w4 e$ X0 x
maturation even after stopping treatment. It would appear
% D$ m( J+ V( y; V5 @* mthat this may be avoided by topical applications of testosterone$ H; W( h0 Q/ v
and monitoring of serum testosterone. Even with this control" \4 R7 U1 A9 Z, y+ s
the duration of our therapy did not exceed 3 weeks at any2 t9 s6 Z* i2 L8 n# j* M
time. It is apparent that the prepuberal male subject may) w" d% Q$ K: s7 K( y: h7 _
suffer accelerated bone growth with testosterone levels near0 ~* D3 ^7 k1 Z
200 ng./dl. When skeletal maturation is complete the level of% w. n8 N& r5 Q! Z1 P6 d
serum testosterone can be maintained in the 700 to 1,300 ng./
8 A5 }8 d# m( A3 k# g0 |1 Qdl. range to stimulate phallic growth and secondary sexual7 \8 Y5 `# F2 V* y2 f$ h
changes. Therefore, after skeletal maturation parenteral tes-
/ J5 p0 M" Y) R0 \9 a8 Gtosterone may be used to advantage. Before skeletal matura-
4 X' [, K( y5 j: {3 n5 M# P* a( Vtion care must be taken to avoid maintaining levels of serum# i/ I/ H# X& p9 j9 k. L
testosterone more than 100 ng./dl. Low-dose gonadotropin
; G# r! D0 i0 y9 _4 m  [depends upon intrinsic testicular activity and may require
. u. I' z( v  u. A1 S$ z/ L" Lprolonged administration for any response.) E$ S! ~7 y! W# {" [
Alternately, topical testosterone does not depend upon tes-0 I: w; p, J9 h
ticular function and may provide a more constant level of
+ t- C# }0 r0 o+ bREFERENCES9 D7 r% C7 ^8 m0 g  L7 h7 Z
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,- H( q* A/ o( }+ i
R.: The local application of testosterone cream to the prepub-
/ M3 u5 R3 B+ Lertal phallus. J. Urol., 105: 905, 1971.
/ m5 ?) k. K: T( z; T2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone- g6 r7 M7 }, x5 ^% ~8 G* C( h
treatment for micropenis during early childhood. J. Pediat.,6 j  y7 N' O, S5 F6 f
83: 247, 1973.4 h! X5 ?0 \" r; W% i8 _
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-  q# y- z. A4 D- \
one therapy for penile growth. Urology, 6: 708, 1975.
) Y9 Y( U7 C- ?! X5 c9 |4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone# J* B, j4 K3 q6 q
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by) H( A0 i) i. x) ^2 s% Y0 Y
skin slices of man. J. Clin. Invest., 48: 371, 1969.
: m8 e8 D" V, m+ b9 n5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth' u8 q; a7 s5 g3 H6 p6 H
by topical application of androgens. J.A.M.A., 191: 521, 1965.
: ]& H+ C$ x, L& \5 V6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local- ~7 e) A2 U3 l  _( o7 f
androgenic effect of interstitial cell tumor of the testis. J., S( Y- |$ P% i
Urol., 104: 774, 1970.4 b' G& v* p- b9 T* D1 m
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
$ M$ U4 c4 F; h$ ^' E- e; Htion in the male genitalia from birth to maturity. J. Urol., 48:
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