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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND" V% K: k% X/ l3 Y, x% m
GONADOTROPIN1 @$ ^* z8 Q7 c9 w8 J
RICHARD C. KLUGO* AND JOSEPH C. CERNY. |  v3 ]5 @0 E; V( }1 o; Z
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan' {) @6 f- R, x$ ?; m
ABSTRACT
$ i; t) O+ ^- H6 O# p4 dFive patients were treated with gonadotropin and topical testosterone for micropenis associated
8 T- T& U8 w, `9 H" V! Rwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
' m# K# C- I( N& p0 O3 q, [tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
2 P  U) `" h. M) hcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
+ ^. `- Y7 d" `6 r( nfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
& \& i  ^6 ^1 Y0 rincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
9 B5 z  V4 Q2 m  ?& B8 \5 Aincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response: \) l6 e! N$ L
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This* p  d6 s( ^) c2 `( d- i. T
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile; \" S4 n3 n/ h# \/ ~& n8 J
growth. The response appears to be greater in younger children, which is consistent with previ-- Z# A8 C0 j# C0 W7 Q, j
ously published studies of age-related 5 reductase activity.
8 V5 x7 `. T; ~1 w& P7 W* u1 s; xChildren with microphallus regardless of its etiology will
+ G: Q. h# b; j" vrequire augmentation or consideration for alteration of exter-
9 Z2 g/ J2 S. O! o/ gnal genitalia. In many instances urethroplasty for hypo-
! A, E: f# z# h% gspadias is easier with previous stimulation of phallic growth.
5 H/ G) v" [* Q, `  N# g- J/ w. q! {The use of testosterone administered parenterally or topically
% H; l$ k4 M- l7 ~5 Lhas produced effective phallic growth. 1- 3 The mechanism of2 K0 D$ E  N0 v2 A
response has been considered as local or systemic. With this8 u& ], ^1 m* B% s3 Z' r
in mind we studied 5 children with microphallus for response
% t, Y: K( T4 |5 C9 }$ yto gonadotropin and to topical testosterone independently.1 Z! V8 a4 z" ^
MATERIALS AND METHODS
1 O2 N. ^6 q. Y( O) k  hFive 46 XY male subjects between 3 and 17 years old were
* t* |1 o5 @( Q+ t! f0 Z8 Xevaluated for serum testosterone levels and hypothalamic) S3 R, n' b! E1 g2 F0 _
function. Of these 5 boys 2 were considered to have Kallmann's1 I  E; c# l3 w) M
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
4 y! M# P6 x8 _0 p% klamic deficiency. After evaluation of response to luteinizing: W% v0 K; m* l8 V
hormone-releasing hormone these patients were treated with4 L2 L+ S! ?6 I; S& F" c; {
1,000 units of gonadotropin weekly for 3 weeks. Six weeks/ r& S8 L9 e6 t
after completion of gonadotropin therapy 10 per cent topical" K( W5 V7 t* w4 m
testosterone was applied to the phallus twice daily for 3 weeks.5 I! j) ^6 i3 y+ T' y8 q9 @
Serum testosterone, luteinizing hormone and follicle-stimulat-
! A2 Q) i: T- xing hormone were monitored before, during and after comple-
2 s$ C7 J1 Y. K$ I, e& u+ i2 C( Z8 I1 Jtion of each phase of therapy. Penile stretch length was3 x  ?; K8 N. Q$ F5 C: O% B
obtained by measuring from the symphysis pubis to the tip of
2 Z. |6 J- I  y7 ~- ~, u# ?2 f# S6 Dthe glans. Penile circumferential (girth) measurements were8 N. I1 M' Z* u( n7 w$ O; `
obtained using an orthopedic digital measuring device (see
3 H% ?: P1 t9 o; efigure).
* g$ ^: R2 f6 ~+ w9 `+ HRESULTS+ M8 b/ a" Y$ |- a, R3 _' Q
Serum testosterone increased moderately to levels between
! N8 g" q5 w8 S50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
$ J! J' n9 c' t# i; h8 |terone levels with topical testosterone remained near pre-3 x! I" q! ?& Y/ c, i' X
treatment levels (35 ng./dl.) or were elevated to similar levels3 g: I; h& m* G8 K
developed after gonadotropin therapy (96 ng./dl.). Higher
) l) L. X9 o7 w: A& d1 n/ o9 Gserum levels were noted in older patients (12 and 17 years old),( n9 ?8 w2 {7 G: e7 `
while lower levels persisted in younger patients (4, 8, and 10
) Q7 `6 a* e- I$ f) P  lyears old) (see table). Despite absence of profound alterations3 s" y8 E/ d$ [7 A! t
of serum testosterone the topical therapy provided a greater1 q  o9 z7 q" I) g3 q  r5 s" I) l# X
Accepted for publication July 1, 1977. ·$ |0 a$ t. i; I0 P: U" F
Read at annual meeting of American Urological Association,
  J5 C) G3 n3 [: i9 C; T1 {Chicago, Illinois, April 24-28, 1977.- h( t4 X! U3 W. q( d# J
* Requests for reprints: Division of Urology, Henry Ford Hospital,
" w& b) C2 o# I! O/ G2799 W. Grand Blvd., Detroit, Michigan 48202.% |% `8 d1 m" F- _
improvement in phallic growth compared to gonadotropin.
9 Y2 e  [+ r9 W, QAverage phallic growth with gonadotropin was 14.3 per cent8 g* m6 D3 U2 m9 c
increase in length and 5.0 per cent increase of girth. Topical
, R8 X. P, A5 `5 E8 L& Z# [8 etestosterone produced a 60.0 per cent increase of phallic length' T. y" U$ @" E2 O1 s
and 52.9 per cent increase of girth (circumference). The' [5 C# T- M* [9 Q' w# d7 x+ w
response to topical testosterone was greatest in children be-2 f& t. O  h2 x, B0 j, d9 N
tween 4 and 8 years old, with a gradual decrease to age 172 ?0 Z7 p. k6 B2 K
years (see table).
" I' j/ p! }* ^9 X0 _9 I' _DISCUSSION9 {+ n' V+ _) x
Topical testosterone has been used effectively by other0 ?4 }# K. q  d/ J' X+ I( m
clinicians but its mode of action remains controversial. Im-  c2 @# ~! q* C, L
mergut and associates reported an excellent growth response3 O, |& y  j5 M2 y, J
to topical testosterone with low levels of serum testosterone,! J3 z. |4 F  {0 y: l
suggesting a local effect.1 Others have obtained growth re-
# J. s, a0 m  O4 F# v6 t1 ksponse with high. levels of serum testosterone after topical) ~) j0 a+ {3 b3 O8 L! {3 c6 S
administration, suggesting a systemic response. 3 The use of; ^$ M- w6 c5 D3 T) e5 U% H
gonadotropin to obtain levels of serum testosterone compara-, J: Z0 e) Q! }& r
ble to levels obtained with topical testosterone would seem to
4 i# |/ k' f2 P0 [provide a means to compare the relative effectiveness of
" x: j, K) |' \% G% Btopical testosterone to systemic testosterone effect. It cer-
( K9 r7 }3 j. W8 f; ktainly has been established that gonadotropin as well as par-
6 ]0 O( w7 B; x5 o) M) ^: t* ]enteral testosterone administration will produce genital
7 A6 Q6 Y# p4 c2 y8 e  Xgrowth. Our report shows that the growth of the phallus was. k; |( V$ C* k
significantly greater with topical applications than with go-0 |4 Z! D4 f( l8 {
nadotropin, particularly in children less than 10 years old.! K8 @& D3 C0 q  f1 V9 `
The levels of serum testosterone remained similar or lower
2 X" e$ h7 U" a% W" Vthan with gonadotropin during therapy, suggesting that topi-
, U& C* t& N" n+ ~0 r2 j6 x1 Ycal application produces genital growth by its local effect as
( B2 \) c4 P) D- W/ Awell as its systemic effect.
# m8 d) \4 T* Q4 d% z! RReview of our patients and their growth response related to$ k3 Z" \1 I( d% M
age shows a greater growth response at an earlier age. This is
# C2 w8 V- S, G/ _/ Nconsistent with the findings of Wilson and Walker, who
% N7 F* b( F/ Y( Q# `, lreported an increased conversion of testosterone to dihydrotes-
3 I7 {/ W2 ^* ^tosterone in the foreskin of neonates and infants.4 This activ-
9 L  P7 n4 c) h# D# W- Hity gradually decreases with age until puberty when it ap-
& X. ^0 P+ X8 Q1 @3 qproaches the same level of activity as peripheral skin. It may
. \( v* S# D+ xwell be that absorption of testosterone is less when applied at; _  c7 u6 S/ j/ w2 `
an earlier age as suggested by lower serum levels in children
( X0 U7 [: x4 Vless than 10 years old. This fact may be explained by the2 G! @; I" t1 F. e9 X* x
greater ability of phallic skin to convert testosterone to dihy-* U5 x% i: g+ l: r: W' U# J
drotestosterone at this age. Conversely, serum levels in older
7 G: e; q( h6 E9 o. ]1 ypatients were higher, possibly because of decreased local% Z2 H8 P: ?! z) d+ |- s
667% X, u5 O3 [) ]$ m' [% b
668 KLUGO AND CERNY) t8 }* I# x6 G
Pt. Age! q6 j+ O( ~( J/ v5 K! g
(yrs.)! w6 C7 j4 F. ~. X7 v+ `
Serum Testosterone Phallus (cm.) Change Length
7 c1 \1 }# ~0 O& a7 d(ng./dl.) Girth x Length (%)
# Q: U) G1 i$ l! Z4
( f9 e" }! L1 ~8' q, S  @9 f( e; ~6 ?' ^9 v! ~
10" e- l. W. j: _$ O8 C, y
12
' M. Z8 u; p8 J9 ?+ K+ v1 K173 i' r. a3 c0 X: {$ `5 j" k- Q4 ~
Gonadotropin( H9 j+ ?! B7 m
71.6 2.0 X 3 16.6
9 c7 Q: L( P* J50.4 4.0 X 5.0 20.00 H1 x7 D' ~9 N! L: m
22.0 4.5 X 4.0 25.0
5 H% g' L1 f; F84.6 4.0 X 4.5 11.1  E' i" ?& j% `- r6 k
85.9 4.5 X 5.5 9.0
+ L. J% M  C% v) K' KAv. 14.3/ A4 y4 h0 R2 ~, I
4
0 w; T# R  h& ~* x8& k/ e9 W5 y, R) S
10
2 F7 a; p/ q; w# [5 x3 M124 m$ K1 Z# a* J8 i7 u: q
17
" h. X( Z0 t% \2 j7 E: o% [Topical testosterone
0 O# Y: Z3 ^  H3 \34.6 4.5 X 6.5 85
1 J  I0 ]$ D; ?: ~( w# c9 [38.8 6.0 X 8.5 70
" C1 A) M/ e* K, r, T40.0 6.0 X 6.5 62.52 g. t) ~6 H9 {# I
93.6 6.0 X 7.0 55.55 g; G0 |* A+ V7 D+ Z
95.0 6.5 X 7.0 27.2  u/ f5 Z5 N, N* u
Av. 60.0( w& ?7 \" y8 t) y/ N3 }# S9 v
available testosterone. Again, emphasis should be placed on6 M( c5 I6 \& G$ ^
early therapy when lower levels of testosterone appear to' D5 Y& E( Z& K  p/ l- s
provide the best responses. The earlier therapy is instituted' s: X) l2 v, ~6 B0 |
the more likely there will be an excellent response with low
2 y1 v) m/ J4 n, mserum levels. Response occurs throughout adolescence as
/ x( K$ x9 Y" x* _4 K. E$ i# qnoted in nomograms of phallic growth. 7 The actual response
( w1 J4 p6 m6 M/ @  S, dto a given serum level of testosterone is much greater at birth4 s1 C% B4 ^/ U7 d- a
and gradually decreases as boys reach puberty. This is most! ]" H: j. k! U$ d+ s+ i# N- ~* f$ k
likely related to the conversion of testosterone to dihydrotes-
; c9 _( b+ {: L1 N8 }8 F! Ptosterone and correlates well with the studies of testosterone
. b7 h* `) Q7 W, b7 G* K+ Iconversion in foreskin at various ages.
; z3 q) p! D# b. s. T5 A* g0 X+ D5 f; H4 CThe question arises regarding early treatment as to whether1 [' n; s9 G2 ~9 j/ q
one might sacrifice ultimate potential growth as with acceler-# L2 E4 q% m+ n! |- y/ I* |) x
ated bone growth. The situation appears quite the reverse
0 a8 D4 t0 B- f8 L% Bwith phallic response. If the early growth period is not used
! o) c- H6 ?0 `' {when 5a reductase activity is greatest then potential growth
5 X( h4 G0 C: ]) q' L* umay be lost. We have not observed any regression of growth
2 H9 O( I" t9 O1 c/ ?0 v' {attained with topical or gonadotropin therapy. It may well4 P' A6 R0 V$ e" ~* g7 t
be that some patients will show little or no response to any8 v0 p% n0 g$ I  w: ]! L3 }) e
form of therapy. This would suggest a defect in the ability to
+ }6 i; G9 d$ Z: l* T3 P4 gconvert testosterone to dihydrotestosterone and indicate that0 ?1 W0 Z, X( H  N
phallic and peripheral skin, and subcutaneous tissue should
9 @  h8 x9 F1 g  i7 e" ]( \+ zbe compared for 5a reductase activity.2 l# z0 N6 L. f. i, r8 K4 K
A, loop enlarges to measure penile girth in millimeters. B," s4 w# x* s# M/ E/ s4 ^
example of penile girth computed easily and accurately.
1 F4 J* c  q. M& I: U: @! |" w7 `conversion of testosterone to dihydrotestosterone. It is in this
" N2 U  R$ X$ g/ u# [+ }/ Jolder group that others have noted high levels of serum
/ [3 F# d" K/ E9 S- otestosterone with topical application. It would also appear! |- r! h* l, r
that phallic response during puberty is related directly to the
* E$ n  O# L6 m# C+ Nserum testosterone level. There also is other evidence of local
0 g2 I3 a, x. v+ lresponse to testosterone with hair growth and with spermato-! @$ h# `0 N; N1 X/ _) x0 v7 D% b( e
genesis. 5• 6& m% b/ z* g% ]9 d  G" W
Administration of larger doses of gonadotropin or systemic
: g: S' v3 c* N0 ~$ o& l$ utestosterone, as well as topical applications that produce
2 X/ [. x$ u7 Q& o3 x! h+ ~higher levels of serum testosterone (150 to 900 ng./dl.), will
9 _6 @0 C2 g' _3 O! nalso produce phallic growth but risks accelerated skeletal8 K- W4 p! P  C/ O" E
maturation even after stopping treatment. It would appear
5 ^# K# Q- |2 B- ?  {: Othat this may be avoided by topical applications of testosterone
7 w# @) p3 S$ g- _; oand monitoring of serum testosterone. Even with this control( S2 t4 C7 i7 d
the duration of our therapy did not exceed 3 weeks at any
, @$ ^5 R; P) Q) Z8 e! R. ytime. It is apparent that the prepuberal male subject may3 ~( r3 d0 y1 g' L( ~6 J. T) i
suffer accelerated bone growth with testosterone levels near
/ O8 ]1 @2 V* d# n0 z8 S! v8 X200 ng./dl. When skeletal maturation is complete the level of
$ o1 @2 z# M& m& n  y% S$ Bserum testosterone can be maintained in the 700 to 1,300 ng./; ?  i2 d4 Y9 |7 @" f
dl. range to stimulate phallic growth and secondary sexual
2 X% `! M5 T( V/ jchanges. Therefore, after skeletal maturation parenteral tes-
9 w4 [6 _) w$ Q/ a/ d8 p8 mtosterone may be used to advantage. Before skeletal matura-3 w$ ]7 K& s4 h1 j0 C
tion care must be taken to avoid maintaining levels of serum
5 S7 x/ z3 A4 ]/ D9 |! u; F3 mtestosterone more than 100 ng./dl. Low-dose gonadotropin
; w( f' v1 s9 o8 O; w' k. s* Z( jdepends upon intrinsic testicular activity and may require
0 y. @% [  H* C$ K( Zprolonged administration for any response.& ~$ u; e  M5 y, V5 k( S
Alternately, topical testosterone does not depend upon tes-
$ A3 e% W( m8 E2 O) nticular function and may provide a more constant level of
3 |9 }4 Z" w& j1 ]% ~: `( p' ^REFERENCES  ?" C2 y( j  O, j
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
) {! R7 Y$ z1 a/ v6 AR.: The local application of testosterone cream to the prepub-
" A: ^! U% g6 gertal phallus. J. Urol., 105: 905, 1971.: K5 V7 e) _: B$ @& u! U
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
, S& O; @  t( M. d: F" g3 Vtreatment for micropenis during early childhood. J. Pediat.,% }. R' Y. i! ]5 t: h; z
83: 247, 1973.
6 a) ?2 p2 @$ s3 O" a3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-1 L: S/ Q6 |+ e- z
one therapy for penile growth. Urology, 6: 708, 1975.4 H2 D# o" u1 c
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone5 @* |/ }0 s5 Q2 b& }
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by; l* q. I, S: i
skin slices of man. J. Clin. Invest., 48: 371, 1969./ D) n. E6 x$ N, w( {1 ^
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
: [. [$ F' z* F& O, Z+ ~3 Z7 Iby topical application of androgens. J.A.M.A., 191: 521, 1965.
- A( V' \+ R9 ^5 z: J! I6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
# ?; C. K4 P7 ~6 Nandrogenic effect of interstitial cell tumor of the testis. J.1 X0 }6 e: D& n5 k/ [: p/ P
Urol., 104: 774, 1970.
: A$ F; e" F# @3 W7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-+ \+ _) |" t3 Z: k( u
tion in the male genitalia from birth to maturity. J. Urol., 48:
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