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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND0 t [( S8 x1 B: r) Q/ m) N7 J
GONADOTROPIN& w5 q( A0 q9 ^4 ~
RICHARD C. KLUGO* AND JOSEPH C. CERNY- M$ Z' L. e- C" m& m2 ^$ O# D
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan0 k, e$ b! m* b# d
ABSTRACT( B0 e# v; @# `
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
- E, f% ]: j) }! ]" l3 Wwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-0 m6 E( O/ r, b* x
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone8 h. ]1 c j; o8 } r7 V
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
4 Z3 X: l' ^( A" k+ k, H9 C6 ofor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
0 P( }% r3 h( T5 w& S. Cincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average! D1 U: S7 {1 n# p u) X) ^
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response/ A# ^4 J7 ^1 G4 q5 O; g3 l
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
# ]9 L7 r4 j; T2 k' L, `9 ]study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
2 T6 A0 w1 f/ s! U. O% P" Mgrowth. The response appears to be greater in younger children, which is consistent with previ-
) A; q! q5 X! O' Vously published studies of age-related 5 reductase activity.
# p9 @4 K& }; x$ I9 WChildren with microphallus regardless of its etiology will
0 e0 a9 z& F% u9 Trequire augmentation or consideration for alteration of exter-
7 D. S5 }7 f- pnal genitalia. In many instances urethroplasty for hypo-6 G1 [( D, Y. d
spadias is easier with previous stimulation of phallic growth.$ O7 L. f/ W+ q+ p! s
The use of testosterone administered parenterally or topically
3 v+ ^; ]$ R/ U, shas produced effective phallic growth. 1- 3 The mechanism of$ _$ p& e* a$ ~) k0 H# M4 d% A
response has been considered as local or systemic. With this! ?/ s. a {/ ?& e$ r4 q
in mind we studied 5 children with microphallus for response
& {9 B# g: _0 R5 w% \, `to gonadotropin and to topical testosterone independently.
4 \4 }! H. h! w6 W8 ~0 b% ]MATERIALS AND METHODS! z+ ], H3 G, g: B4 ]
Five 46 XY male subjects between 3 and 17 years old were
y+ M4 {! w% k; Hevaluated for serum testosterone levels and hypothalamic
\4 w, ~3 Q& E* kfunction. Of these 5 boys 2 were considered to have Kallmann's4 A; @" @6 c& K! e% l$ M9 L K C6 h, x
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-; U: m- n4 S1 v1 ]
lamic deficiency. After evaluation of response to luteinizing4 y+ `" _) h% U# I. Z
hormone-releasing hormone these patients were treated with
" t, k! W2 N& J( J1,000 units of gonadotropin weekly for 3 weeks. Six weeks
0 k- i- @8 X) I, ^. Q, @after completion of gonadotropin therapy 10 per cent topical) h Y1 s1 O* o
testosterone was applied to the phallus twice daily for 3 weeks.
0 l4 l5 b+ ?; E1 w5 ZSerum testosterone, luteinizing hormone and follicle-stimulat-
' l. r' W' T( m& I3 Ping hormone were monitored before, during and after comple- s! o. t) c7 f: c1 w. q; N
tion of each phase of therapy. Penile stretch length was
* v" c4 g# |+ M- uobtained by measuring from the symphysis pubis to the tip of
% y( r4 D' A; |, `5 W2 lthe glans. Penile circumferential (girth) measurements were) r1 k7 |; ~- Y6 v
obtained using an orthopedic digital measuring device (see+ z4 ^0 K- U' ], H5 e- A
figure).7 I; u# p. J) @; K: v+ J
RESULTS- R( U0 H# b2 E" t* \% W4 j/ N4 W6 q- ]
Serum testosterone increased moderately to levels between8 |1 Q/ `# ~% h1 [. ^0 v
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
( M1 l8 _: s. v1 Z$ J( Q; a) q j5 gterone levels with topical testosterone remained near pre-
4 j# ]: z* B) A4 Etreatment levels (35 ng./dl.) or were elevated to similar levels1 m: b4 |3 ^9 d! m5 E: H% F4 j
developed after gonadotropin therapy (96 ng./dl.). Higher
2 t. d* f: H# G3 p& t! @5 jserum levels were noted in older patients (12 and 17 years old),
3 h) z2 Y: A: Dwhile lower levels persisted in younger patients (4, 8, and 10
% E+ A2 b6 i D4 a6 G y. D6 vyears old) (see table). Despite absence of profound alterations- A) _% B& n1 z
of serum testosterone the topical therapy provided a greater
. d# U& ^5 w( U6 v7 A8 wAccepted for publication July 1, 1977. ·6 o6 O6 D2 [9 D2 j9 Q4 R
Read at annual meeting of American Urological Association,
" C6 z4 d5 K( Z9 T. P7 I3 [: M, NChicago, Illinois, April 24-28, 1977./ |: m: `7 w- u( Q6 Y4 f
* Requests for reprints: Division of Urology, Henry Ford Hospital,
' p3 u. J+ {/ L) G+ a. G2799 W. Grand Blvd., Detroit, Michigan 48202.
" P* d4 |+ s" S8 Z9 dimprovement in phallic growth compared to gonadotropin.. F5 o! q9 p0 W# L+ o
Average phallic growth with gonadotropin was 14.3 per cent; }. x/ V$ d" o! p: p) m! }
increase in length and 5.0 per cent increase of girth. Topical
' p* l/ u; z8 S8 c9 G$ D5 m& Q6 d2 Xtestosterone produced a 60.0 per cent increase of phallic length( a- e* ^) ], a
and 52.9 per cent increase of girth (circumference). The
% T- Q/ v7 |* yresponse to topical testosterone was greatest in children be-7 U. N6 R7 u& a3 r4 I2 L( @
tween 4 and 8 years old, with a gradual decrease to age 17
7 c# Z0 i$ J. s: @% k. Zyears (see table)., B4 P2 |+ Z9 p7 }5 g: @
DISCUSSION: k+ `) g& V0 \ H# [4 A6 X
Topical testosterone has been used effectively by other" E" `2 D% n, w5 `2 T2 i
clinicians but its mode of action remains controversial. Im-
3 ~5 e, G2 N, A5 I" r+ i* Kmergut and associates reported an excellent growth response
# S6 S8 F, B6 Y4 p' Cto topical testosterone with low levels of serum testosterone,
0 }! G( d _! W4 c# e* m* Xsuggesting a local effect.1 Others have obtained growth re-
- I5 s# F7 `3 n3 Qsponse with high. levels of serum testosterone after topical
6 ^" \' _; k! F% k- T: Yadministration, suggesting a systemic response. 3 The use of1 @/ {9 K* Q" f/ ~) Q
gonadotropin to obtain levels of serum testosterone compara-
, d. z* D# G, mble to levels obtained with topical testosterone would seem to( w( d& Q, K9 Y7 g7 F
provide a means to compare the relative effectiveness of3 H! {( d8 i6 I9 j2 F3 X( k1 x+ x
topical testosterone to systemic testosterone effect. It cer-8 r c+ B2 g! l! f
tainly has been established that gonadotropin as well as par-8 {1 p) K" g+ j
enteral testosterone administration will produce genital
+ P, F* b9 L4 n5 m- t, U6 tgrowth. Our report shows that the growth of the phallus was4 M0 ~3 P: @6 P
significantly greater with topical applications than with go-
4 L% m0 X) ~% y) O. Bnadotropin, particularly in children less than 10 years old.. [+ y1 M) e/ r$ r" |% N7 m1 ^" Y3 \
The levels of serum testosterone remained similar or lower; M. @9 v% M9 k' x9 p! Q
than with gonadotropin during therapy, suggesting that topi-
/ m: u; \! r5 j+ p% X+ X tcal application produces genital growth by its local effect as/ E+ H0 s, m5 [7 j& v& ?9 D1 L. A
well as its systemic effect.
7 P3 j: E/ j4 IReview of our patients and their growth response related to7 O! Z( c: n9 e* t9 [1 w% ]0 c: h
age shows a greater growth response at an earlier age. This is
6 L" }5 i" k! Y) gconsistent with the findings of Wilson and Walker, who
/ U" i* {- R) E& z% O/ h$ rreported an increased conversion of testosterone to dihydrotes-$ F. f* L! {, H- n0 o( o
tosterone in the foreskin of neonates and infants.4 This activ-
2 \: t# G1 X8 tity gradually decreases with age until puberty when it ap-) P% z- ?5 b3 Q
proaches the same level of activity as peripheral skin. It may
9 _$ {# K$ O8 n- T& c, u, l' bwell be that absorption of testosterone is less when applied at: I( P- k5 _6 h0 R! H: u
an earlier age as suggested by lower serum levels in children+ e2 ` s" z* p$ N: o( C
less than 10 years old. This fact may be explained by the$ P6 C, m# D$ V5 |4 | f
greater ability of phallic skin to convert testosterone to dihy-
: L0 b0 v6 y8 h' ddrotestosterone at this age. Conversely, serum levels in older
; B- ]- r4 b" C8 S8 z9 _patients were higher, possibly because of decreased local7 b. H- V+ S% K$ {, a- h0 O
667: U+ b- j) n9 |. V; |- U
668 KLUGO AND CERNY9 m# d: V6 g/ i0 Z% I; L
Pt. Age
. _$ l5 s% M2 n(yrs.)" l- e8 {% N" i2 T& J! }' J. n
Serum Testosterone Phallus (cm.) Change Length
8 ?# ~: R$ Z8 p4 u(ng./dl.) Girth x Length (%)$ t2 T' |4 {4 l K% l$ \
4) E$ a2 D" H( y2 u; p- d
8
; a" e* M8 H* p L/ B$ R# ~10
* S( W" g! p1 X1 s- Z4 @2 ~12+ G) e- Q1 ] [% m/ F9 R
17" _) J( V# m' N3 c; p0 a h2 v" G
Gonadotropin2 F/ K: q, n% D# y4 T
71.6 2.0 X 3 16.6
! m+ a* i$ P* p; w50.4 4.0 X 5.0 20.0
2 K/ L. e( f+ [; c22.0 4.5 X 4.0 25.0
% d+ z" I, N: p8 w R+ R m6 L84.6 4.0 X 4.5 11.1
e3 f3 ]& h! B$ a85.9 4.5 X 5.5 9.0
, L7 @; p" }4 U. p$ j/ I PAv. 14.3+ v3 e& m6 a. D% i/ z6 T
4# Q# G; M/ G- W* B) B6 R }
8
( i; Z1 n8 c" r) } H9 x: L4 F4 P105 F+ j) _0 t% b K- w7 t
127 D8 {% v- J$ O
17
M9 w1 _3 k1 C& O2 N) oTopical testosterone% P& G% f# T5 {
34.6 4.5 X 6.5 85
( N: }! [( u: _0 v" i* d; }. X, f! H38.8 6.0 X 8.5 70
% Y2 j1 v' g# r& I40.0 6.0 X 6.5 62.5
6 f5 S2 u% o" u) Z/ A ~. c93.6 6.0 X 7.0 55.5
1 w! N3 E8 h( x) C* h95.0 6.5 X 7.0 27.2* B' |" F4 M6 D) ]/ o8 a) L
Av. 60.0+ U5 ~9 O/ @5 s/ J; F
available testosterone. Again, emphasis should be placed on
, o& P) j8 P: ?% f1 @- T+ rearly therapy when lower levels of testosterone appear to$ s1 E2 }, f+ |; L+ @$ \/ M
provide the best responses. The earlier therapy is instituted' ?. T" G: G9 F+ \3 d2 g" J4 T
the more likely there will be an excellent response with low5 U1 a V+ `6 _6 r
serum levels. Response occurs throughout adolescence as* m# y% _3 F; G" m
noted in nomograms of phallic growth. 7 The actual response, J7 [: G" J8 l' y% [
to a given serum level of testosterone is much greater at birth8 P2 ]' T. J, @% Y6 H3 M$ `8 `% Z5 A+ w
and gradually decreases as boys reach puberty. This is most
9 d H. W8 S5 t6 W0 r5 Clikely related to the conversion of testosterone to dihydrotes-
6 h' Q' |* p& t- [- r( ztosterone and correlates well with the studies of testosterone
% B' U8 V5 f" ?; d9 S$ ? W1 g& c X: Vconversion in foreskin at various ages.8 L; ^2 v3 ^6 ^2 O& k, ~7 C- G
The question arises regarding early treatment as to whether
0 x, r y: W, |: m$ U( b0 p6 cone might sacrifice ultimate potential growth as with acceler-
0 }# _- T" R5 b& {7 x( mated bone growth. The situation appears quite the reverse7 |0 F1 \7 k+ E7 ?
with phallic response. If the early growth period is not used' V- `. \7 @8 ^$ G8 p! H1 N4 I7 f
when 5a reductase activity is greatest then potential growth" M6 f( Z1 }4 Q9 I/ p+ O$ k
may be lost. We have not observed any regression of growth1 c, Z# ?2 h/ E- j$ Q2 B. k2 L
attained with topical or gonadotropin therapy. It may well
, x) v p, Z: |) N) W7 R sbe that some patients will show little or no response to any3 p% P/ {& w3 J
form of therapy. This would suggest a defect in the ability to
: Z7 a0 }2 f$ R) iconvert testosterone to dihydrotestosterone and indicate that
# D* L( `; g( v, {* u8 Lphallic and peripheral skin, and subcutaneous tissue should
5 h2 r9 V8 i, s* _# @ Y# zbe compared for 5a reductase activity.
4 L8 q6 e) G# v- P) K8 m3 kA, loop enlarges to measure penile girth in millimeters. B,. G( Z8 a8 S3 H: Z; d
example of penile girth computed easily and accurately.* }" F* @- b5 D: J5 Y
conversion of testosterone to dihydrotestosterone. It is in this; j- L9 _& m# \% H& H, ~- E
older group that others have noted high levels of serum W4 n: l+ d+ t2 b$ a1 @3 x9 D
testosterone with topical application. It would also appear
5 @9 p. l) `) ]1 T) o. tthat phallic response during puberty is related directly to the1 m# B4 i: `0 Q# Z( g: e- s* A- o
serum testosterone level. There also is other evidence of local
' E2 h3 k5 ] U" kresponse to testosterone with hair growth and with spermato- x, a2 l3 s2 t- Q) L! N$ D
genesis. 5• 6
$ F( a j3 l8 m& R9 \! nAdministration of larger doses of gonadotropin or systemic
( H/ t" a4 L) ]& @% C* ?$ @, A! ktestosterone, as well as topical applications that produce1 v$ R0 s [" O- j4 N5 S6 ~
higher levels of serum testosterone (150 to 900 ng./dl.), will
& `7 @, O0 s! z8 W( Valso produce phallic growth but risks accelerated skeletal
5 ^2 @* g4 B/ ~. F7 ^maturation even after stopping treatment. It would appear
/ ?/ h5 F6 k. u- {6 u! Vthat this may be avoided by topical applications of testosterone
- S$ F+ s8 o! C* land monitoring of serum testosterone. Even with this control- }) ^& y. W; P4 O5 L
the duration of our therapy did not exceed 3 weeks at any& p* z% \9 r4 t7 @' ?
time. It is apparent that the prepuberal male subject may e G' d! W6 N+ c* l2 U+ t
suffer accelerated bone growth with testosterone levels near
0 n( w& ?" d6 [200 ng./dl. When skeletal maturation is complete the level of, W1 m4 O0 z, Z* `: n( f) i3 E- x( ~
serum testosterone can be maintained in the 700 to 1,300 ng./
5 w5 k s: H5 f7 Qdl. range to stimulate phallic growth and secondary sexual: B% w& P, r$ ?6 k' W. n; W& T
changes. Therefore, after skeletal maturation parenteral tes-# Q6 E2 Y2 t5 L3 [
tosterone may be used to advantage. Before skeletal matura-. G6 Z4 |0 k: Y% H2 m9 |
tion care must be taken to avoid maintaining levels of serum
# z! _/ ^6 r- g# q, c# Rtestosterone more than 100 ng./dl. Low-dose gonadotropin* D$ g6 w! m* t9 m7 `/ A% U; Y
depends upon intrinsic testicular activity and may require4 ~' ?' U" a3 Y8 F: G' O0 }
prolonged administration for any response.. B4 ^ O0 P8 a$ Z8 U9 e
Alternately, topical testosterone does not depend upon tes-
2 K# X" f, ^8 u$ @& `. Xticular function and may provide a more constant level of. m9 q, }. d1 T4 H! q5 q5 F
REFERENCES
& Y8 J7 ?2 n& }- p% U6 W1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,3 h% B& F/ w6 p& T6 {# @
R.: The local application of testosterone cream to the prepub-2 Z4 [7 [3 ]$ j/ ? X6 b' R; R
ertal phallus. J. Urol., 105: 905, 1971.
7 D5 Z, i( U7 i4 Z. {1 x- [2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
% ?8 m' m: q. Q, t; a: A$ }treatment for micropenis during early childhood. J. Pediat.,8 K- J& _5 k V& O
83: 247, 1973.
" L+ {2 m* g! l! B2 d K3 P3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
6 W6 m" _& l7 q6 X& U$ X3 H8 zone therapy for penile growth. Urology, 6: 708, 1975.
: F+ b3 i& ?" _) Y2 \4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone4 G+ a# Z1 T4 F h: a
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
, Y( R3 {) d, Q7 D! q/ Tskin slices of man. J. Clin. Invest., 48: 371, 1969.6 C+ D2 w9 G) O! J1 ~- J J
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
; S$ [! V! E- Q Eby topical application of androgens. J.A.M.A., 191: 521, 1965.
; K% c n6 Z. i( X g6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local) W1 b* i0 O1 T4 x4 f$ ]! c
androgenic effect of interstitial cell tumor of the testis. J.
3 I/ M7 r/ L; ?0 T5 v. n8 UUrol., 104: 774, 1970.
+ o/ r$ B: z8 V2 n% e$ }7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
$ ` o+ t7 V, V" h6 x8 U- ttion in the male genitalia from birth to maturity. J. Urol., 48: |
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