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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
1 F- {8 V3 O/ ?7 v) ` E, E0 ?9 AGONADOTROPIN
; z& _: I3 B! ~# H& n" HRICHARD C. KLUGO* AND JOSEPH C. CERNY
) s/ S9 g- ~4 b9 VFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan7 ]" ]& A3 i) |3 K
ABSTRACT, C& y/ D$ l6 W' j. W& Z1 Y
Five patients were treated with gonadotropin and topical testosterone for micropenis associated' J @5 ?/ V/ D0 v
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
5 n3 O: Z' X6 I$ K/ Vtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone' X6 j2 {7 R1 G5 _6 C! |; L8 G
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent4 }' H7 O r5 G: b9 g! d/ _# {
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
( z: M- h4 k# n5 n* h) H& S6 Fincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
0 X$ A' G3 T2 H; e3 [increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response& V& ^+ ]! h; w5 T0 r3 {. }
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
- Z# t4 B! \! o9 Z, o/ fstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile- `! n5 S" ]. y: o" \3 ]" O8 j9 A
growth. The response appears to be greater in younger children, which is consistent with previ- @* q, N& v/ ?( n9 G- q+ f
ously published studies of age-related 5 reductase activity.4 L ^& i" u2 l
Children with microphallus regardless of its etiology will& E" B' ~4 X3 w* W9 E2 V
require augmentation or consideration for alteration of exter-
- D: n$ d+ L7 C; ?& N& `3 \& _nal genitalia. In many instances urethroplasty for hypo-# Q) \7 v* V, x
spadias is easier with previous stimulation of phallic growth.
8 c8 O9 x) i# k5 l% Q2 E& v: }The use of testosterone administered parenterally or topically
/ |# O4 u! K6 Y; `has produced effective phallic growth. 1- 3 The mechanism of
6 P L0 K* E( ]+ w' ?/ fresponse has been considered as local or systemic. With this* u7 b: O* [& o. t/ E, T4 F
in mind we studied 5 children with microphallus for response
M& [' [: L0 q4 Y, T( `; [: i) z0 m. Mto gonadotropin and to topical testosterone independently.
+ ^5 W+ ~% n& SMATERIALS AND METHODS0 M& g% c" t- J& K4 l
Five 46 XY male subjects between 3 and 17 years old were3 l7 q/ Q) X- ?, c' q
evaluated for serum testosterone levels and hypothalamic
2 n2 T* V2 D1 P# U& ~9 }function. Of these 5 boys 2 were considered to have Kallmann's% M1 R3 K& c$ P+ c. i% s
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
9 X, o; C( Q* i2 ~) I# Llamic deficiency. After evaluation of response to luteinizing& P9 i. |* \- ]4 b# E8 s
hormone-releasing hormone these patients were treated with
3 d( t7 {% P( R' p1,000 units of gonadotropin weekly for 3 weeks. Six weeks
k- a7 Y/ |- h9 J+ O) s+ V& o+ safter completion of gonadotropin therapy 10 per cent topical
5 x3 q1 ?: ?8 b3 u4 a7 I- stestosterone was applied to the phallus twice daily for 3 weeks./ w$ T C8 Z& B/ k9 K
Serum testosterone, luteinizing hormone and follicle-stimulat-
8 c' I4 h! P# q# _& ~1 L& |( K# uing hormone were monitored before, during and after comple-, r7 z. J5 K; a" S. Y+ [- t
tion of each phase of therapy. Penile stretch length was/ H3 c1 v% X, R8 T
obtained by measuring from the symphysis pubis to the tip of6 H. Z# q6 w7 ?3 Z c+ E1 H
the glans. Penile circumferential (girth) measurements were' j1 l9 ?( J5 A0 O3 ~
obtained using an orthopedic digital measuring device (see! A- w8 T* M0 r5 i/ l
figure).8 y; X( r: S! R2 O& @+ G) V
RESULTS+ V' H s l9 R; u& {; E0 C& K
Serum testosterone increased moderately to levels between6 l! F+ l) |, }$ q# I# o
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-: w( a; _% |! m5 R; M, d6 v
terone levels with topical testosterone remained near pre-
' A& h6 [! p4 e1 F2 [) vtreatment levels (35 ng./dl.) or were elevated to similar levels
8 `! {, q2 u4 y0 r) Pdeveloped after gonadotropin therapy (96 ng./dl.). Higher( O) o; S$ E1 Q3 x5 w0 {( e! J* `# O
serum levels were noted in older patients (12 and 17 years old),
8 b! R! N Q4 Q+ c" Xwhile lower levels persisted in younger patients (4, 8, and 10
) v, k& E% W. M2 m! T, qyears old) (see table). Despite absence of profound alterations
# w# p4 A1 y4 A: T# m7 Vof serum testosterone the topical therapy provided a greater# I; C& u1 X0 y/ H. q; W$ Q8 a& ^
Accepted for publication July 1, 1977. · }. j7 s4 n! b7 W% i1 f
Read at annual meeting of American Urological Association,9 ], }8 @3 K8 P% R) d
Chicago, Illinois, April 24-28, 1977.
5 h# ~ A% d. s* k. C: ~6 B6 }* Requests for reprints: Division of Urology, Henry Ford Hospital,4 v( f% T" V% p
2799 W. Grand Blvd., Detroit, Michigan 48202., b3 ^: V2 ?7 u! \4 W' D
improvement in phallic growth compared to gonadotropin.
, S$ O! Z0 [% ]Average phallic growth with gonadotropin was 14.3 per cent3 { {/ ^0 v8 S I c/ c
increase in length and 5.0 per cent increase of girth. Topical
; O8 z4 p6 N6 U0 ~testosterone produced a 60.0 per cent increase of phallic length
8 p+ n7 W% g9 xand 52.9 per cent increase of girth (circumference). The0 T1 A7 _5 N* n6 ?
response to topical testosterone was greatest in children be-
8 h* ]- e( e3 R. o4 {4 r7 stween 4 and 8 years old, with a gradual decrease to age 17
/ E7 }* ~! e) |% l; q _0 e7 X1 ?3 tyears (see table).
) t7 Z B2 Y5 G) j% J2 K3 v. U& ODISCUSSION
! ~& q. @$ H' ^$ Z6 ATopical testosterone has been used effectively by other$ R7 y2 A+ z7 _1 R& B% x7 V
clinicians but its mode of action remains controversial. Im-4 ]2 D3 _' A5 S% O7 @; ]
mergut and associates reported an excellent growth response" j5 c) }1 _4 H1 C- \5 q
to topical testosterone with low levels of serum testosterone,
/ _$ n$ ~9 Z# J- csuggesting a local effect.1 Others have obtained growth re- L( e4 z7 V X6 d! t* x7 P s7 T! r
sponse with high. levels of serum testosterone after topical! `* K9 J) \$ h/ S. r
administration, suggesting a systemic response. 3 The use of% f ?* P0 A+ R
gonadotropin to obtain levels of serum testosterone compara-4 C. [2 `- @2 ]4 V" `/ n7 T- M
ble to levels obtained with topical testosterone would seem to; C) e' q% Q: [" G( r
provide a means to compare the relative effectiveness of$ F1 @: ]- [, X1 R; {
topical testosterone to systemic testosterone effect. It cer-8 M6 S+ @$ e/ V2 p: i7 @: }2 e) Z% }( o
tainly has been established that gonadotropin as well as par-+ J% p, P X( j5 S- Q
enteral testosterone administration will produce genital
& l7 m; K7 G* n7 Vgrowth. Our report shows that the growth of the phallus was+ Y0 S* C' R3 `4 M! Q7 ^2 L
significantly greater with topical applications than with go-
) ~& M6 X" e* k4 c$ V1 }nadotropin, particularly in children less than 10 years old.
2 e% V2 z/ O+ BThe levels of serum testosterone remained similar or lower; f( B! c9 e3 h: A% f! ~
than with gonadotropin during therapy, suggesting that topi-, q5 Z! j5 ?) c. q
cal application produces genital growth by its local effect as
8 \; o8 u8 a: B6 fwell as its systemic effect.. E ^1 Z9 Q1 m- g1 l3 C
Review of our patients and their growth response related to
; y: J2 G( Q0 G# B, \4 Zage shows a greater growth response at an earlier age. This is2 `: f6 R" t9 e; `( r) g6 x* { }
consistent with the findings of Wilson and Walker, who4 j1 y, z' j! x3 e: u
reported an increased conversion of testosterone to dihydrotes-
& \! k4 M) {$ |# ?7 ~* ~. M8 Otosterone in the foreskin of neonates and infants.4 This activ-5 d. H/ }% E# g8 H8 S5 }
ity gradually decreases with age until puberty when it ap-
* O) j E8 G# Vproaches the same level of activity as peripheral skin. It may* y0 h9 k4 K( G9 N
well be that absorption of testosterone is less when applied at
6 e; S- Y3 X5 T/ C; z; Kan earlier age as suggested by lower serum levels in children
/ r& F7 B. k) _& tless than 10 years old. This fact may be explained by the- c3 @9 d$ g! s( _, H, d5 a, D
greater ability of phallic skin to convert testosterone to dihy-
- \, L; \4 m: s! F6 @drotestosterone at this age. Conversely, serum levels in older% k! q( r% f* `) e4 e9 n' b, V" o
patients were higher, possibly because of decreased local& b# W3 x* s: R8 Z
667, A8 c5 o2 M/ M9 M+ b8 |1 H& v
668 KLUGO AND CERNY6 z; X6 }4 |8 A" l- l; q2 ^
Pt. Age0 ]' s( D3 }9 r$ ^
(yrs.)0 |+ d7 `2 o$ S1 m9 H# N3 b& ]
Serum Testosterone Phallus (cm.) Change Length; H) c* m; j D% K, r' Y( u2 H
(ng./dl.) Girth x Length (%)
1 N: Q6 o% T) U. d v/ \ c! K44 }8 b, s0 I0 f1 a; B
8
9 S; {+ Q e# ~% A% D104 b# D" c$ @( c$ w* Q! C+ b
12
% a4 E: \+ w8 @5 o17 F$ Z+ R7 g' K! a% q
Gonadotropin; K) v! s) m, s y5 e
71.6 2.0 X 3 16.6
* |/ V" X/ M1 o0 X( @% i9 [: S50.4 4.0 X 5.0 20.01 E( Q- d. u* M: [3 h! z- B) }* |
22.0 4.5 X 4.0 25.0: J- o- _6 c' s* U* J3 R) t
84.6 4.0 X 4.5 11.19 T6 V7 @7 E1 J: o0 W) A
85.9 4.5 X 5.5 9.0
+ L0 M* n7 |1 E& r8 g9 MAv. 14.3
# B/ g7 m. R4 H6 O7 U8 u3 `. W4
- X: w% ~/ k' Y" ~! |% r9 B# Q8
& B3 C, B' B7 ?# ~7 l. \- O101 `, R- J) O$ C( p0 ]
12
- \6 ^, k" ]! Z8 Z! v8 l! g* @; x17, j ]% x6 j, {# j+ @2 O
Topical testosterone
8 M' j* J& r! B+ X0 P; G. F, N34.6 4.5 X 6.5 85
3 X& C7 p2 ]0 Z/ W( K6 T1 G38.8 6.0 X 8.5 70
8 @! V' F3 J* }& U/ o: p9 [40.0 6.0 X 6.5 62.5" c2 t! o, W! \/ x. z8 H
93.6 6.0 X 7.0 55.5+ M, o! ]. ?5 ~- K/ p5 j
95.0 6.5 X 7.0 27.2' K' Q9 n, P* W9 {# y* k! j& R
Av. 60.0& o% @7 F, R& [
available testosterone. Again, emphasis should be placed on+ _% C; Z% F% K( N( H* Y9 f
early therapy when lower levels of testosterone appear to
- L+ _; z$ v- G qprovide the best responses. The earlier therapy is instituted
- R5 l7 {+ n# j- a; j; c. P1 W- Ithe more likely there will be an excellent response with low$ L0 x+ ^' }$ V' X* r( b* O# l* `
serum levels. Response occurs throughout adolescence as/ I* j" y; Z0 u I+ z/ s
noted in nomograms of phallic growth. 7 The actual response
) D0 m( ~: [* ]0 K$ O" l- }: Uto a given serum level of testosterone is much greater at birth
; m& H; @1 o8 m f* {: hand gradually decreases as boys reach puberty. This is most
( R1 K: H" o5 J. l1 Ylikely related to the conversion of testosterone to dihydrotes-/ {& P3 U& i& W# H8 |# [; S
tosterone and correlates well with the studies of testosterone
. d8 ~. R' p9 s0 m5 c+ `: vconversion in foreskin at various ages.( P: r* X+ u0 X; u0 I9 c+ y
The question arises regarding early treatment as to whether
/ x; Z; }8 \& r: x# ^one might sacrifice ultimate potential growth as with acceler-
1 Q3 e( g( Q4 P2 _$ Q6 V) | D Rated bone growth. The situation appears quite the reverse
% X8 l" R4 \5 m7 m2 Gwith phallic response. If the early growth period is not used
3 E# \9 I+ v2 @- t* @ mwhen 5a reductase activity is greatest then potential growth P3 i3 U1 b0 X7 V
may be lost. We have not observed any regression of growth, V; s: p, r# n: r; ?
attained with topical or gonadotropin therapy. It may well
+ A3 S* Y. ` [- _0 Lbe that some patients will show little or no response to any4 [# c# ^4 }+ o7 {6 _* Q
form of therapy. This would suggest a defect in the ability to. u, D( L1 X6 a/ k9 f
convert testosterone to dihydrotestosterone and indicate that
k" o: F7 w9 a) r( k9 J) Wphallic and peripheral skin, and subcutaneous tissue should
N0 ]$ H' f3 f+ E- Xbe compared for 5a reductase activity.
- o$ V& m7 l5 Q6 RA, loop enlarges to measure penile girth in millimeters. B,
) h& K$ {" d" B9 g7 Q, qexample of penile girth computed easily and accurately.
3 i$ {) T/ X4 G3 H# fconversion of testosterone to dihydrotestosterone. It is in this
8 ^5 ~: W0 |& r# polder group that others have noted high levels of serum
* X3 C5 U7 v/ ]3 ntestosterone with topical application. It would also appear1 L, i' B: y5 J
that phallic response during puberty is related directly to the
s% ~0 n0 E" o6 ]$ fserum testosterone level. There also is other evidence of local$ g2 S& i8 s7 j# C6 {
response to testosterone with hair growth and with spermato-
( p% D: z. R' f% z# Z$ ^4 Z1 Hgenesis. 5• 6: C# V3 [: b1 @; `5 D5 i
Administration of larger doses of gonadotropin or systemic+ C; \9 w, M* ~3 V
testosterone, as well as topical applications that produce/ V$ C8 f% V" M8 u! _$ G' N
higher levels of serum testosterone (150 to 900 ng./dl.), will: _- l& d1 U# k8 U. o
also produce phallic growth but risks accelerated skeletal; L K; b! j; ^# r: p$ S
maturation even after stopping treatment. It would appear' y% d: R/ \) v
that this may be avoided by topical applications of testosterone
6 K* w! ~, p- L4 mand monitoring of serum testosterone. Even with this control
2 c8 v* Q1 x0 j' L" \2 ]the duration of our therapy did not exceed 3 weeks at any
' d; h+ h6 j, i* i5 w v. }4 stime. It is apparent that the prepuberal male subject may+ A$ p g; T$ _
suffer accelerated bone growth with testosterone levels near
$ n t8 V8 |; ?& ]- G200 ng./dl. When skeletal maturation is complete the level of! c/ {: Y5 `8 k+ w" ~" V0 w( }
serum testosterone can be maintained in the 700 to 1,300 ng./# W7 [2 {0 K' F. z1 Y: v
dl. range to stimulate phallic growth and secondary sexual
1 ~7 ]6 x u' Y- Mchanges. Therefore, after skeletal maturation parenteral tes-+ g: f0 V4 u g. Z( E/ g
tosterone may be used to advantage. Before skeletal matura-
. [$ t+ V8 P# I: F6 T' S" I. M2 ?tion care must be taken to avoid maintaining levels of serum
8 Z5 o% M. r h! \! K+ Itestosterone more than 100 ng./dl. Low-dose gonadotropin
! U2 g5 }# T( e0 _" L6 j0 R3 mdepends upon intrinsic testicular activity and may require7 l) H3 ^+ y) _, m5 E
prolonged administration for any response.
1 d2 c9 [: B6 l% a0 R) tAlternately, topical testosterone does not depend upon tes-
3 m$ _1 S+ E: mticular function and may provide a more constant level of
2 n1 }! ~5 ^7 z$ L7 z5 Q9 ?REFERENCES' V2 {) l$ b( C r. K
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,/ F. q$ H/ J+ J+ ]1 Q
R.: The local application of testosterone cream to the prepub-/ |9 Y" e' ]6 r. Z5 L) x: h: b# _
ertal phallus. J. Urol., 105: 905, 1971.+ k" O4 J N2 }5 D( W* ]
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
' g) Z- f2 p' [) i" Ytreatment for micropenis during early childhood. J. Pediat.,
7 S; k( O x% M6 ]+ J8 P& V% _0 K83: 247, 1973.: e( o/ `) J& w
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-# G5 l W( q7 x# n$ u* u( r' C4 o+ O
one therapy for penile growth. Urology, 6: 708, 1975.
. o% s. S- T& ?" B* `) A8 W4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
; W/ r% D; b9 o- u) D! e! {8 Vto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by/ B3 j9 I# u I0 O0 B) b
skin slices of man. J. Clin. Invest., 48: 371, 1969.
( t. W; {2 v- X8 G1 r5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth( N& H) ]8 N* F! g* D9 a
by topical application of androgens. J.A.M.A., 191: 521, 1965.* ~ r8 a$ O% R% F1 @- W% c5 F
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
3 N; l& m+ C8 e O2 qandrogenic effect of interstitial cell tumor of the testis. J.
m" w, O& V& Z& ~5 OUrol., 104: 774, 1970.
( D1 n$ m6 V7 `3 s7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
# T- w" o1 s: Y( q( G* ation in the male genitalia from birth to maturity. J. Urol., 48: |
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