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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
+ S6 Y) Q. { F0 d A7 mGONADOTROPIN
% `) ~" o5 ]' X2 u) ^4 qRICHARD C. KLUGO* AND JOSEPH C. CERNY1 ]5 o' s6 G- d+ V
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
* k& K9 j/ E I/ FABSTRACT
* V3 t! r% e9 w$ R! V+ I' a$ ^Five patients were treated with gonadotropin and topical testosterone for micropenis associated
3 h5 }) V5 P4 V& x5 V2 @with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
% t8 m- V; [6 p& stropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone d* S$ q9 h( [, J1 C" |4 `3 T. G
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent5 [1 Q6 E+ K" z5 g6 g" _& r
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
* G5 k2 q4 r6 F3 R4 dincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average' K7 O; P6 ^% X* @- A
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
1 y3 k# R% |9 ~$ woccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This; e2 M: t, K& {' d$ _$ t
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
% e% I" T- ?( D# Jgrowth. The response appears to be greater in younger children, which is consistent with previ-
& p3 F' E7 L3 [' Cously published studies of age-related 5 reductase activity." B9 Z7 @4 X! p2 ^+ S
Children with microphallus regardless of its etiology will: e/ K Y: i q8 p1 e `! H* B ]
require augmentation or consideration for alteration of exter-
' l/ j/ j" H' p( u8 W' A* Fnal genitalia. In many instances urethroplasty for hypo-: U3 x+ E" a ~, W1 C% c
spadias is easier with previous stimulation of phallic growth.
9 ]/ O2 H* G1 \: E5 z, [. jThe use of testosterone administered parenterally or topically6 w. V1 J9 x' Z
has produced effective phallic growth. 1- 3 The mechanism of! G# Y/ r* A! L8 V+ \( w" Y' ~
response has been considered as local or systemic. With this" U! c8 D# D5 x2 U0 Y3 v* C+ }
in mind we studied 5 children with microphallus for response
- v/ D! Q! A% x$ mto gonadotropin and to topical testosterone independently.* Q# A2 t8 t# ~# y$ R' u
MATERIALS AND METHODS
7 R) Q0 p! W D8 x2 g% [0 LFive 46 XY male subjects between 3 and 17 years old were
6 Z p2 G; d# ievaluated for serum testosterone levels and hypothalamic, Q9 y" Y/ s' K; C4 i8 T
function. Of these 5 boys 2 were considered to have Kallmann's
* `! S6 N5 i4 ^/ s1 I- X" l+ x0 Asyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
, G$ A9 T3 U y* O& f- ^( Q+ g3 l! c! klamic deficiency. After evaluation of response to luteinizing
; k7 m- x/ V0 q: q) ^hormone-releasing hormone these patients were treated with2 j$ t5 [4 z+ `2 b) g. L9 Z& k
1,000 units of gonadotropin weekly for 3 weeks. Six weeks) o$ f) U2 x& p
after completion of gonadotropin therapy 10 per cent topical. p$ O3 C* J- b. M5 y" ?5 }
testosterone was applied to the phallus twice daily for 3 weeks.3 c2 d: R5 M- L$ v8 Z. E: z/ ^
Serum testosterone, luteinizing hormone and follicle-stimulat-- U; y( J# T2 n* u$ h$ B4 U
ing hormone were monitored before, during and after comple-
6 ~/ j1 F, T3 S0 R& G& Ytion of each phase of therapy. Penile stretch length was; d- H l: `3 c. e
obtained by measuring from the symphysis pubis to the tip of7 j/ v: g/ I: g9 `: i1 Q7 G# T9 L
the glans. Penile circumferential (girth) measurements were: f3 S/ j2 E6 [3 M/ `
obtained using an orthopedic digital measuring device (see a4 v( _3 F2 z7 c
figure).6 A6 Z- J) k3 [+ J \- Q
RESULTS7 I s8 `& l4 |% r
Serum testosterone increased moderately to levels between
' E& U+ [. D- Z, }: ^+ P' c50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-: {! j' Q2 _, ]7 u5 \
terone levels with topical testosterone remained near pre-! v, l/ F& e+ g/ X% o# r
treatment levels (35 ng./dl.) or were elevated to similar levels5 [1 |' z1 M+ R1 ^) ~
developed after gonadotropin therapy (96 ng./dl.). Higher
% d. F- U7 ^. u2 Nserum levels were noted in older patients (12 and 17 years old),
$ p5 p w$ d2 a# @6 Jwhile lower levels persisted in younger patients (4, 8, and 10: r* s* ]9 {3 ?' I* m* M* {
years old) (see table). Despite absence of profound alterations
& h* D3 ]# D( W6 Y# k3 g6 lof serum testosterone the topical therapy provided a greater
* C9 W; r3 i: U, `9 \Accepted for publication July 1, 1977. ·
, M% R) x1 U. z6 o! E4 a7 [Read at annual meeting of American Urological Association,
1 s e3 \1 T& K/ W6 J$ v' y3 a9 UChicago, Illinois, April 24-28, 1977.1 f. l" i3 q4 P; I: b
* Requests for reprints: Division of Urology, Henry Ford Hospital,4 x; Z6 j5 o4 ]6 F1 M. B4 o1 d
2799 W. Grand Blvd., Detroit, Michigan 48202.
. Y2 M, A! ^* |; I5 G. m$ Kimprovement in phallic growth compared to gonadotropin.! l4 X$ t+ F2 J$ D
Average phallic growth with gonadotropin was 14.3 per cent
- H; I$ n" G0 U. z/ }increase in length and 5.0 per cent increase of girth. Topical; [; \6 \$ e: v1 b
testosterone produced a 60.0 per cent increase of phallic length
$ W* J# K! q$ \, X @# Land 52.9 per cent increase of girth (circumference). The7 E: y. P* E4 ]0 a: C3 e
response to topical testosterone was greatest in children be-- G: D4 s- |2 o6 g0 l* g- r4 N+ B/ ?
tween 4 and 8 years old, with a gradual decrease to age 174 B" \# b, a6 v8 q: m, L' A
years (see table).
0 o+ F7 j1 q& U( P# M! H" w9 T9 _5 ~ y9 TDISCUSSION. V8 Z+ M4 z3 h" ~9 y
Topical testosterone has been used effectively by other
4 G2 d& X4 c: `+ m9 Oclinicians but its mode of action remains controversial. Im-2 K4 ^7 h' P" J' {) T# m4 {
mergut and associates reported an excellent growth response7 Y" F3 ^/ J+ o0 R; C) q% s
to topical testosterone with low levels of serum testosterone,5 f; ~4 o- }& ~! ~. v4 Q
suggesting a local effect.1 Others have obtained growth re-2 C, N0 I9 q( V. z- }, T
sponse with high. levels of serum testosterone after topical5 E& e% c0 p& X' r3 S
administration, suggesting a systemic response. 3 The use of
6 H ?6 R6 h- Kgonadotropin to obtain levels of serum testosterone compara-
d* v5 ^" Y, ]ble to levels obtained with topical testosterone would seem to
$ {1 h6 X& B! c$ t5 Nprovide a means to compare the relative effectiveness of
% G$ v4 o7 K1 ?topical testosterone to systemic testosterone effect. It cer-' n7 Q3 B- L( }
tainly has been established that gonadotropin as well as par-* d" {* S. L' H! u
enteral testosterone administration will produce genital" E9 F6 |( z7 {4 T
growth. Our report shows that the growth of the phallus was" |# p1 N3 K8 s, X
significantly greater with topical applications than with go-
5 R- m# m2 R. k" Jnadotropin, particularly in children less than 10 years old.) Z# @2 z) r- ~0 D% N$ Y3 f
The levels of serum testosterone remained similar or lower% i D ]0 _" f9 t. Q- [& e# h
than with gonadotropin during therapy, suggesting that topi-+ {" E! q7 `; ^8 [. `& }! C
cal application produces genital growth by its local effect as: h" G8 @! {5 P* N; m) `5 b
well as its systemic effect.+ e# f3 D9 g0 ?1 h1 X# H& d2 r& }/ f5 M
Review of our patients and their growth response related to$ a+ r6 c$ q5 o- P, B- j
age shows a greater growth response at an earlier age. This is
: {6 J$ y0 u1 C" R0 V- Qconsistent with the findings of Wilson and Walker, who' W% e% D% O0 l
reported an increased conversion of testosterone to dihydrotes-( V7 K q1 w2 H/ m2 W9 H" e. G+ k
tosterone in the foreskin of neonates and infants.4 This activ-% g8 W3 h+ s; {9 Q6 G
ity gradually decreases with age until puberty when it ap-
$ d- t6 L, e. C6 q4 I2 l" Aproaches the same level of activity as peripheral skin. It may
7 I' K* E% m- t3 A7 j3 v* B0 [% `well be that absorption of testosterone is less when applied at( l. b' j( W2 I! S
an earlier age as suggested by lower serum levels in children
" d2 z3 u7 [- b/ N4 s0 ?: cless than 10 years old. This fact may be explained by the( Q$ X5 v' z- V" b* q! H" N( }8 J' k+ _
greater ability of phallic skin to convert testosterone to dihy-
7 u U+ R( K& Y+ Z1 I& ydrotestosterone at this age. Conversely, serum levels in older
0 T% W( {/ }! q+ `* {patients were higher, possibly because of decreased local' Y& q1 Q4 M0 K6 }4 f. o
667
$ I8 J$ ?- L2 m# S/ y3 J668 KLUGO AND CERNY
$ m4 y( b) M5 n0 Q6 `* S' VPt. Age4 i: v3 p* }0 l8 j- y* n
(yrs.)+ S4 D6 n# ]" D+ p) P, |! t
Serum Testosterone Phallus (cm.) Change Length7 w! ]4 q& e( n W( Q: R
(ng./dl.) Girth x Length (%)
( n+ v* v& P/ z, A4$ D" k+ r. @. m
8
1 x0 l( d# U# E$ Q10
% O! t, K; w4 j& ]4 Y& i1 W- y5 B12! i* a, ~, V/ R6 n5 {: ~
17
+ D% T! A1 O2 [9 `" BGonadotropin
) G1 o: g9 }: q8 h71.6 2.0 X 3 16.66 l8 X- w3 j/ @3 Y/ `& N& D' U% N* v
50.4 4.0 X 5.0 20.0
# R" n- \) e; ]3 O& ~22.0 4.5 X 4.0 25.0) z4 y! }* g* W9 |# o: j5 T7 M5 \
84.6 4.0 X 4.5 11.13 s4 B4 J' E0 N9 T- T; N, W
85.9 4.5 X 5.5 9.01 W6 u5 L! s3 }
Av. 14.3
( y( Q7 y0 @; N1 O4
- H: D2 P2 h- ?84 i4 R' I& @! X% v/ v' D) a* ^
10: H* }$ [' m2 ?; M$ ^# F
12% W) G1 f4 w4 w
17
8 E: @; n' y; y" m1 ^, pTopical testosterone( N, `3 Q2 l" Y" @* f2 a8 ^
34.6 4.5 X 6.5 85! _2 k0 k( `+ u8 h5 q7 N
38.8 6.0 X 8.5 70% Q$ i- ?) q( ^0 H! F8 a' B' ?# L. k
40.0 6.0 X 6.5 62.5
7 s+ w4 G$ p N: ?. W/ [93.6 6.0 X 7.0 55.59 X. O' z0 f. Q, J
95.0 6.5 X 7.0 27.2
- C" A7 `- H! j, EAv. 60.0! X: q" Z- w, u
available testosterone. Again, emphasis should be placed on
6 z9 i4 o0 X3 b! R- I7 Z. A/ Iearly therapy when lower levels of testosterone appear to$ t( I! U! O0 Y/ W
provide the best responses. The earlier therapy is instituted
" S& u1 L5 i5 L5 k3 Q- o N2 Tthe more likely there will be an excellent response with low% V* y; J# j3 O4 m1 \ ]; F
serum levels. Response occurs throughout adolescence as
' }/ P: \& K: [- T B3 wnoted in nomograms of phallic growth. 7 The actual response
E$ E8 L4 x5 ?- h1 F0 xto a given serum level of testosterone is much greater at birth5 O+ ]1 C" q0 s: y6 X6 O
and gradually decreases as boys reach puberty. This is most% L0 [# M. u, g" A, |% S5 J
likely related to the conversion of testosterone to dihydrotes-
/ Q' c8 h6 W0 A& L- utosterone and correlates well with the studies of testosterone6 b6 [' G" ~5 l" K
conversion in foreskin at various ages.8 v2 b8 W4 F0 W! o: |
The question arises regarding early treatment as to whether8 n. \* N- ]3 O; s2 M: W* b
one might sacrifice ultimate potential growth as with acceler-
- d w' c, H: e7 h: vated bone growth. The situation appears quite the reverse
) R' |, c+ w" m- j$ T, awith phallic response. If the early growth period is not used" t b9 k, i1 s% W. @! h# _2 O
when 5a reductase activity is greatest then potential growth0 [) H; H5 n* Y' [9 R- l* N" h
may be lost. We have not observed any regression of growth l- @ ?; ^9 ?: N8 `4 n
attained with topical or gonadotropin therapy. It may well
H- E9 f( t$ hbe that some patients will show little or no response to any* X& h5 ? E0 y# l' g4 C
form of therapy. This would suggest a defect in the ability to- o3 |% V: n( ]
convert testosterone to dihydrotestosterone and indicate that( Z3 g* w# E1 |) m+ _
phallic and peripheral skin, and subcutaneous tissue should8 t% ?, T# F; f2 `1 V2 r
be compared for 5a reductase activity.9 v+ z5 y. q* b8 S. b; r" i4 j1 n% Q: u
A, loop enlarges to measure penile girth in millimeters. B,
2 O3 W' ]# S$ Z5 k) yexample of penile girth computed easily and accurately.
8 w' J1 V' f: d' \4 dconversion of testosterone to dihydrotestosterone. It is in this
# }3 w5 C' C3 D+ T h2 colder group that others have noted high levels of serum
{- m" a w9 q! j7 l& @testosterone with topical application. It would also appear$ M9 S9 o& R# a- y# Q7 K
that phallic response during puberty is related directly to the7 M$ w/ U! F: Z% X' o3 Q
serum testosterone level. There also is other evidence of local
6 S4 }) Y; P* w0 Jresponse to testosterone with hair growth and with spermato-8 l! }) Z( B$ q0 h; j* ^( T
genesis. 5• 6( \- @& d% E7 |- ?/ k8 S' c
Administration of larger doses of gonadotropin or systemic6 \! [. l" |) ?7 Q' x8 k
testosterone, as well as topical applications that produce
( I1 X: i; A, _* P: M+ Mhigher levels of serum testosterone (150 to 900 ng./dl.), will
' ]" x% y/ G. ^1 Z- |also produce phallic growth but risks accelerated skeletal5 q/ x( S% V; u6 z
maturation even after stopping treatment. It would appear
) R7 l9 F8 `5 N0 I8 A$ u* ?that this may be avoided by topical applications of testosterone7 r1 {) O1 d+ P4 {- g
and monitoring of serum testosterone. Even with this control9 v& h( }# b9 v, X9 n
the duration of our therapy did not exceed 3 weeks at any, O4 U: C5 t% s; |7 u" H) r# W
time. It is apparent that the prepuberal male subject may D) b. S) L# p8 R
suffer accelerated bone growth with testosterone levels near
0 y# o. f1 w2 v7 d200 ng./dl. When skeletal maturation is complete the level of4 r7 T0 p' b$ N9 @" f; o
serum testosterone can be maintained in the 700 to 1,300 ng./
/ X9 B! H) `8 F) Z( E+ x$ Sdl. range to stimulate phallic growth and secondary sexual
! u7 ]7 i9 @; Gchanges. Therefore, after skeletal maturation parenteral tes-2 Q# {0 q- V! C$ G" @
tosterone may be used to advantage. Before skeletal matura-# n, f, ?; ^- J" H2 u! l
tion care must be taken to avoid maintaining levels of serum
3 _4 S8 g0 q$ F2 E. T. Y3 Stestosterone more than 100 ng./dl. Low-dose gonadotropin
- q" j2 _6 t' v8 Z9 jdepends upon intrinsic testicular activity and may require
9 X% H5 {( X' P# C# pprolonged administration for any response.
# p4 M* e* N* \* ^6 SAlternately, topical testosterone does not depend upon tes-# F1 ?, y* K: h% ?( j! T
ticular function and may provide a more constant level of1 G9 D' T8 H& P" o- u; Y( s7 J) t
REFERENCES
( @; V1 C# u# S0 r' j% K1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,; d9 b% u" A, h" h& X/ g$ N7 `
R.: The local application of testosterone cream to the prepub-
2 V0 G9 I+ Z2 K8 ?ertal phallus. J. Urol., 105: 905, 1971.
2 L v @0 ~ d5 F3 O2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
1 C% v) @+ i+ ~2 z1 z# jtreatment for micropenis during early childhood. J. Pediat.,
8 l v* o% u: M3 n83: 247, 1973.
# T7 B+ Q# y" ~4 c' R( W3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
; p! d8 t" D: b4 R' F' B, Pone therapy for penile growth. Urology, 6: 708, 1975.8 ^% B" T8 P& j* J [9 o
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
8 |8 [5 y& [4 n; V1 Xto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
$ Z! _6 B; `' y- O0 B/ ^3 G4 Uskin slices of man. J. Clin. Invest., 48: 371, 1969.1 P1 }+ L* h) S5 D
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
. e1 D. }4 ^/ Z9 iby topical application of androgens. J.A.M.A., 191: 521, 1965.% j }+ ?* N% ?# d& W9 J
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local* R$ q! F& r5 b5 Z
androgenic effect of interstitial cell tumor of the testis. J.
* K) z2 b* e0 I' A; x& m2 ~# RUrol., 104: 774, 1970.
# @3 I! M$ q6 `. H* x- m7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-& p7 _- e3 \5 {: U( e7 l
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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