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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
9 g4 a$ k. s$ Z% g) S4 VGONADOTROPIN
3 _; @( k2 t4 U. XRICHARD C. KLUGO* AND JOSEPH C. CERNY ^7 ^+ V9 r5 O+ }( r
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan- `; P @9 c" s" M/ t
ABSTRACT
3 k1 `* O3 ~9 h- d( Y+ eFive patients were treated with gonadotropin and topical testosterone for micropenis associated
% `: I. |/ B3 p0 k+ X4 {6 E: vwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
/ l) v, s! ^# d Y/ P( I# {tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
6 z) W; a3 D8 O1 A/ O3 }$ k! e0 a1 gcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
% u0 e+ V8 N2 j2 u7 Pfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent$ `) P/ x2 B; r. c/ a- ~
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
! R" |0 N6 Q2 R7 Iincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response6 ]0 }6 r/ u% ^6 z* O
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This$ E8 \. M. R& N0 {
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile5 A5 t. `; C* N" m
growth. The response appears to be greater in younger children, which is consistent with previ-" E* \' | }) F1 ? _7 h. u% j
ously published studies of age-related 5 reductase activity.
F+ h: O' F) l" a+ a* SChildren with microphallus regardless of its etiology will6 l- ?% O$ Z I; {
require augmentation or consideration for alteration of exter-
. j# @. `/ R& G* e: }, E$ Onal genitalia. In many instances urethroplasty for hypo-
; s$ Y8 s' [' h3 A8 g' M* Nspadias is easier with previous stimulation of phallic growth.
1 C- `4 @4 \, W4 }: z' k2 ]; tThe use of testosterone administered parenterally or topically
- b) p0 x: A2 B7 e" Yhas produced effective phallic growth. 1- 3 The mechanism of* {6 B, w' g- C
response has been considered as local or systemic. With this
3 m; Z$ d5 U; [* d* i3 f# F! Gin mind we studied 5 children with microphallus for response7 ?+ V, F8 U Q2 R6 R7 \
to gonadotropin and to topical testosterone independently.' \8 u* n6 t2 v. O& U" v; z
MATERIALS AND METHODS
4 ~4 H( k- v% e8 T% w5 a s. l; FFive 46 XY male subjects between 3 and 17 years old were
/ o7 R' D! a6 k/ ~+ `& tevaluated for serum testosterone levels and hypothalamic! B. z# O7 `4 [2 O7 f
function. Of these 5 boys 2 were considered to have Kallmann's+ K2 ~: u1 B& w" B4 A$ o# |' G
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-; I. r* J; l7 r, s5 N/ S
lamic deficiency. After evaluation of response to luteinizing
8 m$ A0 k0 n- I: Whormone-releasing hormone these patients were treated with6 Z, ?6 H5 a, s& y
1,000 units of gonadotropin weekly for 3 weeks. Six weeks& T! @: ~7 Q. G: E- s* c
after completion of gonadotropin therapy 10 per cent topical7 u6 G4 Y! { k7 _8 ~
testosterone was applied to the phallus twice daily for 3 weeks.& V; Q1 i. Z' e+ `8 q+ O1 V
Serum testosterone, luteinizing hormone and follicle-stimulat-
+ M2 E6 N: f6 ^ing hormone were monitored before, during and after comple-2 e5 u5 v& I/ y7 L
tion of each phase of therapy. Penile stretch length was
+ p) w4 I/ P5 N2 Jobtained by measuring from the symphysis pubis to the tip of. P9 [1 }/ L% `% ]2 q5 ^
the glans. Penile circumferential (girth) measurements were
5 v* e* A/ Y" R( F" E3 Eobtained using an orthopedic digital measuring device (see4 C0 H5 F) j) Y2 @" f% c7 J- |& |
figure).# l8 L5 ]! \: A, q3 M; h7 j
RESULTS% {3 q+ L$ f6 b" ? F6 t( P; @
Serum testosterone increased moderately to levels between: K7 J; n. _, ]* B1 @* G5 C
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-6 z2 y" k7 z& x4 ^3 S
terone levels with topical testosterone remained near pre-
" L' x, r0 J. n0 ?! C+ xtreatment levels (35 ng./dl.) or were elevated to similar levels) n. D+ |: o: U* r
developed after gonadotropin therapy (96 ng./dl.). Higher) P: P9 Z1 ], u3 X: R2 m. V
serum levels were noted in older patients (12 and 17 years old),% P! T l" D8 \1 ?7 V7 ]5 I9 ^4 K+ @$ Q
while lower levels persisted in younger patients (4, 8, and 10
" A( q9 s! X( z0 W& U# {9 N! iyears old) (see table). Despite absence of profound alterations
+ c7 W& _. N9 u. Q3 N8 l6 ~of serum testosterone the topical therapy provided a greater. K6 S2 ? B! [9 A3 r$ |( Q& m
Accepted for publication July 1, 1977. ·! ?$ f5 H' N' A3 n; X
Read at annual meeting of American Urological Association,& t5 f: }! B' |4 j
Chicago, Illinois, April 24-28, 1977.
/ k* k W& N% u+ P* Requests for reprints: Division of Urology, Henry Ford Hospital,
6 c8 ]0 X* a% W w2799 W. Grand Blvd., Detroit, Michigan 48202.; R7 t8 t6 O1 T0 W
improvement in phallic growth compared to gonadotropin.
8 O; S! y7 d# n7 SAverage phallic growth with gonadotropin was 14.3 per cent
- `- z% L! B7 ^5 h' U) F. iincrease in length and 5.0 per cent increase of girth. Topical$ q3 ? }$ X, U# \+ w# u
testosterone produced a 60.0 per cent increase of phallic length
, K- V) b0 a- X* i* O8 {and 52.9 per cent increase of girth (circumference). The
! H/ Z8 ^* k7 L0 G/ W& lresponse to topical testosterone was greatest in children be-1 u( D0 W: g- h9 ?1 U M$ T6 @1 ^6 l
tween 4 and 8 years old, with a gradual decrease to age 17
5 u; L8 {8 C$ i) v' o3 @' G4 N& i: Byears (see table).
5 m+ K/ b( C _/ M7 l" ?7 ADISCUSSION
3 E+ Y6 B8 n$ x, K1 c( z e0 bTopical testosterone has been used effectively by other
# ?& X/ `/ B# C( S; pclinicians but its mode of action remains controversial. Im-
; T1 {7 J' d5 m6 {+ b) ^: Imergut and associates reported an excellent growth response8 ~% h6 H( d. [3 o; ?: E+ X. q
to topical testosterone with low levels of serum testosterone,3 N0 Z3 ~# x1 V' {
suggesting a local effect.1 Others have obtained growth re-
! F# D3 {$ e5 V- N" S" F) K" U* \sponse with high. levels of serum testosterone after topical
, M; E5 k/ ]$ zadministration, suggesting a systemic response. 3 The use of
: e; z0 p9 B% g9 U) p0 {% ^, fgonadotropin to obtain levels of serum testosterone compara-" D4 P4 `8 ^8 U B. R4 k
ble to levels obtained with topical testosterone would seem to* n1 b) v7 N, r
provide a means to compare the relative effectiveness of
# T. V" `5 t. T+ N" q7 Vtopical testosterone to systemic testosterone effect. It cer- N r8 ? s7 f2 G( y
tainly has been established that gonadotropin as well as par-4 j; n" L1 O5 ^; D& ^
enteral testosterone administration will produce genital
& m5 V. D |! F5 i Ggrowth. Our report shows that the growth of the phallus was
8 d1 i( W8 v; P& B" V' f; j3 v1 gsignificantly greater with topical applications than with go-: V3 ~) P4 p/ m% c) g6 B
nadotropin, particularly in children less than 10 years old.0 H) K) s# v+ s# h0 H
The levels of serum testosterone remained similar or lower
; d" D! i$ I8 O8 D! f/ Jthan with gonadotropin during therapy, suggesting that topi-
u {6 {$ @' f- z2 }cal application produces genital growth by its local effect as% e3 l; N+ l0 u# {( Y& @
well as its systemic effect.
4 d! e) y; a" E/ h7 c9 AReview of our patients and their growth response related to/ B! j, Z. a3 Y+ c( d+ a3 u
age shows a greater growth response at an earlier age. This is, g) V) }7 o9 _+ @
consistent with the findings of Wilson and Walker, who
0 P& G; v# ]2 l7 U! J1 x& I- A% X" nreported an increased conversion of testosterone to dihydrotes-
, r2 `% y, w. s8 `2 l& V$ Ftosterone in the foreskin of neonates and infants.4 This activ-# f4 E5 Q9 e8 w3 {6 A
ity gradually decreases with age until puberty when it ap-
9 _8 y7 G. P+ U: }proaches the same level of activity as peripheral skin. It may9 k6 A/ m6 z9 \9 L6 x! A
well be that absorption of testosterone is less when applied at
* M. e1 F1 O- V$ a4 Dan earlier age as suggested by lower serum levels in children' ], A3 M/ q" s; n$ o. G
less than 10 years old. This fact may be explained by the8 c$ w6 p% d4 }8 b# `$ S0 N
greater ability of phallic skin to convert testosterone to dihy-
4 ~( c8 x/ J) U7 t5 ?; m9 ]drotestosterone at this age. Conversely, serum levels in older
: ^ ^, _3 p2 `, n! }% K6 _patients were higher, possibly because of decreased local
% @' M& m0 g% K2 i( o667
2 H# [4 N. Z7 A2 f0 u* M1 [9 U; z668 KLUGO AND CERNY
8 \. G: ^! @7 T" L& BPt. Age. O3 O) `0 Z! v" U, d
(yrs.)3 f4 S3 |( y$ X: {( ^6 \, Z- ^
Serum Testosterone Phallus (cm.) Change Length
$ d3 i. g+ {; V: ^1 ^! C9 {: ~4 t(ng./dl.) Girth x Length (%); |/ X1 }) Z& Z- @: x8 H" ^$ f
4
. _) _; n) V, g- J8; f2 c8 I) r6 N6 [1 y$ b7 V
10
8 I) ]: r$ q% N' u! F5 c12 L7 a' f" `, P9 a! f$ |4 a. C& h1 @
17
! F+ _9 p, ?0 \9 ?4 [Gonadotropin
, T9 g+ {! r6 x, {! j" T6 z71.6 2.0 X 3 16.6
( c0 }' a1 u1 z6 w2 I$ `. M3 m50.4 4.0 X 5.0 20.0
+ R+ \) M( ]0 X$ ]22.0 4.5 X 4.0 25.0
' | {5 z1 `6 b- O. Q84.6 4.0 X 4.5 11.1
B H" B; G4 s/ O/ w85.9 4.5 X 5.5 9.0
7 L! i( U t3 K% D. t) lAv. 14.3( f0 }2 V( }5 V3 V. d( |
40 j! k `* \4 U! Y3 s% z
8
7 l* {: Y1 \& h0 q5 ^5 z3 L10. c( Y( o) @ g. d g
12$ ~8 X& w, C) W* S. T
17& I) {/ x) x" U# c2 N) Y4 N
Topical testosterone
$ [6 f5 M' H! T/ R |) G# v( N34.6 4.5 X 6.5 85) A; y U) i4 J# ]. V7 ]
38.8 6.0 X 8.5 70
( r0 p" v9 X/ B1 ~40.0 6.0 X 6.5 62.5. Y- o. u; v) q( E; S) b' }/ h9 t
93.6 6.0 X 7.0 55.5
/ Q% c" U& b" W) Q K95.0 6.5 X 7.0 27.2+ l9 ?9 P2 v/ T Z# b, @( x
Av. 60.0
, t& s, a: z! E" q$ Pavailable testosterone. Again, emphasis should be placed on
0 _# T3 |8 W: @! r6 l7 Bearly therapy when lower levels of testosterone appear to
7 ]% {9 b$ l+ w& h& K* _$ y2 O' |provide the best responses. The earlier therapy is instituted
3 {0 g( i1 G8 ^6 ]the more likely there will be an excellent response with low
7 k! s, F7 k1 i3 g& f0 u: b. W: Xserum levels. Response occurs throughout adolescence as. j0 R4 Y1 }& u+ V4 W
noted in nomograms of phallic growth. 7 The actual response
" J, {6 V5 @2 j; ]& o8 t6 wto a given serum level of testosterone is much greater at birth
# q8 n: U& X6 c5 j# Q band gradually decreases as boys reach puberty. This is most
6 M( K( V5 L1 E0 u: Clikely related to the conversion of testosterone to dihydrotes-7 F( h2 X3 M2 b% W
tosterone and correlates well with the studies of testosterone
+ Q# A5 @' o$ [& b/ T4 {6 |conversion in foreskin at various ages.' L* t) i1 N" c a
The question arises regarding early treatment as to whether
' w7 T7 @ @( l5 Kone might sacrifice ultimate potential growth as with acceler-* L! U% z0 {3 \& j$ P0 ]4 u( `- X
ated bone growth. The situation appears quite the reverse8 Z+ Q6 l7 @; {
with phallic response. If the early growth period is not used
3 v/ j$ v; Y: u/ L {6 nwhen 5a reductase activity is greatest then potential growth; ]% a# N0 M5 s0 s0 u2 k
may be lost. We have not observed any regression of growth G1 a$ v+ C4 K$ G6 p
attained with topical or gonadotropin therapy. It may well
6 t5 Q. @3 J8 x" ~be that some patients will show little or no response to any
: g3 C( U2 H$ v1 cform of therapy. This would suggest a defect in the ability to4 s$ U5 D1 |( e' [: V& ]
convert testosterone to dihydrotestosterone and indicate that4 Z s3 u/ v ~! }5 h4 H
phallic and peripheral skin, and subcutaneous tissue should
: U X c0 N+ c/ k$ I5 \be compared for 5a reductase activity.: W+ b/ }5 t2 J+ [+ n
A, loop enlarges to measure penile girth in millimeters. B,% o- \1 p2 g- g; b
example of penile girth computed easily and accurately. x( k/ A9 w a
conversion of testosterone to dihydrotestosterone. It is in this; J$ @8 n) G9 U% i7 t# T A# v2 Q
older group that others have noted high levels of serum$ ]1 t6 x& A4 u
testosterone with topical application. It would also appear/ F) |) B" R8 C/ w; ]. t* w. E
that phallic response during puberty is related directly to the) @; O# b6 g: S1 U4 L+ U2 X
serum testosterone level. There also is other evidence of local) \" F4 M1 |2 u& d/ P2 v( u
response to testosterone with hair growth and with spermato-
$ q/ t! k* v7 i Sgenesis. 5• 6
# |! j; R \$ B2 l+ t# A7 BAdministration of larger doses of gonadotropin or systemic
* Y) G$ t1 L2 Y2 Ytestosterone, as well as topical applications that produce. _6 t2 G# l; R, W' Z
higher levels of serum testosterone (150 to 900 ng./dl.), will& o8 m( ?9 ^& Z7 d
also produce phallic growth but risks accelerated skeletal3 n$ y- D3 H ]5 A$ L$ B" A
maturation even after stopping treatment. It would appear2 x3 n- ]% i# N, n
that this may be avoided by topical applications of testosterone# k) n, C9 v, N' [
and monitoring of serum testosterone. Even with this control5 d6 T- k. w7 t9 R! F* X% l6 R" \9 Y
the duration of our therapy did not exceed 3 weeks at any
7 ?# Y$ A: r0 u( z+ ~ C% `1 [time. It is apparent that the prepuberal male subject may
1 A A: O7 o* H6 Z4 psuffer accelerated bone growth with testosterone levels near. M A+ J8 \# r# s$ w) Z
200 ng./dl. When skeletal maturation is complete the level of
- Z* T3 f( r3 E7 w( M- hserum testosterone can be maintained in the 700 to 1,300 ng./ P# F, |5 h- Y& A1 J, c: O
dl. range to stimulate phallic growth and secondary sexual
$ @" ]7 H+ ^/ R0 Z, K7 tchanges. Therefore, after skeletal maturation parenteral tes-1 G6 r' O/ R9 ]% S
tosterone may be used to advantage. Before skeletal matura-
( k' j- y* s3 e. x% Ltion care must be taken to avoid maintaining levels of serum
0 i0 {7 d" G* P1 x6 I' G( n" Ttestosterone more than 100 ng./dl. Low-dose gonadotropin7 k4 w b# P& @1 B' t: R& V
depends upon intrinsic testicular activity and may require
5 b+ E0 _8 S/ E) H: m9 rprolonged administration for any response.
; ?8 f8 K0 k& m: tAlternately, topical testosterone does not depend upon tes-$ P, ]# V& Y ^% q- o
ticular function and may provide a more constant level of
* t$ \+ D% D6 k' u& JREFERENCES
0 S, x! h9 u5 w1 r. a1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
4 [" }, s9 E9 wR.: The local application of testosterone cream to the prepub-
( }( i" g* w/ Zertal phallus. J. Urol., 105: 905, 1971.
# S% ^: |: d1 f1 u3 {7 q2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone' J0 x/ z4 V Y4 i
treatment for micropenis during early childhood. J. Pediat.,
/ ~6 s4 Z& I6 \83: 247, 1973.' c7 ^" v x8 X2 a) V$ n+ O \
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
( P9 ^( _* a+ B7 B8 | c6 ]. B; ^$ Xone therapy for penile growth. Urology, 6: 708, 1975.0 C$ \6 p3 n8 b% n( O
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone* c. k% h2 m2 D7 D# l
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by3 ]' v" I8 C( P- a9 c: _ {
skin slices of man. J. Clin. Invest., 48: 371, 1969.
" ]3 Z. o8 s0 v2 B5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth3 T* n" s0 S# y4 S9 \
by topical application of androgens. J.A.M.A., 191: 521, 1965.% c; R0 D1 b/ w
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local) N; u6 |0 Y3 W% I0 [/ k
androgenic effect of interstitial cell tumor of the testis. J.* m) N- |- v3 K
Urol., 104: 774, 1970.: h9 h( ]% C: _
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-: A+ d+ t: a* h7 N _, J" Q8 L3 @4 T
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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