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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
7 F8 _$ E' P2 n# L; i' G; k' @" E! KGONADOTROPIN9 w. h5 y( m. |# }, K' _
RICHARD C. KLUGO* AND JOSEPH C. CERNY0 P3 k# X( u9 q
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
0 V' A$ d# ?1 |' g! J8 {8 _+ @ABSTRACT. g: t& O w M9 V6 R
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
5 V# d3 a, O8 `7 H: z1 N z Wwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
% z% d$ q8 K0 O5 S# _ }5 Rtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
$ Y: }+ i, G A3 `cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent' W. H; B1 T6 }
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent$ ]; |9 t" \: u# ?/ s' L2 A0 W
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
9 ?: `$ T& O& G+ ?; B5 p. |increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
* T$ `0 a8 `1 I- ], L. Goccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
' [; _1 e# z) c, Z9 }9 Vstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile2 \8 I( b5 Q4 i; N" F* r; z
growth. The response appears to be greater in younger children, which is consistent with previ-
: F0 b1 O' t6 K3 e. xously published studies of age-related 5 reductase activity.! v) ^# s, x$ y- }0 c
Children with microphallus regardless of its etiology will
/ I5 [( e! }0 Y) ?9 j( grequire augmentation or consideration for alteration of exter-: l* a* V& ?1 [: D5 W0 W+ ]3 }
nal genitalia. In many instances urethroplasty for hypo-
0 n. O/ C7 V. Dspadias is easier with previous stimulation of phallic growth.
% Y, K) f {- s8 eThe use of testosterone administered parenterally or topically3 N7 |1 y# T# c
has produced effective phallic growth. 1- 3 The mechanism of
+ u$ }1 p: q( x5 C0 N- {response has been considered as local or systemic. With this2 O: ~7 `9 T* ]
in mind we studied 5 children with microphallus for response
/ q' @3 J/ ]. w2 O( K0 Wto gonadotropin and to topical testosterone independently.2 _; l y1 K4 m6 B R
MATERIALS AND METHODS
" N3 W4 K3 f! Z& C# EFive 46 XY male subjects between 3 and 17 years old were, n d+ B7 X) t4 f- Y5 k7 d
evaluated for serum testosterone levels and hypothalamic# a9 u" a! |# C0 d/ x: U- r
function. Of these 5 boys 2 were considered to have Kallmann's
) i$ _6 E1 z- dsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
# H8 U' d! o, y! b' z4 k6 C3 k+ Plamic deficiency. After evaluation of response to luteinizing
( [: F" T8 Y" ghormone-releasing hormone these patients were treated with
1 B+ m: @6 C4 ^6 d& t7 p1,000 units of gonadotropin weekly for 3 weeks. Six weeks
/ _5 S3 t; n/ P+ L" z0 c0 R; d5 cafter completion of gonadotropin therapy 10 per cent topical
4 j" t6 ]2 `: O5 dtestosterone was applied to the phallus twice daily for 3 weeks.
2 X5 \# v; J) }# g9 _$ Z" eSerum testosterone, luteinizing hormone and follicle-stimulat-
& o1 U2 U! h8 g L8 s$ a$ X, hing hormone were monitored before, during and after comple-
+ q* R4 M; Q6 T& [& \5 p; C' C% Wtion of each phase of therapy. Penile stretch length was
/ m$ [, k& K: X7 M, K- [obtained by measuring from the symphysis pubis to the tip of
4 J- Q5 J. m8 `5 G) `) Mthe glans. Penile circumferential (girth) measurements were+ }5 {: ~: ?, O$ g* j
obtained using an orthopedic digital measuring device (see
% A8 j2 V% v; F! ifigure).
! z5 g& U9 J9 o v+ B( ~5 ]9 |RESULTS, [7 ?6 y+ A& q
Serum testosterone increased moderately to levels between
% y$ O' i' w+ ~2 U50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-8 d" N5 g' q, g0 Q1 \- w
terone levels with topical testosterone remained near pre-$ A, q7 r: v# t
treatment levels (35 ng./dl.) or were elevated to similar levels7 c1 Z5 W, T" D* f
developed after gonadotropin therapy (96 ng./dl.). Higher
: u) U3 H: ?8 w: T! ^5 cserum levels were noted in older patients (12 and 17 years old),
3 [. W4 H6 Y4 D+ v6 Cwhile lower levels persisted in younger patients (4, 8, and 104 T3 E/ J+ b3 D% G' Z' l
years old) (see table). Despite absence of profound alterations
. @/ T5 B& G5 n2 `0 L' qof serum testosterone the topical therapy provided a greater7 H. j. d8 m/ j5 }$ U
Accepted for publication July 1, 1977. ·
2 U; H, @1 U# [: V4 J% C8 URead at annual meeting of American Urological Association,
5 A# g5 n1 F) }0 @4 FChicago, Illinois, April 24-28, 1977.
) v+ k# l$ x0 e, W# _& w* Requests for reprints: Division of Urology, Henry Ford Hospital,- L: l" e( M+ n" H# C# ?8 f7 |
2799 W. Grand Blvd., Detroit, Michigan 48202.
& M2 ?: I) V5 [ Gimprovement in phallic growth compared to gonadotropin.
/ o1 [4 x) @; a4 Z" _9 dAverage phallic growth with gonadotropin was 14.3 per cent
" W1 g1 b O5 P- F( a5 gincrease in length and 5.0 per cent increase of girth. Topical: R5 E/ I4 ] z u+ i
testosterone produced a 60.0 per cent increase of phallic length9 u- o$ L$ R/ b, l- V% p6 B* L
and 52.9 per cent increase of girth (circumference). The
+ q( h7 h( c9 y! |6 c3 I: h* T- Vresponse to topical testosterone was greatest in children be-. i s- A1 W. T7 v
tween 4 and 8 years old, with a gradual decrease to age 17
, ` P5 m" H5 h! oyears (see table).
4 F. j- t2 N* b1 v% A LDISCUSSION7 O, J9 R0 R0 x
Topical testosterone has been used effectively by other
" ^" ` z" E+ p( p& s3 zclinicians but its mode of action remains controversial. Im-) y0 {- p) Q' p! `% U/ _& O
mergut and associates reported an excellent growth response2 Y5 k3 }/ E" I+ r9 Y7 \0 w$ {2 v. y
to topical testosterone with low levels of serum testosterone,5 I7 }4 q$ L' C% p6 H: [
suggesting a local effect.1 Others have obtained growth re-) r3 z+ b* R9 `+ s9 D# I9 }
sponse with high. levels of serum testosterone after topical% H; j( d e) e* E$ q; B5 C+ d0 D
administration, suggesting a systemic response. 3 The use of
( \ Q( c% x, h; _8 rgonadotropin to obtain levels of serum testosterone compara-
6 o5 }# {1 l" ?1 t) z- y2 wble to levels obtained with topical testosterone would seem to, [5 v7 d+ g+ ^' M8 p1 S, H* T7 F
provide a means to compare the relative effectiveness of
5 P4 J# P# S+ S% D4 Ctopical testosterone to systemic testosterone effect. It cer-+ x1 v" o+ x4 a/ l
tainly has been established that gonadotropin as well as par-
- `3 f- O+ N; i5 g" N- Yenteral testosterone administration will produce genital
. r1 X' F+ ?, O: O- @ ~' qgrowth. Our report shows that the growth of the phallus was7 \( u5 n/ N' J& p
significantly greater with topical applications than with go-
6 X1 a2 M' B* \$ m s# Jnadotropin, particularly in children less than 10 years old.
D+ |, o0 O0 X" Q# y DThe levels of serum testosterone remained similar or lower
2 o7 ^6 T, M) Y+ X% k3 H+ o1 ~. H/ cthan with gonadotropin during therapy, suggesting that topi-
* d5 Z1 \: i9 s) n- R3 \% A- b0 dcal application produces genital growth by its local effect as$ |6 ?9 Q* m- C3 q3 o8 }+ b
well as its systemic effect.$ ^ q6 K$ f5 y8 F5 _( n+ j2 [
Review of our patients and their growth response related to
$ r+ Y6 }! y. u0 W/ H9 ?( z7 kage shows a greater growth response at an earlier age. This is/ C6 R+ v, {& S
consistent with the findings of Wilson and Walker, who
: p( H% z5 o% q9 a! Sreported an increased conversion of testosterone to dihydrotes-2 g# j' k1 H0 S+ a3 O
tosterone in the foreskin of neonates and infants.4 This activ-
* b: X5 b4 g( yity gradually decreases with age until puberty when it ap-, ]: m" a# M+ k! w9 V; [
proaches the same level of activity as peripheral skin. It may6 v; b9 g- D" D1 A: [5 I- @
well be that absorption of testosterone is less when applied at% ~/ O$ G' W0 D7 I+ c* t8 C, h0 J
an earlier age as suggested by lower serum levels in children
" h" q7 d( u, S. h7 K, Tless than 10 years old. This fact may be explained by the
9 t7 m' g5 [3 R/ E; N- k% B7 cgreater ability of phallic skin to convert testosterone to dihy-2 t- |- a7 O0 b B$ O
drotestosterone at this age. Conversely, serum levels in older
* T m) O M$ ` f! Jpatients were higher, possibly because of decreased local
+ \ [/ n. U! @7 n7 S9 t1 T& d667
7 Q0 H8 {6 ]" K* m, i668 KLUGO AND CERNY% N& m5 z3 f0 l8 ?$ {
Pt. Age
5 i9 a! |: h/ h2 w' s(yrs.)4 A$ R5 P0 I" b c O6 m N! w- c
Serum Testosterone Phallus (cm.) Change Length( x1 f |/ F9 ?. `0 H0 ]. `
(ng./dl.) Girth x Length (%)
6 \2 c9 O$ O* `$ d4
& B# ~6 c: G# } w6 u8
' _' h' x& ]+ j6 q) \10' t0 `2 E( e# w3 i/ j9 V
12
) r1 a6 D6 N; y6 N$ L6 H17' ^% G, r# K9 P8 s
Gonadotropin
& G1 m: b# `/ G- T9 d5 x: s+ C71.6 2.0 X 3 16.6
4 F% M: }' z* q$ S2 O0 {$ K1 p# f50.4 4.0 X 5.0 20.0
) O4 f) c8 V$ F/ S22.0 4.5 X 4.0 25.0
9 r1 k/ [! \- A$ \, Z8 M84.6 4.0 X 4.5 11.1
. m# ~% ~, Q9 o' T8 O85.9 4.5 X 5.5 9.0
! ]1 t! a2 _8 B& Z# D1 t3 g- CAv. 14.3, L! B3 ~9 l+ ~
4( F: u( `5 c0 b# n/ V
8
7 Y/ Z- M/ E: B, n/ n/ n10
8 l- z8 [9 w7 z3 I/ [. d6 N12
# y0 v1 Q- D1 ^! o: B) G) J17
$ |" k6 O9 p$ S6 |6 g" u0 E1 ~Topical testosterone6 O! a4 @ n4 `' K, p' Y
34.6 4.5 X 6.5 85
! U* N0 G H! J$ E38.8 6.0 X 8.5 70/ S. a* x/ [7 T+ D2 v* n# c
40.0 6.0 X 6.5 62.5# ~5 }* k9 }" e, P
93.6 6.0 X 7.0 55.5' q9 v0 W0 D' H+ M' W
95.0 6.5 X 7.0 27.2# t4 }8 x0 M$ x7 F& B" w8 r
Av. 60.0. P; D# k3 f. O! G6 O/ V
available testosterone. Again, emphasis should be placed on& U! S4 {( ^8 }/ c2 O' F9 l$ X
early therapy when lower levels of testosterone appear to
; Y7 c5 ?. S' J) cprovide the best responses. The earlier therapy is instituted+ V/ x/ U! C9 O" [3 p
the more likely there will be an excellent response with low5 D( B+ j+ O% C9 m# h( I
serum levels. Response occurs throughout adolescence as
7 E5 t8 c2 s2 [4 j7 _. unoted in nomograms of phallic growth. 7 The actual response
* ~, A7 k( }* V& s5 `% ito a given serum level of testosterone is much greater at birth
1 E. ?/ f& }% b6 z/ }+ z+ Eand gradually decreases as boys reach puberty. This is most
- }+ d* t, x% M# {) y! _, ?" Z( L5 G1 Zlikely related to the conversion of testosterone to dihydrotes-
# a, ~2 u' F0 n7 S# M+ w! S, i6 Rtosterone and correlates well with the studies of testosterone
; J6 @. t3 K: y; L& _, T' m( Kconversion in foreskin at various ages.5 h" a* D' ~" p1 m
The question arises regarding early treatment as to whether
, d2 v3 z5 M2 D# u5 D0 v8 f& t. Gone might sacrifice ultimate potential growth as with acceler-
) @6 n: E3 F/ d+ e7 |2 |ated bone growth. The situation appears quite the reverse1 ^# F! u% S& r4 |$ L
with phallic response. If the early growth period is not used) s1 I: _# i9 H: @
when 5a reductase activity is greatest then potential growth
6 n) i3 C) ?9 D; T: Q" z. Cmay be lost. We have not observed any regression of growth
6 @: J1 j% d q; Z2 c- Z5 _attained with topical or gonadotropin therapy. It may well
" L& H* ^2 i$ pbe that some patients will show little or no response to any& O. } q, m; L; B5 T# q
form of therapy. This would suggest a defect in the ability to4 @6 Y) n4 Z: y" s- S
convert testosterone to dihydrotestosterone and indicate that0 \ {. V3 o9 c9 G, c8 A9 E
phallic and peripheral skin, and subcutaneous tissue should" [4 Z; X% h. E
be compared for 5a reductase activity.4 N2 D9 [0 E, A8 u, Z, E. g
A, loop enlarges to measure penile girth in millimeters. B,, @# @& w: }5 Q0 M: O( t
example of penile girth computed easily and accurately.
1 y* L1 k/ E `/ _7 Wconversion of testosterone to dihydrotestosterone. It is in this& ~( l5 _& A6 Q ` k1 q1 n& A
older group that others have noted high levels of serum
: w1 V) v* }2 \1 C+ K" U. q% ntestosterone with topical application. It would also appear" _: x% R2 F8 l1 G' m4 s _. S8 ?
that phallic response during puberty is related directly to the2 _" q# F% a+ j! H5 S* A# ]% w
serum testosterone level. There also is other evidence of local3 w( x9 y1 u: L$ g+ \2 b
response to testosterone with hair growth and with spermato-. A- Z- `/ b; g5 j4 K
genesis. 5• 64 T& X: c% ?6 I2 ~6 a- A
Administration of larger doses of gonadotropin or systemic+ w, x1 q6 e* G
testosterone, as well as topical applications that produce
1 ]7 p3 j$ v5 j* o9 e. ]5 \higher levels of serum testosterone (150 to 900 ng./dl.), will
! x( j6 I b% h1 N( k! }9 x- P7 calso produce phallic growth but risks accelerated skeletal
/ H! ~( H' s9 T9 u6 f7 t& Smaturation even after stopping treatment. It would appear$ W0 s# J d. G6 I: [
that this may be avoided by topical applications of testosterone4 Z" R3 O0 P% K& T
and monitoring of serum testosterone. Even with this control
9 n* ]. r7 c. o/ Zthe duration of our therapy did not exceed 3 weeks at any
& r1 \) ~# t; {, xtime. It is apparent that the prepuberal male subject may' }# V' j( s2 L/ H9 j7 I
suffer accelerated bone growth with testosterone levels near
$ H5 h, M y+ C! e7 M; v200 ng./dl. When skeletal maturation is complete the level of
% r; ?- l9 x8 p1 ~8 i" i: Sserum testosterone can be maintained in the 700 to 1,300 ng./& W- g2 B' T4 |. v- G& H/ L* t
dl. range to stimulate phallic growth and secondary sexual
" _8 D9 Z: c5 cchanges. Therefore, after skeletal maturation parenteral tes-2 A0 m7 L, R9 t
tosterone may be used to advantage. Before skeletal matura-
5 W: _& f4 j9 ^tion care must be taken to avoid maintaining levels of serum1 M. C) [* { P# Q( [% ]
testosterone more than 100 ng./dl. Low-dose gonadotropin( ?5 p4 v: c8 L2 @! _0 P
depends upon intrinsic testicular activity and may require
" H, f% j6 t& }% P) C. Pprolonged administration for any response.
' a; Q2 ]+ V6 S7 U XAlternately, topical testosterone does not depend upon tes-+ Q* j, _: j% j
ticular function and may provide a more constant level of
8 D+ ?7 d# `. m2 pREFERENCES7 h' i m4 k. c$ ?! D. R
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
, }8 J, e: {) q; @2 ]R.: The local application of testosterone cream to the prepub-6 [. s3 _, Z8 A, |
ertal phallus. J. Urol., 105: 905, 1971.
$ K4 I; Y A1 z" E1 {# {' F" }2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
v% x0 T2 o9 \- R% Ktreatment for micropenis during early childhood. J. Pediat.,
8 e& M! {1 q, ^) F ~, k83: 247, 1973.
$ N! k$ } j# N3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
# B/ C% {9 r+ c& f+ }9 ^4 t1 eone therapy for penile growth. Urology, 6: 708, 1975.8 a0 |9 E V; E$ c; S
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone. t8 Q7 I8 x$ O3 N- Z; s9 ~
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
# X2 p5 b, N5 ]/ A3 {9 f$ Y* X4 Mskin slices of man. J. Clin. Invest., 48: 371, 1969.% U; @" |" P& ~% v
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
2 i& E* m7 ]1 O& _' P6 Bby topical application of androgens. J.A.M.A., 191: 521, 1965." k: v3 B& ~! N
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local# [( C! p2 R7 e8 k" D: H) r6 [
androgenic effect of interstitial cell tumor of the testis. J.
3 m* h$ O& @2 nUrol., 104: 774, 1970.
( X9 d7 _1 f* { v- l7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia- a5 P% B6 c$ i* [9 `
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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