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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND* s- w2 i- D. g/ A/ x
GONADOTROPIN+ V) b8 a6 Z9 t$ ]
RICHARD C. KLUGO* AND JOSEPH C. CERNY; \8 y6 R- ~( b1 ~
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
) U) {/ N m& JABSTRACT
; z3 t: h& ` J4 e: o1 AFive patients were treated with gonadotropin and topical testosterone for micropenis associated7 _* p8 w$ e# w' N8 C) z
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-! q$ o' |" z! |0 \5 @
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
{0 N6 M* s4 [" ?cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent5 Z3 }$ P0 V, C9 |/ N# N# N. T
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent$ `2 k# s: f$ f, a$ }4 C
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
! i/ D4 n$ p9 b. M8 N; q. {increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
9 g8 m ^* V$ j6 U% G7 O4 Voccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This3 R4 R% N6 S. \
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile( y2 w0 q+ C. o& P( n
growth. The response appears to be greater in younger children, which is consistent with previ-) J7 P9 H. C- D1 f- e4 z0 F
ously published studies of age-related 5 reductase activity.0 i0 r3 v9 e$ I; j9 V9 l# e/ c
Children with microphallus regardless of its etiology will& u/ ~5 b$ Q x9 r8 J- A2 c
require augmentation or consideration for alteration of exter-* O6 ]1 I. N: o% v9 M3 h
nal genitalia. In many instances urethroplasty for hypo-
8 d9 O" {, n7 Q% }spadias is easier with previous stimulation of phallic growth.; t% K( ~, x. O J3 e" d
The use of testosterone administered parenterally or topically
- _3 k3 X% _; b" H; qhas produced effective phallic growth. 1- 3 The mechanism of9 k+ O5 v2 {7 J: z
response has been considered as local or systemic. With this8 O: i( e! X" B4 {5 Q
in mind we studied 5 children with microphallus for response
0 r3 ^8 _7 Q o3 fto gonadotropin and to topical testosterone independently.9 X8 h l, y& z
MATERIALS AND METHODS
* d9 z% p* n. ]6 C% k9 w; I1 EFive 46 XY male subjects between 3 and 17 years old were
/ K: v1 ^7 i7 M4 v i) B0 \& Q, b) kevaluated for serum testosterone levels and hypothalamic
2 H& b$ C# A' B) w+ kfunction. Of these 5 boys 2 were considered to have Kallmann's
4 j1 O+ a. v' ~ w' ysyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-8 Q) L1 n7 h2 t
lamic deficiency. After evaluation of response to luteinizing
3 z E6 j. H6 \# E( |' Mhormone-releasing hormone these patients were treated with; a3 \) w0 n3 M i: F- a
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
# q3 Z7 [7 ]7 P/ W& \/ y; }9 J/ @: P$ }after completion of gonadotropin therapy 10 per cent topical
" n" g* q) H, M, etestosterone was applied to the phallus twice daily for 3 weeks.
% J. ?' t& j( P- v9 SSerum testosterone, luteinizing hormone and follicle-stimulat-4 K1 h: m8 K* w2 q/ j3 [: u
ing hormone were monitored before, during and after comple-5 z E+ M/ s1 [
tion of each phase of therapy. Penile stretch length was8 o4 m( T0 [0 d$ y/ G( p
obtained by measuring from the symphysis pubis to the tip of
/ Z, K$ n9 `0 A- Qthe glans. Penile circumferential (girth) measurements were
& J3 } Q. B, ^! eobtained using an orthopedic digital measuring device (see
/ P5 ?" d* J9 P6 Gfigure).8 m& h/ I M7 H8 n4 B
RESULTS
* b+ D- u: N: N4 O9 WSerum testosterone increased moderately to levels between0 F' S) u6 r1 Z& j" U# h, t
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
& [3 N/ q8 U) i; N! ?0 z8 s, C6 U+ hterone levels with topical testosterone remained near pre-) P! y/ P4 s% W7 n6 W6 |
treatment levels (35 ng./dl.) or were elevated to similar levels
! m6 L6 c0 l2 u# c8 F( ^, U. B: Tdeveloped after gonadotropin therapy (96 ng./dl.). Higher4 N( R9 N5 Q1 ]0 f
serum levels were noted in older patients (12 and 17 years old),
% ~6 \* [3 v. y3 z% v- Wwhile lower levels persisted in younger patients (4, 8, and 10
' \% i$ b/ G( }* F- C$ `& z8 gyears old) (see table). Despite absence of profound alterations* v+ ?, ]: }; F
of serum testosterone the topical therapy provided a greater
& Y& t' a) p2 N! O7 L9 eAccepted for publication July 1, 1977. ·
* Y' D4 H8 V# H+ J' r" VRead at annual meeting of American Urological Association,
/ G5 s- ^& A2 y; v3 sChicago, Illinois, April 24-28, 1977.% k, u5 f% V; N4 {5 K1 c( C, `5 s
* Requests for reprints: Division of Urology, Henry Ford Hospital,
+ W' `* P/ `' B* N/ {( j2 _2799 W. Grand Blvd., Detroit, Michigan 48202.& }. N. H) b4 H1 [
improvement in phallic growth compared to gonadotropin.
, B' \3 M% C. x& w8 V8 T o2 ]Average phallic growth with gonadotropin was 14.3 per cent
! i; D& Y3 H, X t% ~- S/ Iincrease in length and 5.0 per cent increase of girth. Topical" X3 f# S6 s k3 d9 e6 _$ K
testosterone produced a 60.0 per cent increase of phallic length
8 E% m+ N4 [2 j9 V, V% `and 52.9 per cent increase of girth (circumference). The6 g' J" g# l2 C* {2 ]- n+ y1 R
response to topical testosterone was greatest in children be-0 U: ]7 G) h; }. `$ [/ _# P( v
tween 4 and 8 years old, with a gradual decrease to age 17+ h, ?. F* U) h, B6 ]8 D
years (see table).; b4 X m, ^/ G; Y6 m4 m# g
DISCUSSION
) |' Z: W- m" L: b4 ?- b% ?2 l/ \Topical testosterone has been used effectively by other
6 X4 T' ?$ J* @7 S4 ]8 mclinicians but its mode of action remains controversial. Im-, ^' K4 V: s, o
mergut and associates reported an excellent growth response- i- a/ q% L1 e% J2 [
to topical testosterone with low levels of serum testosterone,! ~1 k6 l; b: G( c1 D
suggesting a local effect.1 Others have obtained growth re-# n6 ~+ u3 _' C' f( N
sponse with high. levels of serum testosterone after topical
9 y2 L9 W1 K7 O/ \& k0 x5 zadministration, suggesting a systemic response. 3 The use of M/ X* i" f6 W3 _% m
gonadotropin to obtain levels of serum testosterone compara-
% `: K5 c2 t# Q7 K% i" t$ hble to levels obtained with topical testosterone would seem to+ a& L% i$ @0 v. K, k( H1 c3 R6 F
provide a means to compare the relative effectiveness of. f& ]+ @+ k' ?7 @6 z: P
topical testosterone to systemic testosterone effect. It cer-
5 H5 x5 e t% y+ y, utainly has been established that gonadotropin as well as par-
$ X; w7 X, M7 ?enteral testosterone administration will produce genital5 E0 T+ `( P; Q
growth. Our report shows that the growth of the phallus was, }% d( t; } T( l) G
significantly greater with topical applications than with go-
! \( {: ~ |8 z8 Vnadotropin, particularly in children less than 10 years old.
6 I, J- g1 C+ x; T$ }( |& PThe levels of serum testosterone remained similar or lower
2 K6 V- f1 h' r3 f/ [than with gonadotropin during therapy, suggesting that topi-1 K. _' ^% f% p. b4 B
cal application produces genital growth by its local effect as- [ K( H8 d* j# a
well as its systemic effect.& r9 v- z! H E; D* S
Review of our patients and their growth response related to
, P; B. Z; K$ Z, R3 o. xage shows a greater growth response at an earlier age. This is5 G, r3 n- V) ?2 g
consistent with the findings of Wilson and Walker, who7 ?+ v; Q3 P6 ^: }# \: i* C5 N( b
reported an increased conversion of testosterone to dihydrotes-
: N9 ^ |* ?( h; | D+ ytosterone in the foreskin of neonates and infants.4 This activ-
1 K: T& j7 T5 t7 _ity gradually decreases with age until puberty when it ap-
7 b9 U1 s+ n. }: M+ m* h; }proaches the same level of activity as peripheral skin. It may5 v. x e) b; g
well be that absorption of testosterone is less when applied at
, }% r, B- C% ]- Zan earlier age as suggested by lower serum levels in children
& C8 J- w1 _9 w$ \5 I9 \9 M! r8 Iless than 10 years old. This fact may be explained by the9 V( h; K: j4 c; X* ?: ? F+ B- ?
greater ability of phallic skin to convert testosterone to dihy-& z- C8 h1 O. D% w% g' J2 D1 [
drotestosterone at this age. Conversely, serum levels in older
5 n- Y; E% e* n( Vpatients were higher, possibly because of decreased local
1 O) e# F4 {. O2 d4 t) T! s% o6671 ]1 {" |/ |0 e2 I* {6 c
668 KLUGO AND CERNY
9 i y, _5 I/ Y- B5 k/ }Pt. Age- O- |! u# @9 g ?1 M+ `
(yrs.)( p! D) }6 c: U9 Q |7 K# H
Serum Testosterone Phallus (cm.) Change Length( V }/ K6 }" `0 J v( d" X
(ng./dl.) Girth x Length (%)
* M4 C& G n$ V9 Z. j: a% x4& L2 U- Y7 Y& t. F
8
. ~0 |" L+ S. ?, i$ W9 R T100 z5 z' R$ N( ?' o& A9 q" Z
12
: u2 w5 a# ^' S/ n; y2 l17) X) X' R$ n. v& o$ f
Gonadotropin9 h8 g. `6 D& e* L) t: Q8 D+ H
71.6 2.0 X 3 16.6
# v6 ]4 F$ l6 O50.4 4.0 X 5.0 20.0
5 w# u7 r& @6 |+ q9 s22.0 4.5 X 4.0 25.06 a" H5 [8 n7 \" I* u, v( s9 O4 ]
84.6 4.0 X 4.5 11.1
7 R% z" Y4 O6 C85.9 4.5 X 5.5 9.06 x0 u9 B# i ~2 H
Av. 14.3
6 d2 B9 u9 |& O& k8 u* e4# O+ K/ I& `/ T& m' A" E" W
8
0 t, w& t' p7 _2 b3 h, ?10
! C) Q$ O, z' B121 Z. T( O6 Z$ A, C
17
7 k( j9 U( j; C3 W/ ITopical testosterone8 {4 F1 V! j. A7 N W
34.6 4.5 X 6.5 85) k* ^" s3 Z+ S% p- a
38.8 6.0 X 8.5 708 F U6 y1 J. i- }0 K
40.0 6.0 X 6.5 62.5
/ `# |, @& \1 m% g% h93.6 6.0 X 7.0 55.5
4 c$ V r! Q+ u- y5 \95.0 6.5 X 7.0 27.2) r$ p8 Z6 s4 B/ ?3 H" [( K! |" u0 e
Av. 60.0- h9 T( _, X4 D! n- Z* g
available testosterone. Again, emphasis should be placed on
% z% X. t& O" f- q" e4 i& u% F( A* Rearly therapy when lower levels of testosterone appear to5 n, r0 }+ T4 i7 \# m2 F
provide the best responses. The earlier therapy is instituted& h; n H4 @: [& @3 y6 {
the more likely there will be an excellent response with low" S% m1 f! n. D2 t* P
serum levels. Response occurs throughout adolescence as" \; U2 x9 n3 S$ i# J3 L& r" x
noted in nomograms of phallic growth. 7 The actual response! s2 P& z/ F0 q& ?
to a given serum level of testosterone is much greater at birth& ]9 ]1 {' K' {8 y- U6 u$ x m
and gradually decreases as boys reach puberty. This is most" o+ @: b7 a/ C
likely related to the conversion of testosterone to dihydrotes-6 [- R3 Z3 I7 m+ w: @* F. v
tosterone and correlates well with the studies of testosterone
5 N. f8 V: b4 g$ Y8 F! t+ H3 uconversion in foreskin at various ages./ z" B3 u2 V1 |
The question arises regarding early treatment as to whether# F0 K# N/ ]( V1 E
one might sacrifice ultimate potential growth as with acceler-& P$ a/ t* O7 }) ]( l g
ated bone growth. The situation appears quite the reverse" N- f0 x' x: h6 F( Y6 q* `
with phallic response. If the early growth period is not used: T0 n9 ^, b c
when 5a reductase activity is greatest then potential growth. r8 b" |1 ?; H1 B( k
may be lost. We have not observed any regression of growth
# ]& t' k, s0 F2 zattained with topical or gonadotropin therapy. It may well
8 `7 y6 a6 j0 L& P* t* Ebe that some patients will show little or no response to any" W4 P' x9 B: |' Z" @1 K8 J
form of therapy. This would suggest a defect in the ability to- U& s" _! `8 N- t) |
convert testosterone to dihydrotestosterone and indicate that
! \& F$ l( ^$ T4 G% X& mphallic and peripheral skin, and subcutaneous tissue should
7 Q" H3 b. s0 b9 Y- _. m2 k8 q( Obe compared for 5a reductase activity.
2 I% @6 S- u2 SA, loop enlarges to measure penile girth in millimeters. B,
+ @4 K, i/ J0 r% Yexample of penile girth computed easily and accurately.
/ h) G, w2 L* U5 p9 rconversion of testosterone to dihydrotestosterone. It is in this) _+ E1 O; C) `* w0 o6 T
older group that others have noted high levels of serum
, N1 }8 J# P( |( ^; h8 N8 g2 htestosterone with topical application. It would also appear
' E, U6 S V. m; a1 W ~# B( l, p1 O! ?that phallic response during puberty is related directly to the
! z2 d- S9 P7 ?serum testosterone level. There also is other evidence of local
! M& U' u/ @% z h: W) R( ^response to testosterone with hair growth and with spermato-8 I- b# F- U9 h, ^: L4 { v% @- q
genesis. 5• 6, H: t& z- Z, q1 L+ J
Administration of larger doses of gonadotropin or systemic
: O1 }, H3 S6 y) y5 Z. \4 ~6 rtestosterone, as well as topical applications that produce) S$ m7 H8 {- y$ |8 M
higher levels of serum testosterone (150 to 900 ng./dl.), will+ j" j, ]3 n& Y/ A7 ?0 }; b; f
also produce phallic growth but risks accelerated skeletal e, O, B% Z0 m# ^
maturation even after stopping treatment. It would appear
. t7 @3 y* N1 F- k. V% m# Ythat this may be avoided by topical applications of testosterone
7 f$ v0 v" b+ I( g" {and monitoring of serum testosterone. Even with this control
; `" G; H5 Y7 o' r+ S9 kthe duration of our therapy did not exceed 3 weeks at any x0 Y+ H0 P9 e
time. It is apparent that the prepuberal male subject may
+ j; ~, N2 x' Nsuffer accelerated bone growth with testosterone levels near) B; C6 b& [& V( W7 e( c( u- V$ x
200 ng./dl. When skeletal maturation is complete the level of
7 u5 F# @, O( p6 e" d1 t' G/ I' Xserum testosterone can be maintained in the 700 to 1,300 ng./
! a( J% S0 y2 e; Gdl. range to stimulate phallic growth and secondary sexual
, q! n# e2 t0 Z- f' achanges. Therefore, after skeletal maturation parenteral tes-
9 o2 I+ `* e" K4 a" }# Ctosterone may be used to advantage. Before skeletal matura-
$ T3 V4 M2 e$ c E0 @; p6 ]) ~7 Ction care must be taken to avoid maintaining levels of serum
# m0 |- t4 J+ D! s, ~' G2 Ptestosterone more than 100 ng./dl. Low-dose gonadotropin
6 P- F! g* j# R6 b8 Q9 U6 O# Cdepends upon intrinsic testicular activity and may require
' U5 Z7 y! x4 `4 Cprolonged administration for any response.# H" G5 l2 s& K% M8 g+ A- v/ o7 j
Alternately, topical testosterone does not depend upon tes-2 f0 e; g8 k4 @3 p) M: v5 J8 ~$ W
ticular function and may provide a more constant level of# p; Z- s- s) P: m: \# A8 _. n
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; P+ S5 m& D$ M2 `$ eR.: The local application of testosterone cream to the prepub-" L, i" k7 P) a5 M2 T
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2 N+ n( I( o1 i; z2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
8 c5 z6 n7 y, Etreatment for micropenis during early childhood. J. Pediat.,
7 A' c0 A) C2 ~8 ?8 h; n83: 247, 1973.
" F- @% n$ y- q+ v% \: Z9 e3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-: B* F. I7 ]1 R
one therapy for penile growth. Urology, 6: 708, 1975.
: \; e4 i4 ~+ d4 w; y5 H4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone+ ^6 W3 n- d" L+ x" d+ Q7 E. d
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by, b% D2 U( Z' Q( o9 t4 d
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Urol., 104: 774, 1970.) l' R7 w& S5 L8 A; L( i' W
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5 ?" S! P3 q8 \; ztion in the male genitalia from birth to maturity. J. Urol., 48: |
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