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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND9 Q) H% X- e- r6 P
GONADOTROPIN" T8 h, \) q& e9 O# a$ N
RICHARD C. KLUGO* AND JOSEPH C. CERNY: Y B9 t ]$ {" L$ Q7 W& G+ C
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan5 s3 N h3 I9 O* e3 h
ABSTRACT
( w3 V; a, u: Y, vFive patients were treated with gonadotropin and topical testosterone for micropenis associated9 w% a" t7 x. E6 [- P
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-& D( \; Y$ |9 s. C/ K1 S
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
/ u( N; s$ x* r. M% U/ J, M9 Zcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
* r* c6 b) p1 L \) x7 Rfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
) q- i( R% g3 Hincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
; C! I4 u i/ [9 H% I# fincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response7 c0 J0 {9 X M
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This8 O5 e& Y( @' f" Q6 [/ m4 \. R$ Y
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
" E% L% H: Q; d& ]growth. The response appears to be greater in younger children, which is consistent with previ-; v+ G* n; h9 V
ously published studies of age-related 5 reductase activity.8 T; j9 O% a; L4 s, h$ I! a
Children with microphallus regardless of its etiology will4 V# d* ]3 h4 z
require augmentation or consideration for alteration of exter-
3 l: Y4 E k7 |, ?# R8 T# J2 Fnal genitalia. In many instances urethroplasty for hypo-
t+ E1 L+ q) ^% Jspadias is easier with previous stimulation of phallic growth.
+ ?* R( _: Y9 ^/ OThe use of testosterone administered parenterally or topically6 k' q3 t. s, F- ?0 @0 `, Q& R
has produced effective phallic growth. 1- 3 The mechanism of: J7 o8 x8 N, Z. a
response has been considered as local or systemic. With this* X* r9 L" I2 \' @7 r
in mind we studied 5 children with microphallus for response
; A5 e" q; P' u' ~4 {to gonadotropin and to topical testosterone independently. u0 `$ {% x! e* ]* y
MATERIALS AND METHODS& Y7 E. n; g1 K7 g
Five 46 XY male subjects between 3 and 17 years old were
9 @% t! B9 Z7 s/ {( Y. Uevaluated for serum testosterone levels and hypothalamic0 ]3 ?, }6 V7 A& @( u9 k; ?
function. Of these 5 boys 2 were considered to have Kallmann's$ w2 z$ t4 | P3 j
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
3 H1 z) x0 ]; Klamic deficiency. After evaluation of response to luteinizing. @/ Z/ ~" @: b/ i, p8 k+ W( y9 d
hormone-releasing hormone these patients were treated with- H/ X" N J* J$ S+ H
1,000 units of gonadotropin weekly for 3 weeks. Six weeks/ T9 @2 I# |1 O5 |
after completion of gonadotropin therapy 10 per cent topical
& q( F7 C5 U! e7 @0 a0 z9 P7 ?testosterone was applied to the phallus twice daily for 3 weeks.+ P7 N; \9 z. ]: J6 e/ n
Serum testosterone, luteinizing hormone and follicle-stimulat-
5 k9 x2 m# W, g) X) B; ^4 Hing hormone were monitored before, during and after comple-
2 h! Q9 c1 K4 Htion of each phase of therapy. Penile stretch length was
6 M, @- e. K8 v) jobtained by measuring from the symphysis pubis to the tip of
/ V X( ^( E7 x$ kthe glans. Penile circumferential (girth) measurements were* h4 X& [' C. t
obtained using an orthopedic digital measuring device (see" x) T6 T( N5 I2 G6 f+ [
figure).
" m( \& W( V5 ^: Z- sRESULTS
6 s& Y6 h2 D1 i$ r6 Z4 OSerum testosterone increased moderately to levels between
) ]/ _7 g* n. d# R% V% x/ P50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
" B( F7 j! a" ]/ q( [- jterone levels with topical testosterone remained near pre-* Y' E3 J" D' L, Q
treatment levels (35 ng./dl.) or were elevated to similar levels
" n' x7 J- A' x( w9 A1 z$ }developed after gonadotropin therapy (96 ng./dl.). Higher2 X) I& H& V% |( J% G# P' s
serum levels were noted in older patients (12 and 17 years old),
: }( t- y) M- o" @while lower levels persisted in younger patients (4, 8, and 10
2 E, T, d1 f C2 Syears old) (see table). Despite absence of profound alterations4 \2 R6 _" i& b( E P' \1 m
of serum testosterone the topical therapy provided a greater% ]& J; ]2 R* @7 {. m5 w' \# h
Accepted for publication July 1, 1977. ·9 [* Y3 i W7 p% }0 \
Read at annual meeting of American Urological Association,, H: d) I1 E0 U* p
Chicago, Illinois, April 24-28, 1977.
" c& M7 q# A5 F, C) @* d* Requests for reprints: Division of Urology, Henry Ford Hospital,
6 o6 c: M( w8 Q3 @2799 W. Grand Blvd., Detroit, Michigan 48202.
! t0 g% }/ b& D- \( Gimprovement in phallic growth compared to gonadotropin.7 w: o" @0 X, H1 G0 n7 x5 z
Average phallic growth with gonadotropin was 14.3 per cent
& l6 ~- I! z/ j3 `) Dincrease in length and 5.0 per cent increase of girth. Topical" [( A' ~2 W. L) R
testosterone produced a 60.0 per cent increase of phallic length
6 G. g2 _6 Y1 z* A2 |! sand 52.9 per cent increase of girth (circumference). The! J) g8 u7 y5 V6 O# U0 L
response to topical testosterone was greatest in children be-' I; }& l4 x- N& v2 V4 D4 ^
tween 4 and 8 years old, with a gradual decrease to age 17 z/ K8 b# s$ ?8 X9 q' u) f( z" V2 ~
years (see table).
* M) \/ c3 S$ s) i8 b5 vDISCUSSION* A" i& Y3 b( L( z9 n+ L
Topical testosterone has been used effectively by other
- G w! k# j$ D' r" g Jclinicians but its mode of action remains controversial. Im-' z4 q; Z$ @. A8 V( c
mergut and associates reported an excellent growth response% N5 R% ~" q$ R$ q
to topical testosterone with low levels of serum testosterone,* Z/ I- a0 o" g% ^) g* Q4 g6 O/ W
suggesting a local effect.1 Others have obtained growth re-7 l+ u% a$ E, r4 h
sponse with high. levels of serum testosterone after topical* `" p# \( w# U5 K# v' g1 Z
administration, suggesting a systemic response. 3 The use of' {) I8 |% Z" F
gonadotropin to obtain levels of serum testosterone compara-
/ o/ h- t8 M# R- w3 N; J; uble to levels obtained with topical testosterone would seem to) ], I3 ?2 a- x$ e5 `
provide a means to compare the relative effectiveness of! `. p' H- }& W7 l
topical testosterone to systemic testosterone effect. It cer-! ~4 }. ^# S4 D
tainly has been established that gonadotropin as well as par-; n$ c$ m6 l" r; m2 p0 m( [! A' {6 B
enteral testosterone administration will produce genital
: F' X' ]% \( v# {6 x/ _% h7 Cgrowth. Our report shows that the growth of the phallus was) t( j2 B4 w% \
significantly greater with topical applications than with go-
/ ?# N. x( o S* cnadotropin, particularly in children less than 10 years old.
6 U- T/ s- p9 V7 T% I$ e; GThe levels of serum testosterone remained similar or lower: t6 w0 B7 I- q' K0 ]" D
than with gonadotropin during therapy, suggesting that topi-
$ o$ X7 I9 z5 Y5 G) F. Rcal application produces genital growth by its local effect as
: M* k4 b8 _) fwell as its systemic effect./ k& V' }& N6 ?/ D0 j, z6 F( O& i
Review of our patients and their growth response related to0 j" Z N" a$ O, X; B1 b
age shows a greater growth response at an earlier age. This is
! U3 @: B* i7 r8 `/ cconsistent with the findings of Wilson and Walker, who
/ s$ z6 {6 {2 |- k& }3 S! yreported an increased conversion of testosterone to dihydrotes-
. B6 G) D/ i. I! @2 j* R! N0 btosterone in the foreskin of neonates and infants.4 This activ-
% _. l& l+ T+ X1 Nity gradually decreases with age until puberty when it ap-
1 j4 L6 Z" k* T! p! p; Bproaches the same level of activity as peripheral skin. It may
0 m1 a% `5 z9 `* T- Ywell be that absorption of testosterone is less when applied at
8 G! C; {) j# u( w- ?* Ran earlier age as suggested by lower serum levels in children
9 Z" O' K y! j$ Y4 e! }* cless than 10 years old. This fact may be explained by the
b& U% N0 ~. P9 D" ~greater ability of phallic skin to convert testosterone to dihy-$ x+ Y* F! M8 l" ^+ s
drotestosterone at this age. Conversely, serum levels in older$ a, C& [- p9 h1 a& O# a) I B# d
patients were higher, possibly because of decreased local
$ G& V' J m9 j6 X3 _( J y( H667. E9 m& L& Y% L, G' d t
668 KLUGO AND CERNY
' L; z0 c: D5 D! ^/ A* @Pt. Age
6 | j) H9 G! i0 B; E* v(yrs.)7 W* t0 V( \. Y
Serum Testosterone Phallus (cm.) Change Length
! z l( w' j, V; @, P: A, Q A(ng./dl.) Girth x Length (%)
; u3 g* ]. X0 @2 o5 {4! g {9 r& S9 u# s
8# U7 h, N0 N' X# M, [! h
10- z! ~+ Q8 `& N/ g3 [
12
, u5 m7 Z) ]! [7 R7 `0 j+ A17
: f5 B* x, _& kGonadotropin; e5 ?1 L7 l# J: A2 H1 d8 s
71.6 2.0 X 3 16.6% _3 }. s' E/ A( p
50.4 4.0 X 5.0 20.0
" Y3 `: z. M; z% J6 b+ M' @22.0 4.5 X 4.0 25.0
5 M! f& \; T9 p$ |: U84.6 4.0 X 4.5 11.1
7 i1 r% v8 G, ]( k" v( d# r/ v85.9 4.5 X 5.5 9.0
" S1 x# g6 Y) T; HAv. 14.30 p7 e; P+ `4 @4 R$ N
4* V4 `/ `. A5 S" }; F$ k
8$ m( Q2 E+ a0 z) r! ? V& u
10
0 X6 O! n3 ~# [6 r12; ~9 U% p8 U1 r7 [6 Y
177 q, {* `& g5 h( `
Topical testosterone& J* }% }: i ^6 b H4 x
34.6 4.5 X 6.5 85
H8 C7 c) g; C$ Q7 l38.8 6.0 X 8.5 70
3 N9 s/ F" d/ c+ \% h3 Y40.0 6.0 X 6.5 62.52 Y' \6 M, `8 b9 L
93.6 6.0 X 7.0 55.51 s) r, A: m' D- h
95.0 6.5 X 7.0 27.2. D+ F$ w- Q: R% k( t7 Q
Av. 60.0
0 D& A, P3 Q" l0 U5 R2 q4 iavailable testosterone. Again, emphasis should be placed on, W4 ^% j; _9 [* Q
early therapy when lower levels of testosterone appear to- k3 y6 U1 `( F+ M$ v' y
provide the best responses. The earlier therapy is instituted
; _3 Q# K! ]# k: ithe more likely there will be an excellent response with low; K6 J J+ P# A) V4 h6 k
serum levels. Response occurs throughout adolescence as
: \$ h9 e9 |8 z- _9 T. Znoted in nomograms of phallic growth. 7 The actual response5 l5 K( P- [8 j$ q$ T) M( \
to a given serum level of testosterone is much greater at birth
( F) r) }6 b6 v$ l6 r1 m, K4 band gradually decreases as boys reach puberty. This is most
% h, N' x/ o: ` |3 Ilikely related to the conversion of testosterone to dihydrotes-
6 N2 d5 l2 U* ^3 u1 Ptosterone and correlates well with the studies of testosterone$ @* V" B K% L* W% p
conversion in foreskin at various ages.6 c, o; S" y( `/ i; G5 x# p6 d8 l: a
The question arises regarding early treatment as to whether7 m4 E- e2 l$ W9 f. d; j
one might sacrifice ultimate potential growth as with acceler-
+ N$ H: k' F- g- t- n% `% w; hated bone growth. The situation appears quite the reverse
1 _' |% e3 n$ Xwith phallic response. If the early growth period is not used
3 b% t( s; y2 m2 o2 f7 ]when 5a reductase activity is greatest then potential growth
6 y+ C' f' R( l9 S" L+ y A, \may be lost. We have not observed any regression of growth
- X& X" p2 I. @$ v) Battained with topical or gonadotropin therapy. It may well7 @0 d1 p! }; c7 Z3 m( v4 y$ O3 `
be that some patients will show little or no response to any V! l3 M- h4 K5 L# L
form of therapy. This would suggest a defect in the ability to$ V! U$ F) u% W- A8 [
convert testosterone to dihydrotestosterone and indicate that
% D; G( v3 Q- C) xphallic and peripheral skin, and subcutaneous tissue should
" C+ C! Y& x# _+ T. ^be compared for 5a reductase activity.
4 i; T G+ K' h3 r1 ?A, loop enlarges to measure penile girth in millimeters. B,
5 q3 \# A1 V8 S, S3 Pexample of penile girth computed easily and accurately.8 ]( x2 ~5 b$ W- m1 K, v3 Z
conversion of testosterone to dihydrotestosterone. It is in this. ?/ }1 S; y+ R
older group that others have noted high levels of serum
, j/ o- u* M" B/ x$ e0 Gtestosterone with topical application. It would also appear& I* K0 T. Z" }8 P4 S _
that phallic response during puberty is related directly to the
0 q9 Y2 x; W& Xserum testosterone level. There also is other evidence of local0 f! {. h3 i5 Z( ?1 O7 R' R
response to testosterone with hair growth and with spermato-
9 I6 C5 v' {) P, v# b. ggenesis. 5• 63 ?! v2 M1 b/ x# o3 c) l
Administration of larger doses of gonadotropin or systemic6 ?! q! l7 T6 k) z0 N8 g& L
testosterone, as well as topical applications that produce* D4 F4 X( N. T- {( q
higher levels of serum testosterone (150 to 900 ng./dl.), will" T* @8 W; T, F
also produce phallic growth but risks accelerated skeletal$ y) f: _1 f% T$ T& z4 w
maturation even after stopping treatment. It would appear
3 R6 o: {9 _" D. ~& u( {" fthat this may be avoided by topical applications of testosterone
( C" u/ G- v) eand monitoring of serum testosterone. Even with this control% H) i: S8 v2 o4 u8 y+ x
the duration of our therapy did not exceed 3 weeks at any
8 ]# L/ \" U: \time. It is apparent that the prepuberal male subject may+ Q& s/ k& k; V
suffer accelerated bone growth with testosterone levels near
! [# T% a! ]! M5 E1 T4 I, A200 ng./dl. When skeletal maturation is complete the level of5 k7 h1 q0 {, z4 a0 ~! E6 d
serum testosterone can be maintained in the 700 to 1,300 ng./
0 i2 x8 H/ B+ Y" ?( Mdl. range to stimulate phallic growth and secondary sexual
& U& f" t% o+ R' j' Rchanges. Therefore, after skeletal maturation parenteral tes-# J% B+ A M1 _" C' n0 U
tosterone may be used to advantage. Before skeletal matura-
4 V. z, t$ a# O/ h, ction care must be taken to avoid maintaining levels of serum9 @- \* E7 m5 l1 Q- i3 X& B, o* ^
testosterone more than 100 ng./dl. Low-dose gonadotropin' i1 y- N5 u! S5 n9 x
depends upon intrinsic testicular activity and may require
% f: c0 `9 T# S$ Dprolonged administration for any response.8 W6 t0 g3 N1 A
Alternately, topical testosterone does not depend upon tes-
/ B, W" F. X/ f9 K5 s8 Qticular function and may provide a more constant level of2 n$ S( I# g6 L9 ]1 q
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1 G7 s0 L" u# @( `1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
, K7 ~# V6 h/ u3 H% Q5 d3 K, KR.: The local application of testosterone cream to the prepub-
5 R+ J4 N0 g+ t3 |8 Uertal phallus. J. Urol., 105: 905, 1971.
' M, F8 ]( ]! h3 G9 y9 |+ j2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
5 v+ o0 ~- u8 T% g: k+ ytreatment for micropenis during early childhood. J. Pediat.,
. O# B: o y$ ~- V3 t83: 247, 1973.
7 x" I/ _: s3 k6 Z3 ~8 ]3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-# J+ m4 N" T) ^( L# s( S3 Z3 h
one therapy for penile growth. Urology, 6: 708, 1975.
0 L" ^3 L% t w7 t! S0 q, s4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone& |' Z+ ~- w; j8 |
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8 }0 K5 l9 I/ L T& F( C* Mskin slices of man. J. Clin. Invest., 48: 371, 1969.
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7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
8 g8 C% i: z$ q: d: p& G/ j Qtion in the male genitalia from birth to maturity. J. Urol., 48: |
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