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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND& P4 A$ {, z; o/ n7 k" Z" o
GONADOTROPIN1 z3 F& B1 G! j( `' G0 k, i
RICHARD C. KLUGO* AND JOSEPH C. CERNY# W# D; B& a: P& I8 A( T8 |
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
5 T. U; K% V0 `0 }9 E9 kABSTRACT
j/ r P) u. `; i6 a( ]3 e9 O1 QFive patients were treated with gonadotropin and topical testosterone for micropenis associated- L/ o, J9 F* V$ L" d1 R+ N
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-/ J% M; p# v. f; a: P
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
\7 Y# F4 N( a! i/ f0 R ]cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent5 @& d. v4 b. ]" }* A" n4 v
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent0 b8 Q6 G9 z! @6 e( Z0 ?, a
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
3 _* Q) R h+ `2 X; }increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
2 V$ n. o" n2 Voccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This$ E; `5 K' S3 D p! R
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
1 _, p8 L" M$ |growth. The response appears to be greater in younger children, which is consistent with previ-$ ~1 o- l' `3 G; @1 H3 |
ously published studies of age-related 5 reductase activity.
4 Q# h- t# w5 X# gChildren with microphallus regardless of its etiology will& W4 e3 v( z! r( N" @ Y, L
require augmentation or consideration for alteration of exter-
- G( Z+ v6 s- X8 c. C8 lnal genitalia. In many instances urethroplasty for hypo-9 D3 s: r: K: I# q# b8 [$ R& i3 m8 q. o/ s
spadias is easier with previous stimulation of phallic growth.
6 Z2 `) L; ~5 N: T2 Z# |. k4 CThe use of testosterone administered parenterally or topically
, ^# a, G: O1 l7 G) C0 Ghas produced effective phallic growth. 1- 3 The mechanism of
; N9 i7 E( x0 [response has been considered as local or systemic. With this: o2 y6 D$ z2 T( ~0 R) K
in mind we studied 5 children with microphallus for response; f5 P2 } j+ [( v
to gonadotropin and to topical testosterone independently.+ v+ w, R1 n- e, T% N0 f: a" Z w
MATERIALS AND METHODS4 p& ?, [# M. r7 M' q' X2 o0 p
Five 46 XY male subjects between 3 and 17 years old were
: [+ s4 `: ~# U2 U$ S* Ievaluated for serum testosterone levels and hypothalamic4 C3 e- z {! l% b, n
function. Of these 5 boys 2 were considered to have Kallmann's
& d% o1 u6 {0 N0 ] Zsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-$ N9 j/ v, }1 E$ `/ q7 q& T
lamic deficiency. After evaluation of response to luteinizing
! u4 g |; b3 {9 n8 Nhormone-releasing hormone these patients were treated with
. \& c2 L4 z' d# m8 d1,000 units of gonadotropin weekly for 3 weeks. Six weeks( T R( ^# ]% |: x2 Q: ?2 k6 S T
after completion of gonadotropin therapy 10 per cent topical: s* O3 w2 x L7 h# w0 d- f, P
testosterone was applied to the phallus twice daily for 3 weeks.
' _, t, P0 G( TSerum testosterone, luteinizing hormone and follicle-stimulat-
- |9 R' Z+ o! T: I/ E' N. T2 @ing hormone were monitored before, during and after comple-, y' b7 y6 T1 o8 O( f- k- j
tion of each phase of therapy. Penile stretch length was3 f1 l, h4 ]" f5 I2 v
obtained by measuring from the symphysis pubis to the tip of
7 E/ s9 l u/ ?. Q" sthe glans. Penile circumferential (girth) measurements were
+ y1 U2 w" N7 s1 H3 N1 P& |obtained using an orthopedic digital measuring device (see/ E6 j4 t, V; R! {: n$ K \. {
figure). B* X8 B4 Q6 K& I9 V9 U
RESULTS9 e3 Q9 Q F' z4 F2 O+ j
Serum testosterone increased moderately to levels between$ @+ i# A3 x: W# b9 k! G) y3 a
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
' S6 O/ x) C s r9 a3 y- @0 Bterone levels with topical testosterone remained near pre-
& k/ v' f: ]; O$ `3 y4 [0 F, @treatment levels (35 ng./dl.) or were elevated to similar levels
- Y# K9 y* h! B# \+ r7 Edeveloped after gonadotropin therapy (96 ng./dl.). Higher
3 d2 P+ z1 e7 Y& iserum levels were noted in older patients (12 and 17 years old),
" v: s9 f( @2 b1 uwhile lower levels persisted in younger patients (4, 8, and 10+ S& _5 |3 t8 Z8 q. j1 h; T
years old) (see table). Despite absence of profound alterations
! a) {) Z4 J+ N, @. D+ p1 Oof serum testosterone the topical therapy provided a greater! P' e5 G& t# m) M" |7 W
Accepted for publication July 1, 1977. ·
7 b h" f7 t, j* _; L1 dRead at annual meeting of American Urological Association,
* Q: [# V3 `* a$ W9 UChicago, Illinois, April 24-28, 1977.6 t9 h; g$ T$ U' r# p) @% ^) x
* Requests for reprints: Division of Urology, Henry Ford Hospital,
8 r: @ i, X2 Z) F5 |, b) d2799 W. Grand Blvd., Detroit, Michigan 48202.( [' S) q# S- C) Y( P
improvement in phallic growth compared to gonadotropin.; N3 S) t% }' M+ x
Average phallic growth with gonadotropin was 14.3 per cent
- E% k$ X) c( Q6 y. tincrease in length and 5.0 per cent increase of girth. Topical
3 _( k: B- u' Otestosterone produced a 60.0 per cent increase of phallic length! U1 A, i% q1 m( ^: Q
and 52.9 per cent increase of girth (circumference). The
8 w4 k. g8 h9 W+ Uresponse to topical testosterone was greatest in children be-7 h7 M( w! y' J; u( a
tween 4 and 8 years old, with a gradual decrease to age 17# P5 k7 w. P) [
years (see table).6 [8 Q3 d( u M
DISCUSSION
3 U; c- x! r j. G0 vTopical testosterone has been used effectively by other$ b$ p t8 g4 d9 u: G: o4 ~9 y9 Z
clinicians but its mode of action remains controversial. Im-! [. x5 [+ C. L1 G7 u, l2 Q
mergut and associates reported an excellent growth response+ U4 w0 {/ P( h# X
to topical testosterone with low levels of serum testosterone," Y/ Z- r. A* v/ M- i, r
suggesting a local effect.1 Others have obtained growth re-/ e* g- ?3 @: l7 @8 K
sponse with high. levels of serum testosterone after topical. \0 g1 n) c$ X! o/ N. A
administration, suggesting a systemic response. 3 The use of P* o. _6 f! @0 A1 ~
gonadotropin to obtain levels of serum testosterone compara-6 z6 X2 ^( Q9 j. e
ble to levels obtained with topical testosterone would seem to
' v* u4 [) W8 N. Zprovide a means to compare the relative effectiveness of0 A' H, J! I8 Q8 ~* Y
topical testosterone to systemic testosterone effect. It cer-
/ Y6 R3 u$ e, m' w, b( n8 O5 Ztainly has been established that gonadotropin as well as par-* \* N1 f- B1 b R: C( r
enteral testosterone administration will produce genital# d& O8 Y: M8 f+ B+ [# Y* T
growth. Our report shows that the growth of the phallus was7 q& {1 ^1 ~. e# m7 F! t: [; \8 {
significantly greater with topical applications than with go-
1 D) i; [; A' m$ Ynadotropin, particularly in children less than 10 years old.' c" b( I; V9 O" U$ i, R
The levels of serum testosterone remained similar or lower6 n( s0 H1 z! [$ _$ w5 `3 R! A
than with gonadotropin during therapy, suggesting that topi-
' Z* [+ J* b0 y h8 Wcal application produces genital growth by its local effect as, w# a2 O6 R5 i0 [
well as its systemic effect.
2 B" [) _1 u$ Q, ~ s' BReview of our patients and their growth response related to* d5 a% ~2 o+ [) o# ~+ J# t9 Y
age shows a greater growth response at an earlier age. This is
5 F7 z$ X+ a+ h4 d' rconsistent with the findings of Wilson and Walker, who/ F9 z! ]2 ^7 S! N- G
reported an increased conversion of testosterone to dihydrotes-
8 r: y# ?& ~) g4 S5 \0 Etosterone in the foreskin of neonates and infants.4 This activ-
) w8 r& V& R) R1 m: F& iity gradually decreases with age until puberty when it ap-0 b' c# G# T, O; q2 o& {
proaches the same level of activity as peripheral skin. It may
( J7 M+ U. c. [9 t; F( twell be that absorption of testosterone is less when applied at
! d5 M% C" V7 [5 J2 S) d7 i8 Xan earlier age as suggested by lower serum levels in children. B4 o; ~9 I5 v# j( x- O
less than 10 years old. This fact may be explained by the- k& ~7 S% q/ ~2 {7 h1 l, B6 k- h
greater ability of phallic skin to convert testosterone to dihy-+ a, u: L5 b) R5 ], K7 [
drotestosterone at this age. Conversely, serum levels in older' o1 S Q2 _2 y% c4 o! D
patients were higher, possibly because of decreased local" u+ _& u- f& i; n- j( Z; k# z% B" @
667
8 G+ F; l; j; Q0 i L) x' f668 KLUGO AND CERNY0 F6 I$ a) V% A3 o( W
Pt. Age
4 N$ _' ]/ }1 N2 f2 p4 ?! w a& s(yrs.)
+ `7 _, i; }0 z! ISerum Testosterone Phallus (cm.) Change Length
. C$ ~7 t5 P2 s(ng./dl.) Girth x Length (%)
/ O2 Q2 H# }* t4' U; |4 f4 A9 ?" m4 B5 B
8
3 e( ~/ w0 x# q: D: z10
( m% E# Q* y1 x0 s12
; `2 O+ |+ Y# Z17* o2 Y s3 n8 M4 Y3 X
Gonadotropin
+ X0 r7 r6 k1 q71.6 2.0 X 3 16.60 Z* ^! z9 k5 w! b3 d* `8 ~# F J
50.4 4.0 X 5.0 20.0+ i; T; q1 Z9 ]$ Y. u3 K. k
22.0 4.5 X 4.0 25.06 u( u( q& t0 o e r1 H; `
84.6 4.0 X 4.5 11.1
+ l8 I g* f( N( @. m) ]" J85.9 4.5 X 5.5 9.0' E9 h" h! `; O7 z2 V
Av. 14.30 g& d4 J) s2 \5 P `
4
- V& U {8 V# u$ \, ?8" K2 |1 K+ {9 R/ u3 w" h: ?) @0 i
10$ H' n2 U- c% N
12
- y; v. S8 A# m) {. u9 c) M C3 Y17
) _- ?/ M* v. A* N/ U$ E* [) TTopical testosterone
% g& U% Y: a+ a/ |1 x34.6 4.5 X 6.5 85
|& n0 C% q/ O38.8 6.0 X 8.5 70! `( N7 C" q$ l& I
40.0 6.0 X 6.5 62.5
8 j8 [1 d. e) u+ q' O93.6 6.0 X 7.0 55.53 d4 ~! x! Q( _
95.0 6.5 X 7.0 27.2
+ I! F4 t5 W$ {6 j; |3 s% W/ U) O/ nAv. 60.01 ~% z# k" J1 j9 f1 p0 } [
available testosterone. Again, emphasis should be placed on
% u6 d8 X3 W) Z0 t* J( m% learly therapy when lower levels of testosterone appear to
+ J2 K6 a' q z/ |6 `: ~provide the best responses. The earlier therapy is instituted" V3 j7 \/ j& t) t- q
the more likely there will be an excellent response with low( T9 Y9 _% s- C( [5 @, j2 h$ o
serum levels. Response occurs throughout adolescence as* o/ ~8 U: S. u7 j- ^% M
noted in nomograms of phallic growth. 7 The actual response# D( c3 n2 w' {9 u4 m
to a given serum level of testosterone is much greater at birth* E6 M! `! u+ l) Y/ P& b& T
and gradually decreases as boys reach puberty. This is most
; l$ |6 E8 d% L7 ]9 H- g# \1 Dlikely related to the conversion of testosterone to dihydrotes-
1 e2 d, q* k! Y- ]7 ^% Z' gtosterone and correlates well with the studies of testosterone
6 G( p& \% H( |; Yconversion in foreskin at various ages.) @& U* g1 ^' D1 x* x0 R
The question arises regarding early treatment as to whether
& m o2 _# s- K- P- `" {one might sacrifice ultimate potential growth as with acceler-
5 T! U, m/ t' ~7 z% ?ated bone growth. The situation appears quite the reverse: U' g2 \, B) a( F
with phallic response. If the early growth period is not used
% T. m; x; ~; Dwhen 5a reductase activity is greatest then potential growth
* B8 M o2 C4 _; ~) ~may be lost. We have not observed any regression of growth
2 j' P4 h" j" F3 hattained with topical or gonadotropin therapy. It may well" t+ {" l5 X8 R, `8 u8 J' e
be that some patients will show little or no response to any
& ]0 h N6 V$ u5 g" Wform of therapy. This would suggest a defect in the ability to* E P! m! \+ T v/ ^
convert testosterone to dihydrotestosterone and indicate that
1 o: v% t% j+ n3 Z( }phallic and peripheral skin, and subcutaneous tissue should2 i t. R7 h: h) y \
be compared for 5a reductase activity.# v4 ]! q3 n$ t f; b
A, loop enlarges to measure penile girth in millimeters. B,
' w* c0 i5 u( _+ Gexample of penile girth computed easily and accurately.8 B i5 X* P* T4 r" @* ^
conversion of testosterone to dihydrotestosterone. It is in this
6 B+ p' H0 h9 Bolder group that others have noted high levels of serum
+ v3 b( V5 X3 F8 ktestosterone with topical application. It would also appear, \4 v* c& ~! N# {& S
that phallic response during puberty is related directly to the: c4 l# ]+ S s9 D7 w! Q: p) H: t
serum testosterone level. There also is other evidence of local
$ X+ I o% [- }, aresponse to testosterone with hair growth and with spermato-
3 N' E7 I; m# \) W: P6 v0 Y0 l0 kgenesis. 5• 6- Q$ q! D+ G$ `# p" y+ Y* f' l1 S4 v
Administration of larger doses of gonadotropin or systemic
8 A1 Z( ^. l! i+ ztestosterone, as well as topical applications that produce
, y F& z( D" f8 Q5 U! c7 vhigher levels of serum testosterone (150 to 900 ng./dl.), will
. u6 i1 T! a; X! u+ w, ialso produce phallic growth but risks accelerated skeletal9 W Q8 y9 W8 t; g3 Y( a! R
maturation even after stopping treatment. It would appear
! u: k3 x5 w# |7 h& Zthat this may be avoided by topical applications of testosterone, [, N# p! A( r# e K* U
and monitoring of serum testosterone. Even with this control
: D. H6 N. b2 @# xthe duration of our therapy did not exceed 3 weeks at any# ?: ~+ Q; Z5 Q0 a2 n
time. It is apparent that the prepuberal male subject may8 k+ g" W+ t8 ]! J* M% A
suffer accelerated bone growth with testosterone levels near8 P! N; ~2 f. }0 a x
200 ng./dl. When skeletal maturation is complete the level of
6 S: I" \8 A3 o4 [" e* eserum testosterone can be maintained in the 700 to 1,300 ng./2 C, ^! x v, I1 H2 {
dl. range to stimulate phallic growth and secondary sexual0 N+ A* s) b6 ~
changes. Therefore, after skeletal maturation parenteral tes-- u# m( l( A& }* ]. L4 |
tosterone may be used to advantage. Before skeletal matura-
+ e! B! x, Z! q G5 ttion care must be taken to avoid maintaining levels of serum6 `: ~0 V4 o/ D+ Q% ]
testosterone more than 100 ng./dl. Low-dose gonadotropin
& l( q2 q6 b& d0 udepends upon intrinsic testicular activity and may require7 q4 F7 |8 o5 F) J' a
prolonged administration for any response.2 v8 P3 D7 K v* q ^# M
Alternately, topical testosterone does not depend upon tes-
$ a3 f4 U* n( u% Q2 z0 D) [4 V& ~ticular function and may provide a more constant level of- _7 K2 C4 M$ E
REFERENCES! p& i# G( X$ U& f
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,6 c. D1 U" |. V- z: H
R.: The local application of testosterone cream to the prepub-
6 g6 x6 G1 B6 m9 i* E! eertal phallus. J. Urol., 105: 905, 1971.
8 d' F- r, q0 g8 w2 D& l1 q2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
- Y4 z" S( n8 ~+ Vtreatment for micropenis during early childhood. J. Pediat.,
7 j4 Z4 H- ?8 C, v83: 247, 1973.0 W/ s$ L" B; h0 e! h: n
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
I @. o: V- S! uone therapy for penile growth. Urology, 6: 708, 1975.
3 C: |. Z. [; J6 Z# n4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
* Z, M4 d) Y$ b. `# F# Zto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
' N* N9 E3 M* ^+ m- Oskin slices of man. J. Clin. Invest., 48: 371, 1969.
* d' e- d4 n/ Q: _; {5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth' g/ r `( _3 U' y$ H
by topical application of androgens. J.A.M.A., 191: 521, 1965.
% V3 ]2 k2 u2 a3 R& z6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local4 K' s9 B: s5 _7 A/ G
androgenic effect of interstitial cell tumor of the testis. J.4 z7 T. j; _9 z% n: v
Urol., 104: 774, 1970.: @' `: X" o9 b; ~) R M0 W! ?0 q% M( Y" F
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-; }9 h4 }0 N8 f. R. c; P! x% `
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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