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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND$ F/ K8 o- i6 I. z
GONADOTROPIN
! P5 O% v8 s$ d; F) hRICHARD C. KLUGO* AND JOSEPH C. CERNY
' G3 B, L2 V0 c5 K: W" l# eFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
1 x$ O6 x- B7 PABSTRACT1 k. O' T& ?7 ~7 `/ Z% }
Five patients were treated with gonadotropin and topical testosterone for micropenis associated) M3 @( s# O, \7 @: q
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-6 |8 |; v! \2 O
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone! {5 @. _; Y3 }) N4 S7 @1 Y) \
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent5 q9 R" ^2 I/ m( B' l9 c
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
3 ]8 j% K7 q, Yincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average5 |4 j- U% J8 Y3 u3 f J
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
, [4 E H1 M: A# o+ H1 r0 Noccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
) E5 G( g6 t$ g" G4 I0 Ustudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
6 k+ l5 Q8 U5 A z7 Hgrowth. The response appears to be greater in younger children, which is consistent with previ-( e) t3 a! [' Y; \1 V& u8 S
ously published studies of age-related 5 reductase activity.6 d& ?& q& ~# q2 m
Children with microphallus regardless of its etiology will
W) n# l( N Y& E: d* Y2 \9 @require augmentation or consideration for alteration of exter-
* u& q$ X( M% o. A7 h% snal genitalia. In many instances urethroplasty for hypo-
- l a* T' k S+ L: Q+ [spadias is easier with previous stimulation of phallic growth.2 M! r2 W1 R) E& R; q- r3 _* r' m5 ?# [
The use of testosterone administered parenterally or topically
! m8 a* v. r, J0 y, @has produced effective phallic growth. 1- 3 The mechanism of2 o! h' W9 {4 v* C% X: d
response has been considered as local or systemic. With this
) Z9 b3 S, e0 L" v' din mind we studied 5 children with microphallus for response
$ k" ]/ @; W/ h0 t5 S9 G" Ito gonadotropin and to topical testosterone independently.
1 Q. k3 N; X3 O3 HMATERIALS AND METHODS8 N# v; B) p. t0 H
Five 46 XY male subjects between 3 and 17 years old were
1 R2 O; M/ J' Y, q: O2 Y0 K/ Fevaluated for serum testosterone levels and hypothalamic
' }2 [8 a; u gfunction. Of these 5 boys 2 were considered to have Kallmann's: W0 t0 k% X8 h
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
) p1 i& Q, Q; u/ c- z+ y5 Nlamic deficiency. After evaluation of response to luteinizing
& E1 t/ o0 {* x6 Ohormone-releasing hormone these patients were treated with
9 T. w u$ V! [" S- [1,000 units of gonadotropin weekly for 3 weeks. Six weeks
. |( ]" [/ s; b% m9 B! Fafter completion of gonadotropin therapy 10 per cent topical
S+ n. W' z9 xtestosterone was applied to the phallus twice daily for 3 weeks.' i) w% |7 z! e. f- w
Serum testosterone, luteinizing hormone and follicle-stimulat-4 _, ?- A, o' |5 ^+ w* y
ing hormone were monitored before, during and after comple-. \5 Q! W0 r# e3 M% P" P
tion of each phase of therapy. Penile stretch length was4 ]% S; {* n9 [4 L
obtained by measuring from the symphysis pubis to the tip of9 l; i" `" U# \
the glans. Penile circumferential (girth) measurements were
! {% Q0 S& _" @/ t% ^. tobtained using an orthopedic digital measuring device (see
- R G, X5 K% ?! p Yfigure).) n5 b8 a1 u5 }8 e' d& d
RESULTS0 S' G$ z+ e6 C
Serum testosterone increased moderately to levels between
1 O6 E1 N O' I' o7 O9 D7 @( g50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
6 ^* F$ W) v6 Yterone levels with topical testosterone remained near pre-4 W8 m) l* d( r( J% h: D
treatment levels (35 ng./dl.) or were elevated to similar levels
8 S6 M X, `/ {) @9 Zdeveloped after gonadotropin therapy (96 ng./dl.). Higher
( K. M9 D2 I0 y1 d; L" yserum levels were noted in older patients (12 and 17 years old),
$ ^# l+ B3 _, B5 u7 Gwhile lower levels persisted in younger patients (4, 8, and 101 g* @/ h2 X8 w
years old) (see table). Despite absence of profound alterations
2 K% [9 d! K) sof serum testosterone the topical therapy provided a greater7 ?' W; K& v& _4 j, v! l
Accepted for publication July 1, 1977. ·
/ X5 Z/ f. c& y) |5 a, i& B! IRead at annual meeting of American Urological Association,
7 w' E* h" s/ n- h5 M* fChicago, Illinois, April 24-28, 1977.6 W4 I, }9 }& R; J/ o4 s
* Requests for reprints: Division of Urology, Henry Ford Hospital,$ w% p# T- {" k
2799 W. Grand Blvd., Detroit, Michigan 48202.3 k9 K4 q! L* q$ p* y9 o- B0 S# U
improvement in phallic growth compared to gonadotropin.- o- [# K+ V- F' ^
Average phallic growth with gonadotropin was 14.3 per cent# _4 z* m4 h0 l
increase in length and 5.0 per cent increase of girth. Topical
; w% t- e5 B7 M" Otestosterone produced a 60.0 per cent increase of phallic length2 n% h/ ?' R8 j
and 52.9 per cent increase of girth (circumference). The
! U2 o5 J0 Q7 y! d8 Qresponse to topical testosterone was greatest in children be-
0 l: \! [2 A( N. Htween 4 and 8 years old, with a gradual decrease to age 17
- x8 S+ L j, j+ T* I5 Gyears (see table).
5 Z' P+ v0 n$ n# W" S( A9 IDISCUSSION( \/ R! X4 o4 A7 g9 c) X3 s
Topical testosterone has been used effectively by other
: L% K$ u2 L' O5 Z3 ~3 pclinicians but its mode of action remains controversial. Im-
% h! W+ [* y% [% jmergut and associates reported an excellent growth response
b4 ]7 w2 C. U; v [: nto topical testosterone with low levels of serum testosterone,& Z$ T. k: \) G- F
suggesting a local effect.1 Others have obtained growth re-
$ j$ q" z+ [ f6 [, ssponse with high. levels of serum testosterone after topical
% b6 H" F* F" c2 {administration, suggesting a systemic response. 3 The use of3 Q9 }( I: x' b9 U2 h" \ e; ?
gonadotropin to obtain levels of serum testosterone compara-' O' D( z w8 |
ble to levels obtained with topical testosterone would seem to
% x# r, G; e! _$ i7 y7 wprovide a means to compare the relative effectiveness of- p1 X& Q3 _* |- q6 X% ?# _
topical testosterone to systemic testosterone effect. It cer-; Z, M6 d& X6 B8 @% Q
tainly has been established that gonadotropin as well as par-6 |5 u$ k8 E2 k
enteral testosterone administration will produce genital$ ]. B3 ?& Y- B0 A8 f) Q4 W& o; t. G
growth. Our report shows that the growth of the phallus was& m, X9 C9 q( u4 [3 u9 C6 H1 s
significantly greater with topical applications than with go-
( K, N+ q* w) T# A. ]nadotropin, particularly in children less than 10 years old.5 D8 [. _/ ?2 s+ J! K/ b
The levels of serum testosterone remained similar or lower
9 w }3 V- s3 ethan with gonadotropin during therapy, suggesting that topi-
: h) \* Q0 g' A8 m7 R- mcal application produces genital growth by its local effect as
/ g3 u4 c" x) p% S( i2 uwell as its systemic effect.
v6 q6 B* f& b, t+ g3 F1 |: j; iReview of our patients and their growth response related to
/ X$ c- \, e3 Dage shows a greater growth response at an earlier age. This is U2 w& h4 u& _6 x2 q
consistent with the findings of Wilson and Walker, who
$ C6 u% M" [/ P: C% q2 L1 treported an increased conversion of testosterone to dihydrotes-0 T: y( k, X2 B* W6 E4 D
tosterone in the foreskin of neonates and infants.4 This activ-, |, } H* f2 m& V- K# S. a
ity gradually decreases with age until puberty when it ap-
- G& s' X" H [proaches the same level of activity as peripheral skin. It may
3 H! j: O/ l- ^ q0 g8 W/ `$ wwell be that absorption of testosterone is less when applied at
& |- m: [2 \5 h3 m1 O4 ^- f5 Xan earlier age as suggested by lower serum levels in children" S% b* l1 P( w% N* t
less than 10 years old. This fact may be explained by the7 S& M) t# A% @8 C
greater ability of phallic skin to convert testosterone to dihy-
3 H" J b0 ~5 o5 Zdrotestosterone at this age. Conversely, serum levels in older D2 ?& r% b7 B
patients were higher, possibly because of decreased local
7 @! k# R/ E1 u& [5 V667# H% r5 m3 q( f
668 KLUGO AND CERNY
1 h! s) S) p% S, B0 G. X# {Pt. Age
3 T. J" p0 J6 A1 b(yrs.)4 y0 e4 F" ?' l& v* F X9 Q
Serum Testosterone Phallus (cm.) Change Length
6 H! S) `* T) Z' B2 j+ Y( M(ng./dl.) Girth x Length (%)* D+ t. p. n& D
44 I% k0 d8 u: \* e- F+ X
8) e. Z( _' _6 x* \2 R: w
10
+ P2 i3 ?. D: g1 m8 V7 ?12
: o/ W; Q: d4 c+ x2 ~' x1 z17- O( `9 k: s3 c6 V1 K( A7 Y- p
Gonadotropin+ J- X9 l R: a1 K& ^
71.6 2.0 X 3 16.6
+ T% A- \7 T; E6 X- b: v% g50.4 4.0 X 5.0 20.0
- \/ y: U3 z# u; c9 B. n22.0 4.5 X 4.0 25.0
6 M4 Z1 P" z) f1 N# Y84.6 4.0 X 4.5 11.1 ^' E3 L8 z. A! B
85.9 4.5 X 5.5 9.0: x1 a- l$ Q# K9 f) ~5 m
Av. 14.34 X! ]6 k/ ~' H3 p" d8 v- Z, s
4
* l2 R0 T, \% m) ?( w7 R2 x8
) L! ?8 e, J" f9 ?10$ g! b- k4 v3 N! M0 ^! }
12
4 i+ ^; i1 T2 O2 a% L# B, ?# |/ Q$ R17
/ i3 k% f( {* c% `Topical testosterone% j- a4 Z: B$ f! q3 l$ T5 o/ x
34.6 4.5 X 6.5 85
. U- J- K: `8 ?: P: }- i38.8 6.0 X 8.5 708 M1 ^" |9 f2 B) L
40.0 6.0 X 6.5 62.5
" k6 Q, i0 T9 J$ K, c6 A93.6 6.0 X 7.0 55.55 z. P, Y$ X: L+ ^2 t* d
95.0 6.5 X 7.0 27.2+ t& B, x8 A( P2 `: x4 W
Av. 60.0
' a' C% N+ b- g5 V3 Zavailable testosterone. Again, emphasis should be placed on: {5 _7 C. A( _: @: g, Q& M* E
early therapy when lower levels of testosterone appear to( o, l. k4 R4 s5 }" J( |
provide the best responses. The earlier therapy is instituted/ m: N1 {( g0 i7 a$ h0 T
the more likely there will be an excellent response with low
& G4 J# L% X; d. Zserum levels. Response occurs throughout adolescence as( n8 `, S) q; `7 c1 G- y7 Y
noted in nomograms of phallic growth. 7 The actual response
# O5 n+ y3 U2 Tto a given serum level of testosterone is much greater at birth) ~" Y! [$ K) h, U+ f8 X5 ]
and gradually decreases as boys reach puberty. This is most+ R( f0 E6 c7 A% r# M: R
likely related to the conversion of testosterone to dihydrotes-" l% x) @* D( x" h* F, a- L& W3 b: L
tosterone and correlates well with the studies of testosterone
0 R+ N, L: S( uconversion in foreskin at various ages.$ w( G" q; B3 f7 W: h# M7 v% g
The question arises regarding early treatment as to whether3 P- R7 @# v1 ?4 J, [, E4 k5 k
one might sacrifice ultimate potential growth as with acceler-
7 c$ w0 s2 m& o7 @- W1 qated bone growth. The situation appears quite the reverse( }0 D6 u& F: B" r8 `* {
with phallic response. If the early growth period is not used2 w4 i% D/ d; e
when 5a reductase activity is greatest then potential growth
* P7 u- B' b G* r; E4 V# Omay be lost. We have not observed any regression of growth
5 p) l8 q K9 y) h4 G7 rattained with topical or gonadotropin therapy. It may well
0 D* T( ]( t, f' {% U5 Ebe that some patients will show little or no response to any8 {2 n+ S' _+ ?2 `# Y+ ?3 Z! K, Q1 {
form of therapy. This would suggest a defect in the ability to
$ j: S/ c- b1 ]2 ^) o% S2 cconvert testosterone to dihydrotestosterone and indicate that
" ~/ G, d* w: _; dphallic and peripheral skin, and subcutaneous tissue should& I7 e# e, j. r4 O: n9 _
be compared for 5a reductase activity., j0 A3 A! K' R$ }7 g* a3 P
A, loop enlarges to measure penile girth in millimeters. B,5 }, V' R7 C3 V5 W; p
example of penile girth computed easily and accurately.% w9 i6 i! l0 J) I* z B
conversion of testosterone to dihydrotestosterone. It is in this8 M% U/ s, o2 C e- V
older group that others have noted high levels of serum4 `' j3 {1 D4 m4 U- R, w# I
testosterone with topical application. It would also appear
5 ]: P. p) I7 b3 x% W& I0 `that phallic response during puberty is related directly to the
4 |# R2 f& m. v, S6 Userum testosterone level. There also is other evidence of local
4 w7 @# G. C) @/ Jresponse to testosterone with hair growth and with spermato-8 e5 f$ J, ? U! T; ?, x
genesis. 5• 6+ K% a1 i, G/ |$ Q, F% J% N" [
Administration of larger doses of gonadotropin or systemic
1 C @) c8 H- @7 C* L {9 H0 V8 wtestosterone, as well as topical applications that produce, U' e( W) ]4 n6 m6 C
higher levels of serum testosterone (150 to 900 ng./dl.), will7 y# O/ S" ]- l
also produce phallic growth but risks accelerated skeletal
+ R* }5 P" n% wmaturation even after stopping treatment. It would appear
o. F+ o' U7 X0 Z- F3 R+ d4 q" Rthat this may be avoided by topical applications of testosterone
& g' R: S; z' w% ^% b8 |* Qand monitoring of serum testosterone. Even with this control
/ s& o# U, ^9 k& R# ` S% Ithe duration of our therapy did not exceed 3 weeks at any
, F+ z# b5 a" otime. It is apparent that the prepuberal male subject may' H2 d K/ Z+ ]3 ~2 R) I
suffer accelerated bone growth with testosterone levels near
" b, a0 b4 g: `( x$ E% a200 ng./dl. When skeletal maturation is complete the level of
. R* l& ?) U6 Q2 z9 ?serum testosterone can be maintained in the 700 to 1,300 ng./# `" u$ N5 ]" K5 A' Y
dl. range to stimulate phallic growth and secondary sexual
$ P0 A: | D! b o$ Z* D( |+ v! Ochanges. Therefore, after skeletal maturation parenteral tes-; O0 y0 { h' N3 c' [: h# y
tosterone may be used to advantage. Before skeletal matura-
7 a) F: p) W- t( Z: Ition care must be taken to avoid maintaining levels of serum
( P" _6 j8 d/ t: Stestosterone more than 100 ng./dl. Low-dose gonadotropin
! F6 w7 @2 W( A$ cdepends upon intrinsic testicular activity and may require
' d- U# h/ J3 j4 R1 Y1 E8 Eprolonged administration for any response.6 R( @% T5 F9 [: o* U- S
Alternately, topical testosterone does not depend upon tes-" l0 f7 k/ n' R f0 [$ w: R3 ]% u
ticular function and may provide a more constant level of
. d v1 s1 H! i% {0 v8 N: Z: }REFERENCES: P: B; h0 \" w9 a6 [$ m
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
U4 s5 g# T( t$ w6 S5 tR.: The local application of testosterone cream to the prepub-
! W- o" n3 C5 U! D! y( Z- R3 Yertal phallus. J. Urol., 105: 905, 1971.
9 k& }$ I8 i& _9 z2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone4 t) A- N. y5 h% W
treatment for micropenis during early childhood. J. Pediat.,6 X9 J% `+ v. Y
83: 247, 1973.
w- m; m6 h! |3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-% s' j. s2 `4 K8 y$ e$ m$ b
one therapy for penile growth. Urology, 6: 708, 1975.; f, ?5 D( ^3 j( I6 ~+ N' ]! H) k; g
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone; g/ f+ g) q/ o3 O, i
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by1 R2 e- G; {7 h, U% E
skin slices of man. J. Clin. Invest., 48: 371, 1969.
# Y9 U7 f( a0 m$ ^9 U0 U, c5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth' O: K: I' Q t$ `
by topical application of androgens. J.A.M.A., 191: 521, 1965." H" c7 c3 u# b" R w" ~$ p: Z0 W
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local/ o, e2 y8 u% M i2 V6 G4 |
androgenic effect of interstitial cell tumor of the testis. J.0 E, s: _- Z b2 {2 e f: j
Urol., 104: 774, 1970.: ^! B" ]: o8 l5 Z1 E
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
( L: S2 ]0 K" m, h2 s! ~tion in the male genitalia from birth to maturity. J. Urol., 48: |
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