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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND' u# \& M: ?: V1 _8 B* K. C
GONADOTROPIN& P$ n% n1 G. L% \$ t4 s2 \& C
RICHARD C. KLUGO* AND JOSEPH C. CERNY
8 j, N" k& a9 k% F# P# lFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
& u% [* A: i& X; KABSTRACT. N, C- Y, ~( k ~. m- v: V; [
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
8 W. t. o# ^$ {: Lwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-0 W/ w5 S$ i2 [+ B' N
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone& Q2 |' f, y* U
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent# M) u' N- T" d: ]4 V
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
j R3 p2 }9 I6 l8 Lincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average! W& ^2 k/ {. D% h. Y" o
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
2 K) C; ^( L: a$ N. {# c2 ]occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
0 b' ]2 S" G ?+ a( m: e! Tstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
" ^7 M8 d4 j2 \4 y8 G# ]2 fgrowth. The response appears to be greater in younger children, which is consistent with previ-
5 g; x! u9 n; K+ hously published studies of age-related 5 reductase activity.
8 M$ C5 K9 v K8 K7 h. pChildren with microphallus regardless of its etiology will' ~ X( l+ j. b8 w. E
require augmentation or consideration for alteration of exter-
1 U" B- Y9 x) Z) v3 y) B4 @nal genitalia. In many instances urethroplasty for hypo-
7 k! H. M, S: ospadias is easier with previous stimulation of phallic growth.+ v* y& }6 P& E; a+ g, e1 Y
The use of testosterone administered parenterally or topically- i6 \4 P: _) A) F+ z3 u
has produced effective phallic growth. 1- 3 The mechanism of
: n' C6 j9 G% Z" z$ u9 e- [* oresponse has been considered as local or systemic. With this8 x! Z. H; d/ J8 D! b
in mind we studied 5 children with microphallus for response8 p1 V, g0 [3 X7 l5 D" O
to gonadotropin and to topical testosterone independently.
- `+ r( n% W; y, j8 m% F+ HMATERIALS AND METHODS
) i2 r: E2 Y) M: RFive 46 XY male subjects between 3 and 17 years old were
- r! w9 K& A6 S5 n6 E Mevaluated for serum testosterone levels and hypothalamic4 }6 P- Z% d* W3 u7 H* V- A( @
function. Of these 5 boys 2 were considered to have Kallmann's
4 F* I+ u) N: o2 h0 b3 l/ W' R( x* gsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
7 Q+ _/ m; y; \. \$ z- Zlamic deficiency. After evaluation of response to luteinizing- I: D' N- Y3 ]3 }8 O* ]- w
hormone-releasing hormone these patients were treated with- t+ c; @6 r7 g
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
0 K* |. W" t7 [5 }2 p2 N1 xafter completion of gonadotropin therapy 10 per cent topical# D4 L. m9 l8 }( Q
testosterone was applied to the phallus twice daily for 3 weeks.
1 f7 ]9 V& O5 }. k/ bSerum testosterone, luteinizing hormone and follicle-stimulat-
) p1 w+ F- {& z" g7 cing hormone were monitored before, during and after comple-3 c0 `- K; \! m) @, a4 d7 ]; P
tion of each phase of therapy. Penile stretch length was9 o, K4 d( D3 |# x2 g+ H. C C
obtained by measuring from the symphysis pubis to the tip of! ^& `& K: U: X( f
the glans. Penile circumferential (girth) measurements were4 a9 T2 M$ R6 E# ]
obtained using an orthopedic digital measuring device (see% N9 M6 w9 P7 S# v9 U+ ]5 ?
figure).
8 M2 D8 B4 r9 m2 T3 {' R# J- o4 a( sRESULTS
; W% M' Y2 w$ i3 P4 ]Serum testosterone increased moderately to levels between
: N: X5 r! {. N# G6 x' @50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
' ^' P8 w+ d- B! ~0 U/ j8 Vterone levels with topical testosterone remained near pre-9 @$ }5 T$ Y- b. T5 {
treatment levels (35 ng./dl.) or were elevated to similar levels0 K! }+ a& g" f* V; b! L; ~
developed after gonadotropin therapy (96 ng./dl.). Higher' d4 G. ?5 F/ u
serum levels were noted in older patients (12 and 17 years old),
8 E3 }7 p3 O+ Z# p9 Gwhile lower levels persisted in younger patients (4, 8, and 107 ~! B$ s( q; o2 F
years old) (see table). Despite absence of profound alterations! ~( h ^! J/ \. g7 y" w& ?
of serum testosterone the topical therapy provided a greater' A7 W- ? f# n) [9 r! `' i1 Y6 @
Accepted for publication July 1, 1977. ·
( |0 ~' |# e4 h4 jRead at annual meeting of American Urological Association,0 A" f6 Y4 H3 q* G8 G
Chicago, Illinois, April 24-28, 1977.
' g! e5 Y4 t& \4 Q+ \ c* Requests for reprints: Division of Urology, Henry Ford Hospital,0 w. E3 U6 A3 D% T
2799 W. Grand Blvd., Detroit, Michigan 48202.5 M' x+ n2 z; d
improvement in phallic growth compared to gonadotropin.2 V+ Z' o) B8 |( @: C
Average phallic growth with gonadotropin was 14.3 per cent6 T, V3 a4 x- e
increase in length and 5.0 per cent increase of girth. Topical7 }7 s' r. x2 d* t" K
testosterone produced a 60.0 per cent increase of phallic length
1 h6 P& {1 S% d/ D7 c! Kand 52.9 per cent increase of girth (circumference). The
: H, L: k' ]1 d5 N* E3 l$ Jresponse to topical testosterone was greatest in children be-
' E4 F. `; U1 J- p. Ctween 4 and 8 years old, with a gradual decrease to age 17" C {! n0 ^* m/ f
years (see table).+ E0 U* G+ Z# u2 s3 C% S2 g8 ]+ k
DISCUSSION8 ?$ U" P3 d3 S, j2 S
Topical testosterone has been used effectively by other
4 f% a6 e! R$ |2 j# X( t/ }clinicians but its mode of action remains controversial. Im-
- l9 v* u1 }2 r. m$ {: H* Pmergut and associates reported an excellent growth response
, J, g7 @7 X0 A! g4 ?9 f% Z: Tto topical testosterone with low levels of serum testosterone," u" V E% W& ]& i P
suggesting a local effect.1 Others have obtained growth re-
: d2 k; G$ f$ h k+ ~sponse with high. levels of serum testosterone after topical* t$ h' M- g, I6 r$ _
administration, suggesting a systemic response. 3 The use of* e$ | ]; R9 h# W: p+ w/ F
gonadotropin to obtain levels of serum testosterone compara-0 Z/ e; E; f4 I) Z. L
ble to levels obtained with topical testosterone would seem to3 l5 q5 n/ ?# M/ G; _; \6 S; u- M
provide a means to compare the relative effectiveness of
- u) e2 Q( r1 r" h& p5 d% @& htopical testosterone to systemic testosterone effect. It cer-" c7 R9 I0 h }
tainly has been established that gonadotropin as well as par-
2 Q+ _. F# a, |3 p5 Kenteral testosterone administration will produce genital
/ h" ^* ~5 q1 ?3 J. E" igrowth. Our report shows that the growth of the phallus was
; k# i; Y! O# Esignificantly greater with topical applications than with go-
4 g6 c3 z5 i/ q# Y! T+ Wnadotropin, particularly in children less than 10 years old.: S* }* \2 z& ~7 E$ l
The levels of serum testosterone remained similar or lower
7 q/ F: [ f2 x# q. H. ~than with gonadotropin during therapy, suggesting that topi-
, Q# S# I1 r& {cal application produces genital growth by its local effect as
: a2 ?9 ?3 k9 z- V/ s0 t! Ewell as its systemic effect.6 U# m4 P8 J) i0 H
Review of our patients and their growth response related to: U1 @4 I, A6 }' T z) B& v
age shows a greater growth response at an earlier age. This is
) _* r* H& V* X: M$ d# Z, Dconsistent with the findings of Wilson and Walker, who
# O# M1 u' X2 Oreported an increased conversion of testosterone to dihydrotes-/ C9 M' V9 J7 j8 `# V
tosterone in the foreskin of neonates and infants.4 This activ-
9 S1 E) `+ R/ E; t9 {' Uity gradually decreases with age until puberty when it ap-7 n4 Z3 F. N& [5 z; t
proaches the same level of activity as peripheral skin. It may; t5 g3 n' g- t( {) I+ `' @2 a
well be that absorption of testosterone is less when applied at
* v. B3 v6 g# f2 I# Aan earlier age as suggested by lower serum levels in children' Z/ a4 d D |
less than 10 years old. This fact may be explained by the
" B" i4 D7 b% z, P( q7 P: m. a; `greater ability of phallic skin to convert testosterone to dihy-
4 Z! L' |/ z6 G( n- _, q. gdrotestosterone at this age. Conversely, serum levels in older; h, d0 n- { q: k( h" l: R k$ Q
patients were higher, possibly because of decreased local
" g6 L3 w4 c+ f6 m2 j667
8 R6 n* m: d% Q4 |- Z8 a3 w* }7 k W668 KLUGO AND CERNY
4 {! F8 ?) N8 a# v; o8 F& MPt. Age
& H. s! H' a% A$ b(yrs.)
% R( {$ o2 J" n9 C+ J8 N# S9 KSerum Testosterone Phallus (cm.) Change Length
6 x6 h2 ~" F* a3 q(ng./dl.) Girth x Length (%). V2 M: B' k0 O _9 u1 ]# b9 [
4& _0 Q4 d: b% B% T0 M3 E% s% J
8
0 P0 x# w% h& Q' G3 P9 d( w/ y. I10
) |4 h% u, i" q12
* H" k5 E# B' }# v) k17, |! v: D7 I6 c1 [$ S$ E4 ]
Gonadotropin7 B! c+ n- W! W; H5 Z
71.6 2.0 X 3 16.6
$ f' F( e, d; g$ S, Y: B4 A50.4 4.0 X 5.0 20.0
/ w8 S" ]: i+ O7 q; h+ J3 w! S22.0 4.5 X 4.0 25.05 Q+ o0 Z$ B4 H6 c$ O, U
84.6 4.0 X 4.5 11.1
, @/ a" G4 }( p; {9 R, ]85.9 4.5 X 5.5 9.0
: v; r7 `4 m. h/ I' |: e- ]" S' s/ Y5 XAv. 14.3
/ c ]! m, U. b1 v e1 X4+ v% S# N: f& ] r( {
8
& E, h8 ~% S* z6 U, X8 C8 r10
0 \3 o# O8 C" s8 P12! m, I2 {; i7 |6 ]# ~3 K6 x' [
17# ~. U+ X$ q, T/ H4 m
Topical testosterone
/ M# l3 E1 W! O: ?2 U34.6 4.5 X 6.5 85
8 D" V C: K# D/ H* R38.8 6.0 X 8.5 70+ _( r5 J3 I5 D5 T
40.0 6.0 X 6.5 62.5
y+ L( K$ _. @6 P. ?93.6 6.0 X 7.0 55.5( y( n3 e' ]( j7 Y8 z
95.0 6.5 X 7.0 27.2
+ W( O" H8 w2 h& }. ]Av. 60.0
+ `6 t$ m4 H1 f' l$ ?* m, Q8 s. Havailable testosterone. Again, emphasis should be placed on
3 K3 ^7 U8 p. g/ W# zearly therapy when lower levels of testosterone appear to+ ~0 _4 a+ {7 ?8 j7 f" Z2 F0 G. W
provide the best responses. The earlier therapy is instituted3 z$ e- G4 S2 i/ M9 [7 ~) F
the more likely there will be an excellent response with low. v8 H& ~% @. v( y1 v+ ^7 q
serum levels. Response occurs throughout adolescence as
9 n7 G) l# `" T2 dnoted in nomograms of phallic growth. 7 The actual response& x* g) s: ?& q
to a given serum level of testosterone is much greater at birth
9 r, P: K( b, ~$ F% Hand gradually decreases as boys reach puberty. This is most1 P- t) F! } \# D+ g
likely related to the conversion of testosterone to dihydrotes-
8 |2 @5 a9 B; T. ztosterone and correlates well with the studies of testosterone
% b9 ]! p& g8 N! s/ ^9 ]conversion in foreskin at various ages.
8 z4 o) W% o$ L2 _/ N* E8 }The question arises regarding early treatment as to whether, h# z p* \5 a1 k: p) Z
one might sacrifice ultimate potential growth as with acceler-0 Q: `7 Y$ t* I7 N3 C/ L6 L
ated bone growth. The situation appears quite the reverse
7 q) U- w( [2 ~$ a, j- @- _with phallic response. If the early growth period is not used
% s( P5 }# \/ K8 s5 H7 [, Y3 M- ]when 5a reductase activity is greatest then potential growth
2 C* K) j$ |& y+ D& Omay be lost. We have not observed any regression of growth# s m) j; a: z( M+ y" d5 C
attained with topical or gonadotropin therapy. It may well
2 g ^3 U" n. Kbe that some patients will show little or no response to any3 v; a- I4 N0 D" J7 m) s
form of therapy. This would suggest a defect in the ability to
4 z9 \1 Y0 H' }' a3 j/ R3 X- v Qconvert testosterone to dihydrotestosterone and indicate that, J/ }: V% D L0 v( \8 D' W2 p* {
phallic and peripheral skin, and subcutaneous tissue should
' [6 ~6 [; D9 zbe compared for 5a reductase activity.
; {1 M' A7 h8 ^; S) YA, loop enlarges to measure penile girth in millimeters. B,: v0 D2 }4 ?4 [
example of penile girth computed easily and accurately.$ U/ n* x8 a8 a, ~2 |/ S
conversion of testosterone to dihydrotestosterone. It is in this; h. J! l/ G* s/ `2 T6 Y4 j
older group that others have noted high levels of serum
7 t3 i9 B7 F6 F! ~. w# z# ltestosterone with topical application. It would also appear8 I2 B4 K( |0 H
that phallic response during puberty is related directly to the6 ~- ^( O3 ?6 d2 q
serum testosterone level. There also is other evidence of local
; o; ~& c6 P1 Jresponse to testosterone with hair growth and with spermato-
4 G' h- Q. E, W+ `- ]3 o5 Ogenesis. 5• 6
/ K6 o! F0 n7 ~4 D4 dAdministration of larger doses of gonadotropin or systemic6 v# s h7 Q1 R
testosterone, as well as topical applications that produce
1 q0 [8 C, K* k' W: t' \higher levels of serum testosterone (150 to 900 ng./dl.), will
1 [7 r1 w3 q# _1 m( T) h' q' r( k5 calso produce phallic growth but risks accelerated skeletal9 P8 a1 w- J- ]. t6 `: x
maturation even after stopping treatment. It would appear
6 Q6 T5 e! _/ `- j/ Gthat this may be avoided by topical applications of testosterone+ j7 y4 q: M) w8 \( `4 W. C
and monitoring of serum testosterone. Even with this control1 x( M0 p5 ^; w0 ?7 e; b7 P- y
the duration of our therapy did not exceed 3 weeks at any' V7 G, N' X& P2 H
time. It is apparent that the prepuberal male subject may
' W+ M/ j% d+ a' o7 {; ]6 @! W4 ssuffer accelerated bone growth with testosterone levels near
+ c h+ a% d% D5 k" E$ w" g' n200 ng./dl. When skeletal maturation is complete the level of+ i8 z5 l7 H$ \- |( y0 A
serum testosterone can be maintained in the 700 to 1,300 ng./5 m9 S: Q4 \) l8 W( g$ u8 e
dl. range to stimulate phallic growth and secondary sexual
1 `8 X5 y y. o( j0 n8 Uchanges. Therefore, after skeletal maturation parenteral tes-
0 r% R, t o4 h/ H) U# ]tosterone may be used to advantage. Before skeletal matura-
5 K* G: ?9 V0 w4 Y5 t# L' a+ Ntion care must be taken to avoid maintaining levels of serum
5 o& A8 m3 L6 z$ H0 Z1 R( \2 Utestosterone more than 100 ng./dl. Low-dose gonadotropin
! r) g' P' Q. g6 K% g, pdepends upon intrinsic testicular activity and may require' Q9 C0 [& {, U( c5 o- f
prolonged administration for any response.) P& {1 B7 H3 ^' f% w* f1 v
Alternately, topical testosterone does not depend upon tes-
( T$ g, A) N9 C7 sticular function and may provide a more constant level of$ v% a; c7 w% q
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) c- G H3 Q$ w; _8 u, ^R.: The local application of testosterone cream to the prepub-, l* `+ ^( k" s. n( V
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]: F; b; L" _' [% _2 }6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
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0 U) b5 B0 j: ?/ }" x G/ m1 _Urol., 104: 774, 1970.
+ v3 t/ z; A! b7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-, \6 ^4 y# } X" T/ t
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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