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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND" s9 C- D3 r) p3 g. G, t
GONADOTROPIN* v8 w3 r/ S7 x% | S8 z3 E3 w
RICHARD C. KLUGO* AND JOSEPH C. CERNY0 d7 S6 A# A% g
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
, @4 d0 [2 A& P$ d* {6 RABSTRACT: C. `$ C, T4 A" `
Five patients were treated with gonadotropin and topical testosterone for micropenis associated" _, O( \$ Y% a* e) V
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
1 C% x8 z. u' ~% Itropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
% `% V+ K* ]' K. Gcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
; Y4 J; e- ?7 p/ mfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
* ?& \% d. j; R" F% j7 {increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
+ I, H0 T1 n; T8 r: I/ [: Aincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response" ^0 ]' D* d; ^/ ~" r) {
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
3 M/ Z4 c7 h; G$ J2 m8 sstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile6 E# @. l5 d7 g' ~8 X4 s
growth. The response appears to be greater in younger children, which is consistent with previ-* i: Y+ G: e( e
ously published studies of age-related 5 reductase activity.4 z) B, I8 c5 L6 s2 E: Y: U+ |3 i
Children with microphallus regardless of its etiology will
- J g/ a2 |! m/ _require augmentation or consideration for alteration of exter-; x. [: W/ I* V# O2 p+ c) W
nal genitalia. In many instances urethroplasty for hypo-" g5 {1 m! m3 o3 o. o* L- c( D
spadias is easier with previous stimulation of phallic growth.
: _, ^9 b! Q1 i4 pThe use of testosterone administered parenterally or topically" u8 D# e' ^4 u
has produced effective phallic growth. 1- 3 The mechanism of$ U% |- T0 B: k9 j3 U
response has been considered as local or systemic. With this) _. P( L( ~ }' o
in mind we studied 5 children with microphallus for response. g J7 h8 G4 B$ }3 {/ o
to gonadotropin and to topical testosterone independently.- D: V& V. m/ I- U% x- t I
MATERIALS AND METHODS6 U5 i i4 D* M
Five 46 XY male subjects between 3 and 17 years old were
* V9 \7 Z3 z; r' R2 S/ ] `' Yevaluated for serum testosterone levels and hypothalamic2 f" t& Z! o# N+ T+ f1 u
function. Of these 5 boys 2 were considered to have Kallmann's
^0 O- k. D `+ i3 o3 j# _# Bsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
* t5 t* S- \1 P) G. |9 r# Tlamic deficiency. After evaluation of response to luteinizing
1 F$ N0 e/ q6 j4 d# W5 }' y/ hhormone-releasing hormone these patients were treated with
5 z. a ^3 b9 l0 P1 R' X h1,000 units of gonadotropin weekly for 3 weeks. Six weeks3 N+ [, j* c- b2 j) Q- Q1 z7 ^
after completion of gonadotropin therapy 10 per cent topical
& f) W. b5 s1 Ctestosterone was applied to the phallus twice daily for 3 weeks.3 g4 `# i! t' } [3 d p' p( t
Serum testosterone, luteinizing hormone and follicle-stimulat-
2 ~5 |/ v. L' `ing hormone were monitored before, during and after comple- x( o* A8 a( ^5 I. o. P
tion of each phase of therapy. Penile stretch length was
' p' U9 c; F+ m" Q, _/ Kobtained by measuring from the symphysis pubis to the tip of$ q1 W8 V1 H T& U5 H) [
the glans. Penile circumferential (girth) measurements were
1 x# ]! |2 f2 m+ B/ P4 ?! I5 nobtained using an orthopedic digital measuring device (see, c3 f; \9 f8 y; `, W- b- G" P! y
figure).$ G% }% t2 E* r; S' t
RESULTS2 D' `! N. \! d- J
Serum testosterone increased moderately to levels between
) @: O: h8 L: ?3 X! X8 b+ U; k% W50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
8 b$ Q' T. S8 m- c7 pterone levels with topical testosterone remained near pre-
% K4 j2 M. ^$ R( [treatment levels (35 ng./dl.) or were elevated to similar levels
" G" ~2 M) F% e* g0 Y" w' |developed after gonadotropin therapy (96 ng./dl.). Higher
4 s" ^9 g! n$ R+ nserum levels were noted in older patients (12 and 17 years old),( e$ j; ^; C, }, u" ?) E
while lower levels persisted in younger patients (4, 8, and 10+ r/ j5 X h1 o( q
years old) (see table). Despite absence of profound alterations
% v4 i, |' D; m; Z+ D, a% u gof serum testosterone the topical therapy provided a greater
' M; v, U$ B" qAccepted for publication July 1, 1977. ·
6 P: C5 ~& T8 ?Read at annual meeting of American Urological Association,! z( I: k% `1 q5 L2 o2 K+ l3 U
Chicago, Illinois, April 24-28, 1977./ U) e2 D Z9 P6 A! |- s) M
* Requests for reprints: Division of Urology, Henry Ford Hospital,. j: }2 u7 `$ A" |9 _
2799 W. Grand Blvd., Detroit, Michigan 48202.( j( l. s$ j# [) D8 h2 ^1 A+ e/ H
improvement in phallic growth compared to gonadotropin.
^5 y( x1 G x' j; _& r) @Average phallic growth with gonadotropin was 14.3 per cent
% O* \* R2 r$ {$ N) G! Bincrease in length and 5.0 per cent increase of girth. Topical. B6 `; }0 O: h' X+ B% Y! ]
testosterone produced a 60.0 per cent increase of phallic length
1 D+ ]5 N- [6 J; n9 H: nand 52.9 per cent increase of girth (circumference). The& @* X" r( {0 R# a
response to topical testosterone was greatest in children be-2 D, v7 K' r. I+ D/ O
tween 4 and 8 years old, with a gradual decrease to age 178 N& X; v0 s$ L. y; T/ K
years (see table).3 ` Z) d. A/ b. o: o" N
DISCUSSION
/ y c- p3 |- eTopical testosterone has been used effectively by other
; c. M6 T0 z( p! c# Z- iclinicians but its mode of action remains controversial. Im-
& e. w) K* I% H$ J5 X, Xmergut and associates reported an excellent growth response$ F( D7 u5 }" u
to topical testosterone with low levels of serum testosterone,5 r2 R7 T+ a6 k; ~( R- ]" ]
suggesting a local effect.1 Others have obtained growth re-
4 ?/ g; |% v, x/ Jsponse with high. levels of serum testosterone after topical2 o: f& S$ X3 v; |- D
administration, suggesting a systemic response. 3 The use of- W& Y, E( W9 Y2 r2 P- Q2 T
gonadotropin to obtain levels of serum testosterone compara-
' g: C, j4 M8 B5 Wble to levels obtained with topical testosterone would seem to
/ }" c2 s' {# Lprovide a means to compare the relative effectiveness of
% O5 W0 B9 |& ^! x: D) n8 W- }topical testosterone to systemic testosterone effect. It cer-
" L/ K0 d5 k- o M0 z/ x" stainly has been established that gonadotropin as well as par-
$ n5 g0 I) z! P8 n& S* Ienteral testosterone administration will produce genital1 ?( f2 |5 p9 f- w+ F# }
growth. Our report shows that the growth of the phallus was. o+ q S1 C6 Z/ {: h+ {3 a
significantly greater with topical applications than with go-
5 _, ]% C, U1 i& G0 z6 rnadotropin, particularly in children less than 10 years old.2 [* J& O' u- \
The levels of serum testosterone remained similar or lower5 r: r) W( R( B# I$ Z
than with gonadotropin during therapy, suggesting that topi-9 f) o# ?; q5 `; ~: e
cal application produces genital growth by its local effect as0 E2 R- L, w* x- F# X
well as its systemic effect.2 s! p, Q, ?6 A1 @- m9 Z: a* c5 _
Review of our patients and their growth response related to# g. c% X2 N$ @' l
age shows a greater growth response at an earlier age. This is# k. S s0 a# d4 F% O( e, E7 w. t1 O
consistent with the findings of Wilson and Walker, who
' q; C5 ` k* {! f: ?reported an increased conversion of testosterone to dihydrotes-
* w$ S3 `5 x# U, x. U. v" K' K' ztosterone in the foreskin of neonates and infants.4 This activ-
3 i7 r6 @8 E. S2 d' Qity gradually decreases with age until puberty when it ap-! i+ e$ Y6 a T2 h% |2 q5 ?% h
proaches the same level of activity as peripheral skin. It may/ q+ l6 w9 ]. z" ^: o
well be that absorption of testosterone is less when applied at
3 k( s: J: |% K8 @& @( s& d5 {an earlier age as suggested by lower serum levels in children& k; e' |& a$ u& g7 Z+ n
less than 10 years old. This fact may be explained by the8 O N! W# d6 F3 j+ V8 `% ?7 r
greater ability of phallic skin to convert testosterone to dihy-5 R5 X* F1 z! j6 V3 c3 R% g
drotestosterone at this age. Conversely, serum levels in older4 m$ O( _& h6 N' F
patients were higher, possibly because of decreased local
6 h7 j4 U" b( i; H: v1 ~667
2 P4 ?3 Y; b6 }/ z7 G; c$ ]" l, T668 KLUGO AND CERNY+ }- w; _0 I5 C: l6 g' v' ?# V; b1 e5 d
Pt. Age
( b8 Y' J0 R; d8 p; a+ L(yrs.)4 t" a7 o+ G5 W. [
Serum Testosterone Phallus (cm.) Change Length/ Q& ~; M$ g) o/ n6 X
(ng./dl.) Girth x Length (%)
6 ?3 L' G' s# `# c: ]9 N4; v$ ?; F, e& i4 M
82 K. f3 D3 c! s$ O, B5 V
10
& N% H# E! C: r6 P12
% o+ e5 _+ r" O2 D7 G17& h! k( p8 p3 @9 W: R# ~$ ^3 J
Gonadotropin
1 c' A! g/ r. \- G4 q) }6 N9 r71.6 2.0 X 3 16.6! _* B' w4 Y$ H; c+ ~ b% t
50.4 4.0 X 5.0 20.0
" ~; k" D, }9 i% B22.0 4.5 X 4.0 25.0
- S: L7 n6 z5 O" z84.6 4.0 X 4.5 11.1
& F k- f n" L' T, ~$ i( N85.9 4.5 X 5.5 9.08 u3 R1 n. ]. y. n3 }- c
Av. 14.3
0 T8 u6 [7 b ?% N8 f ~4
% l& x- |8 F8 ~8 I. p83 a) _8 `6 E2 W: r$ N; T J
106 e. c" [8 p8 y( `5 V9 d& q/ m; Y
12# D& D1 {' u; M6 b
17. j0 a9 W; q- q4 T
Topical testosterone4 C; G) N3 a2 a5 T: g7 w- _, |
34.6 4.5 X 6.5 85
' T1 a2 K* v; N38.8 6.0 X 8.5 70
& O3 s4 ?$ G) R @# D5 R: W/ \- e40.0 6.0 X 6.5 62.58 N8 Z8 [0 y- }
93.6 6.0 X 7.0 55.54 }- W0 C" U( P$ i5 c' `
95.0 6.5 X 7.0 27.2
" ?' R' B9 _' K' `- ^5 r" QAv. 60.0/ N& S; I, V, O
available testosterone. Again, emphasis should be placed on. f& O7 x4 m: B* B- T
early therapy when lower levels of testosterone appear to
0 W0 _ V$ y4 R5 [% o8 vprovide the best responses. The earlier therapy is instituted
\8 R: r- e$ n7 H" h% t I3 o8 ?the more likely there will be an excellent response with low: [% @: D8 r7 P* ] h2 ~
serum levels. Response occurs throughout adolescence as( Z+ N8 ^+ U: E; g8 d1 t
noted in nomograms of phallic growth. 7 The actual response& N1 V5 [8 i% U0 P4 O0 P0 R. E
to a given serum level of testosterone is much greater at birth; W3 J& O- {. h2 v
and gradually decreases as boys reach puberty. This is most1 I1 f! r# E" }' ^8 c7 b4 v, j8 ?+ v$ J
likely related to the conversion of testosterone to dihydrotes-
2 t: w* `9 t. A/ Y2 G7 ]1 Otosterone and correlates well with the studies of testosterone
1 h) O3 k% u" m0 c! `# O5 Hconversion in foreskin at various ages.
+ a d9 n4 O+ J3 g( G N% wThe question arises regarding early treatment as to whether
, m1 k. B5 ~9 J$ W; i" Sone might sacrifice ultimate potential growth as with acceler-
, `5 g9 b( k0 C+ d. ]" Qated bone growth. The situation appears quite the reverse5 w+ m5 G, k; f! `+ c
with phallic response. If the early growth period is not used) t* c% B O! g; V `0 }
when 5a reductase activity is greatest then potential growth6 I( U( v" N2 m4 Q
may be lost. We have not observed any regression of growth9 _5 k _6 C& g- k& O2 |
attained with topical or gonadotropin therapy. It may well! }+ Y& W& L2 F. {. k/ v5 U
be that some patients will show little or no response to any( T; X& ^. i: S" R$ [9 C! i
form of therapy. This would suggest a defect in the ability to/ a! {6 h# x T% o$ R0 E9 q# {
convert testosterone to dihydrotestosterone and indicate that* i, y" Q- P/ A' Q
phallic and peripheral skin, and subcutaneous tissue should0 V: O1 w4 ]& u6 n. d" v( d. M
be compared for 5a reductase activity.
* ~# R4 H0 {4 S% L3 [2 o8 ]/ t vA, loop enlarges to measure penile girth in millimeters. B,* Y6 s; c% H7 h
example of penile girth computed easily and accurately.
% B6 V$ j( g' c2 \conversion of testosterone to dihydrotestosterone. It is in this
, K4 Q Z# y, P O7 x3 p' p: `older group that others have noted high levels of serum% i# \3 \) J( x' G+ {! X7 V
testosterone with topical application. It would also appear
* g: e" x- W+ p% ]( t3 hthat phallic response during puberty is related directly to the* \+ \# ?, \9 k7 {% I% Q; V' ~
serum testosterone level. There also is other evidence of local
& A! o' r$ e$ ]* B, W8 Iresponse to testosterone with hair growth and with spermato-4 t3 o" f! I9 s2 r' @3 @3 U U
genesis. 5• 6, K# C" z( E' f& a l
Administration of larger doses of gonadotropin or systemic
8 z- S- X+ r! S0 xtestosterone, as well as topical applications that produce
0 a5 w( C/ `- vhigher levels of serum testosterone (150 to 900 ng./dl.), will
* y e5 c" U$ @- ~" balso produce phallic growth but risks accelerated skeletal1 Y1 d' w' ~8 G) {7 l1 ]3 P% L
maturation even after stopping treatment. It would appear i+ y6 V5 Z S# J& B
that this may be avoided by topical applications of testosterone
5 c6 H: O/ m% B9 ^, t/ vand monitoring of serum testosterone. Even with this control
. ?6 F8 O6 S. Tthe duration of our therapy did not exceed 3 weeks at any! W4 ]4 `. l# c4 g4 \7 J! d
time. It is apparent that the prepuberal male subject may
" {# _. a4 n, F' Csuffer accelerated bone growth with testosterone levels near
( O7 U1 d2 ?$ H) [. {! h# ~1 o! V200 ng./dl. When skeletal maturation is complete the level of
3 I% h+ [4 G& ^( @3 {) zserum testosterone can be maintained in the 700 to 1,300 ng./1 Y* k0 ]% G- W, R
dl. range to stimulate phallic growth and secondary sexual& }! y; o0 e) H
changes. Therefore, after skeletal maturation parenteral tes-
" K8 ]1 r) G' @: ]3 rtosterone may be used to advantage. Before skeletal matura-( O0 k g; h0 n, E. S
tion care must be taken to avoid maintaining levels of serum
" F7 y7 u* G( v T$ R+ L0 L% ytestosterone more than 100 ng./dl. Low-dose gonadotropin4 Q. E2 m. x- ]2 g4 h3 w Z' a
depends upon intrinsic testicular activity and may require* Z+ d% }: i0 X# v ]3 Y
prolonged administration for any response." z' b0 D5 K9 s- o
Alternately, topical testosterone does not depend upon tes-
# ^4 }8 @9 D: k% |ticular function and may provide a more constant level of0 u* m3 J1 O7 x5 Z+ q! z" Z
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0 D& Z7 o! D- X' w: g1 ?' hR.: The local application of testosterone cream to the prepub-
1 G6 |$ S4 z8 i3 K3 zertal phallus. J. Urol., 105: 905, 1971.! c: |' I: e3 M
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0 c' X7 G4 y( ^1 u$ Q3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
$ K$ Y3 J( u: O) _- Q3 Tone therapy for penile growth. Urology, 6: 708, 1975.
. c: `; e- L* f6 M6 a' ]. Z1 H% P4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
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5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
+ M2 I' v/ g7 k7 p3 X; R1 Fby topical application of androgens. J.A.M.A., 191: 521, 1965., |, S' Y0 [" b0 e4 h: \2 ~" X
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
& g$ {0 Z- f7 yandrogenic effect of interstitial cell tumor of the testis. J.
6 _. s/ u; ?, L7 GUrol., 104: 774, 1970.
$ A$ ^) w" _/ t k5 g; [7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-$ {9 \. z V1 Y# h
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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