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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
) S1 B6 K9 U1 KGONADOTROPIN9 I: O' s/ r. |1 M; L+ l
RICHARD C. KLUGO* AND JOSEPH C. CERNY
( ^6 c) U9 q4 VFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
$ \) }2 F- i, A; @- a9 x* eABSTRACT3 S" W- `8 H6 [' z
Five patients were treated with gonadotropin and topical testosterone for micropenis associated$ m# C3 q6 y; r/ X4 K
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-2 t1 m, Y& s' \5 h3 S3 V
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
5 {, d2 Z9 @$ G/ Lcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent N9 F9 a! i k; M5 \
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
$ M2 j5 p, i6 z( Uincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
+ l1 |' D& @, o4 w" y' y; ?increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
8 B0 w# m M" p. W! B, q% K: qoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
2 n7 m! F7 P b2 n2 dstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
! R- s# R. W6 F0 H3 l2 j8 @growth. The response appears to be greater in younger children, which is consistent with previ-
8 j/ x9 f: r! G/ j& \ously published studies of age-related 5 reductase activity.
2 a p- s/ A/ {" u$ |4 e7 I9 _Children with microphallus regardless of its etiology will# F7 h* m; O2 v! ~# t
require augmentation or consideration for alteration of exter-
- B. a, D( H9 `& `# ~0 Vnal genitalia. In many instances urethroplasty for hypo-" W8 T. a3 a+ u# v0 d
spadias is easier with previous stimulation of phallic growth.
) G* x7 z: n9 K& Q! G3 _$ `8 @5 EThe use of testosterone administered parenterally or topically* h- r, U, c% u5 F
has produced effective phallic growth. 1- 3 The mechanism of% N( U+ U) e4 C2 K
response has been considered as local or systemic. With this1 v: K) v7 D+ [: [) S* c
in mind we studied 5 children with microphallus for response' p- j/ G" j2 g- @% {4 y. i
to gonadotropin and to topical testosterone independently.
" [# G; p) \* o8 u8 O0 y- [MATERIALS AND METHODS
( t" x' o; [! JFive 46 XY male subjects between 3 and 17 years old were
5 |2 @9 B1 P* eevaluated for serum testosterone levels and hypothalamic
4 A" n: n% d* y( tfunction. Of these 5 boys 2 were considered to have Kallmann's8 e1 V2 Z6 d- d; }; j( V. I" F
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-7 B" X) ?/ x: @' g B
lamic deficiency. After evaluation of response to luteinizing a6 D; s( t" y5 u) h
hormone-releasing hormone these patients were treated with
: T$ a, Q& W, q1,000 units of gonadotropin weekly for 3 weeks. Six weeks9 S1 e, r. H! }4 h# D* F4 H
after completion of gonadotropin therapy 10 per cent topical
- r# F- |, }' y! S$ b0 {7 Stestosterone was applied to the phallus twice daily for 3 weeks.( d" r1 c: o8 a8 r. x6 z; D
Serum testosterone, luteinizing hormone and follicle-stimulat-
% p. x* [9 W# c- P* f; E6 i' `ing hormone were monitored before, during and after comple-
8 V9 W) B, P+ r4 C: `) v2 T+ a) Ntion of each phase of therapy. Penile stretch length was
1 p' }; `( ~0 b* A, _7 y a# yobtained by measuring from the symphysis pubis to the tip of* R6 X, n3 d* ]9 Y! |7 k
the glans. Penile circumferential (girth) measurements were
( Q' G7 D9 u/ c8 X' _+ Dobtained using an orthopedic digital measuring device (see
5 \. q8 g( l# I! p6 Cfigure).
3 |0 h& P7 o% m9 I- w: X( @7 vRESULTS% v3 D# F. o# j5 H
Serum testosterone increased moderately to levels between
4 [5 b. F2 ?9 @# X3 R8 R( _50 and 86 ng./dl. with gonadotropin stimulation. Serum testos- ^. r( C; B' X% B! n9 o) U1 M
terone levels with topical testosterone remained near pre-1 K" k2 A6 K6 F; d
treatment levels (35 ng./dl.) or were elevated to similar levels
8 F/ J/ h1 f4 {$ hdeveloped after gonadotropin therapy (96 ng./dl.). Higher
6 u% W" e9 x' J, F" _! hserum levels were noted in older patients (12 and 17 years old),$ I, c$ L0 ]2 T" s m
while lower levels persisted in younger patients (4, 8, and 10
9 C6 k) F5 D3 Z+ s( c& wyears old) (see table). Despite absence of profound alterations, h& ~6 J; [, b) G5 @6 y, v
of serum testosterone the topical therapy provided a greater+ W2 Z, k8 S, p
Accepted for publication July 1, 1977. ·0 s' d3 u1 Y( \+ x& B
Read at annual meeting of American Urological Association,
; l+ f0 Q+ o# [: DChicago, Illinois, April 24-28, 1977.
) }! p/ L' w5 X5 c6 P4 l4 g$ o8 R* Requests for reprints: Division of Urology, Henry Ford Hospital,
0 ?3 l( f3 ^' O6 f" W9 L1 v5 e2799 W. Grand Blvd., Detroit, Michigan 48202.% Z; ~8 Z' l+ V3 K' l% j7 A9 E
improvement in phallic growth compared to gonadotropin.4 n3 D% K' r& G, N3 z5 [3 e
Average phallic growth with gonadotropin was 14.3 per cent& X# v( H C2 c
increase in length and 5.0 per cent increase of girth. Topical. Y" p! L5 F* ?0 j1 K
testosterone produced a 60.0 per cent increase of phallic length2 ]5 U2 t6 A. w7 e5 p
and 52.9 per cent increase of girth (circumference). The- d6 J. H% Z9 D
response to topical testosterone was greatest in children be-! Q* v# B6 S8 V# ]9 i' f. H J
tween 4 and 8 years old, with a gradual decrease to age 177 m2 D# x( B; \; w3 J
years (see table).- B- o/ b* y& K0 u1 X) a7 z$ _6 [
DISCUSSION9 X/ V2 G: D" ]! O& d7 Y
Topical testosterone has been used effectively by other
1 }8 l' M2 G% N0 O& Y) ~. ^% @clinicians but its mode of action remains controversial. Im-' j2 J7 r. o2 `* w/ X
mergut and associates reported an excellent growth response$ w' a+ E& N! ]/ I1 K0 _
to topical testosterone with low levels of serum testosterone,
% o6 g, f4 P% z, F8 H6 o6 o2 Q$ Lsuggesting a local effect.1 Others have obtained growth re-: n$ M4 D* |& s/ @
sponse with high. levels of serum testosterone after topical
2 j7 T! B3 u3 Z) L" u9 n5 madministration, suggesting a systemic response. 3 The use of
7 r3 K0 T! p4 d( a# O$ i zgonadotropin to obtain levels of serum testosterone compara-- `3 ?; @; B6 \
ble to levels obtained with topical testosterone would seem to
8 }/ ^6 E) v& a1 N6 o+ A8 n7 sprovide a means to compare the relative effectiveness of; Q6 c' W0 d1 C4 Q/ V' L4 ~- I
topical testosterone to systemic testosterone effect. It cer-
, {4 C9 X' ^* S% p9 {+ `) h* |, }tainly has been established that gonadotropin as well as par-$ ?# l+ ^' }; h) I& T+ C
enteral testosterone administration will produce genital
$ R1 T6 D0 z% a! ~growth. Our report shows that the growth of the phallus was$ Z& A4 O/ K9 ]# @
significantly greater with topical applications than with go-" d0 z [& u1 k ?
nadotropin, particularly in children less than 10 years old.- E! I( ?9 H, N% y, x; d
The levels of serum testosterone remained similar or lower
- r! ]6 E% Y* v# \- t2 Jthan with gonadotropin during therapy, suggesting that topi-/ f3 @6 R! }) \) ^) W( y
cal application produces genital growth by its local effect as! m& P4 C0 t- x/ a
well as its systemic effect.
7 `' R' J1 d. s* aReview of our patients and their growth response related to
. @" {2 C6 T& m2 hage shows a greater growth response at an earlier age. This is: Z8 M8 a X9 F3 x5 v; d$ v( l
consistent with the findings of Wilson and Walker, who
2 V0 h2 |6 [# K) Creported an increased conversion of testosterone to dihydrotes-4 ?6 }+ J% @$ _6 A# R
tosterone in the foreskin of neonates and infants.4 This activ-" r& h' z' c6 N4 v
ity gradually decreases with age until puberty when it ap-
1 `2 U) [3 g1 A" N% c' A0 d. x3 v. r+ Sproaches the same level of activity as peripheral skin. It may6 V( R- s4 ~# P& x4 T1 Y. C. O* `, s
well be that absorption of testosterone is less when applied at
) y( f. m& X: L5 S$ }/ h( zan earlier age as suggested by lower serum levels in children
2 R( x9 X9 S9 U5 y& j+ ^0 Vless than 10 years old. This fact may be explained by the% V7 O6 z' \4 \7 ^4 n( n
greater ability of phallic skin to convert testosterone to dihy-7 v; p1 o5 `4 g1 w. d
drotestosterone at this age. Conversely, serum levels in older1 `) `" b7 [3 p, K6 ^9 D, D
patients were higher, possibly because of decreased local- g) A. U$ H e" e: m" u' x' g
6677 j1 x; X+ n$ a, ]2 n7 d% x
668 KLUGO AND CERNY! |' X5 y7 R( G' W, ^6 p1 @
Pt. Age* @9 J3 p0 l# `5 r* i% O
(yrs.)) L7 D1 j6 Z. ^9 \8 t4 y
Serum Testosterone Phallus (cm.) Change Length. L* D$ I2 E* E6 w
(ng./dl.) Girth x Length (%)
& p+ C: f0 v8 w8 S; \4
/ w4 a7 n7 T2 o( E! w3 T, e83 }* ?# f% ?* t
10. ^' d: F) e4 \
12
6 v4 J, A; i4 s" C4 W. g6 A17- s: Q" B/ B/ g# x: M
Gonadotropin1 U# n: Z6 t- C
71.6 2.0 X 3 16.6, x G5 E5 j4 W5 b0 H
50.4 4.0 X 5.0 20.0" [* w" F* |- |+ P: m' k2 g
22.0 4.5 X 4.0 25.0
6 Q7 _- M6 O; R, w. ]8 g84.6 4.0 X 4.5 11.1% W2 E" \1 Y1 q! t
85.9 4.5 X 5.5 9.0
! S( M7 v' R$ {9 e3 B }7 g# s4 ~Av. 14.3
' r+ F; f5 f! L. \; o4 s0 l/ W" o4
2 D+ |+ e( z: l& `, t0 ^3 @8# u3 M* U' L/ t& F
10. d- Y9 E5 w1 }
12+ w: W- H6 @& r/ `" O
17
, S9 f0 k. P5 [1 v' `! v1 H9 GTopical testosterone/ B" ]. g1 I+ m. z* T' K
34.6 4.5 X 6.5 85
, ^) U* t7 y+ ~" T38.8 6.0 X 8.5 70* V8 S: ~4 B) L3 Y
40.0 6.0 X 6.5 62.5$ W! R2 m3 G6 ?; K) ]' a% P
93.6 6.0 X 7.0 55.5
- o* a7 z( E, h" r1 j7 |! L95.0 6.5 X 7.0 27.2
' i8 ^; t8 a+ rAv. 60.0& k. x. |. `& B! G
available testosterone. Again, emphasis should be placed on: E1 u; L% [# Y9 Y2 \
early therapy when lower levels of testosterone appear to, }/ z4 G0 Z6 \7 L! l. R
provide the best responses. The earlier therapy is instituted; s9 m/ k/ T! N4 Y% y( J- g! k: j; _7 c
the more likely there will be an excellent response with low7 }0 R# n/ F) c1 k) j6 H' b1 g0 x( |/ C
serum levels. Response occurs throughout adolescence as
- M& s) E( O; n5 cnoted in nomograms of phallic growth. 7 The actual response7 `/ ~8 o: h& v" C
to a given serum level of testosterone is much greater at birth, s5 f0 w: O% ~, q' a
and gradually decreases as boys reach puberty. This is most
' y; y! g; K0 e7 m6 Elikely related to the conversion of testosterone to dihydrotes-9 q# U/ A; u& }0 ^8 M6 W
tosterone and correlates well with the studies of testosterone
/ `* a5 A7 B5 D4 i( N2 {conversion in foreskin at various ages.
2 {5 o/ ?" t1 G! r% qThe question arises regarding early treatment as to whether
/ k4 L, q* J. a9 I8 a5 M6 E3 P0 _one might sacrifice ultimate potential growth as with acceler-5 c( l$ W3 D5 \' {+ \0 p& G L
ated bone growth. The situation appears quite the reverse
: ~6 T- R! V9 v- O5 E0 i/ ]/ a5 p; [with phallic response. If the early growth period is not used
. E2 T$ |& e$ p+ ?0 D, @when 5a reductase activity is greatest then potential growth! M- x9 }) ^- O, i8 V
may be lost. We have not observed any regression of growth$ [5 Z5 I% x+ n: \: C
attained with topical or gonadotropin therapy. It may well0 e* N& C% l* W9 P/ {/ x$ X8 {: h9 H
be that some patients will show little or no response to any
% {0 }( @2 r! P1 E8 e& uform of therapy. This would suggest a defect in the ability to
2 j9 o: { q4 \2 iconvert testosterone to dihydrotestosterone and indicate that
$ A$ \, n" R* x/ tphallic and peripheral skin, and subcutaneous tissue should) d- j8 _4 p, `0 a6 p' c
be compared for 5a reductase activity.+ `2 r4 w, K9 w
A, loop enlarges to measure penile girth in millimeters. B,$ u. A$ L. r( n
example of penile girth computed easily and accurately.) b# x8 d) r0 N/ h% |
conversion of testosterone to dihydrotestosterone. It is in this# T* O1 a8 u$ c; c6 X3 b; ^
older group that others have noted high levels of serum3 w; E/ z* d, @
testosterone with topical application. It would also appear
1 w, {3 T& v5 w! k4 r7 b3 B5 Jthat phallic response during puberty is related directly to the E$ Z* o. }& Z- x3 m# t ~
serum testosterone level. There also is other evidence of local
+ h* b! }5 i8 M2 ^9 l% uresponse to testosterone with hair growth and with spermato-
% R* R% T8 P8 c. S# ngenesis. 5• 6
, Z: l& o5 h* M) TAdministration of larger doses of gonadotropin or systemic3 j% i/ [$ ?, ~( U+ ^, _5 c% U" |( H
testosterone, as well as topical applications that produce" I4 i, Y |3 c7 N6 C1 n
higher levels of serum testosterone (150 to 900 ng./dl.), will
: ? f t. S) O5 N! P# kalso produce phallic growth but risks accelerated skeletal
1 d0 C5 r" Q/ I% t. @8 @: Umaturation even after stopping treatment. It would appear) D* v6 T% o* y
that this may be avoided by topical applications of testosterone4 `3 k/ L! x3 V, n2 F! b* p
and monitoring of serum testosterone. Even with this control* C; v7 g P$ ~
the duration of our therapy did not exceed 3 weeks at any( o+ T' Z( X4 T/ n$ w7 ]
time. It is apparent that the prepuberal male subject may
0 {5 s8 b0 k. A# t. K7 L' xsuffer accelerated bone growth with testosterone levels near
; v# R( v, C/ i* H2 X200 ng./dl. When skeletal maturation is complete the level of
' C8 Z# _3 i/ ^+ u' ]/ aserum testosterone can be maintained in the 700 to 1,300 ng.// l( \6 Y/ a5 ~, ] b- h% y
dl. range to stimulate phallic growth and secondary sexual+ D* {2 W$ A, ^) l
changes. Therefore, after skeletal maturation parenteral tes-
" {: Y- h; L: I$ L8 m$ Ftosterone may be used to advantage. Before skeletal matura-
4 f" ~* Y& F6 { ition care must be taken to avoid maintaining levels of serum& G8 x( P; F7 U
testosterone more than 100 ng./dl. Low-dose gonadotropin
5 h( o3 X o, P. F8 H* Adepends upon intrinsic testicular activity and may require: v- m9 N1 j2 f# z
prolonged administration for any response.* D$ ^% t; d4 b) V' q/ ~& K! y: |
Alternately, topical testosterone does not depend upon tes-# `2 H$ n1 y+ L" H* K! e1 Z H
ticular function and may provide a more constant level of( Y1 @+ D6 e/ f" I- B' H, V( c! N+ a% {
REFERENCES2 r0 s4 E2 k' j0 E3 Y; ^
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
' u; F& {# E+ s5 KR.: The local application of testosterone cream to the prepub-, Z W8 O' K' P) ~& T6 p$ ]
ertal phallus. J. Urol., 105: 905, 1971.' _8 u# T$ R. `8 G1 c
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone/ L+ s2 @; n+ w f4 Y M1 _" }# k
treatment for micropenis during early childhood. J. Pediat.," d, `, E. f# f/ [5 d' b# V; [
83: 247, 1973., H. U! c9 y3 E7 | p
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-) r4 }1 R. |+ L) Y3 f9 Z
one therapy for penile growth. Urology, 6: 708, 1975.) S2 ?/ k% W8 P! q) z
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
" M3 X `' k0 E6 Y$ _# ]to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by# j: ~3 H% K3 f+ q4 ]. T/ c9 x
skin slices of man. J. Clin. Invest., 48: 371, 1969.
}5 m+ r4 }3 w/ u5 B8 H5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
; K0 j% d3 A; d2 |. q( I, sby topical application of androgens. J.A.M.A., 191: 521, 1965.
' k H; k# c9 x& s7 F6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
& z% F: M& d5 oandrogenic effect of interstitial cell tumor of the testis. J.
& o, `6 u4 p a' W$ ^ O LUrol., 104: 774, 1970.
: s8 P8 h6 l! Q V' m9 g G7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-1 r$ p. a& C6 J& E* G# w
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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