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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
" n! v w* `: @3 aGONADOTROPIN; U0 ?6 i; a0 f* I3 j. O& y
RICHARD C. KLUGO* AND JOSEPH C. CERNY
" V0 Q7 a5 g4 ^; h, tFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan1 l! k" O6 B* ?* H5 j+ B
ABSTRACT& m8 @! ^7 n O1 w/ `" X
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
2 S# w3 Q+ J8 _4 Cwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
9 p) X; x9 w1 Y3 [. c# Ttropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone! ~5 s6 V* V1 B9 o
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent& |0 G+ e' c% c6 n- F
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent0 Q) E$ F# ?2 D: O3 r$ y
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average( g' S( k. ?2 z! _' N
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response% d; \: A# A. I/ x' J
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
! Z0 r5 E. m9 z" bstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile# @% X6 t: D9 b3 r- |
growth. The response appears to be greater in younger children, which is consistent with previ-
8 p+ M: n/ _+ d- L' }- zously published studies of age-related 5 reductase activity.; o+ _1 ^2 S5 N2 _0 Q
Children with microphallus regardless of its etiology will
2 y7 V5 v* N4 v' b+ {- O# Y$ Urequire augmentation or consideration for alteration of exter-( D! ?9 \; @$ g* \ ]
nal genitalia. In many instances urethroplasty for hypo-
7 U7 I; l) a8 Nspadias is easier with previous stimulation of phallic growth.
. |+ _& D2 k' V6 z0 k' ?The use of testosterone administered parenterally or topically9 C. _% l. e, y; m3 g
has produced effective phallic growth. 1- 3 The mechanism of
* {% Z: a4 p% X) q# jresponse has been considered as local or systemic. With this
4 {- [( m5 z$ u S2 v4 Cin mind we studied 5 children with microphallus for response
7 ^5 e- k$ g+ v4 ]4 X1 pto gonadotropin and to topical testosterone independently.
9 ]: l i4 K! d3 E) w: D8 O5 x% CMATERIALS AND METHODS
7 a! H! `% Y( K/ j; M' |Five 46 XY male subjects between 3 and 17 years old were
: g9 Q" |: K. {9 uevaluated for serum testosterone levels and hypothalamic/ [# E- R1 a7 Z9 e0 K
function. Of these 5 boys 2 were considered to have Kallmann's$ Z3 K1 d' v* o9 ]- `. X6 {
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha- |. B& }6 ?0 t4 `' Z j
lamic deficiency. After evaluation of response to luteinizing
! r3 A8 [, d' V' W) H& Uhormone-releasing hormone these patients were treated with
& e+ ~* S' z, O! H1 s& N; r1,000 units of gonadotropin weekly for 3 weeks. Six weeks
J. j) k) Q/ O; e) Kafter completion of gonadotropin therapy 10 per cent topical( ^: W* s# }( D S' z
testosterone was applied to the phallus twice daily for 3 weeks.
0 R/ T/ G8 P7 K% e6 wSerum testosterone, luteinizing hormone and follicle-stimulat-
- b. n" z7 K( v! t& `ing hormone were monitored before, during and after comple-
8 l5 S: Z d H: Jtion of each phase of therapy. Penile stretch length was
2 `2 _! _2 h9 ]8 e2 `& |obtained by measuring from the symphysis pubis to the tip of) u [& g S4 s0 v, @% o5 l S/ L
the glans. Penile circumferential (girth) measurements were u, X2 f* |3 L
obtained using an orthopedic digital measuring device (see. ^- Q: p4 G! g' |2 z( q6 ~
figure)." G$ n/ G8 v1 V# Y" E3 m
RESULTS# i. o$ `8 a- f7 {8 r
Serum testosterone increased moderately to levels between5 J& n+ q" T3 Q5 }0 o! D& `
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
. L9 R. i1 q) Y8 Bterone levels with topical testosterone remained near pre-
& b! {4 [% I |* Ntreatment levels (35 ng./dl.) or were elevated to similar levels
; W* F. s* Y, Q7 o" ~developed after gonadotropin therapy (96 ng./dl.). Higher' D$ X- @5 b% g5 k9 |
serum levels were noted in older patients (12 and 17 years old),: {- t" t6 S8 N6 a
while lower levels persisted in younger patients (4, 8, and 10
/ o8 y V, ~' myears old) (see table). Despite absence of profound alterations4 z! w0 z+ y0 J6 z4 Q
of serum testosterone the topical therapy provided a greater# A2 b# d- W- }& {8 O, ?" e
Accepted for publication July 1, 1977. ·
: e9 [0 z1 O; L) a* ]Read at annual meeting of American Urological Association,, K! `. z# J# z% z9 o
Chicago, Illinois, April 24-28, 1977.9 S6 H+ `& S& j0 Y+ `: I
* Requests for reprints: Division of Urology, Henry Ford Hospital,
) R u0 y5 |3 B- U: u% l' P, K2799 W. Grand Blvd., Detroit, Michigan 48202.; _/ x% g; U( ?( c
improvement in phallic growth compared to gonadotropin.: L* } E# m* X' j4 o) N- k- z5 c' d
Average phallic growth with gonadotropin was 14.3 per cent7 ], B4 `6 r$ J! A. G# V
increase in length and 5.0 per cent increase of girth. Topical7 i/ a' S% c" z& w+ j3 u6 l) y
testosterone produced a 60.0 per cent increase of phallic length: W* `/ T+ ], ?8 p9 b0 a& P
and 52.9 per cent increase of girth (circumference). The: ?: O4 s1 U' S: Z5 e# P# O; G
response to topical testosterone was greatest in children be-4 ^8 I- V9 }- y/ }) G L1 P8 d
tween 4 and 8 years old, with a gradual decrease to age 17
/ Q% p) G g0 D, {, ]years (see table).! [- c$ w6 f: {+ Y7 q" i, |
DISCUSSION" U$ Q) ^5 B" |, t
Topical testosterone has been used effectively by other
2 D/ a% e1 U) S* Y1 kclinicians but its mode of action remains controversial. Im-
& [0 m5 D$ Y! x. {- W) ~( [mergut and associates reported an excellent growth response
* e- n o. P- x* [8 {6 ^5 h1 ^2 ato topical testosterone with low levels of serum testosterone,
+ ]' p( }+ b- Qsuggesting a local effect.1 Others have obtained growth re-7 I, m9 B7 a7 f: O& S8 l5 c
sponse with high. levels of serum testosterone after topical4 D: ?' M3 d2 u, N+ I$ r; a- K
administration, suggesting a systemic response. 3 The use of" D* N: }6 l; c1 X y E
gonadotropin to obtain levels of serum testosterone compara-
( y0 E! Z/ K" [! W3 Y$ eble to levels obtained with topical testosterone would seem to
$ R, d* O3 g9 E- y. F0 d( C: q9 Qprovide a means to compare the relative effectiveness of
# |2 E2 c! B, z3 D' ftopical testosterone to systemic testosterone effect. It cer-
2 n# \3 ^: u% `2 Atainly has been established that gonadotropin as well as par-
1 ` J) ]" T1 L7 A: m+ n# @enteral testosterone administration will produce genital) Z+ q$ c9 B$ O
growth. Our report shows that the growth of the phallus was( k9 y0 C8 I* T6 P) C; \% q
significantly greater with topical applications than with go-
$ p/ J; Q9 U/ R+ E) Enadotropin, particularly in children less than 10 years old.7 Z8 ~& B2 H, |5 S
The levels of serum testosterone remained similar or lower
5 W1 J7 D5 n, E. n: _than with gonadotropin during therapy, suggesting that topi-
9 X: a7 T4 |& S7 S X: G0 Pcal application produces genital growth by its local effect as& r) _6 r( ~* P' E; W6 H
well as its systemic effect.( S8 ~7 w3 f7 B4 i5 ^
Review of our patients and their growth response related to
% `) B$ d3 O- U% kage shows a greater growth response at an earlier age. This is/ u/ q2 K. F# r. H) i
consistent with the findings of Wilson and Walker, who
, T( B- @' D7 e# l5 D+ Y4 Wreported an increased conversion of testosterone to dihydrotes-2 ~1 r r+ k5 R* c4 D( g+ ~6 w$ f
tosterone in the foreskin of neonates and infants.4 This activ-
/ q+ F& R8 }# s, v1 ?ity gradually decreases with age until puberty when it ap-
" r5 Z3 c, n4 {0 C) ~% S( @( sproaches the same level of activity as peripheral skin. It may
( C5 o/ Y% I. E/ ]" ywell be that absorption of testosterone is less when applied at1 W9 F3 [5 v! ]. Q3 I$ `
an earlier age as suggested by lower serum levels in children
* e, x! ~9 E# M6 yless than 10 years old. This fact may be explained by the @% y) e1 c$ y, r
greater ability of phallic skin to convert testosterone to dihy-
) Y3 u, }! L0 l9 q1 |% Qdrotestosterone at this age. Conversely, serum levels in older
3 [9 m7 R# g* apatients were higher, possibly because of decreased local
$ Y0 B) J/ l0 T. j$ q9 n667
' g, N# c3 `" R) X- y668 KLUGO AND CERNY- s, q( p: c5 C' U
Pt. Age
4 ~+ D4 h) i" b7 t! x6 ]/ ](yrs.)+ v J |5 t( q5 k' P7 S
Serum Testosterone Phallus (cm.) Change Length; ~% U6 z/ U# [! Q5 M% P, e8 V
(ng./dl.) Girth x Length (%)! }4 c+ o# x" z4 j3 d
4( c# p1 o/ q3 W& ~. ]7 N* n
8
9 F3 Y1 a P( G6 X10
5 J/ P& S1 F8 U N- b6 c! @) i12
0 Z: b+ m3 p6 _8 S9 [! L& z( h17
% ~: ?( i+ k U' w9 ~9 ~& BGonadotropin$ f8 F% p$ N3 x& X3 f7 N; t
71.6 2.0 X 3 16.65 F l( W8 T+ b6 F$ N
50.4 4.0 X 5.0 20.0
- j+ j* K* {+ w" ~' E& J: q7 G22.0 4.5 X 4.0 25.0 S l3 @* ?! ]( C
84.6 4.0 X 4.5 11.1
( C. `3 l* w! U7 |. L9 J" v5 |; c85.9 4.5 X 5.5 9.0% G6 z" m# @3 h+ D: a5 ~: Q5 f
Av. 14.3) X: U9 \3 `" T* M6 C3 S$ D
4- v: G7 X1 M- q. `
80 k2 M3 y" t0 @2 ]$ T
103 G1 k! @+ @( [( y7 H
127 B# i8 Z4 V5 O3 w5 G, N
17
# O5 z' Y8 K- _* GTopical testosterone
( d6 y. P7 G- o& K/ `% k34.6 4.5 X 6.5 85
G5 k, }! r! g9 L2 ^" j, U2 N38.8 6.0 X 8.5 70- q( c% B: M( a+ }' v5 {. F
40.0 6.0 X 6.5 62.5
, ?, t! z: H7 R' N1 e$ m; o93.6 6.0 X 7.0 55.5
$ ~7 v% q' e- a3 F95.0 6.5 X 7.0 27.2
" {# E2 ^& N& Z' u! ]0 PAv. 60.0' B" C+ ]$ t+ f @& Y1 G
available testosterone. Again, emphasis should be placed on0 i1 ^# c) I# g9 g
early therapy when lower levels of testosterone appear to
$ {& L1 A/ k" S' [8 [provide the best responses. The earlier therapy is instituted7 d& ]8 V. b% r' @% e6 _' Z
the more likely there will be an excellent response with low
1 L: S: ?3 I9 |! Lserum levels. Response occurs throughout adolescence as' n, _7 X$ _8 K$ L9 t; |
noted in nomograms of phallic growth. 7 The actual response8 g. A/ @: d ~
to a given serum level of testosterone is much greater at birth) g6 k8 m5 m& u: k& N
and gradually decreases as boys reach puberty. This is most
, V! F' V9 s7 [9 U# P. Plikely related to the conversion of testosterone to dihydrotes-2 O5 `, n2 v) }6 P3 U3 S0 U. h
tosterone and correlates well with the studies of testosterone
* P; B9 R+ u% I, Y$ S, W5 [& J4 Aconversion in foreskin at various ages.# N+ `# `# f$ h5 C% D
The question arises regarding early treatment as to whether4 n C3 Y7 o( H; G1 M- X7 t
one might sacrifice ultimate potential growth as with acceler-, ]9 F5 e& Y: |3 K- Q: G8 Q
ated bone growth. The situation appears quite the reverse$ k/ p/ I% Q* v$ ~
with phallic response. If the early growth period is not used
; Z, S* [8 L; ~ iwhen 5a reductase activity is greatest then potential growth; z( r. l5 C6 L) |+ q
may be lost. We have not observed any regression of growth7 p1 S- ], c2 g: ^( w
attained with topical or gonadotropin therapy. It may well
5 H5 f2 Z, |9 Y7 q) F+ J# C2 J' Wbe that some patients will show little or no response to any! L6 r q3 L# p
form of therapy. This would suggest a defect in the ability to
6 c2 @1 w t( g9 bconvert testosterone to dihydrotestosterone and indicate that
" A* j5 d9 C8 n$ z7 a- v# ophallic and peripheral skin, and subcutaneous tissue should
' c6 x0 ]( Q- q/ r0 y: g. ?1 Cbe compared for 5a reductase activity.
8 s# Q5 B) l: A0 B0 k) r. \4 `A, loop enlarges to measure penile girth in millimeters. B,& J; w) o! x" H% O! E
example of penile girth computed easily and accurately.
& q/ Z" V3 E2 U, ^; ]conversion of testosterone to dihydrotestosterone. It is in this7 Y4 [, i {- T
older group that others have noted high levels of serum7 Q( U; s/ r% a+ z" P2 s# I p
testosterone with topical application. It would also appear
W* j& Z9 O# {4 M, dthat phallic response during puberty is related directly to the
+ R `5 d V/ W h4 Tserum testosterone level. There also is other evidence of local
0 q1 v7 B c' U0 Jresponse to testosterone with hair growth and with spermato-' q$ V% O$ [6 f/ s: I! b7 E _
genesis. 5• 6
2 M# U+ z) O7 {2 C# C2 N! tAdministration of larger doses of gonadotropin or systemic, l( n5 S- z% A+ E. U( f
testosterone, as well as topical applications that produce
A S( ^: m* G6 Jhigher levels of serum testosterone (150 to 900 ng./dl.), will
' X t* }1 m2 B; talso produce phallic growth but risks accelerated skeletal
% y* q t/ ~. z; _) d4 Bmaturation even after stopping treatment. It would appear
. k/ M+ i, {2 h5 F. p* tthat this may be avoided by topical applications of testosterone' ~' X& \& j1 N3 I, ]# S$ ^" {% l
and monitoring of serum testosterone. Even with this control" [" k9 T* ]9 V
the duration of our therapy did not exceed 3 weeks at any
! T7 [& _; L9 P4 ]% ^9 z% X& gtime. It is apparent that the prepuberal male subject may
. C: }2 N, D5 ]; d' z4 A6 H8 Hsuffer accelerated bone growth with testosterone levels near3 f% z! |0 @/ M1 T3 d6 O
200 ng./dl. When skeletal maturation is complete the level of' h! a! g" W* V: q( w" o+ t& l! w
serum testosterone can be maintained in the 700 to 1,300 ng./. D, u& D% g ?; y
dl. range to stimulate phallic growth and secondary sexual6 D; R( n I7 u$ _ Z
changes. Therefore, after skeletal maturation parenteral tes-
( {/ i; x" l! G7 Q8 V1 w/ Ctosterone may be used to advantage. Before skeletal matura-
% L7 k/ [& n7 v# Ution care must be taken to avoid maintaining levels of serum J. h" A6 m0 u9 b
testosterone more than 100 ng./dl. Low-dose gonadotropin
8 D- V6 e5 B' s! i& J( R# Ddepends upon intrinsic testicular activity and may require
7 B+ K* n5 `' h1 H$ mprolonged administration for any response.
: G. O: O) h7 OAlternately, topical testosterone does not depend upon tes-
4 ^! J6 ~( W0 R: pticular function and may provide a more constant level of9 m/ f5 g- N' Y* [8 F1 g
REFERENCES! p8 z1 C2 k$ k8 l% O. x
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
; A% Q# v! x; q2 eR.: The local application of testosterone cream to the prepub-0 O. D. h O& c
ertal phallus. J. Urol., 105: 905, 1971.
# x( s2 q. `! t, W2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
3 y7 @: E0 x3 v# e1 h4 b! _" htreatment for micropenis during early childhood. J. Pediat.,5 Q8 S0 M: z3 n8 d' z, M8 d
83: 247, 1973.
5 J/ U; g' v4 E$ U6 t& R3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
6 L$ R. G$ G* F. _- s7 Sone therapy for penile growth. Urology, 6: 708, 1975./ F: F: E8 x+ B( J8 @; c
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
3 S3 F. ^ q x I2 b4 r" eto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
- E: q; D/ o. I8 [" W, _skin slices of man. J. Clin. Invest., 48: 371, 1969.
) X8 L1 N. C6 ~! Z; } \5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
, e/ F# m/ s9 [; H4 Gby topical application of androgens. J.A.M.A., 191: 521, 1965. |0 x. y1 t9 U# c( B0 [
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
1 S/ _9 W* a! H" F) E7 B. z9 wandrogenic effect of interstitial cell tumor of the testis. J.' w5 u5 ?! p( T' A8 _
Urol., 104: 774, 1970.5 Q" I6 j# T2 P5 u% R
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-2 w5 u6 h2 N0 O: S7 f
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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