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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND( j! R9 P7 V# N+ X( c0 }( \( u
GONADOTROPIN0 a- R h9 N. ?/ h" A% N, z
RICHARD C. KLUGO* AND JOSEPH C. CERNY
* n7 }1 O/ U' Q$ g2 ]) `4 _From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
( U* [* U% g( a, zABSTRACT
& Q' ?7 i& r4 h' o, @1 JFive patients were treated with gonadotropin and topical testosterone for micropenis associated, b; E9 b0 ]9 r/ f
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
2 ~4 D' E' j1 I9 [, N2 W% ztropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone% Q9 s" F: H) U/ F$ \- a1 H
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
* X/ D# D7 @* W& f0 A% |for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent" C/ V' R# }, m! ^7 q" R8 D
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average: I6 V$ l& H- v2 O5 [& Y2 T
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
$ J5 j6 Q. N/ p$ t6 r. k+ P4 D4 n& Qoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This3 W+ P& m* b* c$ e% E2 I! g
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
6 z" Y% Y. T* P, Zgrowth. The response appears to be greater in younger children, which is consistent with previ-1 |3 y8 u$ G7 w) V2 D+ W
ously published studies of age-related 5 reductase activity.' L, @, E; I$ x% {* G5 l
Children with microphallus regardless of its etiology will
. }/ Q4 {0 q$ ?6 Nrequire augmentation or consideration for alteration of exter-& r1 ^ M" B T7 o2 w, [
nal genitalia. In many instances urethroplasty for hypo-
3 |7 |+ p6 N7 X p! A6 }spadias is easier with previous stimulation of phallic growth.
) `1 h" O0 i \0 Q% \The use of testosterone administered parenterally or topically
& k: Y+ s) \' \ T# T* shas produced effective phallic growth. 1- 3 The mechanism of( k# S1 q+ f. H3 ]
response has been considered as local or systemic. With this4 {" U- Y; \8 h. a6 Z( R0 b k
in mind we studied 5 children with microphallus for response4 s+ G9 S* A& F8 u$ K
to gonadotropin and to topical testosterone independently.6 ~( K& g8 M' _8 _$ ^
MATERIALS AND METHODS: ~5 s) k T2 S. u9 J2 W# E) X( |
Five 46 XY male subjects between 3 and 17 years old were
; o2 M0 r, O' _1 s, C U9 Cevaluated for serum testosterone levels and hypothalamic, i0 L( o, X& L" B
function. Of these 5 boys 2 were considered to have Kallmann's
) N2 W2 S1 N- V$ F! Ysyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
) B* g4 y) ]$ w2 elamic deficiency. After evaluation of response to luteinizing* ^7 o+ T' H8 U. ]9 C
hormone-releasing hormone these patients were treated with' ~0 U( U+ P) q0 v! D9 d
1,000 units of gonadotropin weekly for 3 weeks. Six weeks2 D2 {9 f0 m! o) R5 X% @
after completion of gonadotropin therapy 10 per cent topical( b: p" o6 F0 @
testosterone was applied to the phallus twice daily for 3 weeks.
3 K1 G8 s m8 N$ p8 L/ z, w4 FSerum testosterone, luteinizing hormone and follicle-stimulat-
9 a3 l9 a$ @3 b) xing hormone were monitored before, during and after comple-) s8 J/ s! |3 {3 C6 U1 H2 R/ H2 }4 _
tion of each phase of therapy. Penile stretch length was1 G. [* R* D; Z2 Z: z
obtained by measuring from the symphysis pubis to the tip of1 {) G, T5 r" ] V3 i( V# @3 @
the glans. Penile circumferential (girth) measurements were6 r5 w8 Z$ P v4 ?
obtained using an orthopedic digital measuring device (see
6 G# T0 _7 k( Q' s8 T/ E, Y- e1 Z1 sfigure).9 n8 _8 u$ G+ \
RESULTS" _7 l. X: `) ?9 H4 r |; E9 A
Serum testosterone increased moderately to levels between
$ p% s- O) j! Q6 z50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
* Q! `0 ]* T( u% k, g3 cterone levels with topical testosterone remained near pre-6 b) E6 Z0 W- i) s4 ]1 O
treatment levels (35 ng./dl.) or were elevated to similar levels
+ t6 L0 d5 H; b$ a- \1 xdeveloped after gonadotropin therapy (96 ng./dl.). Higher3 X- q* _/ U% J9 w
serum levels were noted in older patients (12 and 17 years old),
M8 r/ G+ u* e% A: |& Uwhile lower levels persisted in younger patients (4, 8, and 10
/ s% T( ]7 t2 y! Z- a9 @. Hyears old) (see table). Despite absence of profound alterations5 Y( n4 a- h6 J
of serum testosterone the topical therapy provided a greater
# u0 y. H$ D! o7 b- P9 Q6 q8 a/ OAccepted for publication July 1, 1977. ·/ t- G9 m) Z# A1 E/ h
Read at annual meeting of American Urological Association,
% }, a5 \, N, {' q4 f: SChicago, Illinois, April 24-28, 1977.
4 ~ W/ y9 Z+ p2 j" E7 ?5 f* Requests for reprints: Division of Urology, Henry Ford Hospital,5 g# {# n$ P% E9 O
2799 W. Grand Blvd., Detroit, Michigan 48202.
5 ~* H5 n/ `4 x. ]improvement in phallic growth compared to gonadotropin.
( W) \7 [8 U% DAverage phallic growth with gonadotropin was 14.3 per cent: Z* y' x; B, d! H6 c' U
increase in length and 5.0 per cent increase of girth. Topical3 Q i4 W& t' q1 H
testosterone produced a 60.0 per cent increase of phallic length
* F1 K# u" s+ l; q9 vand 52.9 per cent increase of girth (circumference). The
- D8 A/ M' B4 ]9 j1 n# A1 }$ xresponse to topical testosterone was greatest in children be-
4 r) @+ h P- n; Ntween 4 and 8 years old, with a gradual decrease to age 17. J4 @# N6 m* ?: q% t' o7 |& c
years (see table).6 j, H9 D {( Y, }# E
DISCUSSION' D( d2 C7 j* I5 Q6 x5 P" w
Topical testosterone has been used effectively by other2 f' @, z4 M' L6 m& f" f
clinicians but its mode of action remains controversial. Im-& O1 \, E8 L2 u8 t' C
mergut and associates reported an excellent growth response
{ P1 ^- N7 D# |, ito topical testosterone with low levels of serum testosterone,
8 {6 z$ Y1 d+ K; {$ J8 xsuggesting a local effect.1 Others have obtained growth re-$ z! z: [" Z, R( ]8 p5 i; j) R
sponse with high. levels of serum testosterone after topical4 P9 Q. C7 K3 o6 i2 g
administration, suggesting a systemic response. 3 The use of
2 [- O$ U, ~; ]- mgonadotropin to obtain levels of serum testosterone compara-' i; t* c5 k9 K1 E# {6 J
ble to levels obtained with topical testosterone would seem to
# a- A" A% H5 S, l$ bprovide a means to compare the relative effectiveness of
# K" F0 J6 J# i" M7 o; vtopical testosterone to systemic testosterone effect. It cer-
8 S' G7 |1 m) {! B7 ktainly has been established that gonadotropin as well as par-
4 J, N0 h& X+ s, y. Ienteral testosterone administration will produce genital
# s; p5 J) l& s& S+ B. C6 Agrowth. Our report shows that the growth of the phallus was. c- @8 ~& D- _0 M( D
significantly greater with topical applications than with go-
1 z- [1 v. s& S9 V5 [+ Wnadotropin, particularly in children less than 10 years old. L0 N% s, u) e. q& z
The levels of serum testosterone remained similar or lower! u- ]# t! l: P }6 e( G
than with gonadotropin during therapy, suggesting that topi-
, i7 ?" P! w j& T! Pcal application produces genital growth by its local effect as
$ y8 o2 f1 {4 L( ^. F' h2 c Kwell as its systemic effect.5 d6 B- N E6 S) J/ @! y% K; K' x
Review of our patients and their growth response related to3 Q0 D# T8 o& p
age shows a greater growth response at an earlier age. This is: \4 U9 |7 ? T1 ~; g
consistent with the findings of Wilson and Walker, who, U8 m2 n" [! _7 |
reported an increased conversion of testosterone to dihydrotes-
5 Y0 G6 X- E! x9 Mtosterone in the foreskin of neonates and infants.4 This activ-+ L) S3 w$ F9 O( d
ity gradually decreases with age until puberty when it ap-+ f; t. i" }' v+ ?
proaches the same level of activity as peripheral skin. It may7 G$ }; G9 Q$ `$ b3 T# l* \
well be that absorption of testosterone is less when applied at
+ K$ R( C% w2 F4 o7 a! v2 Xan earlier age as suggested by lower serum levels in children
2 d1 q( k& S7 J0 Dless than 10 years old. This fact may be explained by the
5 e" } z- ?4 M: i* `greater ability of phallic skin to convert testosterone to dihy-
; p4 z1 N* m( V7 d; Zdrotestosterone at this age. Conversely, serum levels in older# J& N5 n; ]7 Y5 a1 s, R# W* P
patients were higher, possibly because of decreased local) ~: K- }2 j, o2 p, _
667
- S# a9 l2 E* G3 J. W' h9 S668 KLUGO AND CERNY3 F& y6 g: {6 b1 j+ L; U6 q9 h
Pt. Age( z# D( H+ Y% b4 K; V
(yrs.)6 T# Z% r) m8 k, x+ M
Serum Testosterone Phallus (cm.) Change Length
( R+ M: n. e) E/ w, p$ D: }0 _; X. [. U(ng./dl.) Girth x Length (%)" ~5 t" h) h. M% j6 C
4
k8 o, i; t- D6 a8
$ i% M. [9 S) r2 `! g) j; s M% ~10/ n. d! R* L( p
12
+ ^6 Q! W: s- Q& l2 o- v, K17
* x) n/ J$ a6 lGonadotropin5 s( K' ^6 q/ P
71.6 2.0 X 3 16.6
p5 S4 K) z2 g- U0 [50.4 4.0 X 5.0 20.0
5 d Q# X: u/ W' K22.0 4.5 X 4.0 25.0
& {% N& Q9 J. [: ^8 v; E84.6 4.0 X 4.5 11.1
2 g5 W( a" r# W( v- |7 ^85.9 4.5 X 5.5 9.0
" M" ]* w9 U, p! TAv. 14.37 k* U; [; {; M0 X
44 \3 X! X. }9 J$ k! _7 O2 M% V
86 ^( O) x( A3 a) r6 s: x
10" `8 i# e9 _) T1 P j
12
. ]7 `- K, e, A/ u. \, r- S, H" ~# {2 ^17
4 _9 ~5 m. H0 X5 ^* J$ `Topical testosterone+ ?8 s2 B) X0 a3 w& g7 u; B
34.6 4.5 X 6.5 856 L J }( w* N9 t7 U/ g
38.8 6.0 X 8.5 701 e* Y8 Q0 X/ `; A
40.0 6.0 X 6.5 62.5
0 O4 I6 B: v8 O7 s* B3 E" F93.6 6.0 X 7.0 55.5
! [- K: c1 T6 _: J+ N95.0 6.5 X 7.0 27.29 H' v/ E- ?3 H0 v+ p- T
Av. 60.0
3 a) N& |+ `- K) x# |available testosterone. Again, emphasis should be placed on
7 x' n8 ]- I F3 `; xearly therapy when lower levels of testosterone appear to4 U9 q, T) h+ ~3 U
provide the best responses. The earlier therapy is instituted" R0 N9 U2 i& ~2 @
the more likely there will be an excellent response with low4 ^4 i/ g# Z6 ~, n# H, S% e
serum levels. Response occurs throughout adolescence as
) X/ k! i# _9 _$ A# Pnoted in nomograms of phallic growth. 7 The actual response: a" G- W4 v8 e8 ]& v( l
to a given serum level of testosterone is much greater at birth
$ v9 W, [9 k% C( q4 X4 Q C$ E: uand gradually decreases as boys reach puberty. This is most
@$ m) }* H. F& \likely related to the conversion of testosterone to dihydrotes-8 l/ j! T6 X( t/ q4 R i! o5 {2 U6 Z
tosterone and correlates well with the studies of testosterone
# a' K- o6 x9 c# o: }conversion in foreskin at various ages.
6 B3 i2 ]. u$ o9 C h) O1 L! z2 FThe question arises regarding early treatment as to whether- }. z' p, {# p
one might sacrifice ultimate potential growth as with acceler-
* }* c0 d2 o1 c2 ]- q( A3 q" aated bone growth. The situation appears quite the reverse5 t; \# M- E1 u5 L7 v
with phallic response. If the early growth period is not used6 H: J4 c2 A8 s* D! M
when 5a reductase activity is greatest then potential growth/ o' ?* O# t# K$ a
may be lost. We have not observed any regression of growth
" j' \$ A+ z' ], D! L! q/ fattained with topical or gonadotropin therapy. It may well) Q p7 q7 I; n! d6 X4 M. \* } J& t
be that some patients will show little or no response to any4 T2 }% `* R) y8 T
form of therapy. This would suggest a defect in the ability to
2 U+ c: ~; X4 F$ o5 e' R3 F; Cconvert testosterone to dihydrotestosterone and indicate that
i: w& C) z1 U4 w' j; dphallic and peripheral skin, and subcutaneous tissue should2 G+ P$ l5 j- D, Z K- d
be compared for 5a reductase activity.
& U' {! w5 W8 u& VA, loop enlarges to measure penile girth in millimeters. B,
7 X. E$ [' _: |$ s( E0 N4 w% rexample of penile girth computed easily and accurately.
6 H7 _2 d& ~: m9 |- Y* o6 Q2 ~conversion of testosterone to dihydrotestosterone. It is in this: `- b |0 q0 u4 h5 c
older group that others have noted high levels of serum
7 Q* a. Q1 M: g/ [testosterone with topical application. It would also appear( c) t$ @ @9 X9 \+ S8 @
that phallic response during puberty is related directly to the6 |3 G* l A8 _- z
serum testosterone level. There also is other evidence of local
{, [$ \: U2 jresponse to testosterone with hair growth and with spermato-
+ Q, Z/ {$ w9 H9 J5 cgenesis. 5• 6! O) K! s* B( V5 J8 W
Administration of larger doses of gonadotropin or systemic
% b; g9 _, S8 K" E& vtestosterone, as well as topical applications that produce
a" m. o! G% O+ @: }higher levels of serum testosterone (150 to 900 ng./dl.), will, d* Y1 ]' c& ~; X I z
also produce phallic growth but risks accelerated skeletal
( i3 a7 z, w. y' cmaturation even after stopping treatment. It would appear2 l- d; T# h5 m7 T1 e2 U, j
that this may be avoided by topical applications of testosterone# b7 H, J/ Q, w# h: z
and monitoring of serum testosterone. Even with this control
. I3 [* i& X$ ~) v# athe duration of our therapy did not exceed 3 weeks at any, h- V- w0 C( x3 e
time. It is apparent that the prepuberal male subject may& I1 I2 Y5 f( F2 a, U9 ?/ g. U
suffer accelerated bone growth with testosterone levels near+ q* ~, O% o1 @9 P2 R; K' o9 s
200 ng./dl. When skeletal maturation is complete the level of
% v& Y/ j% h C- y8 d8 Xserum testosterone can be maintained in the 700 to 1,300 ng./) Z4 l5 b+ m$ E _! V
dl. range to stimulate phallic growth and secondary sexual" {4 w/ l! G, z _/ \# i
changes. Therefore, after skeletal maturation parenteral tes-& B5 `2 w5 x0 _6 l6 Z& N
tosterone may be used to advantage. Before skeletal matura-9 I( C# k, b _1 t& L! E9 _
tion care must be taken to avoid maintaining levels of serum" _/ g9 n+ ^ I9 h0 q* _/ ?
testosterone more than 100 ng./dl. Low-dose gonadotropin6 `: {3 P! W; {
depends upon intrinsic testicular activity and may require
6 ?! g- H. C1 Z$ u6 x+ A. gprolonged administration for any response.
) ^2 G0 d: I6 j9 }Alternately, topical testosterone does not depend upon tes-$ j, W; i$ ?8 V0 u1 r
ticular function and may provide a more constant level of
' } ~0 L5 y X2 ?! w+ E" HREFERENCES4 h) I4 L) }8 ?5 e' ^
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
6 F) X, |* ^/ M1 @$ BR.: The local application of testosterone cream to the prepub-
) ^9 v' Y% C& qertal phallus. J. Urol., 105: 905, 1971.
7 L: R1 @1 y" w: ^; B3 C3 ]2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
8 B- d' S, y' rtreatment for micropenis during early childhood. J. Pediat.,
- t7 m5 m2 H+ ?% D; e83: 247, 1973.
: w `+ r. Y+ f! Q9 ~' U3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-& k C& K, G$ c) ]' C6 O! D2 E+ t
one therapy for penile growth. Urology, 6: 708, 1975.
1 H5 J) p7 ?. B" c/ T0 G4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone1 b# R) p9 U$ E% g
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by* d3 l3 l$ d- e6 |/ U' e
skin slices of man. J. Clin. Invest., 48: 371, 1969.
' v2 W5 z7 k6 f) ?) s' ]0 ^5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth* z x1 c! g k2 i9 `1 `( w. t7 y
by topical application of androgens. J.A.M.A., 191: 521, 1965.
S+ \( W8 d/ r: s" k1 z6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local9 V9 f* u8 ^6 m; U, `
androgenic effect of interstitial cell tumor of the testis. J.
2 r& o+ D3 b" k) ]Urol., 104: 774, 1970.; Q8 _" v0 m) b. [# f; U, b7 W! [
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
* ] ^3 k/ d$ I& otion in the male genitalia from birth to maturity. J. Urol., 48: |
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