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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND3 ` C/ m+ ~! ?- l+ I
GONADOTROPIN: D9 ^. `2 D- y& T' D* t3 J
RICHARD C. KLUGO* AND JOSEPH C. CERNY
3 t) R7 n# {4 N) RFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan2 f: j" b9 T" M% u# @" h
ABSTRACT
8 |7 r8 q; E4 X! C7 zFive patients were treated with gonadotropin and topical testosterone for micropenis associated( S0 ?. N% N& N' }0 ^# H
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-6 N. ?$ p& I* k0 V1 z5 }1 z. f
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone/ d1 I% P: L& t9 W8 x/ u0 M8 k
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent3 d% P/ \! P1 D
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
( M* i+ _8 U2 g2 W4 ^increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
4 C9 J! W- y# ^6 K% nincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
0 E4 u" Q& |; n! T) ~3 F; boccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
& p O8 F5 H; e1 V* l; gstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile+ H9 N* k; m; S; \9 }& X
growth. The response appears to be greater in younger children, which is consistent with previ-/ ?) y; `& n$ }8 ^% q8 x: r, `( v$ y
ously published studies of age-related 5 reductase activity.
i" K4 |, A; O) x2 a' _- XChildren with microphallus regardless of its etiology will
9 E$ s$ p8 Z; ~7 {require augmentation or consideration for alteration of exter-
# j0 H% Z s* H% rnal genitalia. In many instances urethroplasty for hypo-" Y( [# ^& h/ E. w/ `) i% J
spadias is easier with previous stimulation of phallic growth.0 _8 V c6 C$ P" F
The use of testosterone administered parenterally or topically
/ y* ~2 A8 z% }: y4 l- Xhas produced effective phallic growth. 1- 3 The mechanism of
4 b3 m; M' A9 B+ ? Cresponse has been considered as local or systemic. With this1 P0 E5 h& O7 o3 H
in mind we studied 5 children with microphallus for response1 k$ t7 y# V9 r7 H
to gonadotropin and to topical testosterone independently.
/ R/ `$ C ]( p8 F- X$ ?MATERIALS AND METHODS9 U7 P A# u$ j2 v4 T& W
Five 46 XY male subjects between 3 and 17 years old were
& R, ]% m" T6 G1 L/ v: }' L/ Gevaluated for serum testosterone levels and hypothalamic
. _0 Y! | Z, z& ~$ G* ufunction. Of these 5 boys 2 were considered to have Kallmann's; I" Z* B1 H$ S$ h* U
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
$ y2 s. u- h& elamic deficiency. After evaluation of response to luteinizing
5 Q* Z, L8 s% Y9 Nhormone-releasing hormone these patients were treated with7 R3 [) W# {! C4 i$ P$ i
1,000 units of gonadotropin weekly for 3 weeks. Six weeks+ _5 o T; q. l1 R
after completion of gonadotropin therapy 10 per cent topical
' g2 g7 X7 q8 R3 L7 Ctestosterone was applied to the phallus twice daily for 3 weeks.1 q+ N v1 T+ Z3 W$ r. J4 y/ S
Serum testosterone, luteinizing hormone and follicle-stimulat-- }7 d/ w j: S( ?
ing hormone were monitored before, during and after comple-, ^2 }2 N( {0 J7 l% E. F) p
tion of each phase of therapy. Penile stretch length was
4 K; Q m3 ~: G, ]# ^4 q" Lobtained by measuring from the symphysis pubis to the tip of2 J/ j5 e( F: [8 k8 f6 q0 P
the glans. Penile circumferential (girth) measurements were
" T1 B4 ?( C }! y. i; qobtained using an orthopedic digital measuring device (see# d3 I8 c( [$ C8 Y* U7 S9 s
figure).
7 a5 u2 s' f" e: c# ]3 c# ^& S5 fRESULTS$ @6 A! i# C$ e6 M. P0 Y x
Serum testosterone increased moderately to levels between
* s2 q; [: Q9 ?50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-) L/ v- @! k: M( L
terone levels with topical testosterone remained near pre-
% v0 t* r) @, v! ktreatment levels (35 ng./dl.) or were elevated to similar levels1 X* Q9 G7 a" T Q) ?8 L
developed after gonadotropin therapy (96 ng./dl.). Higher5 ]' @. u( k7 b' R- h
serum levels were noted in older patients (12 and 17 years old),
% q; |) y8 t0 d8 ^9 I& |- I4 _while lower levels persisted in younger patients (4, 8, and 104 D [/ d6 i5 G
years old) (see table). Despite absence of profound alterations% n b. z3 n M; z' D0 s* `1 L9 z
of serum testosterone the topical therapy provided a greater9 P5 s# C: S1 C3 x. p8 g% L g
Accepted for publication July 1, 1977. ·# L& h/ W7 |" H) j
Read at annual meeting of American Urological Association,9 A8 v9 {' f: M6 k# n
Chicago, Illinois, April 24-28, 1977.
) f- j. x- x: o, I* Requests for reprints: Division of Urology, Henry Ford Hospital,
9 ?9 B0 O6 D# S, I: g7 z2799 W. Grand Blvd., Detroit, Michigan 48202.
* ?+ L+ u2 r, f2 U7 P; _4 Fimprovement in phallic growth compared to gonadotropin.
4 p* x, g1 ^" G1 KAverage phallic growth with gonadotropin was 14.3 per cent$ g% O* e+ |" g/ |
increase in length and 5.0 per cent increase of girth. Topical' B! T1 \5 P! W" i! v, ~
testosterone produced a 60.0 per cent increase of phallic length c' ~! s# T- J! ~/ |
and 52.9 per cent increase of girth (circumference). The6 J; r, D6 `# ]
response to topical testosterone was greatest in children be-$ R7 x" B1 Q% p1 z$ l; s* [
tween 4 and 8 years old, with a gradual decrease to age 172 g, q/ n# A: e% j
years (see table).
1 y& r9 Q0 |+ o2 O8 ^5 E4 WDISCUSSION
5 _% O9 b( f% w- F Z+ {Topical testosterone has been used effectively by other
- j5 q$ L" X* H) {6 V. ?clinicians but its mode of action remains controversial. Im-. P7 e2 \6 i# l/ {* Z2 |
mergut and associates reported an excellent growth response2 v1 o* U! l& S8 Z+ x4 U% h
to topical testosterone with low levels of serum testosterone," [" h, s {: X# ^
suggesting a local effect.1 Others have obtained growth re-* _& p: r6 z7 ~: j
sponse with high. levels of serum testosterone after topical* z8 c9 n1 @* `9 A# B8 Q+ S" @6 \& X
administration, suggesting a systemic response. 3 The use of4 ]- r4 h- a) G7 m' t3 g `
gonadotropin to obtain levels of serum testosterone compara-
2 @! \. Q! ~' o7 `+ `/ { K; X: Hble to levels obtained with topical testosterone would seem to
& q" t0 ?% p' a! Cprovide a means to compare the relative effectiveness of. K7 B7 b2 E. q; f, p
topical testosterone to systemic testosterone effect. It cer-' ?2 y* g* `8 ?9 T% M
tainly has been established that gonadotropin as well as par-* [, B# G' Z8 [
enteral testosterone administration will produce genital" c) V b* F/ { n
growth. Our report shows that the growth of the phallus was; }* z5 k% D l8 z) G0 D* ?
significantly greater with topical applications than with go-- |+ }" H, e; e$ E v R' u
nadotropin, particularly in children less than 10 years old.* J+ A3 B" b, o
The levels of serum testosterone remained similar or lower
" j2 v: v! k8 T( ~6 I4 O4 a+ cthan with gonadotropin during therapy, suggesting that topi-( s9 k; L3 T+ e' u
cal application produces genital growth by its local effect as6 Q5 t8 _9 J; V; y( _
well as its systemic effect.% ]3 a& J5 |" Y3 N! S
Review of our patients and their growth response related to9 b% x1 D* p' H
age shows a greater growth response at an earlier age. This is' `$ v' C/ F, c9 y$ o0 }6 q
consistent with the findings of Wilson and Walker, who
* v: Y0 D9 z1 `; `9 [& @reported an increased conversion of testosterone to dihydrotes-
- \! G' T; X( P# j5 [7 Z0 Jtosterone in the foreskin of neonates and infants.4 This activ-
5 s1 d$ [1 o8 x9 mity gradually decreases with age until puberty when it ap-$ T+ D% I* {" R( R( i$ x( `8 O
proaches the same level of activity as peripheral skin. It may6 b( l3 p2 V# T; h% m3 n5 n$ [+ O
well be that absorption of testosterone is less when applied at- K) k) A1 q! a( w# m; [& E
an earlier age as suggested by lower serum levels in children" e: ^; p4 x# Z7 \: m2 z* N
less than 10 years old. This fact may be explained by the8 p e$ B1 B0 S5 P0 z- a
greater ability of phallic skin to convert testosterone to dihy-
) y$ b3 [& h1 S4 @& t" @drotestosterone at this age. Conversely, serum levels in older
' \. b, k0 P+ h+ D! ypatients were higher, possibly because of decreased local
8 ?3 U! P+ p) C; J% o( `6671 \+ o" J. }- R8 i) Y* _" O( ~
668 KLUGO AND CERNY
8 C* S9 f' o* U" X% t, I3 x" iPt. Age
/ K- S, t$ H0 `* }(yrs.)
+ l- S+ p+ z. R. `2 q, wSerum Testosterone Phallus (cm.) Change Length
. L5 P; z" S3 z- M5 e(ng./dl.) Girth x Length (%)& w7 u7 ~0 W, N5 @3 ?0 `. ?0 d
4
! @4 s/ h! X) ^3 R$ ]7 w8
; V$ [( `( S4 N; c' u: m0 X10
1 [2 J% f8 Y }# ]) S9 Z( D% Y3 d12
! U6 Z! R/ B* e( `& D& c. F17
& X3 x+ o- O# z* C/ EGonadotropin
, U! \) H: f6 ~! H71.6 2.0 X 3 16.6
+ n3 F% K5 [! \) J) G6 `1 ~9 w50.4 4.0 X 5.0 20.0
6 r6 ]5 v3 |. j' f q7 ]) u22.0 4.5 X 4.0 25.0
; c$ s/ X1 g& w2 T" m6 C% R. @84.6 4.0 X 4.5 11.1
+ j8 e3 p3 } |" B$ o5 J85.9 4.5 X 5.5 9.07 L- [' [" y. h+ w6 _% G
Av. 14.3
! r: E( x4 J# `) T- T. B$ U' l [; r4
1 [6 M4 B8 d2 F2 _4 Q0 s8
! S( Q) \3 L2 I% l/ z) p8 P: ?10% e- p/ ~4 p. W
12
- Q- ^9 G z/ k. N8 x17; g+ e7 i1 Z& |6 F- W
Topical testosterone$ }0 D2 [% v( d9 g* d
34.6 4.5 X 6.5 85; c1 u; C* s. B1 R& P6 j" M
38.8 6.0 X 8.5 70( z O& n8 q9 X6 W
40.0 6.0 X 6.5 62.5
1 S$ D" Q" }" N+ x+ V5 Q93.6 6.0 X 7.0 55.5
! F" M* k8 u9 S0 n! P/ G( l95.0 6.5 X 7.0 27.2% w# B$ ^7 |% g `% j0 E8 q
Av. 60.01 D9 y& P }* ]( l2 B" U; o( Q
available testosterone. Again, emphasis should be placed on
: ^" n6 d X- o5 J$ w- ^( vearly therapy when lower levels of testosterone appear to0 G) l& J, J; o; L! Y+ J% f
provide the best responses. The earlier therapy is instituted) b9 i: _; m) C! m" }! F
the more likely there will be an excellent response with low
4 G% i# r2 c" C5 U5 yserum levels. Response occurs throughout adolescence as
) w$ o W6 f9 q% u3 O8 w8 M0 Dnoted in nomograms of phallic growth. 7 The actual response
4 ]; }' M% y$ X4 B! Wto a given serum level of testosterone is much greater at birth
0 J X$ ?1 o& G# tand gradually decreases as boys reach puberty. This is most, [. b) V6 f7 S& d0 _' p8 X
likely related to the conversion of testosterone to dihydrotes-& `/ J6 x; [" e" v7 Z
tosterone and correlates well with the studies of testosterone- o3 j+ `6 B* A4 F5 C ]
conversion in foreskin at various ages.
$ m4 n) {) P' t. O# O8 vThe question arises regarding early treatment as to whether
+ c1 c8 K3 b5 ~6 g- Z- Tone might sacrifice ultimate potential growth as with acceler-
2 i% f: L$ w9 v& z& bated bone growth. The situation appears quite the reverse& `3 X: f7 n! y+ ?9 ~( \' p# ~" A7 S
with phallic response. If the early growth period is not used6 ]. }0 S/ E6 T8 K6 W: N) j
when 5a reductase activity is greatest then potential growth6 O1 T/ }4 ~5 ~3 P" b
may be lost. We have not observed any regression of growth( {. | ~7 t6 D( K
attained with topical or gonadotropin therapy. It may well
" P: s& x: L5 p# V' k1 g+ mbe that some patients will show little or no response to any; t& T5 O% x/ X1 |7 T8 w
form of therapy. This would suggest a defect in the ability to
* E$ J0 ]0 t5 q6 [7 wconvert testosterone to dihydrotestosterone and indicate that
+ \! F4 Q* z; O, R F: Wphallic and peripheral skin, and subcutaneous tissue should. g! {! _$ x* M" r$ V9 W
be compared for 5a reductase activity.
6 p& \+ S9 A$ P9 ]( OA, loop enlarges to measure penile girth in millimeters. B,
: p, F5 T$ `6 Q% d' nexample of penile girth computed easily and accurately.
# N- E+ [( O- m6 V$ M- D6 K* k- _conversion of testosterone to dihydrotestosterone. It is in this
$ c* I! v8 I, [3 O2 A W! V# rolder group that others have noted high levels of serum
* @* m& P9 r6 b" Q1 V2 x( S5 Z7 N: xtestosterone with topical application. It would also appear- b5 G% i# {4 r+ O( l
that phallic response during puberty is related directly to the
1 ?% I& n. d+ l1 e7 z. @serum testosterone level. There also is other evidence of local
; V r0 L7 @* R3 P+ y3 Sresponse to testosterone with hair growth and with spermato-
. B5 F" J6 f+ L) Q* zgenesis. 5• 6
! n" G/ ~' V6 cAdministration of larger doses of gonadotropin or systemic& C9 a8 X! y6 T% \, U
testosterone, as well as topical applications that produce; g f6 \' C( i" i& b
higher levels of serum testosterone (150 to 900 ng./dl.), will
4 ?0 V/ y7 ~9 e5 [also produce phallic growth but risks accelerated skeletal- N" j! F2 R& Y" m# q& ]% F
maturation even after stopping treatment. It would appear8 I0 x2 F8 ~8 |. P
that this may be avoided by topical applications of testosterone
- i5 Q2 W# ^$ n; u0 `and monitoring of serum testosterone. Even with this control
6 d* _1 ?; q- o0 ?, @) [% A* vthe duration of our therapy did not exceed 3 weeks at any% r. d5 W& o% b0 k3 F' Q- w: r' c
time. It is apparent that the prepuberal male subject may0 o. J# V0 \, ?5 Q
suffer accelerated bone growth with testosterone levels near
9 p C0 I% t o5 M. y. ~$ l( v200 ng./dl. When skeletal maturation is complete the level of
3 {* L, S4 b X$ oserum testosterone can be maintained in the 700 to 1,300 ng./
% ]: \: a' M8 k; a, adl. range to stimulate phallic growth and secondary sexual0 V0 w. ~, D* f7 T
changes. Therefore, after skeletal maturation parenteral tes-
) R. B6 |" E4 k0 ?$ Q" l+ c$ g5 {1 otosterone may be used to advantage. Before skeletal matura-1 G% m; W& ?* F' R. V7 R
tion care must be taken to avoid maintaining levels of serum
7 x& o+ `+ t# C6 Utestosterone more than 100 ng./dl. Low-dose gonadotropin
5 S! q2 ?* ?! S& _9 x5 P- [depends upon intrinsic testicular activity and may require6 y) C% ~# b# N" l. p
prolonged administration for any response., |& }8 k/ Y' x
Alternately, topical testosterone does not depend upon tes-
8 a5 m8 s- f0 X# ~& Mticular function and may provide a more constant level of
( J/ F0 o3 d" H3 a4 ?5 h9 fREFERENCES
- z% V3 P2 p# c" b# M1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,' `" h) K7 y/ F* T0 h7 I
R.: The local application of testosterone cream to the prepub-
' G8 @4 D) o8 \- Eertal phallus. J. Urol., 105: 905, 1971.
) |( A( W; N) k8 R! r2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
* h: z3 I$ M$ f. h7 o1 x. ^- Etreatment for micropenis during early childhood. J. Pediat.,9 @3 g) c5 y5 Q' I; S* a# F* ?
83: 247, 1973.. v! Z" y8 D0 X, d, J% V% \$ |: @
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
6 @, o$ T: J: B) _one therapy for penile growth. Urology, 6: 708, 1975.6 o y$ X5 q) f* R, \0 r: h
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
7 f, o, s5 v" R1 u! |to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
6 o& \& D* S( s. Tskin slices of man. J. Clin. Invest., 48: 371, 1969.
; {! e8 {' H6 B( Y- ~9 O5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth4 ^$ G; L4 Y. H$ s( z8 Y$ J0 M
by topical application of androgens. J.A.M.A., 191: 521, 1965.1 Y4 U9 {9 U% P7 D
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
, y" L* n& e( C q }" D: Yandrogenic effect of interstitial cell tumor of the testis. J.
8 n4 D7 f& T/ L3 m! P+ k' z* ]Urol., 104: 774, 1970.3 H# a# u3 u5 Q% N7 l# w8 W
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-5 M+ O+ w `5 _4 Q/ [0 |
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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