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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
, K7 x& w/ e: U; ?4 p& |GONADOTROPIN ]5 _' h3 @9 l7 J6 T. v
RICHARD C. KLUGO* AND JOSEPH C. CERNY
. Q- f6 |* k2 {# T' zFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan, P5 I" Z4 ~+ V6 p1 q( S2 z
ABSTRACT' c+ Y5 Y. O( s$ S4 e- f [
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
" R7 F H! _7 j7 Z/ l9 {* |with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-4 t: B+ a4 S* l) c1 s8 z
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
- D6 v [8 t/ D- Bcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
( h4 l& X1 N3 p" tfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
& m) q, i! O3 l4 n; nincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average9 n3 e; d& ]9 ?
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
3 a! R6 Y0 k" m" S4 [& Y' eoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This6 [0 |! y7 i, m2 _% _6 r9 N! o/ d1 U6 ?
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile" i |% `0 G& {/ L: F d! \
growth. The response appears to be greater in younger children, which is consistent with previ-
7 [8 H( o$ R$ K" B* D' h' n; Sously published studies of age-related 5 reductase activity.
% O, B- b) l' ~+ `3 CChildren with microphallus regardless of its etiology will' Y/ [1 l; d3 {/ b7 k
require augmentation or consideration for alteration of exter-. h1 k/ E" ?( E+ ^
nal genitalia. In many instances urethroplasty for hypo-! L, z. `2 m9 |* p0 |" Q! E8 {
spadias is easier with previous stimulation of phallic growth.
3 A3 ~4 W# t! @9 [The use of testosterone administered parenterally or topically
& p/ ?: A0 i/ a+ w) b6 U% ~" f5 H, bhas produced effective phallic growth. 1- 3 The mechanism of7 Q8 F( v3 u% A5 w( D
response has been considered as local or systemic. With this
) w5 l0 A" ?4 p# j0 e% o' L S% lin mind we studied 5 children with microphallus for response# u% ?: s5 u3 ]& ~& f' Q
to gonadotropin and to topical testosterone independently.7 A( v3 p8 |' t, v$ P T# }$ u/ J {
MATERIALS AND METHODS" T5 |' w$ }$ f: R
Five 46 XY male subjects between 3 and 17 years old were) J( |* s# \' ?) F! ^0 \
evaluated for serum testosterone levels and hypothalamic
$ U% o4 Y! \0 Hfunction. Of these 5 boys 2 were considered to have Kallmann's. }2 j; g+ v+ C
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
$ [/ y) }1 ^! i. u1 glamic deficiency. After evaluation of response to luteinizing
" [4 H4 n: i2 h+ thormone-releasing hormone these patients were treated with+ { l# m9 p( M( l" p8 F( u9 F" q8 k& T
1,000 units of gonadotropin weekly for 3 weeks. Six weeks; x; ^3 B3 G$ l3 u; _: g
after completion of gonadotropin therapy 10 per cent topical$ w9 ^$ F$ Q) N2 L! m: n6 d
testosterone was applied to the phallus twice daily for 3 weeks.1 T4 p! K) w4 L- |1 a) o
Serum testosterone, luteinizing hormone and follicle-stimulat-# I u) | U6 P' ?5 R
ing hormone were monitored before, during and after comple-/ c9 |1 P0 O% v" G# \! q4 A, L: A
tion of each phase of therapy. Penile stretch length was* u4 [& S8 S4 |
obtained by measuring from the symphysis pubis to the tip of# y' L+ @( D9 l% @# f. ?8 I# l( o7 `& s
the glans. Penile circumferential (girth) measurements were
" Z3 u8 ?8 ?2 h+ U0 Uobtained using an orthopedic digital measuring device (see
* S; m, }" m" N `6 a9 Bfigure).
. q$ p8 l1 ]& N$ N5 @! \' y0 Z% YRESULTS$ w- v" \3 O) C9 L
Serum testosterone increased moderately to levels between5 ^; d5 Q9 G% N) N
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
) L6 N2 }1 Z4 F: F. T8 J |terone levels with topical testosterone remained near pre-5 n& n2 n% E, X5 Z) m6 J8 { w; J
treatment levels (35 ng./dl.) or were elevated to similar levels
+ B. c5 } Q0 L- V/ Cdeveloped after gonadotropin therapy (96 ng./dl.). Higher
' @ L. K! b% V* K! m5 D9 Oserum levels were noted in older patients (12 and 17 years old),8 L7 r& o- T* D* @3 @( ~/ R
while lower levels persisted in younger patients (4, 8, and 10
) e' U7 O' t$ S4 S0 |" ?1 S5 `( Ryears old) (see table). Despite absence of profound alterations
7 A/ h- ? U# C- Y* Rof serum testosterone the topical therapy provided a greater& d9 @4 U+ z6 u( S7 s
Accepted for publication July 1, 1977. ·
, Q# O' T9 H7 Z% h! G) w5 a: fRead at annual meeting of American Urological Association,
3 ?- x( K# @* R, w1 h0 RChicago, Illinois, April 24-28, 1977.4 r' a! z( S, P* T' l0 |, A, R
* Requests for reprints: Division of Urology, Henry Ford Hospital,
7 Y( a0 e; M* p$ `# |3 E2799 W. Grand Blvd., Detroit, Michigan 48202.
! G9 x1 t) m6 P1 m" u$ q i, V# @improvement in phallic growth compared to gonadotropin.
, ~: _6 Z: J3 {* H( ?/ ~' I6 p7 U& L% MAverage phallic growth with gonadotropin was 14.3 per cent
3 x( T0 `3 }. q5 dincrease in length and 5.0 per cent increase of girth. Topical6 ]# L3 ^% X" y* @
testosterone produced a 60.0 per cent increase of phallic length
' w. j& X' e# ^ s# r( c" z$ a. @and 52.9 per cent increase of girth (circumference). The
P* V2 H6 c9 Jresponse to topical testosterone was greatest in children be-" m; w2 G+ I3 k e* z/ x* O
tween 4 and 8 years old, with a gradual decrease to age 17
; `) P' E# }' E- C& Y0 O/ c7 Lyears (see table). f0 e* k$ ~# a; s4 P: n) }2 s9 W
DISCUSSION
. L; N2 W" v: y" ^. E+ k( TTopical testosterone has been used effectively by other
, G6 X3 q, K5 U2 f- ], bclinicians but its mode of action remains controversial. Im-
* ~" A; }" g8 y- f) |mergut and associates reported an excellent growth response5 \9 x% E) t! X" V- a# L- U* X
to topical testosterone with low levels of serum testosterone," v* L4 e. P5 V) B$ g+ i
suggesting a local effect.1 Others have obtained growth re-% E. [: h; }1 d6 @8 O r
sponse with high. levels of serum testosterone after topical
0 Y8 p# s( K2 k* Badministration, suggesting a systemic response. 3 The use of5 K; A2 N S" `! q' l
gonadotropin to obtain levels of serum testosterone compara-
% C, S& }+ @$ Q7 o/ Jble to levels obtained with topical testosterone would seem to% v0 g$ ~' N( E4 A _( c; [: Z8 P
provide a means to compare the relative effectiveness of$ r- V% G/ \ h1 A( r7 S
topical testosterone to systemic testosterone effect. It cer-$ y# g; m8 Z9 t8 e) @9 d
tainly has been established that gonadotropin as well as par-# |! A6 z8 S/ z+ i/ H- q
enteral testosterone administration will produce genital2 j. L0 N- r; M( ^2 G: ]
growth. Our report shows that the growth of the phallus was* [1 n4 X3 l Y X7 {' c
significantly greater with topical applications than with go-
! Q9 ~( n, P# enadotropin, particularly in children less than 10 years old.! S) p" ]" X4 B) }/ A
The levels of serum testosterone remained similar or lower5 k6 k) h* b7 r! |3 [4 Y& A
than with gonadotropin during therapy, suggesting that topi-
* ^) {( H1 d1 t" j7 \cal application produces genital growth by its local effect as
9 y- }4 W/ [0 Lwell as its systemic effect.! ?2 T, V2 Z# h
Review of our patients and their growth response related to
3 p) p' _4 q8 t8 l/ K; Nage shows a greater growth response at an earlier age. This is" j$ ]6 ?( P/ D* d
consistent with the findings of Wilson and Walker, who
/ x! u) {( @/ D0 U: F5 I: vreported an increased conversion of testosterone to dihydrotes-
. L* U. D$ y. e, Y" p& Qtosterone in the foreskin of neonates and infants.4 This activ-
8 x4 p' G* G5 X. p5 C8 k3 Uity gradually decreases with age until puberty when it ap-, M. k- P8 A' c# m) {
proaches the same level of activity as peripheral skin. It may( D7 z& N/ E3 d4 ?' w
well be that absorption of testosterone is less when applied at
* X9 N3 h& s- M- P% lan earlier age as suggested by lower serum levels in children4 O# h9 p2 X, O% v& `2 H, S
less than 10 years old. This fact may be explained by the/ r5 x5 J' a& q+ z
greater ability of phallic skin to convert testosterone to dihy-) x' P' T5 H7 ]6 t& g1 h- y: }/ |: N
drotestosterone at this age. Conversely, serum levels in older
' ^0 d3 B) `* ^* h. C* c! Apatients were higher, possibly because of decreased local! ]: h+ \! v; n
667
( P5 p8 y3 B# @7 N/ g/ z1 Z668 KLUGO AND CERNY
?+ u( [' P4 Y" qPt. Age
0 J* m+ z, i! J6 }( ?. Q9 J(yrs.)
) d h& } j- z" c8 t+ s( B' |Serum Testosterone Phallus (cm.) Change Length
2 ?+ r( e- y2 q" o(ng./dl.) Girth x Length (%)
" [& T% x! C' [2 s4
8 ~" s- `; U: G" S: }8 f' `. l# L6 U3 F& @
10) l; _# C' b; u1 P* X# [. F: n
121 c( P; ~* n$ M" }' C7 o( Z: e
17
8 B8 [' |& s3 n2 OGonadotropin
' W- _* B- x( B. h71.6 2.0 X 3 16.6# }, I- S8 M ~4 H- s! p
50.4 4.0 X 5.0 20.07 A5 {( z! |" F# D
22.0 4.5 X 4.0 25.0
" b% t& Q( Q% G* F X84.6 4.0 X 4.5 11.1
: O C' {- J* X2 @. ~) ^85.9 4.5 X 5.5 9.0/ p6 L& }6 ~8 g1 l
Av. 14.3
7 D& H4 E& ~$ Z* F& }: Z- |47 g* j3 Q8 I4 }3 }2 {. m; Q- B& N q
8
' {5 I0 e0 G- P U) d7 v# \10
& n! F/ y: f1 j$ U12' Z* M* t& ~7 c# J" B; T
17
& M- G9 \+ k, c& r! x5 wTopical testosterone
- c- T$ W5 x+ g# B34.6 4.5 X 6.5 85 P3 x, d& A A0 ^( ?& t5 p
38.8 6.0 X 8.5 70
6 U' r" s. N$ f40.0 6.0 X 6.5 62.5$ l" M4 Q# R. G. u! L, a. j2 l9 C) ~
93.6 6.0 X 7.0 55.5
. ?$ V& N, V X6 a95.0 6.5 X 7.0 27.2
~$ [1 D! C O9 [. E) j, JAv. 60.00 _/ @' H6 j# B
available testosterone. Again, emphasis should be placed on
. @' ?5 K* |5 |! G5 uearly therapy when lower levels of testosterone appear to
4 h% F' U- J+ g9 x5 u! fprovide the best responses. The earlier therapy is instituted
8 H9 c! n3 T4 V" E$ w% Pthe more likely there will be an excellent response with low
* g1 h: ^/ b( u, Nserum levels. Response occurs throughout adolescence as
( L/ _( x0 T+ X) Rnoted in nomograms of phallic growth. 7 The actual response4 m! y8 |) Q+ I0 B
to a given serum level of testosterone is much greater at birth2 ^. e9 s0 L7 `. G$ Q- ]/ h$ t
and gradually decreases as boys reach puberty. This is most
4 H& B/ ?; o3 ?$ Q$ t( Q& Mlikely related to the conversion of testosterone to dihydrotes-: K+ z O2 k- D8 |1 R
tosterone and correlates well with the studies of testosterone/ c9 F+ D# E8 h- S4 O2 d; B
conversion in foreskin at various ages.
) c" e4 ?2 Z# x' g# P& n% I2 iThe question arises regarding early treatment as to whether( ?# N6 C- u6 K+ B3 T# M
one might sacrifice ultimate potential growth as with acceler-
3 q8 R; N! Q8 y8 b( s1 Sated bone growth. The situation appears quite the reverse, o2 g& [$ Y0 d% d0 W: J
with phallic response. If the early growth period is not used; X }, n$ |2 b0 L6 H
when 5a reductase activity is greatest then potential growth
9 N- ]9 o2 z3 F/ r: umay be lost. We have not observed any regression of growth
8 r9 g/ H( e7 B v: \attained with topical or gonadotropin therapy. It may well& v8 }! Y" m# K* _/ ^" k8 |
be that some patients will show little or no response to any
# d' M j9 H3 `' G# o3 bform of therapy. This would suggest a defect in the ability to# G+ a! G' a: v) D
convert testosterone to dihydrotestosterone and indicate that
. b) r8 L/ r) }8 |4 Uphallic and peripheral skin, and subcutaneous tissue should
* J/ U* M( {: t5 s5 \( Wbe compared for 5a reductase activity.- A8 E" E- d3 A8 W: s
A, loop enlarges to measure penile girth in millimeters. B,# c& `; U7 |+ f, p. d
example of penile girth computed easily and accurately.4 M8 H# Y C" L) a
conversion of testosterone to dihydrotestosterone. It is in this h: J' j& r4 X7 m
older group that others have noted high levels of serum% c; N& O( R2 `. k8 r3 b, m
testosterone with topical application. It would also appear1 u+ w' r8 d3 U; W i9 F9 ^
that phallic response during puberty is related directly to the5 Z2 ]: \3 a( i# L4 j1 G
serum testosterone level. There also is other evidence of local
4 p( P! j4 G# Z. x, j; Q! Sresponse to testosterone with hair growth and with spermato-
2 x7 Q! l' B( C" _% a; k+ @genesis. 5• 6
6 d" @, [' T$ V; T& _# Q$ X2 VAdministration of larger doses of gonadotropin or systemic
- N: n+ F" i! ^- G" ctestosterone, as well as topical applications that produce
+ y0 s" i3 M9 r Z, @0 t4 Uhigher levels of serum testosterone (150 to 900 ng./dl.), will& t6 j0 e3 a( I. r7 ?
also produce phallic growth but risks accelerated skeletal
& X5 C9 p! Z2 y" |# t0 R, Ymaturation even after stopping treatment. It would appear
/ Y7 X* |7 [) Z! cthat this may be avoided by topical applications of testosterone" H! q: i( W& V; s
and monitoring of serum testosterone. Even with this control
: f% }$ y! w, ~6 R; |the duration of our therapy did not exceed 3 weeks at any9 b2 @3 X, a7 o" s: c
time. It is apparent that the prepuberal male subject may
* N) K& K$ |, X6 ~. T! Jsuffer accelerated bone growth with testosterone levels near4 Y+ J) a# E1 {4 H
200 ng./dl. When skeletal maturation is complete the level of2 \8 }2 A# l% K" M
serum testosterone can be maintained in the 700 to 1,300 ng./
# Y% a* k* P3 M- Z0 qdl. range to stimulate phallic growth and secondary sexual
3 h: ~% m4 v7 ]4 i+ Qchanges. Therefore, after skeletal maturation parenteral tes-" P1 g# i' o6 z" z i- W% R7 M3 v
tosterone may be used to advantage. Before skeletal matura-! Y, _: p- d6 K7 {+ H. I& C
tion care must be taken to avoid maintaining levels of serum
5 m) T [- n" J2 R6 ~# M2 Mtestosterone more than 100 ng./dl. Low-dose gonadotropin
/ a3 m, r" M. y* G2 s- x0 qdepends upon intrinsic testicular activity and may require
% [5 n6 u& {5 }% S2 T; d* Mprolonged administration for any response.' `* c; C6 r. p1 N6 D
Alternately, topical testosterone does not depend upon tes-; g$ K) o: U6 P% K
ticular function and may provide a more constant level of
4 e3 h& T, A/ W& |2 NREFERENCES
6 j) [1 h1 w. Q) o# a1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,8 A( R7 \& P7 f& S) L
R.: The local application of testosterone cream to the prepub-' F& i. o$ Q! G( A) h
ertal phallus. J. Urol., 105: 905, 1971.
3 Z8 H1 z6 Z) P% }, Z: \2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone, L& }/ Y% N+ C, d# G9 W3 E
treatment for micropenis during early childhood. J. Pediat.,7 [9 ~& T+ ?: Q& i6 b
83: 247, 1973.
: S* H* {1 p. o! C, Y; _3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
% h7 G$ {' N4 p* lone therapy for penile growth. Urology, 6: 708, 1975.2 _) g9 B% E6 B: c- l8 H& K
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone W) x0 D5 L: D. m% n6 ] f
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
# x$ X7 N1 x( C; I; Gskin slices of man. J. Clin. Invest., 48: 371, 1969.; I4 n( G0 k, z7 U( |- }
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth, }2 O4 R& u; \2 g" ]
by topical application of androgens. J.A.M.A., 191: 521, 1965.. t7 X v. ?- F; E( f, \$ ^3 m
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
( d( f8 P" S8 W; y! landrogenic effect of interstitial cell tumor of the testis. J.& u+ h2 h/ t6 {
Urol., 104: 774, 1970.. U6 p2 t" p! r& i7 e: I
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-" P) l9 J2 Y7 T. }' K. V
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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