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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND: x j+ a9 R( @
GONADOTROPIN3 [1 U! j+ a# ?3 @' s; a9 H
RICHARD C. KLUGO* AND JOSEPH C. CERNY5 `# C0 x9 v U
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan* R G0 }# r9 `# ]
ABSTRACT
: d0 |; N5 C6 {' c9 m2 P3 G: rFive patients were treated with gonadotropin and topical testosterone for micropenis associated
% I' G" E* U) R( `: Nwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-$ C' L) P3 L4 b% y/ k2 o& P
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
' t9 ]4 e! [4 L2 p& [ S3 R* M Wcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent |* x6 i( W+ e+ r( n+ o$ Q
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
: l8 [9 `, a9 A Aincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average7 b k$ q/ M3 N1 f
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
$ H& a3 f1 V2 @* ]4 N* _! f. doccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This5 [3 c" n1 l* z2 M4 E1 L
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
- R, T* u3 \; \- E' b/ Z: n8 fgrowth. The response appears to be greater in younger children, which is consistent with previ-
) O0 A6 E! w( E7 u, d- o! eously published studies of age-related 5 reductase activity.
$ H3 l* b' u% m i A# S1 aChildren with microphallus regardless of its etiology will
4 v& S, u1 t- R, ^. F' ~9 k2 k r. V" vrequire augmentation or consideration for alteration of exter-
+ Z3 g. Z& L+ c( e4 Gnal genitalia. In many instances urethroplasty for hypo-
- V' \2 j* U- y/ P" t F4 ispadias is easier with previous stimulation of phallic growth.
. v" h. |" [) {1 b5 W& w/ i6 Z i9 KThe use of testosterone administered parenterally or topically
4 s. e) P% H! K: C/ g& Jhas produced effective phallic growth. 1- 3 The mechanism of
( @+ ?3 \4 G2 l/ R8 o T. Xresponse has been considered as local or systemic. With this
% O6 Y. u' M4 gin mind we studied 5 children with microphallus for response3 V4 h& M7 ?3 k U# j: H
to gonadotropin and to topical testosterone independently.0 `! J+ }$ [* W" v3 A: V
MATERIALS AND METHODS" Z6 A/ ~1 n9 n2 Z. j% e6 N
Five 46 XY male subjects between 3 and 17 years old were6 S0 S) P% ]* h7 s H
evaluated for serum testosterone levels and hypothalamic+ _6 e0 `7 l- i9 d' H* d& u
function. Of these 5 boys 2 were considered to have Kallmann's; D+ G. S" [- q
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
. e2 B" i$ m/ B' _( |; flamic deficiency. After evaluation of response to luteinizing
8 h, q3 J; E: a, O8 Q4 M' ahormone-releasing hormone these patients were treated with" l" g. i/ M% p8 G5 ^" Q( N8 A
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
: O5 [0 x: ]* A7 ]after completion of gonadotropin therapy 10 per cent topical; n+ k1 x/ I* l& n6 ~% R7 u
testosterone was applied to the phallus twice daily for 3 weeks./ y0 C" u4 E6 \; C
Serum testosterone, luteinizing hormone and follicle-stimulat-# |+ e+ t$ z1 ]4 v* E$ T+ i
ing hormone were monitored before, during and after comple-" V' G d" b0 W- }! w5 \" k6 |
tion of each phase of therapy. Penile stretch length was: j: M% }4 N, r; p
obtained by measuring from the symphysis pubis to the tip of& @8 w' m- N# S" U# F) e/ K0 d. H' R( P- T
the glans. Penile circumferential (girth) measurements were+ V$ p* ^) h) f9 v
obtained using an orthopedic digital measuring device (see5 \! J, ]) y$ Z( f2 k
figure).
6 h2 s: n0 `6 s z S }) mRESULTS
; F; j0 S) c1 G( z$ s9 KSerum testosterone increased moderately to levels between
: t/ M p) r0 E: @50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-5 M4 T {" B z4 x% b, M
terone levels with topical testosterone remained near pre-
9 ]' c. b0 a5 [6 btreatment levels (35 ng./dl.) or were elevated to similar levels7 Y! ]7 ?* _" k# i& u$ o( N
developed after gonadotropin therapy (96 ng./dl.). Higher
* S* H2 ^2 @2 ?3 y2 Zserum levels were noted in older patients (12 and 17 years old),
7 Y/ ~7 D! K8 K- M2 Xwhile lower levels persisted in younger patients (4, 8, and 103 R4 E+ i; y" n/ x w& j; V9 {
years old) (see table). Despite absence of profound alterations
* K) B% t) ?+ s& E; H: kof serum testosterone the topical therapy provided a greater b. J8 e0 B/ k
Accepted for publication July 1, 1977. ·
. V- R) [7 E% I8 z. P% @! eRead at annual meeting of American Urological Association,
& z' C. {: l, z/ s* ?Chicago, Illinois, April 24-28, 1977.
+ O! A: w$ o+ ]/ C* Requests for reprints: Division of Urology, Henry Ford Hospital,9 D# I( |% m6 A0 K
2799 W. Grand Blvd., Detroit, Michigan 48202.
( Q3 w2 k5 F6 zimprovement in phallic growth compared to gonadotropin.
: k) e; s/ z) E" GAverage phallic growth with gonadotropin was 14.3 per cent+ |! [6 L6 z6 S6 C! v ]0 G' M7 F
increase in length and 5.0 per cent increase of girth. Topical
7 d* B+ Q2 u+ Ptestosterone produced a 60.0 per cent increase of phallic length
7 K% D8 N9 @4 T- [; M0 J5 A/ qand 52.9 per cent increase of girth (circumference). The
: _4 l* B( ]8 L P3 u! fresponse to topical testosterone was greatest in children be-; W: j* ^8 G) ^/ U E4 @
tween 4 and 8 years old, with a gradual decrease to age 17
- p7 _( h, ?7 Pyears (see table).
5 _' O6 ?( C% @: qDISCUSSION5 x) @% `; t# @
Topical testosterone has been used effectively by other' o& d4 V# t/ V k! O, e) ^
clinicians but its mode of action remains controversial. Im-! a+ H' u) Y: }$ p2 \ {
mergut and associates reported an excellent growth response
# s5 [6 [! A. B8 i' b' }to topical testosterone with low levels of serum testosterone,6 v% N. s! _! T5 u: `: T
suggesting a local effect.1 Others have obtained growth re-
3 ?: s4 L8 x0 L: Q# a d8 dsponse with high. levels of serum testosterone after topical" T: v V8 [' S: Y
administration, suggesting a systemic response. 3 The use of, \3 c0 r. s5 }8 o
gonadotropin to obtain levels of serum testosterone compara-
$ M% [$ _$ K9 r0 {' `5 Uble to levels obtained with topical testosterone would seem to
f+ o; l3 v* a/ yprovide a means to compare the relative effectiveness of
$ \- u! H @) {topical testosterone to systemic testosterone effect. It cer-5 {# C( a* N# h6 k1 G3 D3 i
tainly has been established that gonadotropin as well as par-
: n$ w6 |, j6 m- _: Q$ f$ ]enteral testosterone administration will produce genital8 Q2 J0 r' {2 j* C
growth. Our report shows that the growth of the phallus was3 M1 Y. t) E. N- p5 s4 G$ Z* z1 ~
significantly greater with topical applications than with go-# X% s: \8 T( u2 J+ o
nadotropin, particularly in children less than 10 years old.+ i8 {% S4 ^ t
The levels of serum testosterone remained similar or lower
6 g" U2 g8 X" R3 {; t/ Gthan with gonadotropin during therapy, suggesting that topi-
6 b* ^& Z0 B' ~9 w! Ccal application produces genital growth by its local effect as4 y! ~* i3 P( ~$ T) O/ b% P
well as its systemic effect.
0 P! u4 b! T! C) w6 KReview of our patients and their growth response related to: M: A- A: \" P
age shows a greater growth response at an earlier age. This is
+ b# y; \& h: {- h# uconsistent with the findings of Wilson and Walker, who3 d, O: y/ j4 F# ^" w$ A
reported an increased conversion of testosterone to dihydrotes-( j G# m6 ^, r5 T) E
tosterone in the foreskin of neonates and infants.4 This activ-
" z5 i1 D, S; s/ @& Mity gradually decreases with age until puberty when it ap-
, d, S/ |2 s$ aproaches the same level of activity as peripheral skin. It may
$ P+ F% E& \7 | [well be that absorption of testosterone is less when applied at
1 {+ q7 O, `% k3 ^! R( C/ Qan earlier age as suggested by lower serum levels in children
# e/ a- Q% ]8 {" c! |/ lless than 10 years old. This fact may be explained by the; ^: v) a& N) Z( w! \/ }
greater ability of phallic skin to convert testosterone to dihy-
/ W3 |1 Y2 ?9 m( Vdrotestosterone at this age. Conversely, serum levels in older; l$ B- f. B6 j' H) D4 ?9 G
patients were higher, possibly because of decreased local
" g/ G0 @3 n8 k# z( d8 N2 z8 v667( Y( w8 n$ J- L* {: q# r' \; k
668 KLUGO AND CERNY7 N$ \0 A+ b6 o H
Pt. Age
% S4 L7 X. {2 j+ m% `6 b3 Z(yrs.)
9 t. S. v/ O f' ASerum Testosterone Phallus (cm.) Change Length5 C2 n/ |2 k2 b8 f
(ng./dl.) Girth x Length (%)5 j( f& M- W! ^
41 T; i8 o( g% V
8- }5 {1 ^" L% D; d2 ^" E9 t
10
/ ~% A& |3 p; B, A' b* d12& W6 j$ z# h- S6 Q+ q
170 b8 [6 r) z4 l( p/ }! [
Gonadotropin
0 N- D$ \4 `& O w8 r/ Q71.6 2.0 X 3 16.6
1 D, ?$ U! `4 [50.4 4.0 X 5.0 20.0
6 Z5 `, t4 }& p* a* u+ q1 C) `22.0 4.5 X 4.0 25.00 M( f, ^% d9 ?# P' R% Z, g
84.6 4.0 X 4.5 11.1
3 {" P# Q* L$ k+ Q% B85.9 4.5 X 5.5 9.0+ p% T, H" b3 X7 l
Av. 14.3) F3 X7 w" j* \
4
) C- E+ E- {6 [ R9 o& v3 e8" D- K* D( r1 D$ G. ?5 T; l
10
& b2 {4 g" x/ `' Y9 C12
4 c5 z9 B( ]6 P170 R! `" n9 r( D
Topical testosterone6 M) j# ~) j! b5 N. F9 Z
34.6 4.5 X 6.5 85
% ?! k! T6 r: Y8 s8 z38.8 6.0 X 8.5 70
1 k) C0 L0 O4 [0 u# q40.0 6.0 X 6.5 62.5
8 _1 H2 P; C1 ^* T1 i93.6 6.0 X 7.0 55.5& r( `' d* M W e# g9 \
95.0 6.5 X 7.0 27.2" ^) k2 T, g, l) _: z5 |, h$ P$ d
Av. 60.0! z m6 Y' M; v% K4 F0 {7 {8 X+ }
available testosterone. Again, emphasis should be placed on
6 Q" m" F% g! H; F5 U1 a4 {early therapy when lower levels of testosterone appear to6 a! ?3 y! t$ T8 Z, F0 E/ h1 w) z
provide the best responses. The earlier therapy is instituted
5 H0 Q- A9 p4 z' c: ethe more likely there will be an excellent response with low" @8 c/ I' o; Q2 y2 T1 y. o+ L
serum levels. Response occurs throughout adolescence as' o5 J3 h+ }: \, V- b( A l" z7 r
noted in nomograms of phallic growth. 7 The actual response" g: A' _% ?" Y# B$ s
to a given serum level of testosterone is much greater at birth
( E; J8 P8 A2 O6 q+ e% kand gradually decreases as boys reach puberty. This is most
8 Y( L3 f0 r& ?& @0 ^- n6 wlikely related to the conversion of testosterone to dihydrotes-
" y; g! a0 A% ftosterone and correlates well with the studies of testosterone" T: t( f0 ^' S, b- u
conversion in foreskin at various ages.
6 ^ ~ |* X( D4 E; zThe question arises regarding early treatment as to whether- G/ Y7 z; [3 P8 v( J
one might sacrifice ultimate potential growth as with acceler-4 L- s7 [9 T4 _
ated bone growth. The situation appears quite the reverse
Y0 x6 x6 J' ?: iwith phallic response. If the early growth period is not used
8 {3 | @2 k: lwhen 5a reductase activity is greatest then potential growth9 {3 _9 Z# i1 O% X
may be lost. We have not observed any regression of growth
% a3 t3 e: I7 J5 X2 }1 n7 |attained with topical or gonadotropin therapy. It may well5 r; ^ A* e d/ i8 H) ~
be that some patients will show little or no response to any3 m6 Z) R7 _) M7 k% F1 z
form of therapy. This would suggest a defect in the ability to8 _7 M) J' P, O% D8 O1 a0 X
convert testosterone to dihydrotestosterone and indicate that" L0 Y5 N0 e$ V- S; @# o
phallic and peripheral skin, and subcutaneous tissue should6 r) x; L% I5 [) S1 t% [1 D
be compared for 5a reductase activity.
* u J8 ^7 |( b2 L. x( w& TA, loop enlarges to measure penile girth in millimeters. B,
& r% w. \+ D a3 G- Yexample of penile girth computed easily and accurately.& s4 \3 B9 s% y5 j
conversion of testosterone to dihydrotestosterone. It is in this
, u7 U" N( a3 O. x6 z, U rolder group that others have noted high levels of serum
0 D' _' n' _) R" G" e. A7 Ttestosterone with topical application. It would also appear" E+ w9 {+ ^0 U3 A: A
that phallic response during puberty is related directly to the
5 H! v% k/ @' j# V6 y! ]serum testosterone level. There also is other evidence of local1 @+ W4 \$ i5 e8 A9 P! B! I
response to testosterone with hair growth and with spermato-
8 Q9 u% T5 ^" F: v Mgenesis. 5• 6
, M6 N) `& M# T- N1 xAdministration of larger doses of gonadotropin or systemic% o1 y% l1 q! `# j1 k
testosterone, as well as topical applications that produce6 }# K! x; g* K3 r8 j5 r
higher levels of serum testosterone (150 to 900 ng./dl.), will: Q' ? I7 p9 |6 E, K1 P k
also produce phallic growth but risks accelerated skeletal- w% w0 Z% r$ B$ l
maturation even after stopping treatment. It would appear
2 p* u& h* u2 z' J5 H5 l" jthat this may be avoided by topical applications of testosterone
. E. G) F2 A9 E# l+ {. }and monitoring of serum testosterone. Even with this control
( H! O' V% ]7 F3 P8 M9 ~the duration of our therapy did not exceed 3 weeks at any ]+ b5 w4 U( Y8 [' O
time. It is apparent that the prepuberal male subject may) P% K1 f3 j X, X
suffer accelerated bone growth with testosterone levels near
( f: h1 r. E+ e9 U- b2 b; V200 ng./dl. When skeletal maturation is complete the level of
9 l, w1 u+ X8 z$ Tserum testosterone can be maintained in the 700 to 1,300 ng./
' v0 P; C7 _/ |, C$ {$ a8 E" mdl. range to stimulate phallic growth and secondary sexual
% E% U4 S" e* x# rchanges. Therefore, after skeletal maturation parenteral tes-
5 }7 B- ]# w1 }tosterone may be used to advantage. Before skeletal matura-
% l) o: L3 Q# \* F: C; X1 q2 Ytion care must be taken to avoid maintaining levels of serum( R- J; \6 O1 a) g1 `9 s2 P
testosterone more than 100 ng./dl. Low-dose gonadotropin
. @% v2 G5 G- o: |depends upon intrinsic testicular activity and may require/ g$ L/ o9 f+ U' L! L+ {
prolonged administration for any response.3 a& Q' J: i. I, f. w1 t0 r
Alternately, topical testosterone does not depend upon tes- [8 I) X/ a$ f5 \; q' W
ticular function and may provide a more constant level of: n8 X- Y3 v0 E9 R
REFERENCES& l8 K% w& p: I8 b9 b
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
6 A0 ]& C9 a4 sR.: The local application of testosterone cream to the prepub-
5 T5 ?2 ]2 @$ Nertal phallus. J. Urol., 105: 905, 1971.
! e- V2 v5 @4 Q* J2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
" h; [9 J- `& K5 ~treatment for micropenis during early childhood. J. Pediat.,) ]4 ^4 W8 n& E0 G
83: 247, 1973., Q/ h4 o+ }, ?% f1 X+ W$ v T
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-+ |6 N5 o4 f# X$ N O2 F' K) ^
one therapy for penile growth. Urology, 6: 708, 1975.: R9 O' K0 }) W$ R0 {
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone. d4 F0 A# o8 C; c2 ^+ @
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by# }5 `! |6 O* e$ P% x F: f
skin slices of man. J. Clin. Invest., 48: 371, 1969.
5 q7 o+ o+ v, h/ b5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
) i& X- G* O {2 Mby topical application of androgens. J.A.M.A., 191: 521, 1965.# _+ w( o W; x
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local: a2 E3 y. Z- u6 \! N3 ^& M
androgenic effect of interstitial cell tumor of the testis. J.
4 r& C1 B9 g, x. TUrol., 104: 774, 1970.
- h+ y6 h+ n6 ^4 S+ j# V) [7 D# E7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
3 }+ T' ^$ F. x+ \8 Rtion in the male genitalia from birth to maturity. J. Urol., 48: |
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