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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
& a5 f& S. V7 i5 m2 P9 BGONADOTROPIN
% |8 p( ~# x& R% e" o! E2 q( q! wRICHARD C. KLUGO* AND JOSEPH C. CERNY/ T9 B. L& }4 H7 w' P& t# ^
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan) P+ G) _9 u6 ~7 `5 y- h7 H
ABSTRACT6 d5 h! d5 R9 d$ W- g6 B/ F7 N+ F
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
2 M8 E' X/ z# }2 e9 Q' `# Iwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-7 V7 Y, Z) [ V( u( A" T
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
8 o! {3 i f. H9 Ucream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent* R2 a4 V# ?9 k( |) k. b. j
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent) V: R! Z7 y0 c% S1 D
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average# b( v0 x2 \; L
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
' {7 Q+ p. f, L/ N: d+ f; O8 C* Doccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This$ M+ m0 w# X% P7 R" M; J! K
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile" g8 N& X$ E1 q1 T4 Z8 q
growth. The response appears to be greater in younger children, which is consistent with previ-
& M3 L$ R- N. s2 `. V; [/ bously published studies of age-related 5 reductase activity.
8 i0 b( G6 q, e5 P: Y6 MChildren with microphallus regardless of its etiology will
! y2 R' ]1 |9 K3 ]require augmentation or consideration for alteration of exter-
4 S& G; E4 v3 Q+ f e" B9 Wnal genitalia. In many instances urethroplasty for hypo-
3 r& t& w9 a" bspadias is easier with previous stimulation of phallic growth.* ]$ H4 V5 n+ \" G7 m
The use of testosterone administered parenterally or topically; m0 h$ m- ]9 h4 O( R8 s3 ?! ?
has produced effective phallic growth. 1- 3 The mechanism of1 Q) ?5 D9 n$ P) Q6 G8 O
response has been considered as local or systemic. With this8 K8 k' L+ @& g6 o5 B
in mind we studied 5 children with microphallus for response# B6 x# f1 G2 ^
to gonadotropin and to topical testosterone independently.; Y7 E9 r5 r2 T
MATERIALS AND METHODS
# D; J9 ]9 a' ` V8 SFive 46 XY male subjects between 3 and 17 years old were; B+ j# d4 O p
evaluated for serum testosterone levels and hypothalamic
9 u7 [' N# A) \! z2 k$ R' Qfunction. Of these 5 boys 2 were considered to have Kallmann's/ G/ K) j' t( Y& \( z- p
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-: c$ u2 X2 }6 o8 ?6 f
lamic deficiency. After evaluation of response to luteinizing
! y, n0 B* | b6 ]6 T. G/ qhormone-releasing hormone these patients were treated with
9 j) r! y4 Q c1 ]1,000 units of gonadotropin weekly for 3 weeks. Six weeks R. Q; C% s6 \$ c
after completion of gonadotropin therapy 10 per cent topical p; U n% ~( y/ X0 R8 K
testosterone was applied to the phallus twice daily for 3 weeks.! b) J3 n" f$ O+ z q
Serum testosterone, luteinizing hormone and follicle-stimulat-: B& k L7 }0 c: p) o
ing hormone were monitored before, during and after comple-
4 Q L6 Z4 U/ E0 `3 T! g. }tion of each phase of therapy. Penile stretch length was3 ^2 w; A f! u2 r' F
obtained by measuring from the symphysis pubis to the tip of
& P# t. u) X Q5 ^" Z* _the glans. Penile circumferential (girth) measurements were) K% b+ H& X( _5 W/ z6 q! _! L0 m
obtained using an orthopedic digital measuring device (see
. n# t" o% S+ |5 }$ B4 z8 Cfigure).* B) z) ^5 n' F! X0 s( M. n F' ?
RESULTS
0 L2 }; O* a. ?! S7 g7 h9 K; p+ @# G, uSerum testosterone increased moderately to levels between
" P8 o" F: L" t8 Y* _50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-! {+ P2 r! R5 i. @9 A6 R6 c
terone levels with topical testosterone remained near pre-- b4 r2 x& o! u% Y
treatment levels (35 ng./dl.) or were elevated to similar levels; N% Z* A0 X) X) a' l% ~" o
developed after gonadotropin therapy (96 ng./dl.). Higher
2 j- L" F. Q x9 m5 ~2 [9 Z& Tserum levels were noted in older patients (12 and 17 years old),
$ y( b8 d4 \# P+ j3 V. p- B$ B/ Iwhile lower levels persisted in younger patients (4, 8, and 10! m& F/ B9 l, B& ~
years old) (see table). Despite absence of profound alterations
) `" ~0 j3 j" m1 ^/ [of serum testosterone the topical therapy provided a greater
8 b7 p, ?4 O' X( ]& l- S+ EAccepted for publication July 1, 1977. ·; a' Q. J! k- g' Z
Read at annual meeting of American Urological Association,2 M, Y1 {/ c) ]7 g' t" \; u. A
Chicago, Illinois, April 24-28, 1977.# Z, ?$ h& G' L& ?0 W
* Requests for reprints: Division of Urology, Henry Ford Hospital,9 Y4 T/ v- {8 w# q
2799 W. Grand Blvd., Detroit, Michigan 48202.
+ }$ O. P5 U8 G; d. i$ _ e# Y/ Fimprovement in phallic growth compared to gonadotropin.
( e: K; \/ _7 @( C+ c% O5 g4 IAverage phallic growth with gonadotropin was 14.3 per cent
) ]/ ?! J7 W2 r8 q) u0 \increase in length and 5.0 per cent increase of girth. Topical4 `* L8 g. c; A% D) t. t: O
testosterone produced a 60.0 per cent increase of phallic length& {; s2 a! c) a! ^+ B5 k
and 52.9 per cent increase of girth (circumference). The' q0 I1 i3 q* R1 j* X8 e+ Y8 @& H
response to topical testosterone was greatest in children be-
0 u' N+ A: e7 A; {& o6 `' Etween 4 and 8 years old, with a gradual decrease to age 17
. {! G3 ^8 G Yyears (see table).3 q9 K; ?( {' j( a9 q) [
DISCUSSION
( Q! B; A8 r+ t5 ]Topical testosterone has been used effectively by other, ?2 T& \8 l, s) G
clinicians but its mode of action remains controversial. Im-) h: o; @- y3 X
mergut and associates reported an excellent growth response
$ G- p4 k, H- T/ e5 W8 qto topical testosterone with low levels of serum testosterone,
6 H: M, L- T2 x3 t- u7 H& Vsuggesting a local effect.1 Others have obtained growth re-
. c) l; v- i9 o( x8 S, Ksponse with high. levels of serum testosterone after topical+ P4 r* Y& Y+ t! w% z. s1 e
administration, suggesting a systemic response. 3 The use of
" T2 x) J+ E& Q/ Z' igonadotropin to obtain levels of serum testosterone compara-
6 `, B) n7 L2 u* A( }; U4 S" b$ eble to levels obtained with topical testosterone would seem to
' G2 B; F3 d5 [$ Wprovide a means to compare the relative effectiveness of- n3 c5 ~+ J& |5 X
topical testosterone to systemic testosterone effect. It cer-7 q$ h. D, o. t Z
tainly has been established that gonadotropin as well as par-
^+ O* i5 k1 Z* Q7 Z! Xenteral testosterone administration will produce genital
; r$ M; E: `: ]1 h4 `growth. Our report shows that the growth of the phallus was
. R! }, P+ k6 l! w+ lsignificantly greater with topical applications than with go-
2 U9 U$ f3 W" ]; E5 R" e- enadotropin, particularly in children less than 10 years old.8 F, O% U/ o1 G5 t
The levels of serum testosterone remained similar or lower
' K. l" z8 f" h7 Y& {than with gonadotropin during therapy, suggesting that topi-0 \- {$ w/ `. Y7 n
cal application produces genital growth by its local effect as
3 M6 u; T) n. c2 C% [2 Gwell as its systemic effect.& l. h% ^# n2 y# }* n. N1 K: J w& u# |
Review of our patients and their growth response related to
1 F4 r- t/ ~6 P. g+ d5 v8 i3 ~age shows a greater growth response at an earlier age. This is
6 c1 l& G! q0 c) J: t% [- Cconsistent with the findings of Wilson and Walker, who
7 L7 d) `# `* \) ^7 Oreported an increased conversion of testosterone to dihydrotes-
$ l* [3 z4 o& L: r ]. mtosterone in the foreskin of neonates and infants.4 This activ-$ ]& C- x3 B+ U
ity gradually decreases with age until puberty when it ap- H& E$ B/ w% \. \
proaches the same level of activity as peripheral skin. It may
" x0 q' p9 X: n# @well be that absorption of testosterone is less when applied at1 S7 R, k( ^1 L3 H- Y2 K. J
an earlier age as suggested by lower serum levels in children
. V: [. Z6 H6 a+ V# r7 y2 \. z! rless than 10 years old. This fact may be explained by the1 B2 M7 y8 K9 u9 l- l
greater ability of phallic skin to convert testosterone to dihy-
% P0 H p! ^7 d/ _! ?drotestosterone at this age. Conversely, serum levels in older8 |. M& W/ s' {
patients were higher, possibly because of decreased local' Z K& r7 `' Y: N% Z
667! S- w5 T' [$ p: ^4 v
668 KLUGO AND CERNY
9 u8 A0 l, h, C z( r C' I* HPt. Age
6 | h1 F+ V$ ~; F( U4 Z(yrs.)
6 k5 d" l2 R& Z8 QSerum Testosterone Phallus (cm.) Change Length1 _- A2 W) y6 W. Y
(ng./dl.) Girth x Length (%)$ o9 P' Y: l, l9 t- [& g
4
1 d# c- J( w* m$ s8 ~81 i: V8 f5 D+ G' ]0 D9 ?, y! H
10
3 d/ v, k% @/ a& O8 f( k! f/ c12- r) K& ~6 A7 h4 E1 q1 u- ?/ i
17/ r, S) l5 x$ @
Gonadotropin
% e( m1 ~3 f q- i U71.6 2.0 X 3 16.69 m, {- C) H1 h* V) k" a
50.4 4.0 X 5.0 20.0
6 Q5 W, x3 _, |# m7 @- ~* \22.0 4.5 X 4.0 25.0. [; v h5 V7 \( z4 e- R5 [* k
84.6 4.0 X 4.5 11.1
6 h- Q5 [+ `, j85.9 4.5 X 5.5 9.0
) {0 C \- r2 g4 V, U# [8 d6 h* \Av. 14.3
5 Y# m) n* A- T1 u9 m4
; R1 _: W6 F: M1 w83 ?+ B) J# g6 f6 ~0 h9 t4 k
10: h* }5 q# s% d1 U
12) R" N0 P* `" d0 F1 ^* y. y
17
$ ]) \. v7 r! b) ?. e) RTopical testosterone J& l1 m J. @% P- P
34.6 4.5 X 6.5 85
' D! m. D( ^1 m+ R. R4 k38.8 6.0 X 8.5 70
& ] Y/ P1 f! P% R9 x- V$ s. F40.0 6.0 X 6.5 62.5' D) J. E: z# j
93.6 6.0 X 7.0 55.59 p5 ] Z4 a0 _( X4 [. g+ F
95.0 6.5 X 7.0 27.2
: i) B* }' Z! q" J* {Av. 60.07 Q+ ?2 d1 M3 e/ i+ k* {
available testosterone. Again, emphasis should be placed on$ F5 T% [, c4 H0 U
early therapy when lower levels of testosterone appear to
8 ?* J- V$ O0 l+ } R. Bprovide the best responses. The earlier therapy is instituted" L- K7 O4 N8 w
the more likely there will be an excellent response with low
9 s! {( V- L; L3 n7 Wserum levels. Response occurs throughout adolescence as" _: J6 A) m5 z$ Q5 }
noted in nomograms of phallic growth. 7 The actual response
4 K8 Q; A& k6 Cto a given serum level of testosterone is much greater at birth
5 {; b; E( Y% j/ B4 eand gradually decreases as boys reach puberty. This is most
& _! K; i! ~' C0 Z& j) ^6 zlikely related to the conversion of testosterone to dihydrotes-
( ^* h0 L% }4 R3 Ltosterone and correlates well with the studies of testosterone8 h* k. q9 g) [: ^9 }" o" I, `
conversion in foreskin at various ages.
/ o% i2 ~$ E* U7 @6 H- B: qThe question arises regarding early treatment as to whether. @3 U9 I. s+ V7 h! g. @
one might sacrifice ultimate potential growth as with acceler-
: `: ?# P; @3 F+ g/ ^ated bone growth. The situation appears quite the reverse
: o2 \& h! Y5 G6 v7 c2 awith phallic response. If the early growth period is not used. j5 g# u: y$ k) k: B" s
when 5a reductase activity is greatest then potential growth8 y9 Q& Z7 V0 U4 S; Y. e* H
may be lost. We have not observed any regression of growth
, R8 m& t; `, k3 K1 F, D" Vattained with topical or gonadotropin therapy. It may well( e- b" V6 X$ l+ b) B" J
be that some patients will show little or no response to any
5 [( _- m+ x; { Hform of therapy. This would suggest a defect in the ability to
0 P2 m, l, P' ~! Q* ]) econvert testosterone to dihydrotestosterone and indicate that
, k! Z' c% x$ q ], s/ d( `0 ?phallic and peripheral skin, and subcutaneous tissue should- x; v- k7 [' p9 e& E f
be compared for 5a reductase activity.
, H! [/ C" d& P; EA, loop enlarges to measure penile girth in millimeters. B,: Z) g. Q2 z: M* g
example of penile girth computed easily and accurately.: J. u) C2 j* }/ j' K+ h& i
conversion of testosterone to dihydrotestosterone. It is in this
; @1 L% w# x$ }' k A: Oolder group that others have noted high levels of serum
5 C# A# Y7 U: {testosterone with topical application. It would also appear
* r$ P- P: @/ Bthat phallic response during puberty is related directly to the
$ _/ Z: Z0 ~, g, r. aserum testosterone level. There also is other evidence of local4 r0 `: \& p- }; `8 e
response to testosterone with hair growth and with spermato-
0 v; j% d) o# F: O4 ? Y( h4 @genesis. 5• 64 `3 H) l/ v( ?
Administration of larger doses of gonadotropin or systemic
8 V! B+ m% t2 H' d% ktestosterone, as well as topical applications that produce3 {1 n) J$ C5 H" |
higher levels of serum testosterone (150 to 900 ng./dl.), will O& f1 ?: q c! @' {4 @; x* n
also produce phallic growth but risks accelerated skeletal
6 ~# L- X! Q5 o/ A) R+ _4 I! |maturation even after stopping treatment. It would appear
& U2 }& s. y& |+ J/ q/ N: vthat this may be avoided by topical applications of testosterone
1 O* W6 x' z& t m, jand monitoring of serum testosterone. Even with this control0 o* w4 ` h2 f6 ^- |4 f: K
the duration of our therapy did not exceed 3 weeks at any
4 q8 j: G* }" O7 ltime. It is apparent that the prepuberal male subject may9 \+ x/ I) J$ w4 Q n" ?
suffer accelerated bone growth with testosterone levels near1 `; P- @. V0 L$ I
200 ng./dl. When skeletal maturation is complete the level of
# L' h" i U' X/ K6 mserum testosterone can be maintained in the 700 to 1,300 ng./
# N$ v+ _! D7 S' F- h" Ndl. range to stimulate phallic growth and secondary sexual$ h7 ~7 m. |3 X3 m7 S
changes. Therefore, after skeletal maturation parenteral tes-0 {, x) y, b& F$ w/ Z0 C2 N
tosterone may be used to advantage. Before skeletal matura-
7 ^ m, B+ `% `4 e: R$ Rtion care must be taken to avoid maintaining levels of serum6 ~4 _+ \3 s- n7 N# g* j( o
testosterone more than 100 ng./dl. Low-dose gonadotropin0 W, K5 w% X+ U1 @; K
depends upon intrinsic testicular activity and may require
9 O& U, n1 b4 i# `0 t8 `prolonged administration for any response.6 z$ K2 y$ k9 ~( Z$ _1 I! k }7 n
Alternately, topical testosterone does not depend upon tes- u2 V& b' Q: Z% E+ E& R
ticular function and may provide a more constant level of
% E0 E. F: Q1 K: tREFERENCES
) I; ^' ?' T) T! c1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,' M) h$ b; v; ?, Z" P: ?
R.: The local application of testosterone cream to the prepub-& p& H! K$ Y7 T; m! W5 T. U
ertal phallus. J. Urol., 105: 905, 1971.
8 L, F. A' l0 i& A7 |7 |8 _. o2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone( R0 [) Z- N7 \2 o/ p5 l: T
treatment for micropenis during early childhood. J. Pediat.,) N! f* t' F8 I. Q
83: 247, 1973.+ |9 K/ W! x/ g' N$ Z0 g
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-6 M J5 ?# Q1 M6 I& S& N
one therapy for penile growth. Urology, 6: 708, 1975.' Q- v3 [) c$ ~* Q8 F
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone$ m5 i# R+ |( m# C7 @
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by* m0 P, L# q) Q7 |) S
skin slices of man. J. Clin. Invest., 48: 371, 1969.# S9 f' Z8 K" O V# H: z5 c
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth: h- I7 S3 \. h1 \1 w8 X& B
by topical application of androgens. J.A.M.A., 191: 521, 1965.
5 Y' q1 A+ \/ j( n) d0 d6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
8 d( i3 `. M: A, A0 D' A5 y; nandrogenic effect of interstitial cell tumor of the testis. J.' T2 W/ N% U0 H5 U6 p+ i
Urol., 104: 774, 1970.6 X5 H% l( G* K; {4 o3 Q
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
# z$ E) x3 f: ]8 X( Z! btion in the male genitalia from birth to maturity. J. Urol., 48: |
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