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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND' h: e/ U/ [( k8 d% m3 a4 ^
GONADOTROPIN
& K7 }+ C1 l8 ~( u. M- P" }/ k; Q RRICHARD C. KLUGO* AND JOSEPH C. CERNY
* e7 F2 _% N+ d' H4 B9 m; t* c: OFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan: Q& l3 ~& ~- x8 i3 o5 ~4 k
ABSTRACT
* e, K% F% Y, c3 ~Five patients were treated with gonadotropin and topical testosterone for micropenis associated: B2 u. f! w0 D* E8 P
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
# r0 _0 n% c( k; C Y/ Ytropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone* x, `/ N9 g3 z7 u8 g
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent% H1 C# {+ w$ |+ u8 k o, o
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
9 M& [# o( f, ~* Mincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average* I( _+ t9 m: c' {5 t
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
! Z( {9 b' S3 k" O' ~7 O+ c$ ?occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This1 N; H) ^3 |1 p1 D; K
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile5 E9 _" g* ^ r
growth. The response appears to be greater in younger children, which is consistent with previ-
! @! p- ~4 K+ J9 f. Rously published studies of age-related 5 reductase activity.
9 Z4 C- Z4 s& PChildren with microphallus regardless of its etiology will
% l) y" K- N/ w, Z2 v7 D. _require augmentation or consideration for alteration of exter-
& z2 a. m% E" O! C! p3 G* `nal genitalia. In many instances urethroplasty for hypo-
! {8 F1 \& _! z5 T7 i3 ~spadias is easier with previous stimulation of phallic growth.1 s0 W: G; Y7 E# X7 ]3 g* e% j! ?
The use of testosterone administered parenterally or topically1 |/ |% D$ p1 @
has produced effective phallic growth. 1- 3 The mechanism of
: r# I ] h, Q# H; dresponse has been considered as local or systemic. With this
/ h, Z- }8 q d& b7 f! j+ Fin mind we studied 5 children with microphallus for response
+ _# u' e2 p/ ^' T) o* ]$ O2 C \to gonadotropin and to topical testosterone independently.8 p8 I" y& W5 d. s: q1 R
MATERIALS AND METHODS
# N5 b- v( R. R+ UFive 46 XY male subjects between 3 and 17 years old were
9 f s( k6 d" C. P; `evaluated for serum testosterone levels and hypothalamic
% l R' @; ?+ F+ T& \) w A: ffunction. Of these 5 boys 2 were considered to have Kallmann's
+ e1 m# X5 _5 |) E# T* [syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-, H$ [ a1 Q! c2 }% N
lamic deficiency. After evaluation of response to luteinizing
% Z! H8 R/ c. | i3 Lhormone-releasing hormone these patients were treated with( \" S' J$ y1 Q
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
# z" |2 n( n# C/ _$ s, k1 ^after completion of gonadotropin therapy 10 per cent topical A2 `" U9 m. F# D9 M) U
testosterone was applied to the phallus twice daily for 3 weeks.
1 |, R5 e' U6 j5 g7 |/ z' M! b1 t3 ySerum testosterone, luteinizing hormone and follicle-stimulat-
" r; }" J: t' u, ]9 Qing hormone were monitored before, during and after comple-
0 j: e0 ^: ]$ ], b6 `1 stion of each phase of therapy. Penile stretch length was
' Z# ?: a+ U: wobtained by measuring from the symphysis pubis to the tip of
# ^) Y) B( P$ tthe glans. Penile circumferential (girth) measurements were
: M; ~& j D& N1 O" h6 v* yobtained using an orthopedic digital measuring device (see) R6 J( j8 P% |3 H" r$ P
figure).4 B7 y5 l& p% Q% Y! j
RESULTS
t! J" j% C7 q3 y$ f( c, TSerum testosterone increased moderately to levels between
9 F2 ~+ n( r4 _6 m50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-" \" r& f: N( L: u
terone levels with topical testosterone remained near pre-
# h& P# ^+ D2 t1 p9 L) ?treatment levels (35 ng./dl.) or were elevated to similar levels+ g8 h" ]2 o U% f% G7 D* k
developed after gonadotropin therapy (96 ng./dl.). Higher: q* F* ]2 G0 r0 J( v
serum levels were noted in older patients (12 and 17 years old),
+ _- ]# e1 E# Awhile lower levels persisted in younger patients (4, 8, and 10
: k8 O0 F9 ^0 U0 E3 cyears old) (see table). Despite absence of profound alterations
2 @5 H- b `$ n' D- m$ gof serum testosterone the topical therapy provided a greater
2 A3 R0 m" l# A2 C2 C+ DAccepted for publication July 1, 1977. ·4 E- y0 X, I4 a" P
Read at annual meeting of American Urological Association,/ Z4 J! Y& t2 \6 C0 a- T
Chicago, Illinois, April 24-28, 1977.
; J9 Y2 R# H) P' r: i& N* Requests for reprints: Division of Urology, Henry Ford Hospital,
: N% s# t! d# ~$ j* p1 E, K9 a4 ^2799 W. Grand Blvd., Detroit, Michigan 48202.' e# s$ Y# v/ b. f5 c2 S$ s
improvement in phallic growth compared to gonadotropin.8 S6 h7 }: M+ ?5 ?; w' i- |
Average phallic growth with gonadotropin was 14.3 per cent: O8 w- E; h- D* n" A( j; }0 V8 V
increase in length and 5.0 per cent increase of girth. Topical8 ]3 P# j: {' k. G: p, s
testosterone produced a 60.0 per cent increase of phallic length3 O# R% `2 Z+ |+ [" z: I
and 52.9 per cent increase of girth (circumference). The8 _- u$ \: T/ Y0 X8 h
response to topical testosterone was greatest in children be-
8 G" g0 y6 A/ X" o0 ~# Ftween 4 and 8 years old, with a gradual decrease to age 172 k. J, N4 F0 w+ Z ?% t/ T
years (see table).7 A; J! c1 Q/ | i8 q9 r. V
DISCUSSION
/ \5 O0 G8 _0 r" e% STopical testosterone has been used effectively by other& v( f% j3 m/ y6 r2 Z
clinicians but its mode of action remains controversial. Im-
+ a" e) f# J M9 Q- pmergut and associates reported an excellent growth response
' n% k. } q5 G, `9 B; I! jto topical testosterone with low levels of serum testosterone,
3 `/ N3 T3 L+ [( Dsuggesting a local effect.1 Others have obtained growth re-
% G8 \. \ h- Jsponse with high. levels of serum testosterone after topical
' z, |+ D; D( p: Qadministration, suggesting a systemic response. 3 The use of
[$ E) X$ x) G0 _8 ?2 fgonadotropin to obtain levels of serum testosterone compara-+ Q( g% _$ r+ f+ W+ f% f7 @- |
ble to levels obtained with topical testosterone would seem to
$ J+ I2 j( O4 J. lprovide a means to compare the relative effectiveness of, [3 Y5 q$ p3 ~* {: ^- G
topical testosterone to systemic testosterone effect. It cer-+ U$ L) Y- f' s5 g. c; R' c
tainly has been established that gonadotropin as well as par-
; `3 t# D- b- s1 ]/ w1 penteral testosterone administration will produce genital0 \4 w! [1 O% V
growth. Our report shows that the growth of the phallus was
& R p2 F% e. z6 f" f( h; dsignificantly greater with topical applications than with go-
" U0 J( C7 z$ D) J6 _: Inadotropin, particularly in children less than 10 years old.; X) t/ ^- G1 k) ?. V A
The levels of serum testosterone remained similar or lower
& l2 g1 Z4 @* r- u( g* fthan with gonadotropin during therapy, suggesting that topi-
9 S) n! V+ w. Q. O4 z7 Pcal application produces genital growth by its local effect as
! P7 F1 V+ t. O& s+ _/ g4 Twell as its systemic effect." l V, k9 S5 `# j$ b
Review of our patients and their growth response related to
F* W+ }7 r: o+ p7 `age shows a greater growth response at an earlier age. This is
, d4 e5 @% L; kconsistent with the findings of Wilson and Walker, who/ C: E$ d _ r
reported an increased conversion of testosterone to dihydrotes-. P c! t, ?0 I9 V4 v9 M& d \
tosterone in the foreskin of neonates and infants.4 This activ-
% ~' A! Q$ I, V, B0 sity gradually decreases with age until puberty when it ap-) o, N/ d/ r" Y1 N
proaches the same level of activity as peripheral skin. It may7 R6 N3 }$ ~, Z) r/ K
well be that absorption of testosterone is less when applied at
) [! ~2 e# z: x: l7 T# Can earlier age as suggested by lower serum levels in children3 `) V5 n4 O% |5 \/ }2 g; P
less than 10 years old. This fact may be explained by the
! {" |. p- L& h3 }% fgreater ability of phallic skin to convert testosterone to dihy-
2 y- N. N3 }$ ?& g @! B7 Ndrotestosterone at this age. Conversely, serum levels in older
; s1 _( z# X7 ^patients were higher, possibly because of decreased local
2 K0 Y- ^2 |! f8 {667
( \/ E, O$ `# C# {; h! y668 KLUGO AND CERNY
; I- l4 Y i \0 Z; VPt. Age
2 g8 j! ^2 ?5 T5 o(yrs.)4 m* |/ h6 t, ?6 T
Serum Testosterone Phallus (cm.) Change Length
8 \/ S- A, o4 H# M* C7 P+ e u(ng./dl.) Girth x Length (%)
# c9 v6 \' E/ T, X, Y9 A0 `44 Y/ [5 @; o: [; u
8* P8 a+ ~7 G, ]0 |
10' e8 Q* x2 S. d: `) Q- W7 C
12
# M$ l7 b# D. d17, B/ ?! s5 W& N: R0 N1 H2 {1 K
Gonadotropin6 N: L0 E3 D+ }, L H
71.6 2.0 X 3 16.6' B; _8 q& \8 G0 b- F
50.4 4.0 X 5.0 20.0
! z7 R4 g: t; ?- \ f6 ?22.0 4.5 X 4.0 25.0
0 z- O+ B0 a6 H' O/ }7 A84.6 4.0 X 4.5 11.1+ |9 L% X$ L$ L- L( e# i. ?) b
85.9 4.5 X 5.5 9.0
: x! ? i T# i# R6 u3 o0 QAv. 14.3
{% n' T, m' m y. p4! o+ z- v. J8 l0 w8 W
8
' G. _( n4 m9 p! W7 u9 w10( V( F. M& u+ g8 W
12
: J" Z _/ P2 }' P* O17
/ E0 a4 \4 B* v/ U' x9 P* L& L1 `Topical testosterone
1 R! O s8 c$ Z& P34.6 4.5 X 6.5 85( M8 t1 X" ^( w
38.8 6.0 X 8.5 70/ |! F. m! K& `2 k3 x* Q
40.0 6.0 X 6.5 62.50 |3 w' I( `0 O9 [
93.6 6.0 X 7.0 55.5
; S" {4 I& D! k- {% {5 d7 Y% H: h95.0 6.5 X 7.0 27.2
) {) W) F2 P" n2 @6 wAv. 60.0% |. S$ l! n. i/ ]6 X
available testosterone. Again, emphasis should be placed on+ E y. u1 j* G/ g5 D, x
early therapy when lower levels of testosterone appear to/ e, Y1 ?& n K) R n7 b. o
provide the best responses. The earlier therapy is instituted1 H* Q! j% a# X5 o
the more likely there will be an excellent response with low
% p6 q: U, Z2 Y9 {5 Lserum levels. Response occurs throughout adolescence as
7 a- [+ X. I) Y2 r5 d3 |( Vnoted in nomograms of phallic growth. 7 The actual response) ?6 q* e1 Z6 ~
to a given serum level of testosterone is much greater at birth
1 Y5 ^1 D9 |0 band gradually decreases as boys reach puberty. This is most
* ?" Q7 J7 u+ C) m9 blikely related to the conversion of testosterone to dihydrotes-8 H% m( d8 H! S% `1 @. Q
tosterone and correlates well with the studies of testosterone: Z/ ` i4 X1 x
conversion in foreskin at various ages.1 x+ z% r$ l" v7 T/ ~ S
The question arises regarding early treatment as to whether/ n8 [# F6 A' i* K6 e
one might sacrifice ultimate potential growth as with acceler-
- ^4 q8 q. ] bated bone growth. The situation appears quite the reverse
! J8 r& J) `& B" {) M; I. S" e! A- iwith phallic response. If the early growth period is not used
3 \& Y, {4 V: t0 _7 S8 Xwhen 5a reductase activity is greatest then potential growth# Z" I! L6 d7 X$ Z: K9 `# ]
may be lost. We have not observed any regression of growth
4 C$ K- U+ B1 zattained with topical or gonadotropin therapy. It may well" G' E4 }) l# V7 ^4 C8 l' T/ ?
be that some patients will show little or no response to any
4 s0 |4 r7 R/ U& b/ H, p2 Uform of therapy. This would suggest a defect in the ability to: M2 p# I3 H E9 } d" o
convert testosterone to dihydrotestosterone and indicate that* p% u/ H" |/ Y; g
phallic and peripheral skin, and subcutaneous tissue should7 U" N7 G, r+ l* y3 |3 `
be compared for 5a reductase activity.4 G* [' ~5 N+ G1 \2 D8 C5 K
A, loop enlarges to measure penile girth in millimeters. B,
( T* c$ G# z8 T, Aexample of penile girth computed easily and accurately.
. ^5 Z" ~' H' F t1 T4 _6 Lconversion of testosterone to dihydrotestosterone. It is in this
- k1 p7 i" H Z% c4 {+ D' H/ Bolder group that others have noted high levels of serum
. W4 g5 s# R$ l- Vtestosterone with topical application. It would also appear6 z* N- q$ `! M2 T( @) c) M3 ~
that phallic response during puberty is related directly to the2 z" E" S) r3 D9 j& X# J; l0 N
serum testosterone level. There also is other evidence of local
5 s. S' s0 S9 |response to testosterone with hair growth and with spermato-2 j) N! L/ ]* t$ U5 v4 [
genesis. 5• 6
, v* W# {' U! ~' h+ RAdministration of larger doses of gonadotropin or systemic
- ^. @$ Z3 [1 _testosterone, as well as topical applications that produce
1 o% a8 i- I9 R- uhigher levels of serum testosterone (150 to 900 ng./dl.), will, c% B, \- x% W$ y" t1 l3 S2 V" F% L
also produce phallic growth but risks accelerated skeletal
$ X0 R/ `* _& S% Qmaturation even after stopping treatment. It would appear j4 d; S" y. A
that this may be avoided by topical applications of testosterone
0 d6 C4 c8 U+ Y' Eand monitoring of serum testosterone. Even with this control2 r1 P# c6 s0 @) ^+ u) c5 X
the duration of our therapy did not exceed 3 weeks at any& P \: G- e Y5 _' [0 D
time. It is apparent that the prepuberal male subject may
S6 |( L( e. e7 Tsuffer accelerated bone growth with testosterone levels near
S, ?5 ~) |; q M R7 I200 ng./dl. When skeletal maturation is complete the level of5 A% |. u: K4 f) s2 u2 _
serum testosterone can be maintained in the 700 to 1,300 ng./
7 g2 E9 {2 Y' G. p. K. F" b0 ndl. range to stimulate phallic growth and secondary sexual
& S# v6 w4 L- j4 K) Qchanges. Therefore, after skeletal maturation parenteral tes-
* A0 c9 f. C# xtosterone may be used to advantage. Before skeletal matura-' t6 @/ {+ y+ k$ f: S! [! |
tion care must be taken to avoid maintaining levels of serum7 P; c; ~/ p& A3 d& H' D6 q
testosterone more than 100 ng./dl. Low-dose gonadotropin
% `& f' b. \" v7 Wdepends upon intrinsic testicular activity and may require
6 B8 t! N/ a) e* k! y" K8 z Zprolonged administration for any response.
3 v* q) X" n& a( s$ KAlternately, topical testosterone does not depend upon tes-1 E9 R; [' w7 W" C' u9 @3 l
ticular function and may provide a more constant level of
Y5 o9 l* I0 o/ n+ lREFERENCES
% Y& V6 V/ E* B4 m& p5 D1 }4 f0 k1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,5 x' e/ S+ o$ b4 m: y; ^/ h, t: D
R.: The local application of testosterone cream to the prepub-# G( ^8 X+ Y+ d: p+ O- ^* v3 S) k
ertal phallus. J. Urol., 105: 905, 1971.
: e: e1 w7 j6 A( E; F- B2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
3 r \% Y3 @5 c0 `! F2 d/ l7 E( v! Y+ ctreatment for micropenis during early childhood. J. Pediat.,7 B# D% `, O* @1 D8 D+ @6 N" a7 W
83: 247, 1973.5 Z1 u! x& T, m* W& g: ^! F" y$ P# p
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
; q2 J' B5 l8 f- `# R, ?one therapy for penile growth. Urology, 6: 708, 1975.3 x; O( m2 B# C% x
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone; ^; k) b5 Y& J p1 P
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by- s9 P1 v$ f/ |4 }7 k; }8 @
skin slices of man. J. Clin. Invest., 48: 371, 1969.
: M l+ [6 R( V& H0 D5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
) G' J( |9 u& P" O2 Dby topical application of androgens. J.A.M.A., 191: 521, 1965.0 _6 i' w; w+ |, m& B: s6 u
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
8 \* y( x# f9 C; e* H" w7 t" u7 uandrogenic effect of interstitial cell tumor of the testis. J.
5 v3 P% G7 A# j# s+ O+ R+ R1 NUrol., 104: 774, 1970.
& w. N8 x6 h* o; I) o7 P8 \5 S0 j |7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
* `! p* J& b! T/ o- o# ktion in the male genitalia from birth to maturity. J. Urol., 48: |
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