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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND) ]# _" @9 j3 T0 f; }
GONADOTROPIN
9 p- F3 M' `, e) `/ I6 CRICHARD C. KLUGO* AND JOSEPH C. CERNY5 p% t. W+ z+ S
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan" M# E* p8 S7 ?' W1 R" |! g
ABSTRACT
* g; t* P/ G; |Five patients were treated with gonadotropin and topical testosterone for micropenis associated
: G# [# t) u; Q1 m! [9 d" v& x  Qwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
3 u% B; j# C) l: s& w4 ]tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone7 k3 f# @. L6 A( B3 ?+ x
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
& t7 K/ j. A' s. e8 Vfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
7 L/ q4 V! i$ d/ Fincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average, p5 ]- J7 u2 |
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
  L+ z) R9 G7 J- ooccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This4 R/ K; ]# b5 Q: T$ k
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
$ _& p6 a) c0 G8 U& t! mgrowth. The response appears to be greater in younger children, which is consistent with previ-6 J4 n7 Z; ^& a' M
ously published studies of age-related 5 reductase activity.
/ _1 M. ^# x$ f' M8 D9 h1 X; |5 kChildren with microphallus regardless of its etiology will
& v, I- r/ z" q' u# Wrequire augmentation or consideration for alteration of exter-3 x" R* x4 }7 k/ T9 s9 K/ M3 \) {
nal genitalia. In many instances urethroplasty for hypo-3 z0 ^7 a. ]: u
spadias is easier with previous stimulation of phallic growth.& v# a! Y& n, U- S; a# Z
The use of testosterone administered parenterally or topically
( S: N9 x# B% `; L* Ohas produced effective phallic growth. 1- 3 The mechanism of
9 E% V* A3 ?8 U" v) Z$ cresponse has been considered as local or systemic. With this1 O9 L/ |  |$ U; h; |. b& I
in mind we studied 5 children with microphallus for response6 h4 Q- Z, S8 e: k
to gonadotropin and to topical testosterone independently.9 V1 r. e! O; k
MATERIALS AND METHODS
( X0 B( d+ M+ Q& l, UFive 46 XY male subjects between 3 and 17 years old were
, ?# {6 l- [* v5 v+ _6 u. C% Qevaluated for serum testosterone levels and hypothalamic
, N7 h4 m: q6 ?( p1 mfunction. Of these 5 boys 2 were considered to have Kallmann's7 a: ?2 ?3 c& F: Y7 c: P9 v* s( [4 }
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-" @$ R  X3 _2 }0 _: B/ M
lamic deficiency. After evaluation of response to luteinizing% k  F+ s2 K4 H  {
hormone-releasing hormone these patients were treated with+ t; f/ x! u9 a: D% v+ U+ j. p
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
2 r, s) w0 h/ k) J* V# Zafter completion of gonadotropin therapy 10 per cent topical3 \8 n) E* c8 r9 Q
testosterone was applied to the phallus twice daily for 3 weeks.
6 \. \& z& I( J4 _  y6 ySerum testosterone, luteinizing hormone and follicle-stimulat-- {4 |2 ^) Z9 G2 I9 j/ U3 ]8 f: K5 V% N
ing hormone were monitored before, during and after comple-
! j' m7 v1 I" D, t: k2 Wtion of each phase of therapy. Penile stretch length was
5 {- [, a2 l3 m# [obtained by measuring from the symphysis pubis to the tip of1 i; J& n% `5 E# _' p( p
the glans. Penile circumferential (girth) measurements were
$ e! t: r; {  g" Yobtained using an orthopedic digital measuring device (see
* I6 P4 d6 c. \* D. Q5 A% ?) j! ~figure).( Q9 n+ w- y4 t' y+ }3 w
RESULTS' I* A! O6 V6 A. J; {
Serum testosterone increased moderately to levels between
0 Q' o$ o% s8 g  E50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
3 h5 R9 C; n$ u9 Cterone levels with topical testosterone remained near pre-
- m# t) m& H# ]: k' `& S$ C0 Mtreatment levels (35 ng./dl.) or were elevated to similar levels
6 `( Q2 F1 N& r6 c, ?developed after gonadotropin therapy (96 ng./dl.). Higher( s% v. x. n1 ]9 q# {0 T  G& Y  _
serum levels were noted in older patients (12 and 17 years old),  r2 P! O: a, `0 A
while lower levels persisted in younger patients (4, 8, and 10
, b1 H& _. R4 r2 @years old) (see table). Despite absence of profound alterations! d. G6 ]  t  U$ d3 O5 G; C6 V
of serum testosterone the topical therapy provided a greater5 j  V! j- h! U$ l% t& t
Accepted for publication July 1, 1977. ·' {; k9 L; r- u7 G
Read at annual meeting of American Urological Association,9 K( z& b( L: f0 c  u' I0 D
Chicago, Illinois, April 24-28, 1977.6 W6 M/ u6 j5 B. j5 c/ M" F. v% b
* Requests for reprints: Division of Urology, Henry Ford Hospital,
2 T3 a, u! M. ~) }9 W2799 W. Grand Blvd., Detroit, Michigan 48202.: D% q* G9 }3 s- ]$ U
improvement in phallic growth compared to gonadotropin.
' j, Q* o/ E9 u3 Q0 Y9 mAverage phallic growth with gonadotropin was 14.3 per cent
8 T# M" v5 h! Y6 Q8 }increase in length and 5.0 per cent increase of girth. Topical
( @. i# Q# y& [8 l: a, h& c' ^testosterone produced a 60.0 per cent increase of phallic length' W) S% M$ D3 ^7 v: [/ Q1 U
and 52.9 per cent increase of girth (circumference). The9 @; @! W* \- e
response to topical testosterone was greatest in children be-# ~. G! Q  G+ F( l7 x" I, @* d, U3 N
tween 4 and 8 years old, with a gradual decrease to age 17, H* c  m1 i% J# O" N
years (see table).3 g0 z0 w9 B2 |
DISCUSSION
8 R1 v9 P- B' \; k3 o" t" b  GTopical testosterone has been used effectively by other( H; K2 P8 |8 x% j
clinicians but its mode of action remains controversial. Im-+ ?1 z: |6 u6 A
mergut and associates reported an excellent growth response; N- |. a8 {* ]5 \# Q
to topical testosterone with low levels of serum testosterone,
( N  A" A3 \  gsuggesting a local effect.1 Others have obtained growth re-; q) k' L. M' @, `3 Z& f
sponse with high. levels of serum testosterone after topical
7 d$ \- h* _; Q- G, Iadministration, suggesting a systemic response. 3 The use of: c) s1 u, S: C1 B5 B5 Q
gonadotropin to obtain levels of serum testosterone compara-
7 b6 U% E% y9 k/ R/ J, }' p# J) Jble to levels obtained with topical testosterone would seem to% \; X1 z) ^2 j7 P4 L+ W, ]
provide a means to compare the relative effectiveness of
$ e0 ~8 r1 u6 q2 E, [topical testosterone to systemic testosterone effect. It cer-7 @  x) g1 q0 e( R1 D& v# b
tainly has been established that gonadotropin as well as par-  m# Z8 d7 O( W, b# B& R' S8 |
enteral testosterone administration will produce genital
2 ~' U$ x- S9 N) Lgrowth. Our report shows that the growth of the phallus was; {2 {9 V/ a4 V% ]4 H
significantly greater with topical applications than with go-
* s2 v; z1 R% g; Wnadotropin, particularly in children less than 10 years old.
. K0 K$ i* v" n: eThe levels of serum testosterone remained similar or lower2 x- W: j& @& M: |3 l
than with gonadotropin during therapy, suggesting that topi-
! W5 i. b/ z- S2 ^0 K1 `  acal application produces genital growth by its local effect as
# z( K! h# O* Rwell as its systemic effect.) \( b& d  L4 ~' C
Review of our patients and their growth response related to1 x% |" ~; F! g) V
age shows a greater growth response at an earlier age. This is' G7 U# o0 P! r1 }
consistent with the findings of Wilson and Walker, who
* R  [; M& I$ t' s. X" U/ e0 xreported an increased conversion of testosterone to dihydrotes-
& Q# H( l( }. A+ U; ptosterone in the foreskin of neonates and infants.4 This activ-6 l8 D9 V" k4 u: }3 }2 s: \& o
ity gradually decreases with age until puberty when it ap-* C7 f- j7 k" t
proaches the same level of activity as peripheral skin. It may
+ d4 P' m! Q# |- p( I5 b: }' `well be that absorption of testosterone is less when applied at
# U0 N- ]1 K' n) w' N! z3 ]" z* qan earlier age as suggested by lower serum levels in children
2 y8 {( W! c' o! V# fless than 10 years old. This fact may be explained by the# e9 S1 Q( t' I' t& V" Y) I
greater ability of phallic skin to convert testosterone to dihy-
$ F( v' j/ ^* Z1 g( Jdrotestosterone at this age. Conversely, serum levels in older+ ?7 i2 T' j& I7 T' `% @& H
patients were higher, possibly because of decreased local
- f. ]- O5 |8 w" ]: K& i667: s: w) S7 j; q7 ?$ t* h* g
668 KLUGO AND CERNY7 d# U* X" Z# N6 j) H
Pt. Age
( k0 D5 c) _8 z" ^1 O(yrs.)& M6 b( |2 v3 X' e+ h
Serum Testosterone Phallus (cm.) Change Length, S+ L( m+ F7 O% @- {- N
(ng./dl.) Girth x Length (%)
, G) C/ O" S/ t, L/ @48 i& R  \9 |1 |$ ?
8
$ Y: \" m- O1 G! `9 y: O10& \" I  k9 K; R* m
120 i: @1 c& h; f( H
17' Z- J4 F& J% L+ w5 F
Gonadotropin1 ~+ K: G- f. ^! [
71.6 2.0 X 3 16.66 L% n+ G8 ^7 O% K
50.4 4.0 X 5.0 20.0" E; L' U8 I* e" j" Y
22.0 4.5 X 4.0 25.05 h7 t  i* B1 }1 ?+ {
84.6 4.0 X 4.5 11.1
; _2 V2 |: i7 N: K* s6 Z% {85.9 4.5 X 5.5 9.0( u0 l& e4 V9 x! R
Av. 14.38 Z# |1 U9 e3 a$ F6 G
4# j0 P2 J9 b6 ?7 P; u. `" K4 M
8- o$ b+ o  z) }% q9 n; }' P" T% j
10
; C" \' E8 l+ x  g) T) U% l125 a, E0 [" ]; X
17/ j" W1 o0 x# _% X2 `* F' ]
Topical testosterone
' H9 F; w2 r1 g* _34.6 4.5 X 6.5 853 D& ?! x! U  _& j6 ^$ V$ _
38.8 6.0 X 8.5 70; ]& P  ?. u1 o5 P. {
40.0 6.0 X 6.5 62.5
0 V# x- N, {! a  I93.6 6.0 X 7.0 55.5
9 l. p/ t" ?' `95.0 6.5 X 7.0 27.2
: h3 a5 u' Y. z3 }; Z, S0 a& ZAv. 60.02 J1 @: @5 a+ C% m5 z. J
available testosterone. Again, emphasis should be placed on+ }; J( p  d3 `% {; i
early therapy when lower levels of testosterone appear to
& D, P- B1 d! t' c! V2 q& i& ~  eprovide the best responses. The earlier therapy is instituted
2 Q; i1 u; Z! L: F: L2 G+ X7 Z  _the more likely there will be an excellent response with low- P% b) E- d" M1 n) u# ?
serum levels. Response occurs throughout adolescence as
( O3 E$ g. J- w9 j  Cnoted in nomograms of phallic growth. 7 The actual response' I' A) T% r& `* ^/ v3 l5 ]" s
to a given serum level of testosterone is much greater at birth, I  \6 V( w- t) \4 q
and gradually decreases as boys reach puberty. This is most
+ e# c) T4 A- D* z4 [2 flikely related to the conversion of testosterone to dihydrotes-* I2 o$ v- q. N8 v% X; B9 w( t0 [* n
tosterone and correlates well with the studies of testosterone
# U  q, b* c- _/ O2 yconversion in foreskin at various ages.- B& Q2 n+ u  s9 @1 h) ?# f
The question arises regarding early treatment as to whether. n8 q6 K5 Z2 {8 U
one might sacrifice ultimate potential growth as with acceler-
6 m+ ^6 l0 d( `3 Qated bone growth. The situation appears quite the reverse' _  o* {% j7 r, |" t8 ~
with phallic response. If the early growth period is not used: u5 W: a/ o2 s  ^
when 5a reductase activity is greatest then potential growth/ p3 V8 @0 T2 \  C2 C
may be lost. We have not observed any regression of growth! b4 S+ o, r6 ]9 ~
attained with topical or gonadotropin therapy. It may well7 _. [' J" |' z2 J4 E0 [9 O
be that some patients will show little or no response to any! ?  Z, g, F# C( Q% Q/ {
form of therapy. This would suggest a defect in the ability to
2 G+ q; P, _4 J, H# M5 p, ]# W, Bconvert testosterone to dihydrotestosterone and indicate that/ J( u8 T& }$ @7 V- n5 l% V, g1 D
phallic and peripheral skin, and subcutaneous tissue should+ d/ G# i) [" P8 L" d* D
be compared for 5a reductase activity.
( F. Q5 z: d" z) KA, loop enlarges to measure penile girth in millimeters. B,
, {7 O& E, ~1 c9 W; M- ]' ^7 W8 Xexample of penile girth computed easily and accurately.% e. e. H8 S4 r8 b5 M8 F6 u- R
conversion of testosterone to dihydrotestosterone. It is in this- Y5 b  o- C4 }0 e, }
older group that others have noted high levels of serum
  P# W, Q$ r5 o0 ~- Itestosterone with topical application. It would also appear( ?5 `0 Y, N& _  _# F) J% V
that phallic response during puberty is related directly to the2 l, L# ~6 z; [  p! c0 t7 ~% F; q
serum testosterone level. There also is other evidence of local
4 E2 ?$ d% i% tresponse to testosterone with hair growth and with spermato-1 i+ D1 O$ }' D+ D, T1 q! {0 [+ L
genesis. 5• 6
6 A2 E/ ]0 U9 X+ r. ^4 j  ZAdministration of larger doses of gonadotropin or systemic
0 E  Q. {2 K% f) g) p9 i6 D& Ntestosterone, as well as topical applications that produce. j# ]6 V# F: S$ C; b) n1 s& R
higher levels of serum testosterone (150 to 900 ng./dl.), will9 k2 Q* T5 }1 `, u' N5 K
also produce phallic growth but risks accelerated skeletal
( P+ D% _% I- _  ^$ vmaturation even after stopping treatment. It would appear. g. t. ]7 o7 c% N
that this may be avoided by topical applications of testosterone
' d6 C- i. P0 [and monitoring of serum testosterone. Even with this control8 b' t# Z' i6 n" R' t7 r6 v7 [4 }" d
the duration of our therapy did not exceed 3 weeks at any
" \/ F$ `- f- q% V6 i- Y6 F( v7 k* Ytime. It is apparent that the prepuberal male subject may
0 m, ?4 p7 |, M2 T2 q; Wsuffer accelerated bone growth with testosterone levels near0 c5 G, N; E1 g, T
200 ng./dl. When skeletal maturation is complete the level of
* g! p. \  k/ i; Y* E1 Nserum testosterone can be maintained in the 700 to 1,300 ng./
. h- X7 W6 X$ ldl. range to stimulate phallic growth and secondary sexual
) a- a5 V% B) q6 Uchanges. Therefore, after skeletal maturation parenteral tes-
6 }1 e: C$ l: X' A. L  l* w! c# gtosterone may be used to advantage. Before skeletal matura-, R. E6 ~- I: A% d2 d
tion care must be taken to avoid maintaining levels of serum
+ O" r' @) O4 Ltestosterone more than 100 ng./dl. Low-dose gonadotropin+ t# l# r: U. c0 G
depends upon intrinsic testicular activity and may require
- E9 S9 l9 H1 T8 W+ a; ?( W+ aprolonged administration for any response.
& ~+ F/ x, f2 d5 ~Alternately, topical testosterone does not depend upon tes-
9 M. Z! l2 u6 m: r3 bticular function and may provide a more constant level of; y. M2 x. `! N6 m3 p7 i
REFERENCES
3 a% R- U7 q7 c7 U2 P# Y1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,$ h" S( ~: q) Q( @: c1 A+ f
R.: The local application of testosterone cream to the prepub-
+ T; q0 k/ x+ V* V& M& tertal phallus. J. Urol., 105: 905, 1971.' f$ ?( t3 g4 [9 }& g- G" u; e
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone  T5 `% i6 U4 [+ Q5 s6 Z3 }
treatment for micropenis during early childhood. J. Pediat.,
: U. x; z" v3 y8 \" ]! d83: 247, 1973.& U4 i4 U  ^' K- U; r, |2 Z4 T( ^2 j
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
' |; D3 |$ H6 `, K& C0 A9 ?6 ~one therapy for penile growth. Urology, 6: 708, 1975.' E' v4 H$ n# B7 H
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone+ _& h! R+ o& w. B# c
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
" }/ f; S9 {  s- X" {/ p8 Mskin slices of man. J. Clin. Invest., 48: 371, 1969.3 N. Y" Y# i" a( m5 l8 `! B
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth7 M# j8 y& N2 X2 T7 V
by topical application of androgens. J.A.M.A., 191: 521, 1965.1 G6 h  _& y/ b3 O
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local) ?2 w* N+ `- u2 k& T) b
androgenic effect of interstitial cell tumor of the testis. J.+ W' R; K9 ]1 n% H% k" n
Urol., 104: 774, 1970.; b8 ?/ ?2 i8 X, S9 a: r( F( C! f& o
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-9 U  k. m  X" i
tion in the male genitalia from birth to maturity. J. Urol., 48:
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