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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
4 s8 t5 F  m" m: r+ nGONADOTROPIN
/ i* T1 k7 I/ o4 E" jRICHARD C. KLUGO* AND JOSEPH C. CERNY
/ q4 m% o, K, B9 {8 gFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
5 }% p, c1 U! o6 f* o& CABSTRACT  I% o- l& J$ D& L: P# Z8 H& E4 d9 q
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
8 a2 U" i9 a1 m# e. }& U; Jwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
3 H1 ?0 Q, g( X9 p: Ftropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
! c7 e/ V7 ~) c) M; S: @  Ecream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
$ Z! b% }8 W- p5 \% E( e$ q; Kfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
7 n, o& G" e6 Uincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
2 b. ?; I. H0 i% D" B( hincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
0 Y: z' X* u- c3 Qoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This$ d0 n2 }, j& c
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile* i9 k/ M2 I! p2 R2 f$ f
growth. The response appears to be greater in younger children, which is consistent with previ-: j  z; Z( H2 g# G4 B; |7 w
ously published studies of age-related 5 reductase activity.- e% ]* m% z1 `
Children with microphallus regardless of its etiology will
9 q. |/ U. U/ b4 Prequire augmentation or consideration for alteration of exter-' T5 s  m5 j1 e( L+ f! ~& M4 J
nal genitalia. In many instances urethroplasty for hypo-1 A/ `( ?( D/ t- `6 F7 E& \
spadias is easier with previous stimulation of phallic growth.
" ?7 N5 W. ]0 w7 V$ Q: x( {: [The use of testosterone administered parenterally or topically6 ~" l+ E; V! A; t* ^4 U
has produced effective phallic growth. 1- 3 The mechanism of
, v. G' S' x+ M9 P2 Zresponse has been considered as local or systemic. With this
; U' [" X9 V) v1 G/ Ain mind we studied 5 children with microphallus for response
+ K& q& P- \2 g& w0 h7 }to gonadotropin and to topical testosterone independently.$ d  B7 l0 o; V
MATERIALS AND METHODS
; O" v- p# z6 \* o8 `8 ?& j+ sFive 46 XY male subjects between 3 and 17 years old were+ `; U6 o/ O" x- k- q: H6 B% k, K
evaluated for serum testosterone levels and hypothalamic
" V9 [: V9 S( e6 O6 R  m5 F7 Y- ufunction. Of these 5 boys 2 were considered to have Kallmann's0 h2 e& B6 @0 u9 ~2 _
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-0 I6 h, s9 u% B9 F! _- A% O
lamic deficiency. After evaluation of response to luteinizing
3 y5 {, V" H8 v7 V" j' w5 h3 T( shormone-releasing hormone these patients were treated with
9 `& s/ s) A2 ?, H8 J* }4 G1,000 units of gonadotropin weekly for 3 weeks. Six weeks
1 l  p6 P# a9 p* n7 V& Nafter completion of gonadotropin therapy 10 per cent topical' r/ M& Q4 p$ z, g' _; f( X
testosterone was applied to the phallus twice daily for 3 weeks.
4 Y0 }& l2 n, k/ rSerum testosterone, luteinizing hormone and follicle-stimulat-
& _* N8 k6 |& Q3 v7 `0 King hormone were monitored before, during and after comple-
4 E  v5 i  e1 v; R: v: ption of each phase of therapy. Penile stretch length was" \, N- w+ l% Z: j
obtained by measuring from the symphysis pubis to the tip of
& ?! y& f$ e- }2 U0 J) _the glans. Penile circumferential (girth) measurements were. u% M! w! s5 E- p# u- L9 C
obtained using an orthopedic digital measuring device (see
" A5 ^& K! |% T/ @figure).3 K% a; {& ~1 q3 D- W4 j1 z# |  U
RESULTS$ }% F3 m& h9 ]; d( O) J. V5 a
Serum testosterone increased moderately to levels between4 N# \  e/ q7 o4 v" v" B- G
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
0 b1 i4 z  Y9 _- m% d* X5 ]terone levels with topical testosterone remained near pre-7 |0 P7 G5 W: p1 ~' x0 V
treatment levels (35 ng./dl.) or were elevated to similar levels
* C1 o" G# }3 x1 ideveloped after gonadotropin therapy (96 ng./dl.). Higher
5 x8 f2 L* j8 b5 z* userum levels were noted in older patients (12 and 17 years old),
2 b) n; D; h( Y- k. j0 i) X  jwhile lower levels persisted in younger patients (4, 8, and 10; e. i% W) ?' Q
years old) (see table). Despite absence of profound alterations1 `: ?! `" X7 E9 f) w% K( {
of serum testosterone the topical therapy provided a greater2 [% `5 b/ @9 b$ y3 l
Accepted for publication July 1, 1977. ·
7 K9 _5 |( P5 K$ E- k8 FRead at annual meeting of American Urological Association,
& o. z- f$ [# u5 r* ZChicago, Illinois, April 24-28, 1977.
" @6 q; L# z- A1 _# N: ^* Requests for reprints: Division of Urology, Henry Ford Hospital,
+ E: p& q3 S6 ?1 v& ~( M  M2799 W. Grand Blvd., Detroit, Michigan 48202.# |3 }) m; z; n! C$ B
improvement in phallic growth compared to gonadotropin.
& D1 w* Z. x5 L2 y7 HAverage phallic growth with gonadotropin was 14.3 per cent$ r7 k3 q& r" Z7 r/ x& J  U; U; `/ X
increase in length and 5.0 per cent increase of girth. Topical
8 r% \% l& |: p; P( T. c  }/ o7 J0 Qtestosterone produced a 60.0 per cent increase of phallic length
( x4 G7 y0 E' n% O# X5 s" iand 52.9 per cent increase of girth (circumference). The- w- n* L3 j( H
response to topical testosterone was greatest in children be-! k& j# T) @3 J. C
tween 4 and 8 years old, with a gradual decrease to age 17
3 F! I/ A* P! ?% w0 }: p! T9 Lyears (see table).0 X5 u6 u% g/ R5 a+ g
DISCUSSION$ x  Y. r# n& U
Topical testosterone has been used effectively by other
* c  E, L. u+ E1 i# ?' {+ bclinicians but its mode of action remains controversial. Im-
: z2 h. L: B: fmergut and associates reported an excellent growth response
& a8 t1 a8 D' xto topical testosterone with low levels of serum testosterone,! F: A, o* v4 E1 u% U% Q
suggesting a local effect.1 Others have obtained growth re-
! ]$ p( w, m8 _8 A0 g& \sponse with high. levels of serum testosterone after topical
5 e3 m" q) J1 b  Qadministration, suggesting a systemic response. 3 The use of* X1 t% [- T1 r5 r# N" ~) _
gonadotropin to obtain levels of serum testosterone compara-- R) G2 v' W* j& c# Y
ble to levels obtained with topical testosterone would seem to
7 X; ^& a. }$ C9 f3 q& {provide a means to compare the relative effectiveness of0 q. @# N- M  {/ ~8 Q
topical testosterone to systemic testosterone effect. It cer-. S& G; m9 }( `7 q5 i" X+ O
tainly has been established that gonadotropin as well as par-
) P5 ~7 I% m+ b. eenteral testosterone administration will produce genital/ E5 u4 N, m1 ^1 ~/ {: M
growth. Our report shows that the growth of the phallus was
& M' V2 b' ^2 Rsignificantly greater with topical applications than with go-& [& }2 @0 Z' F# M/ _/ y
nadotropin, particularly in children less than 10 years old.9 j. S# v. Q# P4 X2 Z! q& j* j' ^
The levels of serum testosterone remained similar or lower! i: y+ ^3 v* i6 z
than with gonadotropin during therapy, suggesting that topi-$ e* e2 K; M8 G3 u$ r
cal application produces genital growth by its local effect as
" X8 T/ C/ A: Q: f- n6 K* p. C; Z' Wwell as its systemic effect.
$ `! _2 U  v# \* m8 y. M+ B* j8 R3 LReview of our patients and their growth response related to3 q$ [5 s3 B8 k+ B9 u4 K  A+ ~$ d
age shows a greater growth response at an earlier age. This is
/ L7 q8 }9 ]8 o) W3 mconsistent with the findings of Wilson and Walker, who
! r  V2 E/ Y( }. w7 n( Ereported an increased conversion of testosterone to dihydrotes-
2 u& y6 X+ c6 |4 Ttosterone in the foreskin of neonates and infants.4 This activ-
$ b- P4 b' C1 L+ V' R2 H3 ~ity gradually decreases with age until puberty when it ap-
8 C7 N1 q6 a# [proaches the same level of activity as peripheral skin. It may8 c) s" U8 L( o) C
well be that absorption of testosterone is less when applied at) Z9 Y) y- s% L* E
an earlier age as suggested by lower serum levels in children
$ d$ {: }8 J' B% O0 U6 \less than 10 years old. This fact may be explained by the' V0 A2 b) m  N* P
greater ability of phallic skin to convert testosterone to dihy-
" @* @6 M) }: Ydrotestosterone at this age. Conversely, serum levels in older9 Q# v6 Q' x3 S  x
patients were higher, possibly because of decreased local$ D# c. ~1 Q+ Z0 `( Y8 p& w+ c
6671 A* e# `0 |9 M/ ?5 N' `
668 KLUGO AND CERNY
9 T. G$ \0 M/ _% |7 @! ~Pt. Age# l6 t  [; L. J+ P' q! b) V' D
(yrs.): q6 I1 U1 B& E" Q1 z
Serum Testosterone Phallus (cm.) Change Length
, c1 P  Z5 R! [# j" {(ng./dl.) Girth x Length (%)4 M4 w% X7 u, m* w, z
4
4 T6 f3 n2 u& p. O9 D8
7 t  q6 }3 ^/ _6 Q) C2 Y/ `$ X10  {, k/ L1 `% @7 z; ^
12; t4 d, g$ F2 C. G/ v$ Q
17: N- G  [# G0 c$ S- |: _' E3 ^
Gonadotropin4 ]" V  }6 m+ {. U5 _$ g
71.6 2.0 X 3 16.6
* d, `, V$ t  f% ^  t0 }+ w/ D50.4 4.0 X 5.0 20.0- n" Q; A  y4 a7 A
22.0 4.5 X 4.0 25.0
; Y, E9 W! K7 x- r, A- ]84.6 4.0 X 4.5 11.1
3 [! E  B# R' `* m& P' l9 w% L85.9 4.5 X 5.5 9.0: \- {4 Y, s6 d& h' m: K& m. u7 X
Av. 14.3
4 d; X% |! a$ G/ T* T  G4
  j( {% b3 {( }4 F* W& ^0 f5 B1 m8& B) w; V6 G& F0 E0 w  K7 L
10
& v/ X+ c, ^- r12
; |  I# D6 N3 ~$ f# b( ^. b# ^5 x17
( y! l. J' y. [) t2 R2 y& R7 l- kTopical testosterone- ^4 S) s5 I5 D) ^2 d
34.6 4.5 X 6.5 850 ]6 e# \. Y0 m) V8 d
38.8 6.0 X 8.5 70% M0 h: e* I. n% e# U8 T" o8 j
40.0 6.0 X 6.5 62.5
: d8 }! ]) V, p/ ]0 S: M93.6 6.0 X 7.0 55.5
1 L& O4 N8 r5 P0 A" y95.0 6.5 X 7.0 27.2
* T4 B) r# A" Z& C: V/ KAv. 60.0
: D8 l- W& i) r# m  p7 Y9 T! @, mavailable testosterone. Again, emphasis should be placed on# R2 r4 J2 Y2 l- N: T
early therapy when lower levels of testosterone appear to$ F3 }3 A- A, O, R' C$ g  q! x
provide the best responses. The earlier therapy is instituted
6 ]7 i8 R& f  m4 @% c' h% {  Tthe more likely there will be an excellent response with low: ?! D/ {9 U' ]
serum levels. Response occurs throughout adolescence as, `8 r; {# N) j2 g7 ~
noted in nomograms of phallic growth. 7 The actual response. H1 g) t- y: E  S3 q
to a given serum level of testosterone is much greater at birth
' F6 P5 m0 V3 h& U) ]- k5 Eand gradually decreases as boys reach puberty. This is most; h1 J+ b3 _2 T8 J8 [, E# J
likely related to the conversion of testosterone to dihydrotes-
+ t- d' s3 m8 s9 b, A; J) ]3 Mtosterone and correlates well with the studies of testosterone
5 s/ \8 w' K! k+ Uconversion in foreskin at various ages.
: f; F5 m$ r! C3 C( H$ O( B- NThe question arises regarding early treatment as to whether& j4 L$ g8 R: H
one might sacrifice ultimate potential growth as with acceler-
6 B2 s$ f- K( \( Aated bone growth. The situation appears quite the reverse
" `; _! X" a: i8 swith phallic response. If the early growth period is not used
+ w9 ?1 W& I, _8 U2 s: Swhen 5a reductase activity is greatest then potential growth
' j0 t' ?" E1 w$ g6 tmay be lost. We have not observed any regression of growth
1 r, U$ b2 H- c; T4 g' battained with topical or gonadotropin therapy. It may well
- Z# r) U( Q, Y1 ]3 L. @. m* Kbe that some patients will show little or no response to any
* j/ T. d% a/ F* Aform of therapy. This would suggest a defect in the ability to) l+ B4 ~5 f  a; y+ _
convert testosterone to dihydrotestosterone and indicate that! W8 N$ V! W! Y* w4 T( u
phallic and peripheral skin, and subcutaneous tissue should+ q8 N+ Y- |7 a1 Q: L& H
be compared for 5a reductase activity.
& Q2 g5 p) Y) `7 H! zA, loop enlarges to measure penile girth in millimeters. B,& r: D2 P3 K9 d6 R% i# k
example of penile girth computed easily and accurately.
. \, M7 i: M; {conversion of testosterone to dihydrotestosterone. It is in this
0 C( m) ^" x0 D, A; N! Tolder group that others have noted high levels of serum
3 R: Z" F9 ~: m& I' utestosterone with topical application. It would also appear
) G  s& U% W+ u4 ?% Bthat phallic response during puberty is related directly to the
. K1 }6 P1 [, x: N7 Gserum testosterone level. There also is other evidence of local
3 \) H% }5 ~# L; g- l6 t0 oresponse to testosterone with hair growth and with spermato-. \3 `! E) F! x* u) o3 V
genesis. 5• 6: H, x5 p# g4 L
Administration of larger doses of gonadotropin or systemic
& i& S) q0 g2 h) jtestosterone, as well as topical applications that produce1 }$ l: C* N# B+ r% v, c
higher levels of serum testosterone (150 to 900 ng./dl.), will0 b9 R0 G6 |# n4 F( m9 d
also produce phallic growth but risks accelerated skeletal
2 A' m) R2 p5 o" E3 ~+ T: L- Umaturation even after stopping treatment. It would appear# o6 r9 y+ A1 c2 p4 W/ f
that this may be avoided by topical applications of testosterone( d; X5 E* p: ]1 w$ n" D# k
and monitoring of serum testosterone. Even with this control8 n- B: f$ y$ f" \) L
the duration of our therapy did not exceed 3 weeks at any
3 E. T5 r* N4 ?' B( vtime. It is apparent that the prepuberal male subject may
% R5 H9 t! ^+ G, B5 {# usuffer accelerated bone growth with testosterone levels near+ c/ ~8 e2 W( D
200 ng./dl. When skeletal maturation is complete the level of
# O+ ]5 _& O# E- j" G1 Zserum testosterone can be maintained in the 700 to 1,300 ng./0 B9 O2 `+ u; H) e
dl. range to stimulate phallic growth and secondary sexual
( f: l# u( o: Z: achanges. Therefore, after skeletal maturation parenteral tes-
3 o% }7 j/ \, T& `+ ~% c2 ptosterone may be used to advantage. Before skeletal matura-
% p$ c: H7 m7 e/ Q8 f5 x: b2 ]tion care must be taken to avoid maintaining levels of serum
8 P& o+ b- K8 q8 etestosterone more than 100 ng./dl. Low-dose gonadotropin
- r6 B' M" t1 j' Gdepends upon intrinsic testicular activity and may require
$ @& q: C! {" B, u6 ^3 I8 Fprolonged administration for any response.
8 I3 g# Y2 s7 k9 ^Alternately, topical testosterone does not depend upon tes-
7 ^  @! M# P2 ?# Eticular function and may provide a more constant level of' S% a' T# @, ^" |. t
REFERENCES  n  f7 u) v) C- b' W: t: N$ V
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
: a6 V  j5 S. V3 e4 E$ t+ lR.: The local application of testosterone cream to the prepub-: ~& W' k# M2 v, a2 j
ertal phallus. J. Urol., 105: 905, 1971.7 N4 ^4 J. t- ?& w3 @! ^
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone# M+ _4 L: d$ U/ e& c
treatment for micropenis during early childhood. J. Pediat.,
9 l. @+ W+ o1 ^8 q. z1 D: x+ z5 _4 z% \83: 247, 1973.# f3 g5 A1 Z4 x: @( g* V
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
4 Y' Z( s7 W/ ~( {1 n" ?( ]7 M: bone therapy for penile growth. Urology, 6: 708, 1975.+ u  ^0 n+ I/ B- ^) e. i
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
6 \" B& \; S& d3 d. H6 [1 q1 E; Nto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
% g9 O0 S4 [0 X" P6 d/ G2 sskin slices of man. J. Clin. Invest., 48: 371, 1969.
$ ~. O1 `7 w3 u% @, D5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth/ |- i4 N  e$ \  A# b* c0 N6 u( v
by topical application of androgens. J.A.M.A., 191: 521, 1965.
; r9 ?: C) t; e) N+ s6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
2 @& p+ V3 e6 G1 R. i. [androgenic effect of interstitial cell tumor of the testis. J.- P; g$ P  f' @
Urol., 104: 774, 1970.
- K7 {$ o; m1 _7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
' n, F" r0 {2 E' m5 R/ ftion in the male genitalia from birth to maturity. J. Urol., 48:
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