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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
9 U2 e. |; u& j0 Y, L8 ~  r) \, dGONADOTROPIN* @8 H* i: ]' }+ `. c* Q
RICHARD C. KLUGO* AND JOSEPH C. CERNY
, u. W1 ^$ }: G: l8 k7 M2 o/ GFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
! e1 V) @8 V! J0 M" n1 NABSTRACT
2 Z. E2 s- c! s+ s4 pFive patients were treated with gonadotropin and topical testosterone for micropenis associated
8 v1 m9 {" [! Xwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-" C& Q1 n, `' Z* g' z8 d
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone7 I, {7 n  i6 l" z+ l
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
  @  e2 M& ?9 n& E# t$ P7 }for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent- T, }/ y) T* b/ Z/ R
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
+ O' q4 Y: M3 i% j7 j% qincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response5 ]1 W1 s7 r' |. @+ l5 L+ a) I
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
3 ^9 S- y2 x8 Q, B0 istudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile) Y  l0 b6 m; J/ y) k6 T: c, Y
growth. The response appears to be greater in younger children, which is consistent with previ-) |+ b& ?* f3 {! j" j) Z4 I  H" ]
ously published studies of age-related 5 reductase activity.
$ ]9 M- `6 H& E+ _2 b1 WChildren with microphallus regardless of its etiology will
6 W* r5 ?: T. |# i" I  irequire augmentation or consideration for alteration of exter-
8 Q1 c4 y* R5 r; y3 Anal genitalia. In many instances urethroplasty for hypo-3 ~2 T* l1 I0 Y
spadias is easier with previous stimulation of phallic growth./ j' M& c; a( |# `6 P/ d7 D/ w1 \
The use of testosterone administered parenterally or topically; e) t+ M6 W0 I1 T, k+ c+ j
has produced effective phallic growth. 1- 3 The mechanism of
/ L1 C# n, L) M5 n6 yresponse has been considered as local or systemic. With this" r1 S# _  |0 ?2 ~
in mind we studied 5 children with microphallus for response
* A$ ]: C5 r) ?" w* U* W& S7 ^8 E: m0 Uto gonadotropin and to topical testosterone independently.
) `$ b$ v" {3 f1 T: U4 aMATERIALS AND METHODS
6 J& A# \- M% B( w" EFive 46 XY male subjects between 3 and 17 years old were
' w9 W$ f* {7 o" o. Sevaluated for serum testosterone levels and hypothalamic$ F* j1 n5 N2 ^. [
function. Of these 5 boys 2 were considered to have Kallmann's9 @: A( i$ T1 ?8 N9 Y1 G. @
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
6 D2 z0 ~" ]  E; e) r. e- Plamic deficiency. After evaluation of response to luteinizing
4 S+ m: i! F/ E! X: zhormone-releasing hormone these patients were treated with
; G# [! m5 t; H- u. T8 {9 ~* W1,000 units of gonadotropin weekly for 3 weeks. Six weeks
6 l4 m7 \/ C$ ~& X& Iafter completion of gonadotropin therapy 10 per cent topical. V" J& i- Q- o+ x' ~1 U
testosterone was applied to the phallus twice daily for 3 weeks.$ @" d4 P+ D; j8 P- j) u# w
Serum testosterone, luteinizing hormone and follicle-stimulat-
! u% [* z5 D6 W% f) Ming hormone were monitored before, during and after comple-! w( L3 ]! R. R% Q
tion of each phase of therapy. Penile stretch length was% `" z7 e8 h  A/ e. t% V) }& J" `2 M" f
obtained by measuring from the symphysis pubis to the tip of  b( H% }0 J' F: i* f% v
the glans. Penile circumferential (girth) measurements were; r$ \- R5 l# [
obtained using an orthopedic digital measuring device (see, }. @* N  o4 v0 y* [4 X: }& b
figure).
! Y: x9 W+ ^' J$ y7 f2 ?% iRESULTS7 O: x' Z+ l. q
Serum testosterone increased moderately to levels between
1 \. R+ F- D6 ^* q50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-! V3 a: N. z6 n
terone levels with topical testosterone remained near pre-/ g4 y  P+ c9 Q' W6 V) X
treatment levels (35 ng./dl.) or were elevated to similar levels3 k6 |( S2 Y6 Y# G2 g. V! X
developed after gonadotropin therapy (96 ng./dl.). Higher
  p5 Y7 ^! A2 U4 E5 qserum levels were noted in older patients (12 and 17 years old),2 R+ ^3 X% T/ X* a5 y$ W
while lower levels persisted in younger patients (4, 8, and 10
. g0 |2 c8 Q, ?years old) (see table). Despite absence of profound alterations5 N; V+ y9 V# m' B; B2 n
of serum testosterone the topical therapy provided a greater: Y0 {+ D  e# u) P0 D) A
Accepted for publication July 1, 1977. ·
: G6 W8 U, e& S  D2 E7 o, dRead at annual meeting of American Urological Association,
# X. b) M& y7 T. A% H8 eChicago, Illinois, April 24-28, 1977.; }# o) W5 J# g$ H' [7 K; J
* Requests for reprints: Division of Urology, Henry Ford Hospital,
4 ]! L& Z/ C) L1 G4 k  e6 H& j! p2799 W. Grand Blvd., Detroit, Michigan 48202./ F9 f4 i" v; o2 p% h( `2 k
improvement in phallic growth compared to gonadotropin.7 A2 B3 Q! ]% {' M# l; k
Average phallic growth with gonadotropin was 14.3 per cent$ E! q7 m, }+ I/ E& X3 x
increase in length and 5.0 per cent increase of girth. Topical
9 X& u$ Q# p$ O6 d5 `& r* wtestosterone produced a 60.0 per cent increase of phallic length
1 S/ C( y8 B/ Z* B) Vand 52.9 per cent increase of girth (circumference). The  J* y* v) {! M9 J: f( @7 q) J
response to topical testosterone was greatest in children be-5 b/ s7 _4 X$ f4 @
tween 4 and 8 years old, with a gradual decrease to age 17
: f+ N; \, A% Cyears (see table).$ C" s) g" v# J: E: R& A
DISCUSSION
3 s4 T- z: u/ [5 }- [Topical testosterone has been used effectively by other* @% y& H% j2 O, n7 e+ o' b% w
clinicians but its mode of action remains controversial. Im-' @. _7 C* g7 y' P  V' w; q
mergut and associates reported an excellent growth response
5 Y! y! }1 y$ i# T: W) `to topical testosterone with low levels of serum testosterone,
5 r/ e2 A" t/ n' Asuggesting a local effect.1 Others have obtained growth re-! b+ f0 z  B! p- P3 T
sponse with high. levels of serum testosterone after topical
+ S0 n" _/ c. ^' a5 M$ Kadministration, suggesting a systemic response. 3 The use of
8 R3 z/ l( a, Ygonadotropin to obtain levels of serum testosterone compara-+ B0 b) K9 l* ~4 n3 Z
ble to levels obtained with topical testosterone would seem to7 F1 x  y1 K8 w: Y5 O2 Y2 S
provide a means to compare the relative effectiveness of
$ S7 K1 ~/ g2 c) Z: Ttopical testosterone to systemic testosterone effect. It cer-; @- l; e! b0 L6 o- l
tainly has been established that gonadotropin as well as par-8 C( y( m- h& {: O( J
enteral testosterone administration will produce genital
. |  S; I5 q! A. ~growth. Our report shows that the growth of the phallus was
8 f% \$ P( y) X7 i5 G, tsignificantly greater with topical applications than with go-
0 e* e. X4 C( ~0 Y$ Y  Hnadotropin, particularly in children less than 10 years old.
$ O" n4 T5 c" \* R! KThe levels of serum testosterone remained similar or lower+ j+ b) P' o7 O4 t
than with gonadotropin during therapy, suggesting that topi-
; B* X( w1 u/ B) Z# h- lcal application produces genital growth by its local effect as4 I; b4 i' k0 l* D
well as its systemic effect.
6 ~8 V  S8 _4 N" S3 Z; pReview of our patients and their growth response related to
3 ]: n# Z1 }9 u2 u' gage shows a greater growth response at an earlier age. This is( J) d& W: K  G& u* v
consistent with the findings of Wilson and Walker, who: a* A+ z8 |/ O4 r$ d- p' i  V( D0 e
reported an increased conversion of testosterone to dihydrotes-
. j7 s: J$ s: I4 I; stosterone in the foreskin of neonates and infants.4 This activ-
0 l2 \  {( h5 w/ ^; E4 y+ {ity gradually decreases with age until puberty when it ap-* b! I* S! r) _( O
proaches the same level of activity as peripheral skin. It may' d4 l- ^# K( D: H
well be that absorption of testosterone is less when applied at
' ]% I: L7 B' U) _) g; n& {# nan earlier age as suggested by lower serum levels in children
, h% A( w$ F* o5 d% |less than 10 years old. This fact may be explained by the9 i# Y) z% z$ |% T& ^+ p
greater ability of phallic skin to convert testosterone to dihy-5 n5 F0 Q- N& G1 r3 R" b
drotestosterone at this age. Conversely, serum levels in older6 x$ P8 {8 a; b- i
patients were higher, possibly because of decreased local( D$ N! ~9 i4 A- \0 P4 z2 ^
667' P& g  ]4 R9 |/ J! h
668 KLUGO AND CERNY
. ^$ k0 y8 D7 o! T1 @8 p% gPt. Age" v& e( a# H: e
(yrs.)
* l) E# z5 F* h8 Z3 oSerum Testosterone Phallus (cm.) Change Length7 \9 {# Y, C9 E5 Y/ s
(ng./dl.) Girth x Length (%)  s8 J- L( Y* G. @
4) @4 s5 h. G7 I6 e% I6 F
8
1 \* S( B2 b7 v103 J0 H6 {) B( }, X* r) y, @6 d4 U
12
. y3 ~! ^; c/ n7 f! h; l17& V, S  [! o% B9 j
Gonadotropin
& b0 I/ [9 d% s, A- c4 s71.6 2.0 X 3 16.62 N  _' l* e8 Y5 N
50.4 4.0 X 5.0 20.02 ]# @; r$ Y6 l' J
22.0 4.5 X 4.0 25.0
/ I: M* S7 f! U$ H5 G1 K84.6 4.0 X 4.5 11.12 `( D% m8 y3 |* w: F/ E0 W
85.9 4.5 X 5.5 9.0
/ |5 Z$ E$ ?6 ^2 b' @, eAv. 14.31 E9 _/ ^: C. h9 I' `. F, h7 Y% \
4
2 r- M: |. Q0 s7 P8
: k9 z1 U# N: L! S1 m8 D) D10
) @8 S% o" o- J& B" w12
; |7 Q, K* r4 N# v17
% l9 L9 x+ n: ^7 l4 cTopical testosterone
4 J; A$ q7 _/ s2 F$ ]9 C34.6 4.5 X 6.5 85
! \" X" n. {+ d9 g9 k38.8 6.0 X 8.5 70
9 S0 R% r' v: K7 l) r! w9 R' f40.0 6.0 X 6.5 62.5( h  o3 U5 Y( L6 V+ J. x$ V: c
93.6 6.0 X 7.0 55.5& f* u1 I8 d: Z
95.0 6.5 X 7.0 27.2* {; t6 q. x; E4 l
Av. 60.0. }* }1 ]. I( i' v: H0 ]% z& Y
available testosterone. Again, emphasis should be placed on
* }0 T" t) A8 O5 j: E3 Wearly therapy when lower levels of testosterone appear to0 ]0 T* U+ l' w2 i: z& E
provide the best responses. The earlier therapy is instituted2 L6 o  m: C' I4 u. l
the more likely there will be an excellent response with low
& R" }( _1 \6 _2 hserum levels. Response occurs throughout adolescence as0 p1 a$ l# c& c' J9 V
noted in nomograms of phallic growth. 7 The actual response
' j8 S& ?% O: y* Y5 w4 f- L/ @: ]# sto a given serum level of testosterone is much greater at birth
; E# G0 w1 d+ e# ]6 f' xand gradually decreases as boys reach puberty. This is most
: N& V3 B) n2 Llikely related to the conversion of testosterone to dihydrotes-
; x. v- T* d4 k6 J6 \  otosterone and correlates well with the studies of testosterone- K3 {+ f3 l* J
conversion in foreskin at various ages.
, T4 H( }( l( g$ Y$ y) ~The question arises regarding early treatment as to whether
) o- J/ C$ H& e% c! Y( Jone might sacrifice ultimate potential growth as with acceler-: O" h  k, [) P7 |. \
ated bone growth. The situation appears quite the reverse
- ~6 n5 s8 f1 _with phallic response. If the early growth period is not used
- p% }8 _' F& hwhen 5a reductase activity is greatest then potential growth+ `7 g$ R+ Q4 M8 h
may be lost. We have not observed any regression of growth
+ ?9 l- r) g2 eattained with topical or gonadotropin therapy. It may well
0 \* e# n0 x. S$ Tbe that some patients will show little or no response to any
# S/ E5 @" l- k3 C  Qform of therapy. This would suggest a defect in the ability to
3 l5 o; F" ?: S# k. o* @. f2 hconvert testosterone to dihydrotestosterone and indicate that
. C/ U* T( U1 F/ b8 q% J; o' iphallic and peripheral skin, and subcutaneous tissue should7 I' V, `9 ?* U4 S- n
be compared for 5a reductase activity.% _6 V2 Q& Q: ]/ k. B- N: f
A, loop enlarges to measure penile girth in millimeters. B,
- v- N; x2 B. \& Cexample of penile girth computed easily and accurately.
5 |" g# p: G- ?! E1 r" I" Rconversion of testosterone to dihydrotestosterone. It is in this
! H1 D# z9 N. ^. T8 polder group that others have noted high levels of serum3 e3 ^$ Z% ^, B+ [+ C+ ]) T
testosterone with topical application. It would also appear* L9 V; E# y; M
that phallic response during puberty is related directly to the
, Q2 O# K( K- y: Pserum testosterone level. There also is other evidence of local
* c9 j/ r: H+ Sresponse to testosterone with hair growth and with spermato-% Y( e- Q% v3 M; X
genesis. 5• 6+ o; _  {4 d$ [
Administration of larger doses of gonadotropin or systemic) R, ?6 P0 A& x8 _1 x: m. [6 E
testosterone, as well as topical applications that produce
( [4 ]- y) S; t5 {. c+ o0 shigher levels of serum testosterone (150 to 900 ng./dl.), will
+ q0 @) r- L8 v. S# z; y1 d0 Ralso produce phallic growth but risks accelerated skeletal; o4 U# D- Z& ?" J  L0 r) ]
maturation even after stopping treatment. It would appear
) K' a- b. `$ W2 k1 Kthat this may be avoided by topical applications of testosterone
/ H; M$ _" n( T+ W0 D6 F* [7 L8 g3 Tand monitoring of serum testosterone. Even with this control
, R! ?2 r8 C, e9 s3 ]the duration of our therapy did not exceed 3 weeks at any
1 `# F3 D1 l/ f4 A4 |6 Qtime. It is apparent that the prepuberal male subject may
: T3 \! e# Y# p( W; u/ Jsuffer accelerated bone growth with testosterone levels near8 z% M1 ^4 e2 w
200 ng./dl. When skeletal maturation is complete the level of2 \$ r0 }( H8 @; S% ^7 y: M
serum testosterone can be maintained in the 700 to 1,300 ng./
% @, o* u) n8 F9 l0 n  f. ^dl. range to stimulate phallic growth and secondary sexual
% R0 j: S- s. ?' m4 V/ m! t* hchanges. Therefore, after skeletal maturation parenteral tes-
! T8 V/ a- ?7 m) m0 f; Itosterone may be used to advantage. Before skeletal matura-/ t' c. J7 L0 M* R; A6 C! K
tion care must be taken to avoid maintaining levels of serum& }" C9 W7 L+ N* z4 T
testosterone more than 100 ng./dl. Low-dose gonadotropin
- ~1 U, N0 ^7 N) E  {6 W0 Ddepends upon intrinsic testicular activity and may require
; u7 [# ~9 j, |* zprolonged administration for any response.
3 B+ W9 M, t. }" g; F1 z# r* tAlternately, topical testosterone does not depend upon tes-# G% r. l. `% R* G# G- I' h
ticular function and may provide a more constant level of
: o" C+ r1 x! h3 I  yREFERENCES: P' \  v! q; \4 I
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,! D2 |2 K. e) {3 I7 _
R.: The local application of testosterone cream to the prepub-
( n4 J3 |; B5 k* lertal phallus. J. Urol., 105: 905, 1971.0 K& h* a7 {6 }0 Y3 Z2 g# d; J
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone4 e! i+ y8 W0 X$ R  x8 Z$ M
treatment for micropenis during early childhood. J. Pediat.,  E7 ^, L  B; N% X5 M) A
83: 247, 1973./ e* N% a: R  J) b  v& t8 a! t
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-2 K3 A6 @0 i% t$ c0 T8 x3 H5 W3 R# ?8 b
one therapy for penile growth. Urology, 6: 708, 1975.* i: N$ c) C2 H( g% }
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone1 _2 L# }0 ~, _- e. J; q- H  k
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by  U! H. d/ ^% m
skin slices of man. J. Clin. Invest., 48: 371, 1969.& h4 D8 P4 _4 m$ `: T
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth- q; U, j& _& _2 |( ^
by topical application of androgens. J.A.M.A., 191: 521, 1965.
7 q; a9 r0 D$ {6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local/ p7 r% Q6 r! L& ^$ f
androgenic effect of interstitial cell tumor of the testis. J.
  A& D- f$ f% H' a# X4 YUrol., 104: 774, 1970.
  d( C$ x9 [: b: {1 i2 o9 Y7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
8 o5 M1 O' M: F5 qtion in the male genitalia from birth to maturity. J. Urol., 48:
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