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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND  K" f7 w- j; j5 r, f
GONADOTROPIN
3 a0 R% X2 p1 g* l9 qRICHARD C. KLUGO* AND JOSEPH C. CERNY0 N6 G* m0 _2 a, H/ C# L9 k
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
9 e( y) @5 a+ [9 s( TABSTRACT
( P( c+ T; P; MFive patients were treated with gonadotropin and topical testosterone for micropenis associated0 }' h3 l7 ]1 g4 V7 C" R0 y
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-" p/ H" b4 f) ^; N
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone5 R& Q4 _" W; A$ k' g0 V. h
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
! o0 ]1 h0 n* q" n$ x( L) _( afor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
8 z+ ^' n% t# @6 V2 P8 N5 S+ {increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
$ Q! V6 v6 B3 i/ N- }increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response+ i4 e: ^  C. _" g$ W
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
( l" |( }8 @3 R) M* L* o1 Hstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile# l# D& g8 ?* y  ]
growth. The response appears to be greater in younger children, which is consistent with previ-. h6 q* d/ \' M" b
ously published studies of age-related 5 reductase activity.! {7 m# |$ |& Y0 _6 F( U
Children with microphallus regardless of its etiology will
5 n& P+ K6 J5 p5 G" `  L6 ]require augmentation or consideration for alteration of exter-
1 l! n2 ]3 f9 enal genitalia. In many instances urethroplasty for hypo-
5 ~2 Y0 d/ C0 j# m1 J' Tspadias is easier with previous stimulation of phallic growth.8 J  g5 q% g, {4 y% l# v
The use of testosterone administered parenterally or topically
( F$ Q! a5 j4 L9 U1 ^- e* Khas produced effective phallic growth. 1- 3 The mechanism of
2 u1 t; W2 u# D8 v" w1 mresponse has been considered as local or systemic. With this, P; v5 M7 T' k: Y. V
in mind we studied 5 children with microphallus for response' p1 x5 K' z4 _% ]2 |
to gonadotropin and to topical testosterone independently.$ F1 {, k6 A- [* @5 ]$ o
MATERIALS AND METHODS
- g% k1 O: p3 f$ x4 M' ?Five 46 XY male subjects between 3 and 17 years old were
/ J) N* A, v" F, B; A! Eevaluated for serum testosterone levels and hypothalamic
+ y9 ~+ q1 F: I' i4 ?' Kfunction. Of these 5 boys 2 were considered to have Kallmann's/ j  Q0 G0 p+ h. A% l
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-- u! @( h+ F# Z2 C5 F- h; R, k* \
lamic deficiency. After evaluation of response to luteinizing7 j* ~9 `4 }2 s7 ?
hormone-releasing hormone these patients were treated with
& Y7 j6 a0 [; N% j" v( a" V( Y1,000 units of gonadotropin weekly for 3 weeks. Six weeks
3 _4 E1 ]7 E5 }" @after completion of gonadotropin therapy 10 per cent topical, m( {% E; n% K5 S! J& L+ T
testosterone was applied to the phallus twice daily for 3 weeks.
! j- ^6 o9 h- x$ a! ~5 ZSerum testosterone, luteinizing hormone and follicle-stimulat-
9 c* y% A4 c/ W9 B9 Z* _3 ning hormone were monitored before, during and after comple-
; N( C) b% G- R/ ~- y2 |" z; Mtion of each phase of therapy. Penile stretch length was4 ~$ @! D  A" m; Q7 z3 K9 c; F. D# P
obtained by measuring from the symphysis pubis to the tip of
0 s& }7 F5 Z# n  H+ f) l5 dthe glans. Penile circumferential (girth) measurements were
/ s; L6 t& @/ K% i0 Hobtained using an orthopedic digital measuring device (see
$ V) E! x4 |. v3 X9 T: b- @figure).
+ L* v2 S) y! E( \4 ~3 s  }! hRESULTS% j. n3 W/ {; u' {; l/ v" V7 Q! C
Serum testosterone increased moderately to levels between
7 z3 C& m" B* ]- T8 `50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
3 R2 C$ c, h9 \4 s; q* A" `" A  wterone levels with topical testosterone remained near pre-% j% L8 |( q! r9 |% l) Z( p( S5 J( E
treatment levels (35 ng./dl.) or were elevated to similar levels
) w! P) u1 H* D8 N9 adeveloped after gonadotropin therapy (96 ng./dl.). Higher  R( ^0 o  W0 t
serum levels were noted in older patients (12 and 17 years old),5 ?8 C1 M& z: q) M" l! e1 G
while lower levels persisted in younger patients (4, 8, and 106 E# M: L: P, X7 [, i+ n8 l
years old) (see table). Despite absence of profound alterations- a$ n% t; C3 W: z
of serum testosterone the topical therapy provided a greater' P6 x; |9 _) V1 ~8 _1 p
Accepted for publication July 1, 1977. ·9 r& m$ M5 s6 I1 @; P7 f. k0 e* ?% ^" h
Read at annual meeting of American Urological Association,0 ~( c. A* ?! C$ n1 l8 b* Z
Chicago, Illinois, April 24-28, 1977.; b3 U. C4 G  n- |% z$ g8 P
* Requests for reprints: Division of Urology, Henry Ford Hospital,6 `  o  Q5 C* Y; j  N& x
2799 W. Grand Blvd., Detroit, Michigan 48202.
/ s7 H% e' e& W, Kimprovement in phallic growth compared to gonadotropin.
, D2 J# A" W0 j$ \" f) I. oAverage phallic growth with gonadotropin was 14.3 per cent" Y4 S) x: P, k5 w
increase in length and 5.0 per cent increase of girth. Topical
3 J6 T; R! w8 I2 t0 Ttestosterone produced a 60.0 per cent increase of phallic length, x- w0 N! d, E. b8 R% c
and 52.9 per cent increase of girth (circumference). The
5 C$ v) n- x+ \, Kresponse to topical testosterone was greatest in children be-
4 o  n* V4 v( E% K. y. gtween 4 and 8 years old, with a gradual decrease to age 17
8 t# e/ Y! h5 a* p7 e$ C% ]years (see table).
3 [- ]% W8 k) Z, V8 X0 i0 d1 T: WDISCUSSION
. Z2 k1 E& V  I! S0 V* r1 n& zTopical testosterone has been used effectively by other
3 V& \0 @/ R* B( O, g, Wclinicians but its mode of action remains controversial. Im-$ y6 I* r, R  b7 o1 q6 j) [
mergut and associates reported an excellent growth response
2 m% n# |1 m) p9 mto topical testosterone with low levels of serum testosterone,
0 {: v  S/ x! _1 ~suggesting a local effect.1 Others have obtained growth re-
( Z* D& z# q4 k6 k( [" ]/ Dsponse with high. levels of serum testosterone after topical
1 R3 }# w0 d8 E& O6 Cadministration, suggesting a systemic response. 3 The use of1 k9 W1 J% s  k3 B  ~7 J/ H1 [
gonadotropin to obtain levels of serum testosterone compara-) `  B. I) j* C  W
ble to levels obtained with topical testosterone would seem to1 E: Y. ]- {; i3 [8 i
provide a means to compare the relative effectiveness of
' D( n  A1 p& ?1 w4 {topical testosterone to systemic testosterone effect. It cer-
# Y' k7 W  s. f: r, utainly has been established that gonadotropin as well as par-. o8 w" q- I( }; p' ~' U
enteral testosterone administration will produce genital
/ `2 {- T6 x) Y! ?/ \' k+ y! n- U: Mgrowth. Our report shows that the growth of the phallus was
- X: R5 a0 l. w/ fsignificantly greater with topical applications than with go-( M5 q/ F% ]% ~; ~" O! ?2 ?( q
nadotropin, particularly in children less than 10 years old.
5 _/ Z6 G0 u& T" z0 Y# `The levels of serum testosterone remained similar or lower' C( W) V$ u( O
than with gonadotropin during therapy, suggesting that topi-
, Z# j! G7 y  i, Y" F7 Mcal application produces genital growth by its local effect as
6 O; x1 Y4 d9 H# Qwell as its systemic effect.
' a6 m" a2 L3 s( |& C4 Q" b: e+ gReview of our patients and their growth response related to
" g1 m/ `1 x& v5 O3 U0 u. i9 E. Wage shows a greater growth response at an earlier age. This is
+ p, ^( i7 V% \8 G) qconsistent with the findings of Wilson and Walker, who
* a- |) v" K) _; ]8 vreported an increased conversion of testosterone to dihydrotes-/ q. @% f& w( O! n9 h$ l% H
tosterone in the foreskin of neonates and infants.4 This activ-
" l3 I+ m9 w1 b1 @$ n" F! |8 Dity gradually decreases with age until puberty when it ap-. {2 h" c2 ~+ n/ y$ i- a2 v- e
proaches the same level of activity as peripheral skin. It may
" I/ C+ ]6 ^& t  _5 u- Nwell be that absorption of testosterone is less when applied at, u9 W7 \" l1 P$ d" J
an earlier age as suggested by lower serum levels in children/ J) a; l( S0 E& @) S9 B
less than 10 years old. This fact may be explained by the
' ~) S# E0 V) G/ `$ Pgreater ability of phallic skin to convert testosterone to dihy-8 Q8 F  Y6 J1 Q9 H' w) x; E
drotestosterone at this age. Conversely, serum levels in older
4 r* Z, G4 H- q; s% jpatients were higher, possibly because of decreased local
6 `1 d/ a% T7 G6670 r& L  i7 G) U( D; i
668 KLUGO AND CERNY1 i% J$ D# P6 u* j7 a2 D) y- Q, A9 |4 t
Pt. Age/ Q2 L5 ?- p9 e" x: o
(yrs.)
; W; u6 t- E1 p9 f1 h9 u+ sSerum Testosterone Phallus (cm.) Change Length
, R9 `3 L( ?2 D(ng./dl.) Girth x Length (%), I. @$ `# v& J5 r$ Q  `
4
" @  K& T- @9 z8
" B, Z4 p0 }6 Z/ ^4 X1 g7 z6 C10
' e: u0 w( c; f" w; }12
( }3 `5 w! f% M- F2 s5 W% K7 e$ D# f+ a17
9 z( J6 s. V2 c0 ~Gonadotropin( ]8 C$ l  Q. l$ j6 U3 B
71.6 2.0 X 3 16.6
3 q7 r2 }/ ~6 p50.4 4.0 X 5.0 20.0+ g8 F( O0 k( k- _2 R/ g+ z4 x0 L
22.0 4.5 X 4.0 25.06 g# m; J' K6 t( y) G( M7 v" _$ @
84.6 4.0 X 4.5 11.1
) W( M6 ]7 {5 u3 E85.9 4.5 X 5.5 9.0  y5 w9 p9 s# \& W
Av. 14.3+ I4 R$ _6 ^1 m! B3 U& r# r* r1 s
4; U  Y: @, ~& X1 G0 X" r9 }
83 B3 L* \, I) Y1 y' h( E5 z
10
3 |; d" u7 e$ N8 h* V12
; o( m. |3 [; y7 R17& S; `, `$ [8 s$ z
Topical testosterone
6 S$ F- u- H% Y# i, H34.6 4.5 X 6.5 852 W5 r- V% b1 \# P
38.8 6.0 X 8.5 70+ |1 L* B2 |7 F' g( t2 q2 p% S* h! ~
40.0 6.0 X 6.5 62.5
- w6 Z) D4 u$ c93.6 6.0 X 7.0 55.5! X  R$ ?3 @! U3 ]( K
95.0 6.5 X 7.0 27.2
/ I9 r- c7 W. r& a: cAv. 60.0! H: q$ G! A8 ?
available testosterone. Again, emphasis should be placed on
8 @3 I/ x+ R/ A5 Aearly therapy when lower levels of testosterone appear to
+ |3 g& ~" r- B" @provide the best responses. The earlier therapy is instituted
' X9 |; q+ o; |: S! B; Qthe more likely there will be an excellent response with low
" F2 t* b+ }0 P& tserum levels. Response occurs throughout adolescence as
' ], X5 h- a2 \, k  B- Dnoted in nomograms of phallic growth. 7 The actual response  L+ t9 A# _, {& M# J- c6 w2 v: _
to a given serum level of testosterone is much greater at birth, O) c( s& V7 S1 i0 J0 A* L
and gradually decreases as boys reach puberty. This is most: \3 ^0 q% n! K: A& j
likely related to the conversion of testosterone to dihydrotes-
) ^0 r! O& g" K$ `: l8 l& Ztosterone and correlates well with the studies of testosterone
3 u# w/ ?/ I' C/ L. I& p% k/ cconversion in foreskin at various ages.
) x8 u- N' f6 {& C7 z. `The question arises regarding early treatment as to whether
) y- w  D  L4 i% ^one might sacrifice ultimate potential growth as with acceler-
4 b# @  Z1 w" h  Z; A3 i7 B) q$ vated bone growth. The situation appears quite the reverse
: o/ y" P2 W. s6 C/ ]6 uwith phallic response. If the early growth period is not used
- J; _6 u0 h, i9 G' U7 mwhen 5a reductase activity is greatest then potential growth1 J6 y  m" J9 N/ O  |) g( J
may be lost. We have not observed any regression of growth) N$ C+ u$ x' e9 K9 T3 j! ]. [; z
attained with topical or gonadotropin therapy. It may well$ t* q+ d% t& j3 r2 A* Y3 ]
be that some patients will show little or no response to any7 e5 p7 H3 {) L7 `- H7 I
form of therapy. This would suggest a defect in the ability to
, D8 b  t/ P$ Zconvert testosterone to dihydrotestosterone and indicate that, W  M4 ]5 k: R* q8 w- M: q
phallic and peripheral skin, and subcutaneous tissue should/ W* X" S# q1 e; m0 B8 R$ _1 R! M% A
be compared for 5a reductase activity.
2 K" Q0 F  [% |2 ~( WA, loop enlarges to measure penile girth in millimeters. B,$ |  F9 ?7 W) e- e
example of penile girth computed easily and accurately.
$ |% P3 _* w2 p* F& ~% f( Zconversion of testosterone to dihydrotestosterone. It is in this; H+ h3 A, {0 p/ u7 t
older group that others have noted high levels of serum
( Q2 s0 n# {- j$ i$ {$ stestosterone with topical application. It would also appear. d1 f' c  F0 g2 |4 g  b
that phallic response during puberty is related directly to the" `7 U# E. F0 V' a
serum testosterone level. There also is other evidence of local
/ ]9 B- m+ S7 R% f0 e& Rresponse to testosterone with hair growth and with spermato-
4 j- I8 |1 @3 v6 A: V) z) [genesis. 5• 6% W% f  t, ]! R! q. \
Administration of larger doses of gonadotropin or systemic
9 h! a/ a. O$ T" w0 v3 o. v6 Ntestosterone, as well as topical applications that produce
/ i! @1 ]1 a& S' K4 ?4 K* ~- g5 Whigher levels of serum testosterone (150 to 900 ng./dl.), will
  m; I( O. n. z4 B) [, J3 j* Y! Dalso produce phallic growth but risks accelerated skeletal
( Y# }! ]/ s* g: U9 d" \" _2 Amaturation even after stopping treatment. It would appear
! i- l1 ]. n7 Q# z8 @2 gthat this may be avoided by topical applications of testosterone
+ |3 t, E5 }+ land monitoring of serum testosterone. Even with this control* |( M! ~5 f4 i" X; w2 F% Z2 l
the duration of our therapy did not exceed 3 weeks at any/ Q3 f; E8 m2 J' h7 r. q8 i
time. It is apparent that the prepuberal male subject may: @4 Y% i& B; J' X* u
suffer accelerated bone growth with testosterone levels near
# l* _2 |& q6 @) V5 }& X- F8 F* |200 ng./dl. When skeletal maturation is complete the level of3 }8 g0 T* r$ B# n  G# {
serum testosterone can be maintained in the 700 to 1,300 ng./
& z: [6 _3 l0 W+ n1 kdl. range to stimulate phallic growth and secondary sexual% A6 E: A( h5 H0 e, f3 b4 _2 x
changes. Therefore, after skeletal maturation parenteral tes-3 G/ Q* a9 H4 |/ d
tosterone may be used to advantage. Before skeletal matura-
* z9 t& V; ]+ i3 k+ ption care must be taken to avoid maintaining levels of serum
8 {6 q' j" k' m  V- Ntestosterone more than 100 ng./dl. Low-dose gonadotropin' s6 d7 Y* n9 g7 |7 t- ?
depends upon intrinsic testicular activity and may require
4 [- o8 ]) }" D: \2 `3 nprolonged administration for any response.
% C) N# \. a% \& B( o- N0 t* PAlternately, topical testosterone does not depend upon tes-
' ^! M0 I1 f+ O! Z$ ]0 b' Pticular function and may provide a more constant level of, f5 H" k6 j- Q+ c8 D
REFERENCES1 U( `% ^7 i2 i
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
/ l7 ?. W# \0 h, |R.: The local application of testosterone cream to the prepub-2 T5 p8 g; {1 `" y: i" q
ertal phallus. J. Urol., 105: 905, 1971.
/ R% \% i# X4 R2 N9 f9 T2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone& H: j3 S- N; B( k0 ^7 i
treatment for micropenis during early childhood. J. Pediat.,
) X: T- Z, Q( }% c83: 247, 1973.- U( j: y2 N) L. x+ F( S& z) B& s
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
$ o" X4 }6 r0 y, gone therapy for penile growth. Urology, 6: 708, 1975.9 R* K# Z: u* K+ d* p
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
' ?- v$ {" v1 f$ {( |to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
" o/ G. Q' [( Y( u! u5 @skin slices of man. J. Clin. Invest., 48: 371, 1969.' |" ^, o$ k8 o4 v: l; z9 n
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth4 Z- A2 L" B6 g% c  T
by topical application of androgens. J.A.M.A., 191: 521, 1965.
( t! H& S6 u9 s3 [5 V" A4 k7 D6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
+ C3 x4 F# j3 h, _( U2 R; u: Handrogenic effect of interstitial cell tumor of the testis. J.7 ^3 D$ z& w5 u: c
Urol., 104: 774, 1970./ X+ g9 A  O3 P3 K6 D5 v( ^5 {
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
" h& Q, j1 \. B2 ktion in the male genitalia from birth to maturity. J. Urol., 48:
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