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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND1 x  s) I! R4 B& Y7 A7 ^* k# Y
GONADOTROPIN
7 E8 K) E; j; E# k! I% i$ JRICHARD C. KLUGO* AND JOSEPH C. CERNY
+ c% G! v, l! a3 T1 `8 PFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
1 P/ z9 m6 j2 r( ~0 n# TABSTRACT
" N9 L8 w8 `' u  f7 q) WFive patients were treated with gonadotropin and topical testosterone for micropenis associated
& z0 |" O6 E: iwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-% v* @3 b) E: T* Z
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
9 D4 J" B# |  z. Tcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
* @3 }& _4 G& e- ?for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent5 e9 C5 t5 u6 W4 Z; W8 e* u  i
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
3 m/ |! L+ o0 c# vincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
: @0 g* j( @6 t7 |0 {- m  a5 uoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
# q0 D' y( o  b' U2 D5 ^study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
( J& n' S: ~. f+ ?- B$ s" R( `$ cgrowth. The response appears to be greater in younger children, which is consistent with previ-% p2 l6 j) W3 w" Q5 W6 i
ously published studies of age-related 5 reductase activity.9 X. o% z! u2 Q8 u; S
Children with microphallus regardless of its etiology will
0 ?, Y5 N$ m$ }' prequire augmentation or consideration for alteration of exter-
' _$ T) j4 \  |3 k5 v) \+ _nal genitalia. In many instances urethroplasty for hypo-% \* X5 J# A" C0 q, ]
spadias is easier with previous stimulation of phallic growth.6 q( d. z6 g% Q- _* `# C
The use of testosterone administered parenterally or topically$ @! d; e/ r/ }' |
has produced effective phallic growth. 1- 3 The mechanism of, i# H3 E0 a8 \$ W: f
response has been considered as local or systemic. With this( E1 S* l$ ^) l
in mind we studied 5 children with microphallus for response
, E' Q# `% `# J4 `# Z6 f4 e9 Gto gonadotropin and to topical testosterone independently.+ B& t: x1 d  N( M
MATERIALS AND METHODS
9 V: x4 |8 Q# {; p+ t3 ?3 D# tFive 46 XY male subjects between 3 and 17 years old were
0 Q2 n/ N, R! t7 E) kevaluated for serum testosterone levels and hypothalamic
& y5 ]: s2 T- I6 e4 v) Sfunction. Of these 5 boys 2 were considered to have Kallmann's( J: }/ c& M% M
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
- {) k  i" _. B' `lamic deficiency. After evaluation of response to luteinizing
- y& |) M" ^6 }9 Q/ Shormone-releasing hormone these patients were treated with  L! s$ ]) U' j' |4 C
1,000 units of gonadotropin weekly for 3 weeks. Six weeks7 b' ?# g5 N" b0 P2 t0 T, v
after completion of gonadotropin therapy 10 per cent topical
$ W" y9 N4 m5 r0 h( Ttestosterone was applied to the phallus twice daily for 3 weeks.( b) v  \3 s+ b& ~
Serum testosterone, luteinizing hormone and follicle-stimulat-
" e+ ^9 {5 r$ M2 Aing hormone were monitored before, during and after comple-
) V& _" W) L/ e& Stion of each phase of therapy. Penile stretch length was
% y, }$ X% g- j) tobtained by measuring from the symphysis pubis to the tip of
# b$ E% T; H" gthe glans. Penile circumferential (girth) measurements were
7 ~. U" m0 U8 l. Mobtained using an orthopedic digital measuring device (see
6 D0 b3 i, D0 s' P* Sfigure).$ t  q/ U* i$ T% V' i7 @$ l
RESULTS
% L# j5 t' Y1 ^% z) p+ P* G. l+ dSerum testosterone increased moderately to levels between
4 J2 E% m) `" H' n$ ~! T50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
' n" i* |2 u& n! Tterone levels with topical testosterone remained near pre-
" t1 J* H# f% M7 S  etreatment levels (35 ng./dl.) or were elevated to similar levels
2 \- N3 a. P. {5 s% ]  g- ~  Bdeveloped after gonadotropin therapy (96 ng./dl.). Higher
8 m5 H8 ?+ j% g  K" o3 x$ Fserum levels were noted in older patients (12 and 17 years old),) \1 m" B: o, O
while lower levels persisted in younger patients (4, 8, and 10
8 c, X( P/ P1 hyears old) (see table). Despite absence of profound alterations
3 ?4 S" C/ ?: H/ d4 z8 aof serum testosterone the topical therapy provided a greater9 b6 g: ~6 O- \6 t5 E8 {5 L6 x
Accepted for publication July 1, 1977. ·1 V$ s$ H" ~3 m3 m3 }7 o# y
Read at annual meeting of American Urological Association,
, ~& c: [% a1 |" R  |( ~Chicago, Illinois, April 24-28, 1977.$ B* z$ v4 R0 C0 O/ g
* Requests for reprints: Division of Urology, Henry Ford Hospital,
9 U. H2 i$ H) w: c/ L2799 W. Grand Blvd., Detroit, Michigan 48202.9 b4 x) n. d( g( M% e/ g1 ^
improvement in phallic growth compared to gonadotropin.8 Z; z5 I( ]1 w0 i, L4 [
Average phallic growth with gonadotropin was 14.3 per cent  L9 N7 c9 |4 k2 S( J
increase in length and 5.0 per cent increase of girth. Topical
3 W1 {$ z" d: d- X6 xtestosterone produced a 60.0 per cent increase of phallic length
! U" I/ k  q6 k3 Yand 52.9 per cent increase of girth (circumference). The6 q: J/ w2 ?, x- K3 ]) {
response to topical testosterone was greatest in children be-4 n0 ]- _* l5 n6 @: N) f6 ~* [
tween 4 and 8 years old, with a gradual decrease to age 17
! t, K. \( h6 R1 x. m' ]. l$ fyears (see table)." N2 o, j6 O$ G2 S8 S
DISCUSSION! o+ o0 f- W! g2 s- m0 D' n6 T' Y
Topical testosterone has been used effectively by other
2 @! r% A) w7 f' Tclinicians but its mode of action remains controversial. Im-: O! C) S8 O$ j0 S6 [% t8 M, S
mergut and associates reported an excellent growth response
' u3 D* `5 f: Nto topical testosterone with low levels of serum testosterone,
) A$ b9 h% O4 asuggesting a local effect.1 Others have obtained growth re-
% G( f9 A9 j/ W9 f4 Y: {5 i& ]sponse with high. levels of serum testosterone after topical
' P( d. ?0 P) [5 U8 Qadministration, suggesting a systemic response. 3 The use of
! N! C8 q% r3 V% i& wgonadotropin to obtain levels of serum testosterone compara-9 A4 i3 s) C7 o7 I  r; b9 W# b
ble to levels obtained with topical testosterone would seem to, ?! K& v- a9 t9 u
provide a means to compare the relative effectiveness of2 G2 O! |! V( y* A+ m/ I) H
topical testosterone to systemic testosterone effect. It cer-
8 Q. Y8 P9 U0 `# Itainly has been established that gonadotropin as well as par-
9 g9 ]4 n( g% Y5 ^enteral testosterone administration will produce genital4 _* C/ }( m7 U
growth. Our report shows that the growth of the phallus was/ E8 B. m4 P* B: ]
significantly greater with topical applications than with go-
* ]. L8 z4 ~0 T0 J5 M) mnadotropin, particularly in children less than 10 years old.
8 ~# z4 T! ~& u3 W; c* M" kThe levels of serum testosterone remained similar or lower
8 s5 Q$ M, ^8 t5 ~" {* A. Wthan with gonadotropin during therapy, suggesting that topi-" x2 M" a2 Z. H$ |- q) g# n/ @% M% A! s
cal application produces genital growth by its local effect as
, H4 d7 g% t( h3 f# Kwell as its systemic effect.
( ]. F# K8 W8 R7 b- GReview of our patients and their growth response related to: ^& m( d" d9 D1 x5 D. g7 @
age shows a greater growth response at an earlier age. This is5 ~7 V6 R1 ]. Y& W5 r' B, h
consistent with the findings of Wilson and Walker, who/ N7 ]* ^& `( l9 n, k
reported an increased conversion of testosterone to dihydrotes-
8 s6 a" s* u& w$ s1 T2 l! xtosterone in the foreskin of neonates and infants.4 This activ-1 o& X2 T& Y' ^% r: @$ v8 B/ Y: `
ity gradually decreases with age until puberty when it ap-
7 e  K2 z, Y: q& s$ k0 }4 b3 F" K: iproaches the same level of activity as peripheral skin. It may9 f# o8 E! `  {3 J& ^7 S% |
well be that absorption of testosterone is less when applied at% S7 {+ ^- t) Z( a
an earlier age as suggested by lower serum levels in children* n6 r9 b4 d; Y7 n! Z( Q5 I% y0 V1 W# r
less than 10 years old. This fact may be explained by the
) _6 x* x* |. ]greater ability of phallic skin to convert testosterone to dihy-
' z9 V9 n* P5 e: g& Z( S: pdrotestosterone at this age. Conversely, serum levels in older* m6 P' f) ?' T% h* [
patients were higher, possibly because of decreased local( A- C% I0 B3 t
667
- g& n' E* V5 P7 l9 l+ [668 KLUGO AND CERNY
( \1 K& n% p1 ~/ ~/ k, uPt. Age
/ x; U: T  N  Y! f& k9 c2 {/ q. y(yrs.)
! I5 s. o+ @3 [; _# cSerum Testosterone Phallus (cm.) Change Length
4 s: N7 k, ?2 n* e. _" u(ng./dl.) Girth x Length (%)- u" g2 }2 N! V
46 r* d7 g6 S( w0 B
8  }' L' C4 q% _- u, h+ k; Z
104 m/ ?' E1 [0 _% H# a& {; n
12
& u# \, I$ ]2 s1 s8 r% q% M1 l17
- R& \1 D" C0 _Gonadotropin
+ u' r7 e  h8 k: _71.6 2.0 X 3 16.6  J" y' X: P4 a# q( E- P
50.4 4.0 X 5.0 20.02 M/ x) X3 `  i. K6 h
22.0 4.5 X 4.0 25.0
5 O: l; T" D) X9 r84.6 4.0 X 4.5 11.1
" c. w/ M. B: Z! e7 g- B85.9 4.5 X 5.5 9.0
. S# }) C/ g+ g# y7 WAv. 14.3
7 q* R* z* B! X% r0 ^+ X% ^4; d6 i: D* p7 N  h$ M* a
82 \6 m9 t+ t* G) Y4 `
10# J6 B$ Q. B0 e/ Q- Z9 Y2 \* b
12! u" j* [% n7 w; Z; l: Z
178 I: `1 U' b3 K5 e
Topical testosterone$ C  F; K8 H; d0 }) }% U, L
34.6 4.5 X 6.5 85: v, N. P/ t# x! {
38.8 6.0 X 8.5 70" N+ d# V! j9 ?& \( _# @2 B7 ?0 a$ F
40.0 6.0 X 6.5 62.5
3 V/ v4 s& a7 w- m/ c* x93.6 6.0 X 7.0 55.5
* x% \1 f( ^# W3 k3 F% k% d95.0 6.5 X 7.0 27.2
; I! G6 g. e9 n; \) Y' i" ^Av. 60.0
9 R, _4 c6 m. q. P4 k, Wavailable testosterone. Again, emphasis should be placed on: u1 I1 e3 [" g$ H3 d; n
early therapy when lower levels of testosterone appear to
, v" \+ c& J8 h2 ?7 K  W- rprovide the best responses. The earlier therapy is instituted
* y. p& @' D" r  i$ kthe more likely there will be an excellent response with low
. r& i. n6 h6 ?3 g/ Y7 iserum levels. Response occurs throughout adolescence as) u8 m) [: I& }; M$ j
noted in nomograms of phallic growth. 7 The actual response
: |! z& `& a" u. J8 \7 ]6 oto a given serum level of testosterone is much greater at birth
( {: w' x3 o9 Z6 k1 Wand gradually decreases as boys reach puberty. This is most' X0 @6 B) |! q) Q, ~: e) o
likely related to the conversion of testosterone to dihydrotes-
+ E. \' M. r9 T! O( z5 i/ ]tosterone and correlates well with the studies of testosterone1 f; X* P- h4 F8 T! h: ?
conversion in foreskin at various ages./ {) [6 R& d2 I5 R
The question arises regarding early treatment as to whether  F/ x6 c" x0 o" s' [* F3 D
one might sacrifice ultimate potential growth as with acceler-
- Q- h  r' C/ n+ mated bone growth. The situation appears quite the reverse) K6 r+ a; V5 V2 C8 }1 Y6 F/ E( u
with phallic response. If the early growth period is not used
0 J, {- B5 o4 s2 mwhen 5a reductase activity is greatest then potential growth
0 s/ W% ^! z; V! ~$ M  x* y0 m& imay be lost. We have not observed any regression of growth  O* ]6 R: N* t" j% u! N  t/ R
attained with topical or gonadotropin therapy. It may well
  K3 L: \0 L) T% t2 l, ?4 `be that some patients will show little or no response to any1 Y( `% h% \- p, v
form of therapy. This would suggest a defect in the ability to# P6 Q" n# E$ B4 Q; P4 z
convert testosterone to dihydrotestosterone and indicate that2 d. C0 f! e" F- P
phallic and peripheral skin, and subcutaneous tissue should
' D/ F6 |. m1 b- ?0 ~be compared for 5a reductase activity.
# V' ^! o4 S+ F5 i* e0 VA, loop enlarges to measure penile girth in millimeters. B,: `7 r! R8 j- v, d6 y! w5 K
example of penile girth computed easily and accurately.
  ]4 a$ x, G! A% L' O' wconversion of testosterone to dihydrotestosterone. It is in this
. l8 B  L2 w  l& @older group that others have noted high levels of serum) h7 U4 o2 K/ A8 l; `$ J, \
testosterone with topical application. It would also appear
3 F0 A/ D5 P! |5 `that phallic response during puberty is related directly to the. ]. Y/ ]8 F% b% h
serum testosterone level. There also is other evidence of local
9 K3 s; i: U' Y. Tresponse to testosterone with hair growth and with spermato-+ _  o' v3 c' M; `7 v- K* I
genesis. 5• 6+ a+ F2 A4 l" _8 M
Administration of larger doses of gonadotropin or systemic
: `) v4 [2 Y: i* xtestosterone, as well as topical applications that produce/ b; z* n& U6 @6 u$ Q+ T! \; p
higher levels of serum testosterone (150 to 900 ng./dl.), will% G' R1 i# y- y1 |2 R( m% h
also produce phallic growth but risks accelerated skeletal; Z6 h9 o8 d2 |% B- G- [
maturation even after stopping treatment. It would appear* q( o: l3 A3 i. [
that this may be avoided by topical applications of testosterone8 j& q( A, f# U+ _& S
and monitoring of serum testosterone. Even with this control5 F; r- L5 {9 m+ n" ]
the duration of our therapy did not exceed 3 weeks at any% P% p- M6 @* K9 G
time. It is apparent that the prepuberal male subject may  n* y1 Z5 L' G8 x
suffer accelerated bone growth with testosterone levels near- e" }9 O1 J% ^- H& @
200 ng./dl. When skeletal maturation is complete the level of
7 Q' Y9 u- ~8 _& ~% Cserum testosterone can be maintained in the 700 to 1,300 ng./
  k# {: H( |  d2 T9 N) Sdl. range to stimulate phallic growth and secondary sexual
! b7 y* Q- c  N0 N- Rchanges. Therefore, after skeletal maturation parenteral tes-
7 w% T" o2 c# E; R, ~# x2 s8 Dtosterone may be used to advantage. Before skeletal matura-+ u+ f/ @, z2 J# ~0 Y  }8 L
tion care must be taken to avoid maintaining levels of serum
- ^! E% m3 Q* M3 Y0 ]0 U; `8 otestosterone more than 100 ng./dl. Low-dose gonadotropin, Z* V, G+ Y6 Q" U- K7 I0 `' _
depends upon intrinsic testicular activity and may require
- ^( B2 ^8 [% ^3 `0 Zprolonged administration for any response.
" Q% m( N( t' G+ X5 HAlternately, topical testosterone does not depend upon tes-: P3 L% J  U' n7 z2 _, x
ticular function and may provide a more constant level of9 v! x. N2 C. g
REFERENCES
# b, f; P1 T; u1 P2 }  R1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,  U( m: W' w' c3 c) c; j  }( m
R.: The local application of testosterone cream to the prepub-
; ^  M( _, L; j: H! N; d+ Gertal phallus. J. Urol., 105: 905, 1971.
' Q/ `1 R0 O7 P( @2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone1 S) R) p& K- ]
treatment for micropenis during early childhood. J. Pediat.,
: d- A( [  G. @6 J83: 247, 1973.6 V) T6 N) X% n8 @1 C0 Q
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
' A2 N& e6 _! E/ x+ f9 C3 uone therapy for penile growth. Urology, 6: 708, 1975.$ Q9 p7 U! c# _# b' H; k9 `
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone5 M% N! e  M" P9 S9 O5 {
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by. s" @6 Q0 ^! z8 e! y
skin slices of man. J. Clin. Invest., 48: 371, 1969.  K9 Y$ Z% r& V( x( @7 J! A
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth% ~9 s) n9 X) |: H1 [
by topical application of androgens. J.A.M.A., 191: 521, 1965.
3 ~$ f+ q& `) ^5 U: D/ V$ G% \8 f) S6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local& L% i# E* k9 m- k, T' Z- V9 _
androgenic effect of interstitial cell tumor of the testis. J.3 x1 H$ t# P: U! @4 u
Urol., 104: 774, 1970.: P! F. {; L8 P
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
- Z7 Z" M# K; L& {" Ttion in the male genitalia from birth to maturity. J. Urol., 48:
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