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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND. y0 Y3 P3 C' R2 u) |( R$ Z
GONADOTROPIN
6 e4 Y+ u  C4 Z( R* U9 TRICHARD C. KLUGO* AND JOSEPH C. CERNY
4 n! O! _4 c! h& F- AFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
  D6 `8 R( m: x# u" {ABSTRACT9 O5 [0 B- E  M" }
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
5 y) _* r6 ?9 c& Y. |( z6 Y: P$ kwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-- u3 f2 A; I! }, U( m* G
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
3 g2 c' w( M/ e8 t7 _6 ccream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
8 W" M1 F4 ~" k/ s' N; z2 efor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent$ z- Z; y4 I4 S4 U- ?9 K1 N
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average3 I7 \3 Y* ~9 a
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
. v& z) n" C- O) noccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This; o, J4 c/ S% i/ j
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile+ u( S% u, t1 I2 J4 X0 T' O
growth. The response appears to be greater in younger children, which is consistent with previ-  f9 G, P8 |* w) {/ L* a) R. q
ously published studies of age-related 5 reductase activity.
* T3 n; E3 M) L$ _6 mChildren with microphallus regardless of its etiology will1 [( l6 [9 R6 o0 \0 E( D# K
require augmentation or consideration for alteration of exter-: j8 a/ ?' _) M3 D3 _0 A. s
nal genitalia. In many instances urethroplasty for hypo-! w% X7 D9 j" m6 p: Y, E4 D
spadias is easier with previous stimulation of phallic growth.* e. p+ G9 A6 o
The use of testosterone administered parenterally or topically* S( b' f$ j# n; j
has produced effective phallic growth. 1- 3 The mechanism of/ [. [9 A1 J4 [9 S5 S$ g0 ~
response has been considered as local or systemic. With this
3 N& e6 b1 g! c$ e( x, ein mind we studied 5 children with microphallus for response
( P7 B. A4 v9 y4 R! o* L+ Oto gonadotropin and to topical testosterone independently.
8 \4 g/ y  u8 }% a, a. S/ I7 Y; `) fMATERIALS AND METHODS
/ Y, L3 q; ~5 q) }% mFive 46 XY male subjects between 3 and 17 years old were
6 ^# v9 p$ N+ `/ f9 {, c" wevaluated for serum testosterone levels and hypothalamic
4 ^8 G' F- Q5 {. ffunction. Of these 5 boys 2 were considered to have Kallmann's7 [2 R3 I! W- r, I% H! F. G7 R
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
% p1 S- l8 Z" N" J) ~. xlamic deficiency. After evaluation of response to luteinizing# }+ L2 J9 d: E% l: H
hormone-releasing hormone these patients were treated with
! r6 t. R/ _/ Y- f! ~+ d$ P8 `1,000 units of gonadotropin weekly for 3 weeks. Six weeks6 U2 v- S2 x0 S% m  q+ W
after completion of gonadotropin therapy 10 per cent topical
$ ~2 L/ z' ~+ r. b& \, wtestosterone was applied to the phallus twice daily for 3 weeks.: @. k! e0 X( P# g
Serum testosterone, luteinizing hormone and follicle-stimulat-2 Q) A. c1 N0 d# D% g, m0 c
ing hormone were monitored before, during and after comple-
1 e6 R5 O# E$ l( d4 a5 `tion of each phase of therapy. Penile stretch length was
9 C  v' E! w; u2 Vobtained by measuring from the symphysis pubis to the tip of: C+ D( l! F9 E  Z% T8 u! [" r
the glans. Penile circumferential (girth) measurements were
5 P- _. n, h/ {3 W6 ]7 Jobtained using an orthopedic digital measuring device (see/ \7 u9 u/ ]5 E
figure)./ L" o# q+ ~5 c% ~
RESULTS& h( q1 S# z* D: P8 @
Serum testosterone increased moderately to levels between
! ^: d8 s2 t9 y7 Q$ u50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
9 X  \. a8 t, Y- {terone levels with topical testosterone remained near pre-
$ S- E) A- l* y. P. ktreatment levels (35 ng./dl.) or were elevated to similar levels8 ^" ~! x- q; s# d$ \  k
developed after gonadotropin therapy (96 ng./dl.). Higher8 \7 v- X2 p2 ?. T
serum levels were noted in older patients (12 and 17 years old),
+ v2 d( }) P5 ewhile lower levels persisted in younger patients (4, 8, and 103 T5 V6 k/ s4 w- Q- P
years old) (see table). Despite absence of profound alterations
/ d, ?, W  }9 C: G! Bof serum testosterone the topical therapy provided a greater7 \* c! j  \: j7 j# P; ?; b
Accepted for publication July 1, 1977. ·
: i" {1 k' ]( [+ pRead at annual meeting of American Urological Association,& e' H) d, P  {+ O& }4 `2 j+ [
Chicago, Illinois, April 24-28, 1977.
" P1 L$ m. S' f  k0 H* Requests for reprints: Division of Urology, Henry Ford Hospital,
1 j( ?0 K% q7 B5 V3 c: |7 b2 U' L& y2799 W. Grand Blvd., Detroit, Michigan 48202.
6 n7 v- J6 C6 X) I9 gimprovement in phallic growth compared to gonadotropin.
  Z9 X4 a. f2 d9 D, U* o$ jAverage phallic growth with gonadotropin was 14.3 per cent
5 ]# \! ~3 o9 e. {5 G7 |$ zincrease in length and 5.0 per cent increase of girth. Topical
: p6 i: v# o9 `: C+ G7 g2 U! P+ N( F- e+ Itestosterone produced a 60.0 per cent increase of phallic length1 ~! T& S  B6 P) U% L
and 52.9 per cent increase of girth (circumference). The; L% K7 b0 }  C; W* t
response to topical testosterone was greatest in children be-
2 n0 f7 s8 s2 w8 P& Etween 4 and 8 years old, with a gradual decrease to age 17
% K5 K& d% c7 k. ?# O! o' Eyears (see table).) t2 W7 l2 V1 a
DISCUSSION) Z7 k( e6 Q$ \8 U( O+ ]+ m
Topical testosterone has been used effectively by other
( }7 }+ G5 P0 i' w8 L! a. V! kclinicians but its mode of action remains controversial. Im-
/ z7 b9 x1 k5 E* z& G7 K+ a) `mergut and associates reported an excellent growth response
, K3 e) Z4 u( X: ^/ p/ Dto topical testosterone with low levels of serum testosterone," d2 J( [1 a8 M' G: |! n! j
suggesting a local effect.1 Others have obtained growth re-
, E1 j+ ]9 q& M# h' m/ n. |: Tsponse with high. levels of serum testosterone after topical
: p0 p5 I) p- m( Padministration, suggesting a systemic response. 3 The use of! t- \. i) y" w4 U% a) g" Y
gonadotropin to obtain levels of serum testosterone compara-
  k# T2 a4 L0 d- ?) Qble to levels obtained with topical testosterone would seem to
5 p5 ~' s/ ^8 y" [2 E3 Xprovide a means to compare the relative effectiveness of# b% j/ W& n" E8 t( l( H: t* I
topical testosterone to systemic testosterone effect. It cer-4 u! |- d1 A! N/ K
tainly has been established that gonadotropin as well as par-
+ ?2 k, R" X% V, Y+ E; i$ h  C3 Kenteral testosterone administration will produce genital
. |7 ?! H; R0 G3 R& t8 Hgrowth. Our report shows that the growth of the phallus was
7 F3 H- N& O  F+ s8 Z4 K* ysignificantly greater with topical applications than with go-
; Q- Z5 I/ u- M# y* d! i# }) [nadotropin, particularly in children less than 10 years old.
% [% S9 Q5 |0 s% jThe levels of serum testosterone remained similar or lower
% d0 B. d1 p5 b2 o- vthan with gonadotropin during therapy, suggesting that topi-3 n  N% q# V: m" M! a/ R
cal application produces genital growth by its local effect as
, V# e, ?- S8 H  {+ f9 d$ z0 Jwell as its systemic effect./ `% ^7 [/ V3 M% ~/ F4 Y4 Z
Review of our patients and their growth response related to
) k. M, k+ _+ v2 g- Eage shows a greater growth response at an earlier age. This is
, K7 d1 s) \, g/ }- A+ l+ w, mconsistent with the findings of Wilson and Walker, who9 |) d' ~3 a9 Q" [1 R4 s& g
reported an increased conversion of testosterone to dihydrotes-
/ f* \: p9 Z/ g/ z- ~# K7 Ttosterone in the foreskin of neonates and infants.4 This activ-+ K. ]0 F" `) Q& I
ity gradually decreases with age until puberty when it ap-* \$ b1 n. M4 |, Q/ o. l
proaches the same level of activity as peripheral skin. It may0 @9 j6 z* W4 r1 O8 D
well be that absorption of testosterone is less when applied at! U7 p6 t: i4 q4 i
an earlier age as suggested by lower serum levels in children
" C0 x% ^! n6 |4 S" a5 Hless than 10 years old. This fact may be explained by the
( j2 ?: F, f  g' j8 Qgreater ability of phallic skin to convert testosterone to dihy-1 j, q" _$ W$ t8 x/ i- s0 v
drotestosterone at this age. Conversely, serum levels in older% T/ L6 w( j" K. q
patients were higher, possibly because of decreased local
3 `' n, b9 M7 ~667
4 K. R9 x+ [  n5 K8 h3 d8 _668 KLUGO AND CERNY
4 j0 f: Z- D) D) S7 S. |# k5 u& SPt. Age; P' h* n5 z, l+ A
(yrs.)
- y5 e- E$ k" V3 V. [9 n& GSerum Testosterone Phallus (cm.) Change Length
& E5 o4 y( m# w% n3 x- m3 |(ng./dl.) Girth x Length (%)0 i; P$ s+ @+ X: f# Z1 n$ o( ~" ?( C: U
4
, x% y& C6 _/ K6 ]8
0 |5 M! l; u! e8 y10" E% ^1 |+ |$ k* |! d. M6 ]+ f! t
12
$ ?1 F* F7 e- j5 I0 a" w178 |9 K& ^" z7 ]2 d
Gonadotropin8 {+ M9 r  H+ _
71.6 2.0 X 3 16.6
9 i6 I4 C( P7 c8 D1 Z8 `' @50.4 4.0 X 5.0 20.0. S8 W$ I8 V# K
22.0 4.5 X 4.0 25.0
) T0 a* W1 M! ~+ a" U% D1 v84.6 4.0 X 4.5 11.10 D3 }, B# S. n7 D6 P1 ?2 H9 u
85.9 4.5 X 5.5 9.0& ?; d( M# C7 U+ Q9 `6 A
Av. 14.30 w% ?7 Y( O9 C7 E8 Q7 R' ?
4
+ d/ y6 C6 {, @- w+ Q+ c( i2 @# ]8' P( _* Y( l0 U& C+ c1 [+ N0 m  r
10
  y! s+ S7 V, ^& f/ |, [12, I- c, ]/ f7 m3 P0 [7 ]
17
- P9 `* u/ w9 vTopical testosterone
( I9 a& |* ^  Z; y34.6 4.5 X 6.5 85  c+ s+ x; t" H8 W) J5 s7 `7 {& M
38.8 6.0 X 8.5 708 ^1 n% R" n+ b$ P" J
40.0 6.0 X 6.5 62.5* s3 k$ }% H/ s9 ]! c$ y: J
93.6 6.0 X 7.0 55.5; R" }8 |' L0 ^* f, E
95.0 6.5 X 7.0 27.2
1 C1 k5 G4 j9 h% X  S, E5 T2 qAv. 60.0, ]3 d" Y* ?# _* x
available testosterone. Again, emphasis should be placed on0 q, Q2 B# D% ~1 U# S, t
early therapy when lower levels of testosterone appear to5 Y' E. J4 T8 O( F( B0 B( v9 K
provide the best responses. The earlier therapy is instituted7 Q! C) L$ y& u5 g0 k& N# c2 J
the more likely there will be an excellent response with low& N3 K* w7 P6 C: \
serum levels. Response occurs throughout adolescence as
: o- T$ j% _  G1 d, R! k9 w: Knoted in nomograms of phallic growth. 7 The actual response2 m% X( B. }8 ~  V) R0 O+ A
to a given serum level of testosterone is much greater at birth+ t+ v' B0 y, k7 F7 X# j1 `, t( i
and gradually decreases as boys reach puberty. This is most8 N: R' Y# |  ~6 L
likely related to the conversion of testosterone to dihydrotes-5 U; V5 f4 s1 l. K8 K
tosterone and correlates well with the studies of testosterone
7 E7 @. U) P4 x6 o8 _conversion in foreskin at various ages.
4 L. R+ G! @9 r2 u% L- S. V: _The question arises regarding early treatment as to whether; \2 z0 p; C  t8 k( M( v
one might sacrifice ultimate potential growth as with acceler-
$ `$ k7 \- _2 ~2 L; u% n7 kated bone growth. The situation appears quite the reverse% n' O9 H, d8 z9 S. |- l
with phallic response. If the early growth period is not used1 G. y9 _% l; @) [5 q& D% {! M/ U' x
when 5a reductase activity is greatest then potential growth0 G8 b2 P9 H4 T8 s8 e
may be lost. We have not observed any regression of growth/ n- q7 q; S0 p
attained with topical or gonadotropin therapy. It may well
# V$ Y2 B% V$ C, [6 U$ kbe that some patients will show little or no response to any- S7 u( f$ M) s/ I
form of therapy. This would suggest a defect in the ability to
8 r, V, O, V4 D, T9 n$ gconvert testosterone to dihydrotestosterone and indicate that' M4 i% |" S1 d
phallic and peripheral skin, and subcutaneous tissue should
* s' n* N9 O" y$ {1 B6 T) K+ {be compared for 5a reductase activity.
' }% O1 ^- S7 N5 j' {A, loop enlarges to measure penile girth in millimeters. B,  G! n, ]+ J( Y" m
example of penile girth computed easily and accurately.4 }0 X# R5 }, ^, m% h) w
conversion of testosterone to dihydrotestosterone. It is in this
; \: q7 Q" K4 a& v  Q! T$ ^% eolder group that others have noted high levels of serum  {# O* @1 O/ U$ a
testosterone with topical application. It would also appear5 Z6 W! r$ v. v+ R% M' D" B2 d$ w/ y0 S
that phallic response during puberty is related directly to the
- U( f# O; b0 ~5 r6 Qserum testosterone level. There also is other evidence of local" _6 u4 Y; I6 m1 \1 [: s
response to testosterone with hair growth and with spermato-
/ I# l' s; n+ Y$ R2 Sgenesis. 5• 6
# R, t% U0 S/ K9 d% B! _Administration of larger doses of gonadotropin or systemic% m1 Y& e" l. L- @
testosterone, as well as topical applications that produce$ v0 M, F) }- m9 x+ g6 k
higher levels of serum testosterone (150 to 900 ng./dl.), will, v1 g5 P% p, Y
also produce phallic growth but risks accelerated skeletal( b1 g$ }; E. n  t8 b3 j
maturation even after stopping treatment. It would appear
2 Z3 M; b. R9 Z5 A8 Pthat this may be avoided by topical applications of testosterone& I* `( r$ ]$ Z
and monitoring of serum testosterone. Even with this control
( ]" G: _" L, ^the duration of our therapy did not exceed 3 weeks at any
2 g! ^& C) u9 i1 C0 Y. Mtime. It is apparent that the prepuberal male subject may# h( w( ]- ^' o' ~$ Y5 G( ^
suffer accelerated bone growth with testosterone levels near4 o! G0 n. I  Y5 C
200 ng./dl. When skeletal maturation is complete the level of/ O0 k" O0 A) m3 |& f
serum testosterone can be maintained in the 700 to 1,300 ng./! b( g" A- ^" Q5 w
dl. range to stimulate phallic growth and secondary sexual6 ^5 k: T3 Y7 F7 L4 f2 l
changes. Therefore, after skeletal maturation parenteral tes-4 `/ U, N7 j! U  ]- F4 F% M! L
tosterone may be used to advantage. Before skeletal matura-
5 b' }8 c  P& m1 [2 ?& }tion care must be taken to avoid maintaining levels of serum
$ s7 l9 ~7 j! H7 P. ~8 _0 f" A4 Stestosterone more than 100 ng./dl. Low-dose gonadotropin
3 Z8 ?, L4 E) J7 sdepends upon intrinsic testicular activity and may require8 B: |$ U- `, \$ M0 q
prolonged administration for any response.
+ V3 Y% ]' l" \$ gAlternately, topical testosterone does not depend upon tes-- f9 h& V$ f2 R! e
ticular function and may provide a more constant level of
- U$ ]$ V, E8 q( Y) dREFERENCES
( w% {& P8 |3 ^2 x6 j1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,+ V6 m+ H6 b" o, ]
R.: The local application of testosterone cream to the prepub-( o: F& e" e3 K( E+ T" }
ertal phallus. J. Urol., 105: 905, 1971.1 o- F) u+ q, m3 _3 ~
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone9 c& B+ O( {" J/ d8 c
treatment for micropenis during early childhood. J. Pediat.," o5 u) I' b0 h; O
83: 247, 1973.
5 V% t  Y2 b8 }2 e% a3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
# S) W; S/ j, y3 F' S9 l' U4 ]. wone therapy for penile growth. Urology, 6: 708, 1975./ j* s- I$ l( v+ |6 F
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
( A7 k' ^4 o7 ^" hto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
* g" W9 S- t# `  v2 D  yskin slices of man. J. Clin. Invest., 48: 371, 1969.
% t6 c* v1 e1 H) g( p5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
8 H, B- ]4 j- ]4 H4 d1 Iby topical application of androgens. J.A.M.A., 191: 521, 1965.! b- \% C6 Q+ H1 d* p
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
7 x2 D$ I$ {, h$ g" Gandrogenic effect of interstitial cell tumor of the testis. J.
- k$ t4 Y$ R3 v1 R* Z+ d1 y. fUrol., 104: 774, 1970.
; a, Z$ H0 P2 B9 d) w7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-% ~' F  K8 d9 ^9 p% x
tion in the male genitalia from birth to maturity. J. Urol., 48:
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