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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND6 b  {1 a& x) o. Y" G9 y) }- D
GONADOTROPIN! `. i7 }; {' z) a7 [9 n0 \6 W& ?- R" ~
RICHARD C. KLUGO* AND JOSEPH C. CERNY1 T+ c( c' c; ~3 \
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
* H8 j# O8 F$ m& CABSTRACT& ?  O* d( y3 C* t. Y
Five patients were treated with gonadotropin and topical testosterone for micropenis associated5 P+ m  M6 u/ A. K9 M* w
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-5 [( X( F8 p2 Z8 n
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone& J! E' z% ^7 A3 Z/ M
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
% H+ g' B4 N. Q6 N9 e) gfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
. r9 x4 w1 c  l# l6 |* sincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
+ m/ C7 O" j: X/ ?$ i4 \increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response* y1 I7 y; k/ g0 D$ D9 x
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
( h: O3 I; |) V/ U9 J# Lstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
$ D: \0 G: Q1 N. Ggrowth. The response appears to be greater in younger children, which is consistent with previ-
9 D! a% B$ j1 w1 M; aously published studies of age-related 5 reductase activity.) M& z& q" `' F1 T/ }8 A
Children with microphallus regardless of its etiology will/ U- S# ~/ v9 P
require augmentation or consideration for alteration of exter-0 w  e! ~+ W8 r; }" U+ ]5 W
nal genitalia. In many instances urethroplasty for hypo-
2 w1 u: r9 N7 ]8 D8 j) L. Q! _9 Tspadias is easier with previous stimulation of phallic growth.7 o6 }/ A# Z0 @8 C
The use of testosterone administered parenterally or topically* V5 N5 w5 T4 V7 X3 r0 `$ m: Z
has produced effective phallic growth. 1- 3 The mechanism of- k& M4 U. V0 _- `' Q* X& ?: F
response has been considered as local or systemic. With this8 h" \  z7 k" {
in mind we studied 5 children with microphallus for response
, [6 S! }3 H4 a' N+ V$ r9 Y! ]; h: xto gonadotropin and to topical testosterone independently.
% e& \- ?8 H" z9 uMATERIALS AND METHODS# v9 M$ Z/ C; a
Five 46 XY male subjects between 3 and 17 years old were; Z( s# q* p8 D; h0 ^
evaluated for serum testosterone levels and hypothalamic
7 }" C/ b4 R' a4 x3 k, J3 J5 @7 Efunction. Of these 5 boys 2 were considered to have Kallmann's
3 Y( x. ^, M3 Wsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-# k. r$ O. _" _( T! D
lamic deficiency. After evaluation of response to luteinizing* ]" |+ K; \+ \! y6 X
hormone-releasing hormone these patients were treated with: K- U% o6 j  \* d4 g
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
* W: `1 J! c/ @5 Xafter completion of gonadotropin therapy 10 per cent topical
3 j2 P4 g* x& _testosterone was applied to the phallus twice daily for 3 weeks.
. V) d: v5 Z3 Z* b$ [Serum testosterone, luteinizing hormone and follicle-stimulat-
/ b2 I* F- U# ?3 A  f' Uing hormone were monitored before, during and after comple-# }7 y1 D4 A+ G
tion of each phase of therapy. Penile stretch length was. ^! G* Y2 f. e- f* o: d, ~' b9 C" O
obtained by measuring from the symphysis pubis to the tip of
" E. w) Y% q( A8 Pthe glans. Penile circumferential (girth) measurements were8 r' Y0 _, n% z, R( t1 j
obtained using an orthopedic digital measuring device (see
  i- a$ ?/ P* V& s5 H! N4 _figure).1 h0 x2 h. S+ g
RESULTS9 \! M7 b3 |/ ~! n* o7 g3 k4 }4 v
Serum testosterone increased moderately to levels between
# J( X, f: f" V# n  P4 o8 U50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-0 e; G9 t' c* ?. c7 [9 W" p7 R
terone levels with topical testosterone remained near pre-, u. j6 |8 p9 k
treatment levels (35 ng./dl.) or were elevated to similar levels
. P  [, {( c$ k* O& Ddeveloped after gonadotropin therapy (96 ng./dl.). Higher
' f+ o- j9 e6 ]5 }% e% t' B  i% X: Pserum levels were noted in older patients (12 and 17 years old),1 J9 `/ \5 n$ s2 L; Q
while lower levels persisted in younger patients (4, 8, and 10  y( Y" V8 W+ e; e$ c5 s4 j8 D
years old) (see table). Despite absence of profound alterations
: F6 s+ C) b, f: [( z& @/ J! Kof serum testosterone the topical therapy provided a greater
2 s  G5 i) o. b. V7 V7 lAccepted for publication July 1, 1977. ·2 ~$ W5 h8 W# S1 X) _8 k. N
Read at annual meeting of American Urological Association,7 y- }7 o- S1 [0 x5 Z0 D
Chicago, Illinois, April 24-28, 1977.
1 c6 @4 c( {7 F  L* Requests for reprints: Division of Urology, Henry Ford Hospital,' i( Y  p  @- ^9 f& f. t' u
2799 W. Grand Blvd., Detroit, Michigan 48202.
7 i( g  ~+ a% T  B! [) H) Aimprovement in phallic growth compared to gonadotropin.
3 J4 X% J& y7 U! H4 m6 ?7 A) x4 UAverage phallic growth with gonadotropin was 14.3 per cent: y$ V# X' c% X
increase in length and 5.0 per cent increase of girth. Topical, e9 Y% ]6 s  `# S! S
testosterone produced a 60.0 per cent increase of phallic length0 e+ m8 M+ D" o" D) K) V! H
and 52.9 per cent increase of girth (circumference). The
9 ^2 Z9 Y/ R2 C" `* g& hresponse to topical testosterone was greatest in children be-: ~6 q2 H8 @* W' X& ~. Q! [& B
tween 4 and 8 years old, with a gradual decrease to age 17
2 e5 \; t9 V$ d2 q3 byears (see table)." k3 K; @8 Z" q' w
DISCUSSION
4 O6 L3 {' N8 k. K; @1 lTopical testosterone has been used effectively by other/ W1 \+ P  [0 S
clinicians but its mode of action remains controversial. Im-
3 [3 U0 j! ~: M8 Vmergut and associates reported an excellent growth response0 z  }( t( E$ Y) `: X
to topical testosterone with low levels of serum testosterone,% t# _- d6 C( ~
suggesting a local effect.1 Others have obtained growth re-
% b4 R8 n, E) {" ?# b- S0 bsponse with high. levels of serum testosterone after topical
' M# g, C4 L" ~administration, suggesting a systemic response. 3 The use of
* [* T& k, g5 ?' [gonadotropin to obtain levels of serum testosterone compara-
. |+ f- h2 n& @$ k  hble to levels obtained with topical testosterone would seem to
! E6 ?8 Y6 K# rprovide a means to compare the relative effectiveness of& R( F: v8 M+ S0 \/ g$ |; Z3 z5 O
topical testosterone to systemic testosterone effect. It cer-9 p& Z$ M! z3 m& }4 I2 X! K
tainly has been established that gonadotropin as well as par-7 O1 X' H6 T& Q: \0 t) ]
enteral testosterone administration will produce genital
5 c" `/ |5 z8 e" U8 Kgrowth. Our report shows that the growth of the phallus was! p+ i. i9 T. Q3 m, _. Y
significantly greater with topical applications than with go-
. ?* ]+ Q$ F( inadotropin, particularly in children less than 10 years old.
6 o) ~8 L* i8 U# [4 yThe levels of serum testosterone remained similar or lower( ~1 h- `' X5 W
than with gonadotropin during therapy, suggesting that topi-
6 r. f: r1 `# @* s* {) Xcal application produces genital growth by its local effect as
# ?; u" m9 z8 R* z+ Lwell as its systemic effect.9 A7 [7 X% @# ~& q8 j2 y* ?# r
Review of our patients and their growth response related to: O! e' [. a* v" }0 e9 z7 q/ `
age shows a greater growth response at an earlier age. This is$ ~" z$ x0 ]0 k1 K2 \* m. m  y
consistent with the findings of Wilson and Walker, who
1 q" @' l# ?: q/ G* N$ v6 Wreported an increased conversion of testosterone to dihydrotes-* H+ O6 A6 c4 b1 t* o
tosterone in the foreskin of neonates and infants.4 This activ-8 S/ C4 ^) D+ A( P3 J
ity gradually decreases with age until puberty when it ap-
! w! U/ S" @' w! Sproaches the same level of activity as peripheral skin. It may: X) A& w0 m. g) q% p4 B
well be that absorption of testosterone is less when applied at5 ^0 h$ r2 B1 b% B# j5 y
an earlier age as suggested by lower serum levels in children& f' N0 [6 |! G3 |" T0 o
less than 10 years old. This fact may be explained by the
7 G$ r6 V1 H  X2 X( \% g) qgreater ability of phallic skin to convert testosterone to dihy-' D) {  p1 [8 ]9 ~" {
drotestosterone at this age. Conversely, serum levels in older+ t  z# e, Q% ]5 t- U! W0 ?2 u
patients were higher, possibly because of decreased local
% }" B6 L. a/ O' ~# l4 J8 i0 K# `* s667
' B- l0 |( o5 q, k; M5 b9 p668 KLUGO AND CERNY" K- _3 A! c: g5 E) z& a" _
Pt. Age  I2 \, h- f1 y: ?
(yrs.)" a( N' P0 O9 g8 M1 w) m6 X
Serum Testosterone Phallus (cm.) Change Length; t0 F3 `$ F7 ?7 X
(ng./dl.) Girth x Length (%)
, {# G+ t/ o' r0 N- h, v7 ^+ ]41 @' Z8 O9 G" ?* {$ {
8
2 w( W1 J: r% @$ P/ b10
) K( a' q! O; q12
8 p: V1 C$ R: \8 m  s, m17/ x8 v$ I' \- L
Gonadotropin8 V- e; Y5 @9 i& y9 t, S
71.6 2.0 X 3 16.6
' [; E0 h* `  w8 Y8 ^) n# {. A% t50.4 4.0 X 5.0 20.0. N( }! j( [. {7 z8 E
22.0 4.5 X 4.0 25.05 T3 x+ l5 H- d* y
84.6 4.0 X 4.5 11.1; ?4 u: I% \  G6 M$ p
85.9 4.5 X 5.5 9.08 K2 {2 X( C, I( q0 Y# d
Av. 14.3
2 _! d: h  r5 Z6 G" |5 a4
% u! b% p$ i( }! `6 h8
0 P# |6 g$ s3 N2 p" V  M10
2 @6 g# y. N" z* ]! I3 [+ I1 I  P120 \: ]1 l0 B; K! Q) y9 |
17
; H1 e# A3 `# q+ ~Topical testosterone. r# b9 S) A! `) s' L
34.6 4.5 X 6.5 85
1 h  r, X1 b; a: f38.8 6.0 X 8.5 70. t* g8 `& v3 d
40.0 6.0 X 6.5 62.5! q+ ?3 N' c" A) g/ c
93.6 6.0 X 7.0 55.5
8 c9 j* x+ a9 K. j8 @7 d" E95.0 6.5 X 7.0 27.2
$ C& W: c- ^2 z3 O1 cAv. 60.0
! T1 y7 |; R3 _( T3 |6 eavailable testosterone. Again, emphasis should be placed on4 Z$ }$ @- X! c/ P9 x$ Y
early therapy when lower levels of testosterone appear to
( ?' [; Z, ~: [$ k$ r* _provide the best responses. The earlier therapy is instituted! D2 n% p+ Q& C& V! ~5 g: N
the more likely there will be an excellent response with low
+ Y9 q8 {1 ~0 Z; Cserum levels. Response occurs throughout adolescence as7 O, p4 m: m2 D
noted in nomograms of phallic growth. 7 The actual response
7 v: D/ J  d9 i+ t( v* bto a given serum level of testosterone is much greater at birth. u. A( J- H7 f  ]; v
and gradually decreases as boys reach puberty. This is most
+ Y, a% n6 `2 e# O  I% Vlikely related to the conversion of testosterone to dihydrotes-6 U; V8 f$ z( C  d
tosterone and correlates well with the studies of testosterone; _2 @; `  A7 M
conversion in foreskin at various ages.! `( S/ y: S, y8 a
The question arises regarding early treatment as to whether
  q/ T6 v9 j# E2 b' o8 @, `one might sacrifice ultimate potential growth as with acceler-
' K. N0 L" Q. H% E: B. K% _  S  Mated bone growth. The situation appears quite the reverse
2 ?/ E$ s' k, e- k! _9 Q( Hwith phallic response. If the early growth period is not used4 B" h4 J* e% \: _
when 5a reductase activity is greatest then potential growth' Z  y, R. U/ z3 T" q
may be lost. We have not observed any regression of growth/ e/ D0 P- K9 Z/ ^' a6 |
attained with topical or gonadotropin therapy. It may well7 U, W3 q  o8 e+ R
be that some patients will show little or no response to any$ ]+ D: |& K) h: x
form of therapy. This would suggest a defect in the ability to7 X& K( R9 W7 ]2 e" ]2 n& K/ d
convert testosterone to dihydrotestosterone and indicate that
8 Q1 y2 ]2 a7 ], ~% j* M* O( ]phallic and peripheral skin, and subcutaneous tissue should/ \% M" s3 @  P6 a: d
be compared for 5a reductase activity.
3 W/ a0 ]3 L4 Q5 a* b7 lA, loop enlarges to measure penile girth in millimeters. B,* Y+ t0 X" x9 v0 \4 j; J2 S4 K( s
example of penile girth computed easily and accurately.
* z! R' I# m9 S6 `, r7 F/ Sconversion of testosterone to dihydrotestosterone. It is in this4 u% ~8 H- y. S1 T# u
older group that others have noted high levels of serum8 a, K# x, ?7 \  ]) ]
testosterone with topical application. It would also appear
" H' ?7 k8 t" u) _7 wthat phallic response during puberty is related directly to the3 {- u* q& b/ `/ ^
serum testosterone level. There also is other evidence of local& _, w7 `( o* t
response to testosterone with hair growth and with spermato-
0 w2 }- C: e- O, r7 Dgenesis. 5• 6! w" K7 \0 H& Q6 R4 t7 @
Administration of larger doses of gonadotropin or systemic
( j, M& s! V$ D5 o3 y: rtestosterone, as well as topical applications that produce/ ~) C0 X, R& N  d5 n
higher levels of serum testosterone (150 to 900 ng./dl.), will0 H  W2 ]( ]2 F9 u9 g3 R! A
also produce phallic growth but risks accelerated skeletal
+ L6 v( q) F6 K) M, ?maturation even after stopping treatment. It would appear: x2 o1 v: \' R$ g) w) H
that this may be avoided by topical applications of testosterone
  @, N( m% [* l& [2 H+ N! ~and monitoring of serum testosterone. Even with this control8 X" O" s0 A: J0 }2 T, X
the duration of our therapy did not exceed 3 weeks at any
9 y* X6 x$ }* v# ]! itime. It is apparent that the prepuberal male subject may0 p" s7 ^* F; H
suffer accelerated bone growth with testosterone levels near. m( {% Y5 l9 S! R5 P
200 ng./dl. When skeletal maturation is complete the level of/ s3 H0 d1 L7 j6 u( o  h* F9 m
serum testosterone can be maintained in the 700 to 1,300 ng./
8 t/ Q2 x! z% [8 h7 A9 }  _dl. range to stimulate phallic growth and secondary sexual
/ \& L, Z/ W! A4 ]# ychanges. Therefore, after skeletal maturation parenteral tes-" c% h  W, n! Q0 S1 e4 `: l
tosterone may be used to advantage. Before skeletal matura-4 p- t  s! g) d
tion care must be taken to avoid maintaining levels of serum! \! @; U: J3 c1 W8 C! `
testosterone more than 100 ng./dl. Low-dose gonadotropin1 a& R7 G1 ^, q% b: [
depends upon intrinsic testicular activity and may require* I. c5 \- |8 y3 B9 f
prolonged administration for any response.& q4 ~$ O6 K5 A/ M# P7 M" y
Alternately, topical testosterone does not depend upon tes-
; |/ a3 r; r! J( _/ H4 Z( B3 Fticular function and may provide a more constant level of
  L- |! N9 Y3 P; @+ S# P7 BREFERENCES3 a( j% }1 f$ v
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,! t3 ~: L$ F4 J6 D5 l
R.: The local application of testosterone cream to the prepub-3 F( x; U& e+ M( M
ertal phallus. J. Urol., 105: 905, 1971.' R% X' h" _* f# j+ K- Z  l9 U" c
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
$ j+ m0 \  n1 S% P$ f6 {treatment for micropenis during early childhood. J. Pediat.,
; z3 P8 F: |2 P$ N8 \5 U  X83: 247, 1973.
/ X8 c  H. z0 k0 N7 ]$ I3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
5 t9 f" P0 \7 G: r2 m2 x% T7 x# v  Kone therapy for penile growth. Urology, 6: 708, 1975.
+ z9 }$ z  J+ H6 M4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
7 l( S$ I- J- Jto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by* r* P6 B  t& R( l5 [7 H; Z( S% f
skin slices of man. J. Clin. Invest., 48: 371, 1969.! x. K" Y* u4 R6 ~  ?
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
& l8 g3 h, h6 V/ lby topical application of androgens. J.A.M.A., 191: 521, 1965.8 R( x6 p, ]( c& O5 J
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local$ ~  t/ J2 c* K% B3 r/ x' W
androgenic effect of interstitial cell tumor of the testis. J.
5 X6 x, _% V7 G2 |( EUrol., 104: 774, 1970.; Q4 c4 q! M- e2 z
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
/ u. g3 b9 e' ^tion in the male genitalia from birth to maturity. J. Urol., 48:
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