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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
, T+ X0 i) j8 |5 u: R  eGONADOTROPIN
2 f% I1 i/ w9 o3 e8 SRICHARD C. KLUGO* AND JOSEPH C. CERNY
* @& x. ]) Z% B. }& k) a! C+ @/ T/ kFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan( L0 M6 t8 q# ]5 U6 n
ABSTRACT
0 O; d, j7 @+ f4 g. C2 b4 p$ u6 _Five patients were treated with gonadotropin and topical testosterone for micropenis associated
" ~" K- |7 B- g) Fwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
4 A" M# n$ j! F2 w- c! Ttropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
$ H& v- N% ], S6 |; y2 H: k2 P* |2 @cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
, ~7 U2 D% Q$ c  ~4 z8 Q; Cfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent: X- X9 G% h  ~% F% Z# h' \/ U- y
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
3 b, ]4 _2 Y; k% Qincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
+ [1 o, ]4 V) Z0 K% doccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This1 Z' H& _# z- d8 F
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile2 ]' y( w: E: T4 C& H9 L. d5 j
growth. The response appears to be greater in younger children, which is consistent with previ-
8 J& P5 L4 w$ W% ]- {7 W  _ously published studies of age-related 5 reductase activity.
( U7 q# w; M- x; tChildren with microphallus regardless of its etiology will
# k; x# Z0 G3 lrequire augmentation or consideration for alteration of exter-1 i- P9 c# ^1 U  U7 G
nal genitalia. In many instances urethroplasty for hypo-- g0 e6 @1 C. h* J' x& M- ]0 ]' g
spadias is easier with previous stimulation of phallic growth.
3 `" n* |* N( g: `The use of testosterone administered parenterally or topically. D" x& z5 `  x& C9 B5 v; ~
has produced effective phallic growth. 1- 3 The mechanism of& R1 x" M" D7 ]( Z2 j+ W3 E
response has been considered as local or systemic. With this
# U5 k# J% v( j: z3 E" Sin mind we studied 5 children with microphallus for response1 A  D* m. \& q1 s: Y9 t3 |0 L* e& S
to gonadotropin and to topical testosterone independently.& _8 n3 m! A$ j: v& B+ ]
MATERIALS AND METHODS
, W5 l# }; }  m2 l) q1 W7 T. [Five 46 XY male subjects between 3 and 17 years old were
  ^* a8 x- \/ L& N/ }$ @evaluated for serum testosterone levels and hypothalamic
( r0 e: d2 U$ K) s/ ofunction. Of these 5 boys 2 were considered to have Kallmann's
) l% x7 }- k! J' O# qsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
% S( E! y! B8 O* _lamic deficiency. After evaluation of response to luteinizing
4 W+ q/ Y- _' b! k: Nhormone-releasing hormone these patients were treated with
, ?$ w& r$ c# D9 e1,000 units of gonadotropin weekly for 3 weeks. Six weeks  c3 R+ J5 E& l8 A% G/ T( O+ X
after completion of gonadotropin therapy 10 per cent topical/ q  Y0 \( f2 v  V! E6 O9 f
testosterone was applied to the phallus twice daily for 3 weeks.
) K, m( x5 _: F( d; r, V# s" \: HSerum testosterone, luteinizing hormone and follicle-stimulat-7 {8 d8 ]$ m& E! R3 ]- n4 e
ing hormone were monitored before, during and after comple-, p" t+ ?* d  g
tion of each phase of therapy. Penile stretch length was
% Y& K( x  }0 v8 C8 B+ m1 ~2 Bobtained by measuring from the symphysis pubis to the tip of& U8 M# u/ W* [
the glans. Penile circumferential (girth) measurements were# Y3 N& U4 V7 p  _# K
obtained using an orthopedic digital measuring device (see5 d: ?' D# T; v' r8 v* ~) H
figure).; E5 O+ _% @8 M' P
RESULTS
# j, I# k4 g0 p# L0 q7 n6 }Serum testosterone increased moderately to levels between( o, I. a4 \( a! y
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
  w% n. L; `+ k  k% m0 K. iterone levels with topical testosterone remained near pre-
4 ]; [& p+ J1 {0 x( o( u, qtreatment levels (35 ng./dl.) or were elevated to similar levels
- }$ z# L/ B( }, @% \. B( _developed after gonadotropin therapy (96 ng./dl.). Higher1 y) T5 c8 f" n$ |# p
serum levels were noted in older patients (12 and 17 years old),+ |7 Q% m0 }, u0 ~+ ~
while lower levels persisted in younger patients (4, 8, and 104 N" G% n1 r+ W3 O
years old) (see table). Despite absence of profound alterations9 I9 g! D! L' v$ L; L/ X6 o( p
of serum testosterone the topical therapy provided a greater
1 a* B5 c5 p( a) {) CAccepted for publication July 1, 1977. ·' {) G# \* P* m( B7 Y) i
Read at annual meeting of American Urological Association,0 S; U& a2 E- t  A& ?2 K
Chicago, Illinois, April 24-28, 1977.- K3 O/ A$ W, |0 K( j% _& K
* Requests for reprints: Division of Urology, Henry Ford Hospital,
. i; W; y5 j. u: a1 c5 N2 `) d1 r2799 W. Grand Blvd., Detroit, Michigan 48202.
4 g- s$ O. x1 ^; [+ `' z/ Fimprovement in phallic growth compared to gonadotropin.! d7 i$ s- P0 w
Average phallic growth with gonadotropin was 14.3 per cent3 Y( l+ [0 H; C4 ?' H$ R; c
increase in length and 5.0 per cent increase of girth. Topical( t& `6 @6 M7 {
testosterone produced a 60.0 per cent increase of phallic length1 M* t5 c: U, x& M0 l  ~
and 52.9 per cent increase of girth (circumference). The; b+ o$ v2 W/ Z: y4 |4 t) y
response to topical testosterone was greatest in children be-
- O( l  ~$ y9 R  Utween 4 and 8 years old, with a gradual decrease to age 17
8 ]2 ]* Z, ^- t+ @3 x' o( Vyears (see table)./ X5 D* k% d7 s8 x8 g0 A# t+ [
DISCUSSION& o& L5 _' M7 C# V7 ^, r
Topical testosterone has been used effectively by other1 p8 c. ~% T  @# U
clinicians but its mode of action remains controversial. Im-+ p/ s- j1 Y6 e5 c+ k7 n* A
mergut and associates reported an excellent growth response
; t& }: a. y- w7 A" |to topical testosterone with low levels of serum testosterone,
* e* t, {$ j! Y) o0 k' ?% M( Tsuggesting a local effect.1 Others have obtained growth re-
% ?+ L3 A$ ]0 j* Tsponse with high. levels of serum testosterone after topical% V" G; W1 N8 F6 N9 {9 K! D
administration, suggesting a systemic response. 3 The use of, _6 ^1 y+ e8 d5 R3 M
gonadotropin to obtain levels of serum testosterone compara-
% M- ?; w/ C" {5 w0 ]ble to levels obtained with topical testosterone would seem to! ^( T9 I' x9 y) Z0 {3 D9 N% k. V
provide a means to compare the relative effectiveness of) I6 c2 b  b# ^2 O( q
topical testosterone to systemic testosterone effect. It cer-* s: R# @+ H- c; ]6 a9 v
tainly has been established that gonadotropin as well as par-
* m2 F9 {; i6 H5 p0 |1 n5 @8 }3 t0 L5 _4 Tenteral testosterone administration will produce genital
9 m9 w  n4 M7 J6 O9 s5 ]8 U& `! Cgrowth. Our report shows that the growth of the phallus was
" T' O$ n) l0 O+ Z" t# q' O/ |9 g: hsignificantly greater with topical applications than with go-. b6 ~4 ~, |: F" T# v* O
nadotropin, particularly in children less than 10 years old.
; a& v/ u9 G9 k7 }9 R8 F, PThe levels of serum testosterone remained similar or lower
% l4 L- A+ m% R$ Q* ^" Gthan with gonadotropin during therapy, suggesting that topi-
- n4 P7 ]4 C$ n, a/ mcal application produces genital growth by its local effect as: g) u, s2 u% m
well as its systemic effect.4 p5 Q3 g& C% T, S* K+ w
Review of our patients and their growth response related to
. M' X& Y( Z( `7 A5 ?9 |6 Tage shows a greater growth response at an earlier age. This is
  r, N5 `3 C+ W. I7 {consistent with the findings of Wilson and Walker, who  I6 D' I: x0 n9 C
reported an increased conversion of testosterone to dihydrotes-0 R% s1 V, P7 g; l* t& M! H
tosterone in the foreskin of neonates and infants.4 This activ-
5 w" Z" b* F+ H$ X% ^ity gradually decreases with age until puberty when it ap-# M( Y. E, L0 A  }* x. o
proaches the same level of activity as peripheral skin. It may
* C- u* F" c6 ]- c  Y/ f0 kwell be that absorption of testosterone is less when applied at
+ W+ B# s5 \( T* s1 e1 @7 m( @4 kan earlier age as suggested by lower serum levels in children4 E  @" A, y$ w' L: h
less than 10 years old. This fact may be explained by the! R) Y9 |  v- N- b, I
greater ability of phallic skin to convert testosterone to dihy-- z9 j# C' W: }( \9 i* `; D0 d* A
drotestosterone at this age. Conversely, serum levels in older2 K# d) C9 G% N8 W2 q1 G* m
patients were higher, possibly because of decreased local
% n) P% |. A* @) [" v667$ e- q( \) o, i
668 KLUGO AND CERNY
# m+ h9 S+ \$ ]( d7 W9 R. jPt. Age
# _( P, ?( j; t2 n(yrs.)9 ?9 n, N! _& N
Serum Testosterone Phallus (cm.) Change Length; v% {" L' a. D
(ng./dl.) Girth x Length (%)
, I: |* Y" j% y. X% ~5 d: d4+ t' ?" `4 a! Y! q) S) m
86 J3 q$ T. \1 S
10
; ?+ q( C; ^+ u* [5 O12* K) \6 }. C9 u: ]3 X8 d1 C0 j
170 g' D. u# ?/ X0 k5 [! W3 i( I
Gonadotropin) n! p! N1 u( f+ {$ f- O# E
71.6 2.0 X 3 16.6
9 d! l0 T  S/ v- V, r6 o* d+ W3 v50.4 4.0 X 5.0 20.0
" s* a2 H0 I7 Q1 t# p2 p22.0 4.5 X 4.0 25.0
$ X* V' I2 U7 c) b- e- I+ N84.6 4.0 X 4.5 11.1
( i0 ^& M2 L1 Q9 G: C) x85.9 4.5 X 5.5 9.01 q$ g5 B# t3 z+ G( g7 o6 r( A
Av. 14.3
* H8 @9 k+ }- W/ e8 B4
3 s, ]3 d1 J$ \8 l/ q) \8
6 P7 ~4 K" D! P' Z1 u! P! ]' x" {10
2 l3 b8 \; |2 `# T  ?8 ~120 W* g7 |0 K+ K) x' v& M/ F! W
17
7 E1 r4 u. u. j* rTopical testosterone9 m9 T( U, B: b7 |; J
34.6 4.5 X 6.5 85
: @+ }# H. s' G38.8 6.0 X 8.5 70
. F) C( Z6 u; \40.0 6.0 X 6.5 62.5
  O# ], B2 \3 E, H& N2 s93.6 6.0 X 7.0 55.57 l4 |$ E& V7 j- p8 Y* V& p
95.0 6.5 X 7.0 27.2
7 y3 @: n, h* ~% j& x0 FAv. 60.0' }, B0 Z  N0 C. M8 Z6 P
available testosterone. Again, emphasis should be placed on( y# m; M& c6 y, y0 i* Y+ h
early therapy when lower levels of testosterone appear to5 z# P# u: h, y8 e3 Y+ n; ~6 E! J
provide the best responses. The earlier therapy is instituted$ z: [# _# {1 ]% A" V5 {
the more likely there will be an excellent response with low
8 a( e1 _. c/ a) @# C) j5 R0 qserum levels. Response occurs throughout adolescence as: R: ?* Z2 n" n" F" W
noted in nomograms of phallic growth. 7 The actual response  i+ M# I; ^, r$ ~4 @
to a given serum level of testosterone is much greater at birth
+ u6 ~6 K5 c; R$ mand gradually decreases as boys reach puberty. This is most
7 o& d1 ~; B; g8 v* @) }likely related to the conversion of testosterone to dihydrotes-- Q+ H( i8 ]9 D. ]$ ~2 k$ V1 J
tosterone and correlates well with the studies of testosterone
3 W( W9 {. r' o$ V# jconversion in foreskin at various ages.
- q/ E5 W/ m( K* h$ VThe question arises regarding early treatment as to whether2 ?; Z2 ?0 _  d& \7 m+ B% U
one might sacrifice ultimate potential growth as with acceler-
8 ^0 a% q, b& q% Z! t6 \; t: zated bone growth. The situation appears quite the reverse
# K: ~$ R0 l- D) o7 L; h+ v8 Qwith phallic response. If the early growth period is not used0 W9 @" Y7 c( ]' g  i
when 5a reductase activity is greatest then potential growth
3 t* B( k7 m* R# \may be lost. We have not observed any regression of growth1 a3 T; T- T$ N( [/ Q
attained with topical or gonadotropin therapy. It may well0 E1 j' {( D+ h$ p3 \) i* x
be that some patients will show little or no response to any1 m6 b2 {+ e3 w6 F
form of therapy. This would suggest a defect in the ability to
( E) \. e8 \! G9 W( ?convert testosterone to dihydrotestosterone and indicate that7 ]4 L2 H8 w8 J* e9 b" Y+ \
phallic and peripheral skin, and subcutaneous tissue should
1 e* H8 ~( A' ibe compared for 5a reductase activity.7 z5 E9 t: g3 ?8 e% Q
A, loop enlarges to measure penile girth in millimeters. B,
: j5 s# L8 Z: N4 G+ \% Fexample of penile girth computed easily and accurately." c2 d8 J7 A5 j* E& ]
conversion of testosterone to dihydrotestosterone. It is in this: I( v% y6 C9 c! F
older group that others have noted high levels of serum" o1 y3 u/ E  T9 U( [' P9 H7 t$ y
testosterone with topical application. It would also appear
9 r. b4 o" Q* f; M+ uthat phallic response during puberty is related directly to the( \0 P( ~# C. M
serum testosterone level. There also is other evidence of local* v& n0 R. f: a" ~) T% k( [
response to testosterone with hair growth and with spermato-- P# R4 ^+ B% E1 A) Y) J
genesis. 5• 6
% `6 Z) ^2 U/ Z1 m  f' zAdministration of larger doses of gonadotropin or systemic
5 {, x1 W/ A1 [9 Jtestosterone, as well as topical applications that produce
( o. X$ j/ X6 E! Y- Ohigher levels of serum testosterone (150 to 900 ng./dl.), will" v; Q! ?& c$ ~" H
also produce phallic growth but risks accelerated skeletal& j; f8 m% K7 h: d" l/ Y" v5 G
maturation even after stopping treatment. It would appear  B8 o8 O; M! d' z6 _
that this may be avoided by topical applications of testosterone' }+ T+ P6 j8 |  n2 K
and monitoring of serum testosterone. Even with this control% c, v# A6 o! ^7 ^' \
the duration of our therapy did not exceed 3 weeks at any$ E' a/ ]# T( `7 |- N
time. It is apparent that the prepuberal male subject may( b, W3 e, ]* X9 C- ]) l
suffer accelerated bone growth with testosterone levels near
  r+ |/ |' @, W& P200 ng./dl. When skeletal maturation is complete the level of
# e/ x2 O7 ^6 Q" g* B8 Rserum testosterone can be maintained in the 700 to 1,300 ng.// `2 @' @; j" }  `" p- G* u, y" O* O
dl. range to stimulate phallic growth and secondary sexual
$ w& x2 T$ Q$ f/ Zchanges. Therefore, after skeletal maturation parenteral tes-
1 O1 S1 V! L* o- R0 j4 Q0 ftosterone may be used to advantage. Before skeletal matura-
* _) {( t/ A1 x& ?1 Rtion care must be taken to avoid maintaining levels of serum
# h. s' o  H" V& Vtestosterone more than 100 ng./dl. Low-dose gonadotropin
$ C) g1 M& Q, }depends upon intrinsic testicular activity and may require# @! s8 r1 f) p2 y* A
prolonged administration for any response.
! M$ l4 G( E2 j0 S- J' |" s5 a, ZAlternately, topical testosterone does not depend upon tes-( I5 p* @- t. L9 d; S! U
ticular function and may provide a more constant level of0 O5 y5 u' B# Z/ t" H* S$ A
REFERENCES" A% x) b& J" F
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,' W; T0 h/ z& Z+ y9 i+ h
R.: The local application of testosterone cream to the prepub-
9 |: ]( X- {7 o0 j& ?/ x$ \& r5 mertal phallus. J. Urol., 105: 905, 1971.
" R2 \5 l3 A3 Z/ `2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
2 }+ {% ?2 J7 dtreatment for micropenis during early childhood. J. Pediat.,
1 |4 |; J7 B( I3 X6 t# a83: 247, 1973.
! U( N! G' B4 K. [2 R3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
% h! m( N8 v# }" L( k5 _one therapy for penile growth. Urology, 6: 708, 1975.# V# d7 P/ K+ K: E
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
' P: J5 B" e2 \+ wto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
% [) _* W5 H* J' l" b% Iskin slices of man. J. Clin. Invest., 48: 371, 1969.
# Z; \, b/ a! l* j2 q# V# h5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
  Y8 p5 ^  _& ]7 G) Q- Rby topical application of androgens. J.A.M.A., 191: 521, 1965.; |5 c% I& ^) z  W
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
; ?8 G7 f4 B& Y7 f8 u& S6 B3 oandrogenic effect of interstitial cell tumor of the testis. J.7 q# P" m0 d, S
Urol., 104: 774, 1970.2 t; K( H! t! G! K) @
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
1 z: D" c, c+ @+ y3 Jtion in the male genitalia from birth to maturity. J. Urol., 48:
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