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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
/ @. \3 z' Z4 e. Y. DGONADOTROPIN
/ g  J2 Z8 t" p) C4 YRICHARD C. KLUGO* AND JOSEPH C. CERNY/ L$ P# \% l& [# a
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
: h% |( G* R0 nABSTRACT' ^  X. A" T# G: C, e# ]. X
Five patients were treated with gonadotropin and topical testosterone for micropenis associated8 f5 l! }# \0 H; b  ]/ |
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-3 j. n% d( |- d, n$ X4 @# c
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone7 g: B- T- p  ?
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
8 K4 ?3 d' W7 A4 I0 G. u* F% K( Ufor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent2 |) e, O" i+ h- X6 N0 @
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average& c2 }8 C7 M- G1 r, q2 s
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
; p9 w# x7 a. L8 i, Moccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This4 C0 J0 P3 A6 s/ @$ t' {! [
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile$ l  F% G+ j% F1 F# b5 E9 z
growth. The response appears to be greater in younger children, which is consistent with previ-
! L7 f% [4 U* vously published studies of age-related 5 reductase activity.
2 h& _6 C1 z2 b5 b% X# u" IChildren with microphallus regardless of its etiology will
' `: {9 t5 M' k2 j% q& N* l/ V5 vrequire augmentation or consideration for alteration of exter-; S6 f/ g1 y, [3 H
nal genitalia. In many instances urethroplasty for hypo-
$ T5 Z% ~+ E. xspadias is easier with previous stimulation of phallic growth.
3 O5 W7 x5 w' Y7 L5 h" yThe use of testosterone administered parenterally or topically
6 [# d% c8 j- B$ \has produced effective phallic growth. 1- 3 The mechanism of
( x  \( w; j; presponse has been considered as local or systemic. With this6 e, \4 m( M+ {% a, k2 Q' O. S! X
in mind we studied 5 children with microphallus for response
4 h8 u& b  N, m$ ato gonadotropin and to topical testosterone independently.# f+ f7 f* D& t! y1 G
MATERIALS AND METHODS
7 l4 X/ A3 B& `& }8 oFive 46 XY male subjects between 3 and 17 years old were+ M* Z8 {1 K- z$ m
evaluated for serum testosterone levels and hypothalamic
# I& y6 l& L( F1 M4 V* y" Q# Y, D5 Qfunction. Of these 5 boys 2 were considered to have Kallmann's  f. B4 B, p/ a: \
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-$ {" U2 f5 [% M. |) \3 R0 W$ _' x
lamic deficiency. After evaluation of response to luteinizing( S9 N9 ~& R0 S9 B4 G+ ]
hormone-releasing hormone these patients were treated with
5 y6 F; {0 R8 }6 _) F- s% b! K1,000 units of gonadotropin weekly for 3 weeks. Six weeks
/ b5 x5 w3 p2 wafter completion of gonadotropin therapy 10 per cent topical5 R& Z) e' |; A( F4 X5 t
testosterone was applied to the phallus twice daily for 3 weeks.: P( v, j- l) S! K5 ^; h9 Z
Serum testosterone, luteinizing hormone and follicle-stimulat-8 g! ]! l7 Y* W+ f0 c
ing hormone were monitored before, during and after comple-3 _3 p+ u" a+ s+ L  r
tion of each phase of therapy. Penile stretch length was/ P  e  ?( q9 p2 Z
obtained by measuring from the symphysis pubis to the tip of* H9 {/ J) S2 K6 d, e% }: D
the glans. Penile circumferential (girth) measurements were
: N- {: C# J9 Z# q) [8 n, a3 B( L  O: Oobtained using an orthopedic digital measuring device (see
4 E4 M7 F" L. j4 mfigure).$ n( {' E+ t7 ^
RESULTS
+ m  n1 d3 D7 o5 ^" }* `4 \; Z& h) ?Serum testosterone increased moderately to levels between
) Q! `; l" o( z, [3 N- {3 F$ {50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-' P" n, ?3 w4 L4 n: D6 W
terone levels with topical testosterone remained near pre-
7 h1 n2 y) x; w4 Y0 |3 Atreatment levels (35 ng./dl.) or were elevated to similar levels
' \/ G- R8 O) W' K; o$ `: Ndeveloped after gonadotropin therapy (96 ng./dl.). Higher
8 F2 v+ j$ F+ T, y% M' Vserum levels were noted in older patients (12 and 17 years old),
  D7 s0 K6 D6 qwhile lower levels persisted in younger patients (4, 8, and 10
% I5 `8 X( b) |years old) (see table). Despite absence of profound alterations0 ]* y  X% i: y% k8 O
of serum testosterone the topical therapy provided a greater; Z2 i+ M, w6 {3 z
Accepted for publication July 1, 1977. ·. w8 @& M; j# A, z8 M& g$ J8 q
Read at annual meeting of American Urological Association,& N* N0 ~% m) v! E: h* C
Chicago, Illinois, April 24-28, 1977.& a2 F' ]* s& i3 ]. B/ v
* Requests for reprints: Division of Urology, Henry Ford Hospital,
  @9 [' h0 t' b( P; h9 j* `1 t2799 W. Grand Blvd., Detroit, Michigan 48202.2 Z7 ]0 r# h) P9 L1 B
improvement in phallic growth compared to gonadotropin.
: e! h; f7 h' A* W* f0 [+ PAverage phallic growth with gonadotropin was 14.3 per cent
0 q+ u7 K/ E- j# dincrease in length and 5.0 per cent increase of girth. Topical! d; x  l4 X+ j  R+ J
testosterone produced a 60.0 per cent increase of phallic length
, q- U% v0 X5 I: |and 52.9 per cent increase of girth (circumference). The* T& P' T; W, t
response to topical testosterone was greatest in children be-  ~- e2 O" ~) {8 L& C
tween 4 and 8 years old, with a gradual decrease to age 17
5 ]2 O& C+ ^7 K5 H; I/ J3 Syears (see table).& A- e' k& I9 _5 B% d
DISCUSSION
! k2 I; H( u1 [1 |Topical testosterone has been used effectively by other
' l6 U# x9 w+ i4 S; \clinicians but its mode of action remains controversial. Im-8 I  h2 i, `' u) O+ K
mergut and associates reported an excellent growth response
9 X1 f; v# g( Y, M$ q! G, jto topical testosterone with low levels of serum testosterone,- F% W) c4 H0 L9 t
suggesting a local effect.1 Others have obtained growth re-
+ L0 E1 O2 I( d& ]" {* H6 Z4 asponse with high. levels of serum testosterone after topical
6 B5 P6 l2 @8 u0 M) x, G$ l1 Qadministration, suggesting a systemic response. 3 The use of2 V! l7 E5 D7 o+ Z' D  L' r& ]
gonadotropin to obtain levels of serum testosterone compara-$ {8 W- l/ R3 m7 D1 i4 W
ble to levels obtained with topical testosterone would seem to* P) G  K9 B$ q9 ]  z! U- @
provide a means to compare the relative effectiveness of3 Y* P8 ^% s7 Z
topical testosterone to systemic testosterone effect. It cer-+ p( K0 k, i6 f4 t; j7 j
tainly has been established that gonadotropin as well as par-
% T6 h: L" v$ J  u6 G3 ^enteral testosterone administration will produce genital5 O, b3 P) z8 Y2 z- g3 t. P
growth. Our report shows that the growth of the phallus was, z3 P. Q+ E' e2 G+ B: L
significantly greater with topical applications than with go-1 |  v4 t3 ]) t* M
nadotropin, particularly in children less than 10 years old.8 d% p  e7 W3 {
The levels of serum testosterone remained similar or lower( j  r/ |. s9 y7 q. `
than with gonadotropin during therapy, suggesting that topi-7 n  P2 z2 [0 M; e
cal application produces genital growth by its local effect as5 _8 o8 f$ }6 v. l& _
well as its systemic effect.# Z' n. b4 z$ @0 s
Review of our patients and their growth response related to: U* g+ H$ O, v; j
age shows a greater growth response at an earlier age. This is
* H/ q' c  L& w) w6 Cconsistent with the findings of Wilson and Walker, who6 n; `; `! \% S1 u
reported an increased conversion of testosterone to dihydrotes-
5 c, `; n1 ]* H, |$ \) [! rtosterone in the foreskin of neonates and infants.4 This activ-9 q% R& u) A) K+ u$ v
ity gradually decreases with age until puberty when it ap-2 U, D  W  ~8 B8 Y: ~$ N
proaches the same level of activity as peripheral skin. It may1 I% w( n; w2 @
well be that absorption of testosterone is less when applied at
, `0 P, X9 m/ L+ k" R% u: Kan earlier age as suggested by lower serum levels in children6 a8 e! Q5 I% h9 }* E; l: W
less than 10 years old. This fact may be explained by the
! @% X* h  i7 b4 K. X. Dgreater ability of phallic skin to convert testosterone to dihy-
! n2 @9 y: F( Y& mdrotestosterone at this age. Conversely, serum levels in older
. ~/ c6 t3 c) }) e5 f) \: kpatients were higher, possibly because of decreased local4 m1 u) q  \5 |6 ?. F$ b- i: p
667
5 _0 C  I/ W. y6 Z; i2 E668 KLUGO AND CERNY
# `6 H$ d. Z' h- c# RPt. Age
" w( B; x) n5 ~(yrs.)9 {3 t' ^" ]* }* k  E/ Z1 s
Serum Testosterone Phallus (cm.) Change Length/ S9 k, }9 |% \' x( Q/ P
(ng./dl.) Girth x Length (%). j7 ?1 _1 Y0 L% m* X6 b( U* V- g
4% E) \5 K) o+ b9 k  S
8
+ T+ z- m0 E  i$ f10
8 a" j+ d) m3 @! E  K12
7 e7 U7 {/ l! Y& ]17- C/ q$ S7 w# b
Gonadotropin
; x2 I8 Z! s: Z3 A9 q71.6 2.0 X 3 16.6( [2 t  `5 `/ A1 F* [; e
50.4 4.0 X 5.0 20.0% ]  W( z! @0 a% g( B7 V
22.0 4.5 X 4.0 25.0$ c4 V& W5 ]$ j7 q" p
84.6 4.0 X 4.5 11.1
% Y9 f* B1 x- o6 P85.9 4.5 X 5.5 9.0' y5 s* X$ R/ `5 p4 n6 N1 n
Av. 14.3: }  W0 B9 L' W# C
4
( i  p2 ]3 o* V% l9 D3 X8
4 W  B: w- Z! u: w: t* k: O) ?10
/ Z" m5 o5 J, A, q12+ b( Y1 j3 k2 i) P7 f6 v4 w
179 b" ^$ C! {6 R
Topical testosterone
1 [2 E; m$ w) E3 [2 @1 B3 k$ O34.6 4.5 X 6.5 85  m% w8 @, W# `
38.8 6.0 X 8.5 70, h9 b3 z8 ]& P' t9 F0 _
40.0 6.0 X 6.5 62.5
& z/ \' [: G1 A# S93.6 6.0 X 7.0 55.5  F; a) w) ~: |7 C9 }" k4 f
95.0 6.5 X 7.0 27.21 a6 O. d) ^% R+ i5 z9 k
Av. 60.0
6 H& M- U9 W/ S+ F7 k2 [* Gavailable testosterone. Again, emphasis should be placed on7 p" T+ W4 W) i" h- S& J
early therapy when lower levels of testosterone appear to
' M0 x% M. l% Q1 r) L8 ~4 W9 lprovide the best responses. The earlier therapy is instituted3 J! B5 N  N9 U: M
the more likely there will be an excellent response with low
$ ^9 X" u* H7 L- }* Q8 d7 a' pserum levels. Response occurs throughout adolescence as) |3 [+ m6 H) V
noted in nomograms of phallic growth. 7 The actual response
; l! \8 a( E# |; M: T$ \* k0 ?to a given serum level of testosterone is much greater at birth
, a, L3 E  ~5 e5 Q" A9 {and gradually decreases as boys reach puberty. This is most
/ Q) K) Z1 ~( ?' o9 Z; `  f( ~likely related to the conversion of testosterone to dihydrotes-9 E5 Z! Z2 V- y
tosterone and correlates well with the studies of testosterone
. P9 G8 I; m4 w' @$ aconversion in foreskin at various ages.
- ]7 H; W" L  E" ?# r! v, l+ EThe question arises regarding early treatment as to whether
. o3 Y2 j$ l1 wone might sacrifice ultimate potential growth as with acceler-+ C+ }# [6 q" ~  S5 v
ated bone growth. The situation appears quite the reverse( Q* C* J2 a% y, g
with phallic response. If the early growth period is not used& k+ z/ o2 s' k5 n
when 5a reductase activity is greatest then potential growth( `4 s, f3 E( K9 c/ {' D  J1 F6 w
may be lost. We have not observed any regression of growth
+ d& _3 p2 a0 Y) M% lattained with topical or gonadotropin therapy. It may well
( m+ T3 b2 j% zbe that some patients will show little or no response to any0 U' t. ]3 W8 d, U7 _* I; D
form of therapy. This would suggest a defect in the ability to
7 n7 U/ n+ s; l6 hconvert testosterone to dihydrotestosterone and indicate that
  r4 l/ H1 K- C0 f. Z; Z1 {, Ephallic and peripheral skin, and subcutaneous tissue should7 D; Z: O6 p4 w" k
be compared for 5a reductase activity.; F1 d4 Q6 R5 c) f) H
A, loop enlarges to measure penile girth in millimeters. B,7 e' O# c% t- I3 R/ x; [
example of penile girth computed easily and accurately.
1 k9 d7 P4 @' I4 Econversion of testosterone to dihydrotestosterone. It is in this3 ~2 {; n" b9 i0 E' k
older group that others have noted high levels of serum
9 D& j  J+ t5 @. E" _testosterone with topical application. It would also appear
) g0 i0 I. O4 E- c5 x2 M6 zthat phallic response during puberty is related directly to the- k! P6 q5 t  ]( S3 W8 X6 ~$ X
serum testosterone level. There also is other evidence of local
: k8 L9 X% N3 @/ y" M% Mresponse to testosterone with hair growth and with spermato-- ?" D2 V% x5 n( y/ x% R) _4 X9 u( |
genesis. 5• 62 h+ }! I9 s. m0 B' m
Administration of larger doses of gonadotropin or systemic% d" a1 {& e; x% N
testosterone, as well as topical applications that produce+ |% q7 S) T# P2 q2 \4 @4 f7 W
higher levels of serum testosterone (150 to 900 ng./dl.), will- e/ _* |$ Y  w0 V7 S
also produce phallic growth but risks accelerated skeletal; [, _1 B6 k4 o
maturation even after stopping treatment. It would appear' l9 I/ ?* V3 p5 ~
that this may be avoided by topical applications of testosterone
. Y: c6 \6 y$ R: q0 xand monitoring of serum testosterone. Even with this control
9 {& O! ?9 t0 J- \8 W/ Kthe duration of our therapy did not exceed 3 weeks at any6 J4 q3 z/ O! i9 g2 d
time. It is apparent that the prepuberal male subject may
0 C: v/ p- `: O' d: V7 gsuffer accelerated bone growth with testosterone levels near
# N- S  I# _, m. Z200 ng./dl. When skeletal maturation is complete the level of* {' A0 C! x1 y) T3 f- I- A
serum testosterone can be maintained in the 700 to 1,300 ng./1 w/ V' H- R# Z8 R; g$ K  L, r$ v
dl. range to stimulate phallic growth and secondary sexual
6 a% u4 u+ ~6 q2 w& bchanges. Therefore, after skeletal maturation parenteral tes-
, a7 q9 s; S$ z' Itosterone may be used to advantage. Before skeletal matura-8 p( e  E& f/ D  p4 ?, Z0 b
tion care must be taken to avoid maintaining levels of serum
) [! x  G+ y7 S) U5 otestosterone more than 100 ng./dl. Low-dose gonadotropin
1 t4 s  X4 o0 B, r; `depends upon intrinsic testicular activity and may require
* o  J8 |9 t) y% g: L, }6 ?prolonged administration for any response." ]7 ~3 t5 O6 Y# {7 c7 x$ x# I9 Q
Alternately, topical testosterone does not depend upon tes-
3 a' e. V% r  o/ Q+ g3 {; E% Uticular function and may provide a more constant level of
8 W2 x4 ]' p/ {3 Y( T5 I/ }REFERENCES
" |, m( Y% `4 m; ]" V1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,/ x% U  _$ k3 t& z
R.: The local application of testosterone cream to the prepub-, K' z5 N" |8 c- u& W
ertal phallus. J. Urol., 105: 905, 1971.
8 g* |# ]) Y5 m8 Q, F- b. Y2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone$ K1 M2 v: T2 w3 G
treatment for micropenis during early childhood. J. Pediat.,# O* a% M' w# u. @
83: 247, 1973.9 _4 o2 b3 d% Y/ N
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-9 k0 s) r& B. B. p+ }/ a
one therapy for penile growth. Urology, 6: 708, 1975.
. ?$ G  m  t1 ?$ ]* u4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
1 t- `1 f3 r% n( U0 E* e, ~) Cto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
- S$ L" Z0 J. M- ~& X/ ]skin slices of man. J. Clin. Invest., 48: 371, 1969.- p7 q$ d6 a" @9 B- Y2 d' U: J
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth  `8 ?8 E4 C5 V4 _3 {
by topical application of androgens. J.A.M.A., 191: 521, 1965.: H6 Y/ J7 @1 I+ s( X, H7 S/ q
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local3 ], T; M4 S6 A8 H
androgenic effect of interstitial cell tumor of the testis. J.5 n% I* j# z( p# w8 ~1 `
Urol., 104: 774, 1970.
) c! \! N, Q$ R8 M, _7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-, z- ~3 G' P3 C* R5 A3 e: V- R
tion in the male genitalia from birth to maturity. J. Urol., 48:
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