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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
  a+ f2 t" v; y( N( F0 ~# }$ BGONADOTROPIN( F5 E" G6 P, S# S* N( K3 d9 ~/ S
RICHARD C. KLUGO* AND JOSEPH C. CERNY
9 k, I* d; k" Y! g$ P6 oFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan' l5 ^/ a3 i# V9 n5 N4 C
ABSTRACT9 v* z( e6 b2 S- j: I2 t& Y" k
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
" S* ?% ?3 a- d. ^: Y( s+ j; M5 b0 Bwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
) A( \' _2 H: Q' S* H" ^tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
7 q2 r) S; i7 v) ^* Wcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
- d; H2 e* N/ o) O; Jfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
9 T& Z- D- v0 k/ H2 Yincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
8 @7 G7 V0 D3 N4 hincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
# ]  Q3 C7 ~7 x* U" u& v: \+ R* S* {occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This( s" ]5 e9 v# k& Y+ P. F+ Z
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
& B7 v+ L4 C+ U  y% wgrowth. The response appears to be greater in younger children, which is consistent with previ-* q' Y8 i! s# x% ?2 y! ?% k
ously published studies of age-related 5 reductase activity.
  z' i( j( G8 `# ?Children with microphallus regardless of its etiology will
7 x$ k. I# f, x# Orequire augmentation or consideration for alteration of exter-
& d: e  a4 c/ t/ E5 v3 H1 onal genitalia. In many instances urethroplasty for hypo-8 g7 h/ L* h- Z
spadias is easier with previous stimulation of phallic growth.
* ?9 m# ?  `0 L2 I2 KThe use of testosterone administered parenterally or topically. @( L5 Z, Z- ?6 W7 R" u, h
has produced effective phallic growth. 1- 3 The mechanism of) I! S6 q+ D8 v0 x' }% B
response has been considered as local or systemic. With this  D/ f# Y$ F' ]% i$ t5 |9 I
in mind we studied 5 children with microphallus for response2 g8 C" R1 b" ~3 b
to gonadotropin and to topical testosterone independently.
9 g( p) H6 H  k( Y; u% h* vMATERIALS AND METHODS
% M* |4 c, c' ^8 I4 M! e$ eFive 46 XY male subjects between 3 and 17 years old were
, S/ C' G- p9 R) A2 Qevaluated for serum testosterone levels and hypothalamic8 W, q9 W' a5 `3 r
function. Of these 5 boys 2 were considered to have Kallmann's, e/ ^" X8 Z0 ^
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
8 O! u. m5 W; Olamic deficiency. After evaluation of response to luteinizing7 B4 U8 _6 T; j2 x4 D
hormone-releasing hormone these patients were treated with5 S8 u+ G% Y3 j
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
/ Q+ P8 [3 \0 j1 y. t5 Y7 pafter completion of gonadotropin therapy 10 per cent topical
3 F' f- z/ K( o9 }5 gtestosterone was applied to the phallus twice daily for 3 weeks.
& R0 u$ i" O) N' {Serum testosterone, luteinizing hormone and follicle-stimulat-) R4 S7 M# a$ F0 r# N
ing hormone were monitored before, during and after comple-
/ ~& k2 c1 Z. e3 t# [- Ntion of each phase of therapy. Penile stretch length was
% @' i: b  i2 robtained by measuring from the symphysis pubis to the tip of
- L' J5 r, v/ j& }the glans. Penile circumferential (girth) measurements were9 d1 g/ w* X6 \
obtained using an orthopedic digital measuring device (see% G. R8 X! U7 Q% A3 M( E$ s) @- W
figure).; ~; p, H5 I( D5 E$ B1 |
RESULTS& f- U& T8 U/ C' i( j+ t( Q/ U
Serum testosterone increased moderately to levels between8 s" G- }# H) x* m1 g3 q; D' X- P' Z$ z
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
* v  L. L% p) s4 J- Q# v7 tterone levels with topical testosterone remained near pre-
9 G* J8 j8 r9 b3 J! B% D) [, ztreatment levels (35 ng./dl.) or were elevated to similar levels/ f# A6 o) P9 q2 b
developed after gonadotropin therapy (96 ng./dl.). Higher: a# I3 x& ]% x8 w7 U1 K. m
serum levels were noted in older patients (12 and 17 years old),3 J: d7 E+ y, y! w! n
while lower levels persisted in younger patients (4, 8, and 10
+ n- T! `# u$ X/ v  t, d! Zyears old) (see table). Despite absence of profound alterations3 ]* @6 X6 ~6 d8 ]: g
of serum testosterone the topical therapy provided a greater
" W- S3 E! ~1 T4 T' qAccepted for publication July 1, 1977. ·2 E. d: Y! P0 O/ ^
Read at annual meeting of American Urological Association,
: x4 w. ~5 s; t$ T/ }Chicago, Illinois, April 24-28, 1977.
( w+ D( W% d- m: F) A* Requests for reprints: Division of Urology, Henry Ford Hospital,
. u- ~, E. t! N7 B2799 W. Grand Blvd., Detroit, Michigan 48202.! M0 W/ h# X, M: t# `# C7 ^: U
improvement in phallic growth compared to gonadotropin.$ R& k9 r4 D& N& ?3 a4 I& I
Average phallic growth with gonadotropin was 14.3 per cent
/ {- Q5 ]5 M9 D& p9 |increase in length and 5.0 per cent increase of girth. Topical
6 K3 ~1 C. l' T: btestosterone produced a 60.0 per cent increase of phallic length
4 Z, l' {+ H0 m  tand 52.9 per cent increase of girth (circumference). The4 d) o1 C  s! D' J5 G3 K5 O
response to topical testosterone was greatest in children be-$ G9 V. B  J& M0 U6 V* E
tween 4 and 8 years old, with a gradual decrease to age 176 G6 U! ]+ I, y
years (see table).
, r! S0 n5 f( gDISCUSSION% W* e$ d  h4 f% G/ W2 q
Topical testosterone has been used effectively by other( ]  r% O) j3 O- r% s/ h0 V
clinicians but its mode of action remains controversial. Im-
& W8 `8 o( P) G; R' Vmergut and associates reported an excellent growth response
: w0 n) i( T! J+ E  P/ @; r2 ?to topical testosterone with low levels of serum testosterone,
7 {7 z! G8 k0 zsuggesting a local effect.1 Others have obtained growth re-
9 f4 U4 \$ H9 ?7 f: i3 G/ B# `sponse with high. levels of serum testosterone after topical; O: Z+ e9 J. [4 a; j7 Y
administration, suggesting a systemic response. 3 The use of# c7 X. {& q7 b
gonadotropin to obtain levels of serum testosterone compara-
9 d* e" l( u; Q# w  q5 I/ hble to levels obtained with topical testosterone would seem to2 d' T- S6 t: g! \, h, h
provide a means to compare the relative effectiveness of
+ G) |5 X4 [, R$ z; Ctopical testosterone to systemic testosterone effect. It cer-
, F- L- X  p' l0 ytainly has been established that gonadotropin as well as par-$ R% [: R7 m& a  J% i
enteral testosterone administration will produce genital+ v: u! h6 m6 p
growth. Our report shows that the growth of the phallus was; M% v4 P, b- H# h
significantly greater with topical applications than with go-1 H8 V* c3 K* ~6 H" A
nadotropin, particularly in children less than 10 years old.' o# k# w4 s; Q
The levels of serum testosterone remained similar or lower
/ O3 O% z; E' Mthan with gonadotropin during therapy, suggesting that topi-, F6 O+ G  `7 C/ f+ i5 q
cal application produces genital growth by its local effect as
% D9 f8 i4 W/ m5 Z4 }. d7 k* K8 awell as its systemic effect.) J0 F3 k5 w, S  i! v9 `
Review of our patients and their growth response related to
" y4 m$ q& a7 q+ mage shows a greater growth response at an earlier age. This is1 J# W4 m$ s5 X  q- e! q9 j2 s
consistent with the findings of Wilson and Walker, who' b  G- `* ?' m, K; c$ }( z. o  {
reported an increased conversion of testosterone to dihydrotes-' }% T: R0 D3 u# _$ x( q7 l
tosterone in the foreskin of neonates and infants.4 This activ-8 d, }/ c/ X+ h' k# b# J$ c9 u
ity gradually decreases with age until puberty when it ap-
0 k, c. M$ y- b' `) ^$ G8 [proaches the same level of activity as peripheral skin. It may
5 Q5 X0 b  `- h7 v" L& ~4 `" x% B+ Zwell be that absorption of testosterone is less when applied at8 S) z# T: r9 I* L$ O7 C5 l7 |/ n
an earlier age as suggested by lower serum levels in children
! {3 V0 r0 B- x3 R6 S7 v: s) f& m& b; eless than 10 years old. This fact may be explained by the
6 Y# s" `& a( s& ?+ \1 B4 d9 egreater ability of phallic skin to convert testosterone to dihy-
% C2 v- u& D/ ~& k9 o- @" Y5 ldrotestosterone at this age. Conversely, serum levels in older$ o* S3 x3 x* i" U- i+ B# U: W6 Q
patients were higher, possibly because of decreased local
7 D; r& R5 {. F) z: q+ z667. X9 |2 {* j# o* j' Q
668 KLUGO AND CERNY# }! A% X0 b$ T% x+ d+ m) c
Pt. Age
3 P* c' K3 J( M- O% K' W(yrs.)
/ {3 h; c# F* C7 I+ ?2 iSerum Testosterone Phallus (cm.) Change Length, Z. n' N7 M1 ]( Y. K
(ng./dl.) Girth x Length (%)
. {) o* }0 U0 `9 X/ W5 @4
4 E+ v: K- Q0 U, e* q2 C8
: z5 I0 Z: V  C* S( q0 _' |10' x) z& I( e% @
12
$ O. r6 h1 Q0 D17# I- n, q1 Y  _& r* _
Gonadotropin
  V3 b8 i- Z  p0 w$ ?& O& Q  \! @71.6 2.0 X 3 16.6
! L4 Y' S  z6 F, a5 L( O# k50.4 4.0 X 5.0 20.0
$ {& F% O: q, Y2 F. y22.0 4.5 X 4.0 25.0
+ C! U7 C' a: s) R% W) x2 Z84.6 4.0 X 4.5 11.1$ a4 O# k% L# ^4 N* x
85.9 4.5 X 5.5 9.0
% m% ^/ N. c5 J; b( rAv. 14.3
& Q" n6 s4 {" T4. {' f2 j; ~. ]) U( \/ V6 M
8
* X9 _; [1 L: ?- }0 o; i10
9 A% ~7 l) U3 W8 `# r12
! F: [" _" e" q  _, B4 m( j, o17
& @8 v3 X7 m- STopical testosterone
7 D5 k8 {4 w* G% u7 {: S3 g, f" \) [34.6 4.5 X 6.5 85# k0 W; V# _' n' Y; _
38.8 6.0 X 8.5 70
6 a  v/ s$ d* G+ k3 |40.0 6.0 X 6.5 62.5" f- H4 V/ Q( A  B0 E# P
93.6 6.0 X 7.0 55.5: n5 q9 t. L/ A- C& t
95.0 6.5 X 7.0 27.2' `5 }3 P& J, K+ E% b
Av. 60.0) _$ E: C- ], V8 ^5 P6 i2 Q
available testosterone. Again, emphasis should be placed on
9 m& D. I( M5 \0 s/ Zearly therapy when lower levels of testosterone appear to
  d+ o& y& `: [( lprovide the best responses. The earlier therapy is instituted: t  I' I0 f+ |& D7 Z, C4 h
the more likely there will be an excellent response with low0 }) {8 m, c( {: Y) K! E0 L& A
serum levels. Response occurs throughout adolescence as6 Z5 I/ q6 R9 {  {
noted in nomograms of phallic growth. 7 The actual response, O, y  O+ `0 H  H* U9 K
to a given serum level of testosterone is much greater at birth
3 Y9 `$ s4 Z$ z& xand gradually decreases as boys reach puberty. This is most
9 g+ I% c) v: ]- `/ T4 n4 glikely related to the conversion of testosterone to dihydrotes-
7 k+ M% _: b4 p8 }0 r  t" Xtosterone and correlates well with the studies of testosterone' R+ ~8 i' z3 D; S
conversion in foreskin at various ages.% m# ~6 H, h5 _' M( F1 e7 T
The question arises regarding early treatment as to whether% i0 G6 a  Q+ ?0 H
one might sacrifice ultimate potential growth as with acceler-
" F% v$ J! z7 o( ~ated bone growth. The situation appears quite the reverse
# G! o# E+ X% }. A7 V5 y/ S8 _with phallic response. If the early growth period is not used0 n$ p3 r# O# e) U" g0 \$ |- H6 l
when 5a reductase activity is greatest then potential growth
+ G8 Z' s1 h& [1 c$ X+ `6 xmay be lost. We have not observed any regression of growth: E3 q0 w! H- y$ z% d( ~
attained with topical or gonadotropin therapy. It may well
$ _- ~' m" t; S, Y3 }be that some patients will show little or no response to any
( g+ t0 [# l2 g) T6 L% K# j5 }form of therapy. This would suggest a defect in the ability to: Y; W) ~( v! Q+ @( K. K* B+ I7 x
convert testosterone to dihydrotestosterone and indicate that7 S) G, m7 @, [! [3 f( M# e
phallic and peripheral skin, and subcutaneous tissue should3 B8 t9 ^' X- ?
be compared for 5a reductase activity.& V/ i* l" ^: k! W8 ~
A, loop enlarges to measure penile girth in millimeters. B,7 A% R$ q# U* J- d
example of penile girth computed easily and accurately.
/ [- N- a/ O' }" u$ Rconversion of testosterone to dihydrotestosterone. It is in this  Z) F" q$ K; X% ]
older group that others have noted high levels of serum
! T! l- h6 r0 g9 f3 \5 Q2 Stestosterone with topical application. It would also appear
5 A* _% ~: c/ J* P! d# Dthat phallic response during puberty is related directly to the
! H- O  n) G* e. y2 b2 x; ]& tserum testosterone level. There also is other evidence of local
' R9 |  D) s) I( Q0 q( Z* R4 xresponse to testosterone with hair growth and with spermato-* d" I6 [1 c$ |# w& m  V
genesis. 5• 6
; P' l5 S, b' S4 N1 u9 w/ F- bAdministration of larger doses of gonadotropin or systemic1 y9 M7 q6 ~+ G) n9 `. B
testosterone, as well as topical applications that produce
! Z" m1 x. z# Q2 [higher levels of serum testosterone (150 to 900 ng./dl.), will
" ], `% Q- x8 o! j# Y5 malso produce phallic growth but risks accelerated skeletal) M! ]' D+ s( p) @/ L
maturation even after stopping treatment. It would appear" {8 E# u( z5 b& o- e' \4 U8 l- W. K
that this may be avoided by topical applications of testosterone% b5 E: }* b) V3 s0 c
and monitoring of serum testosterone. Even with this control- u! E% x8 O/ C
the duration of our therapy did not exceed 3 weeks at any
0 G  O# L, g, z0 O8 z) g! B* ctime. It is apparent that the prepuberal male subject may" [5 B( `& U9 {: ~* Z& S- ^* ~
suffer accelerated bone growth with testosterone levels near
1 Q2 q7 `4 K; e6 R5 @+ W200 ng./dl. When skeletal maturation is complete the level of6 q. h9 P9 v% T) \- b# E
serum testosterone can be maintained in the 700 to 1,300 ng./
6 i$ G6 o) V& K* [8 ~! qdl. range to stimulate phallic growth and secondary sexual
: R9 }" W9 Z$ E: V) {1 R2 V" Qchanges. Therefore, after skeletal maturation parenteral tes-$ e" w5 u8 `+ b, x
tosterone may be used to advantage. Before skeletal matura-
5 u; m% c" ^1 A5 E! Ntion care must be taken to avoid maintaining levels of serum4 k- P. B" r5 p3 b
testosterone more than 100 ng./dl. Low-dose gonadotropin
/ ?# E) ?. ^, G5 S. Ydepends upon intrinsic testicular activity and may require( [! r! K7 e# Q
prolonged administration for any response.2 U4 Z, i* C9 T3 K4 o2 S
Alternately, topical testosterone does not depend upon tes-: T. q/ t! y1 }6 X
ticular function and may provide a more constant level of. ?# {% t7 _7 _3 C1 z
REFERENCES
9 Z& C8 K) ?  u1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
4 n! m, h* R! T' K! Q: r; GR.: The local application of testosterone cream to the prepub-
1 z  K% r9 t0 x. r: G- L( Lertal phallus. J. Urol., 105: 905, 1971." A3 c* l1 B+ p& X
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone8 M. z" e7 r2 L3 C
treatment for micropenis during early childhood. J. Pediat.,' S1 D+ U( T- c8 n! s
83: 247, 1973.
1 d3 `; H, F! o6 I& O3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-0 \+ V) s: ^* S6 f) y" F- \
one therapy for penile growth. Urology, 6: 708, 1975.$ s% S' z5 ]* `  Q' a
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
8 C6 C. e8 Z8 y8 e1 s9 Cto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
: j4 [, S0 }# L; ?6 e' x7 D7 ]skin slices of man. J. Clin. Invest., 48: 371, 1969.
, {, \% @2 N  V2 O1 c5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth$ X5 ^4 f) e( Y! g/ }
by topical application of androgens. J.A.M.A., 191: 521, 1965., J% d; l1 ]  E! L8 c* n
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local! v6 ~* b! m% h7 ~
androgenic effect of interstitial cell tumor of the testis. J.0 I+ |% |+ Z7 H9 j* I2 m8 M
Urol., 104: 774, 1970.! d) ?7 I7 A$ P& I: f6 |3 O
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-) p- y, v) ^8 s0 x$ B) e* t# J
tion in the male genitalia from birth to maturity. J. Urol., 48:
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