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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
5 t  {9 w3 {. ]. b) D, p! F' G+ yGONADOTROPIN
# I, W7 M$ R6 y' H1 ~! TRICHARD C. KLUGO* AND JOSEPH C. CERNY* G# }3 H2 s& d
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
( l; H" c7 q# Y# y8 j4 a# L& gABSTRACT
8 T* {/ w4 {& Q- S9 E- pFive patients were treated with gonadotropin and topical testosterone for micropenis associated) L0 }$ U% o6 w) l$ a2 p
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-0 O+ P: x6 P' O  j
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone7 ]& t) a% v! s
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
: ^( v# P; m8 }for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
9 Z2 B6 n: M7 h4 F5 b. Fincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
% K0 }6 S0 e7 @) A* [! F/ t% nincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
% c% |0 A  N) woccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
+ w# _& l& E& wstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile/ A8 G0 q& i0 M' r
growth. The response appears to be greater in younger children, which is consistent with previ-1 L: E  {- o) k; e
ously published studies of age-related 5 reductase activity.+ g6 A) R( G8 Y9 `! I
Children with microphallus regardless of its etiology will) E5 V* f7 I6 v: @, `
require augmentation or consideration for alteration of exter-
% `- e/ Y- o0 }nal genitalia. In many instances urethroplasty for hypo-
. F' |& x9 l' e4 R1 r, J6 n0 E6 Fspadias is easier with previous stimulation of phallic growth.2 H- V4 p: M/ r0 Z7 ]# o- t
The use of testosterone administered parenterally or topically5 R" ]8 w: `1 Z/ U# m0 T4 |$ ~9 Q
has produced effective phallic growth. 1- 3 The mechanism of. e' d) S; O" Y! R3 s9 ]& y
response has been considered as local or systemic. With this
: C6 V! q% D) _0 l  u9 H, L0 {in mind we studied 5 children with microphallus for response2 {$ x% B) q! J8 K
to gonadotropin and to topical testosterone independently.. I9 P0 {& a0 _( d
MATERIALS AND METHODS2 j( J; H9 l+ M4 }# [7 j/ k) {! V5 D
Five 46 XY male subjects between 3 and 17 years old were1 m6 w, |9 H# K0 @
evaluated for serum testosterone levels and hypothalamic
' v6 |, K, _) C. L+ w8 f  ffunction. Of these 5 boys 2 were considered to have Kallmann's! t" @8 _3 e) `& T. K
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
0 q1 Y  R& y' G# j9 `lamic deficiency. After evaluation of response to luteinizing! K5 ~8 r/ p2 m9 U; N& {& v
hormone-releasing hormone these patients were treated with
1 U( b9 X) l# I! X) r1,000 units of gonadotropin weekly for 3 weeks. Six weeks3 C$ M$ S: G$ u# e2 g
after completion of gonadotropin therapy 10 per cent topical
( i) _$ e3 I0 M: y, p& V0 otestosterone was applied to the phallus twice daily for 3 weeks.8 F; ^7 C$ }0 K2 S: R
Serum testosterone, luteinizing hormone and follicle-stimulat-2 P9 Y* s4 r4 ], r
ing hormone were monitored before, during and after comple-
1 v. w7 x; i% a5 l. E: |tion of each phase of therapy. Penile stretch length was) d* H! P, f5 h, @
obtained by measuring from the symphysis pubis to the tip of: E* C+ n% h- x0 g* ~9 M
the glans. Penile circumferential (girth) measurements were
5 Z" D5 p. p% i' p$ X# pobtained using an orthopedic digital measuring device (see
$ i2 ~/ E+ X# M: L6 ]+ Z. xfigure).( e; Z5 k5 ]/ L! R! w6 A
RESULTS
9 p0 j1 A( k5 _) wSerum testosterone increased moderately to levels between8 _9 \% \6 H) M8 a
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-4 \+ z6 F6 g( i, R
terone levels with topical testosterone remained near pre-
& H7 m7 d3 f$ `/ t8 E6 Ftreatment levels (35 ng./dl.) or were elevated to similar levels. M1 T; X0 t5 a+ I$ x! s1 n$ n1 m! m
developed after gonadotropin therapy (96 ng./dl.). Higher0 H7 y! ^8 I2 D0 W/ T% N' U  X, [
serum levels were noted in older patients (12 and 17 years old),
* L) M. ]6 ~, C9 E  z5 Mwhile lower levels persisted in younger patients (4, 8, and 10+ X; V. ~. [+ k7 i0 B- t( K
years old) (see table). Despite absence of profound alterations
/ H  C9 R4 x2 v- qof serum testosterone the topical therapy provided a greater' {/ n4 |' s# y! f$ l8 l9 R
Accepted for publication July 1, 1977. ·! {! ^6 Y$ N! F% D+ `6 O
Read at annual meeting of American Urological Association,/ {- p" S3 R' p' Q
Chicago, Illinois, April 24-28, 1977.3 @! E% V7 [* _* q7 }! }! Y0 O  B. Y
* Requests for reprints: Division of Urology, Henry Ford Hospital,
& [" O: O# F6 r. F, p: i, d+ q9 D2799 W. Grand Blvd., Detroit, Michigan 48202.
# N6 N2 F# n' x0 Vimprovement in phallic growth compared to gonadotropin.* f# G* J% p/ p1 Z
Average phallic growth with gonadotropin was 14.3 per cent
3 Z7 I& C& @0 B( ^increase in length and 5.0 per cent increase of girth. Topical
+ H1 ^& x( I' Z, k6 _2 Ltestosterone produced a 60.0 per cent increase of phallic length
# ]: C7 Q* }5 C7 aand 52.9 per cent increase of girth (circumference). The
1 W0 y" c. D8 e' j; u! A( Rresponse to topical testosterone was greatest in children be-% P5 p2 D; w- h- |  E0 U! N
tween 4 and 8 years old, with a gradual decrease to age 17
/ }$ x+ U: Y7 u* M0 x# Vyears (see table)." {3 h+ F# f& H
DISCUSSION
5 S6 l$ g( F! V! R( |3 yTopical testosterone has been used effectively by other) p. S5 }9 A9 k. M. {4 ]: U
clinicians but its mode of action remains controversial. Im-
- }) z8 L9 @# I' \$ |; umergut and associates reported an excellent growth response) ?- `$ g- p5 T% [9 d  u
to topical testosterone with low levels of serum testosterone,7 j0 q" h! g2 r2 w! f5 A+ |( W
suggesting a local effect.1 Others have obtained growth re-
: p/ h# n' H6 \# k4 ^3 Isponse with high. levels of serum testosterone after topical
6 f4 U/ ^' A* j7 Madministration, suggesting a systemic response. 3 The use of- x1 e8 h3 M+ p( N
gonadotropin to obtain levels of serum testosterone compara-
: c8 \* ]/ v. t2 Rble to levels obtained with topical testosterone would seem to
) K& c) j9 s1 C9 ?provide a means to compare the relative effectiveness of
: H, ?1 m0 v& E# v5 ztopical testosterone to systemic testosterone effect. It cer-# D! z. G7 j5 g% r9 D# g; S4 r5 N
tainly has been established that gonadotropin as well as par-
+ W8 p) Z* {6 f1 m8 s: ]enteral testosterone administration will produce genital
) Z- z* p: e* X+ v9 jgrowth. Our report shows that the growth of the phallus was
4 Q& t7 e2 o9 p7 n7 C+ B& b/ _2 P3 psignificantly greater with topical applications than with go-  ?- A) T2 `9 L3 D/ z( c
nadotropin, particularly in children less than 10 years old.
. K6 L+ }& n3 Q; w, F- mThe levels of serum testosterone remained similar or lower
1 n9 P* X6 K1 I5 }7 e, |: Qthan with gonadotropin during therapy, suggesting that topi-  W1 T; \  C8 \  K
cal application produces genital growth by its local effect as
1 c  ?& u% d; n* Y# L% ywell as its systemic effect.
. M4 C2 A( t- @6 w9 HReview of our patients and their growth response related to) R8 O# j$ H% h, G" ^
age shows a greater growth response at an earlier age. This is
; h- i; I. ^2 W9 nconsistent with the findings of Wilson and Walker, who
2 @$ Q8 \& b6 K$ Q/ c5 T" @( Oreported an increased conversion of testosterone to dihydrotes-
& R0 L# {. Y# j1 Ytosterone in the foreskin of neonates and infants.4 This activ-( `% j( z0 e& b
ity gradually decreases with age until puberty when it ap-7 o0 Q& n4 B( }! T* T, H3 S" L, f- Y
proaches the same level of activity as peripheral skin. It may
0 S  A/ j1 _, q- |  v# Z. Ewell be that absorption of testosterone is less when applied at4 |* u4 O. i) p; S* y
an earlier age as suggested by lower serum levels in children
! c5 ]# {) X2 Wless than 10 years old. This fact may be explained by the
1 x- c! h% v0 Z4 bgreater ability of phallic skin to convert testosterone to dihy-; D0 a- l6 \' F. `2 D5 z
drotestosterone at this age. Conversely, serum levels in older1 }& H  J# p8 t
patients were higher, possibly because of decreased local  N) z9 F+ I7 r3 B
667% L' g) v: x$ C  z& }& O2 u# N
668 KLUGO AND CERNY# i) B( H: A1 t. M9 \' C! }
Pt. Age
: W; ^$ Y# W  d; O3 X) l$ `(yrs.)
: e# B8 r% _  ?: }; F2 b8 s. {+ h- HSerum Testosterone Phallus (cm.) Change Length
1 {* z- m4 u1 R: C! o; @8 \(ng./dl.) Girth x Length (%)
, M) {/ ?$ e- u7 |* N+ r4' f& a* k, C9 H
8
) ?- t' y6 I3 ]9 R) D10
  E9 L# D3 W  v. U- ~  N$ X2 w12; {) @% Z4 C+ ~6 ?
170 F5 W4 r7 c1 v4 E# b* r4 S* D* I
Gonadotropin1 Z4 \, ?3 M7 k5 N# [
71.6 2.0 X 3 16.6
9 E8 p7 z0 k; M9 }; j5 C" ~; S50.4 4.0 X 5.0 20.0
/ i) u8 c' D, g- Y+ ?. |2 L22.0 4.5 X 4.0 25.0
7 ^( D9 o! z+ O84.6 4.0 X 4.5 11.1$ E2 O) b+ g. ^8 j9 t
85.9 4.5 X 5.5 9.0# m( d1 o% R( a! ]0 g1 H' W
Av. 14.3, m3 Q" H; N0 u& Z7 V4 n
4" d. a( ~5 I) |0 @: A5 B( G
8* N5 `. u" T2 ]( V  e
10
! y3 S2 K0 e' K7 ]2 Q123 H; E+ P& W, N" p7 K0 {) _" R
17' v8 \1 d5 T% U# B. e; B- `
Topical testosterone- Z" Y& I; s8 E5 e9 R$ A
34.6 4.5 X 6.5 85
4 _" I9 o3 w' N, R: J1 u1 _6 ~38.8 6.0 X 8.5 70. v  V. B9 Q+ k9 f
40.0 6.0 X 6.5 62.5& E  N7 `% X2 E' Q: r1 N
93.6 6.0 X 7.0 55.5
6 b0 g4 b* @7 N9 x$ d' Y95.0 6.5 X 7.0 27.2
: q: B. h2 r. v5 IAv. 60.0
3 z% _; A" b0 D: W& @! x, J1 Eavailable testosterone. Again, emphasis should be placed on
5 Q) n( {' z5 U' @; ~early therapy when lower levels of testosterone appear to/ [  I/ L4 C1 A
provide the best responses. The earlier therapy is instituted, z# W. l: P% W) D
the more likely there will be an excellent response with low  P+ z7 _" A, m! L8 o1 ^
serum levels. Response occurs throughout adolescence as
$ z( t% Q: H. k# ~6 Mnoted in nomograms of phallic growth. 7 The actual response
5 q" e; z% W6 \# ?4 p0 ~$ {5 gto a given serum level of testosterone is much greater at birth4 P/ Y* `( r! r6 J0 n5 v* _
and gradually decreases as boys reach puberty. This is most2 N8 X9 q" L1 n
likely related to the conversion of testosterone to dihydrotes-! F# O# |2 ^, ?0 s) B- Q
tosterone and correlates well with the studies of testosterone+ u: f8 \- P$ p$ X. o' A, m  y1 ^
conversion in foreskin at various ages.+ u3 P! o; @6 W
The question arises regarding early treatment as to whether) z1 n& s* A; W& a! _3 q2 X, u$ t
one might sacrifice ultimate potential growth as with acceler-
: i; }6 V, x  x. L/ wated bone growth. The situation appears quite the reverse
2 l0 K  j9 Y+ P* b% v! v* D/ a/ Jwith phallic response. If the early growth period is not used
8 H5 M) o# E6 n+ owhen 5a reductase activity is greatest then potential growth+ L$ c8 T0 R; G
may be lost. We have not observed any regression of growth( j1 Z$ w& ^( Z; T
attained with topical or gonadotropin therapy. It may well/ ^# f* q0 ~# E" m
be that some patients will show little or no response to any
/ o- H7 G7 B% Y" t+ y8 l6 `% }; I9 lform of therapy. This would suggest a defect in the ability to
, ~0 n. Y/ r1 B6 {5 }convert testosterone to dihydrotestosterone and indicate that' W; W0 v6 {: \. D, z+ ^
phallic and peripheral skin, and subcutaneous tissue should
; r, h9 b& z/ G' a, _4 y& Qbe compared for 5a reductase activity.
4 K  r3 r& i9 FA, loop enlarges to measure penile girth in millimeters. B," _% U, e1 ]. f+ [* c, Q
example of penile girth computed easily and accurately.
: d( m: e7 X' @& \conversion of testosterone to dihydrotestosterone. It is in this7 s. @+ R3 h- a" R% @
older group that others have noted high levels of serum
" e8 |2 T4 Q9 {testosterone with topical application. It would also appear: _1 }. S" Q4 v/ u# Z
that phallic response during puberty is related directly to the! \3 q5 k" Q) W0 w- E0 N& |: h2 N
serum testosterone level. There also is other evidence of local
. m7 g  U+ ~. h; s$ F8 Iresponse to testosterone with hair growth and with spermato-( W3 j$ Z9 ~6 J
genesis. 5• 6
6 |' A$ T) W' {; p& ^Administration of larger doses of gonadotropin or systemic- l2 M1 y5 l9 G5 Y$ h$ X; d
testosterone, as well as topical applications that produce
, y: |& l$ E8 V6 ]higher levels of serum testosterone (150 to 900 ng./dl.), will' k) l0 Y1 \2 |# \
also produce phallic growth but risks accelerated skeletal, q! M7 s4 z/ V3 u, A5 t
maturation even after stopping treatment. It would appear
' `. o: M$ P4 |, ?& k1 T6 f! R- h; U* athat this may be avoided by topical applications of testosterone# Y, ^% q/ w6 O4 K
and monitoring of serum testosterone. Even with this control" {  l& e+ d. r7 @
the duration of our therapy did not exceed 3 weeks at any$ a7 y& v% `9 j+ b  M4 O% W
time. It is apparent that the prepuberal male subject may
- h7 W# V8 k: ssuffer accelerated bone growth with testosterone levels near
+ f: h/ _! ^; J4 p$ F8 X200 ng./dl. When skeletal maturation is complete the level of
- N/ g3 U6 v7 {+ }0 I2 O( J+ Pserum testosterone can be maintained in the 700 to 1,300 ng./4 z2 r1 `" G6 ^, h+ l' i
dl. range to stimulate phallic growth and secondary sexual
  w6 C, Y1 ~, e9 k, }2 \changes. Therefore, after skeletal maturation parenteral tes-
" Z$ j% t, l, P( b  d2 Wtosterone may be used to advantage. Before skeletal matura-
8 }: D7 t6 c" u* C2 Ltion care must be taken to avoid maintaining levels of serum
4 L& L9 Y1 [4 X& I% Ltestosterone more than 100 ng./dl. Low-dose gonadotropin
3 X: E5 W7 P1 Ldepends upon intrinsic testicular activity and may require
& e! y! m6 b& ?% kprolonged administration for any response.
' h, n' k5 y. ?% ], _; CAlternately, topical testosterone does not depend upon tes-
+ f3 ?1 C! ]$ _$ P4 bticular function and may provide a more constant level of
0 c/ p9 ^/ j+ Y$ a6 eREFERENCES
( U$ ]* X  l# M1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,3 j. }/ c7 Q7 @* b( h0 @. D4 E1 u
R.: The local application of testosterone cream to the prepub-  L3 X2 p+ s) ?3 S" \" j
ertal phallus. J. Urol., 105: 905, 1971.& B7 X' y, R& y4 F+ Y
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone7 s" n1 t# _. `, P$ c# Q
treatment for micropenis during early childhood. J. Pediat.,
+ A2 e; F" i2 F3 j( G/ ~6 t5 }83: 247, 1973.
6 e! @( r0 d/ T( e7 x3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
0 [4 j7 L6 L* }! p9 ~( lone therapy for penile growth. Urology, 6: 708, 1975.
, h; ]! R# }, }& I* w  `4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone  L/ H$ V; \/ \
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
, O+ _) f  |2 Q6 h, W. e9 x3 tskin slices of man. J. Clin. Invest., 48: 371, 1969.9 J2 d# T; D% w* @0 i* s
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth% a0 L8 g/ \* N8 S7 m
by topical application of androgens. J.A.M.A., 191: 521, 1965.) P6 V( E% u2 O! c, D
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local1 f+ v( s; N7 H3 U
androgenic effect of interstitial cell tumor of the testis. J.- r8 d3 Q$ J$ C- _3 F
Urol., 104: 774, 1970.% f% y8 r8 w% R$ H9 |$ }: ?  S' f
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
2 p) c" @5 V2 `4 H0 etion in the male genitalia from birth to maturity. J. Urol., 48:
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