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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
  H- J* A! a4 _* bGONADOTROPIN
3 L3 R; d1 S. lRICHARD C. KLUGO* AND JOSEPH C. CERNY
2 ~! x0 v: q+ XFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan! |+ H  b( w. S1 r/ z: a, |$ S# t
ABSTRACT9 f# i2 u; a1 o0 ^3 q# H
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
! j9 `7 ], u8 V2 s& D- |/ fwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-6 V( n2 i9 M/ v* g5 `, \, }1 Y5 {
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
- W  c" E7 G! ]% r2 n7 O. X1 scream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent3 @( ^* [6 v: U4 o+ e( |2 S" o% x8 `
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
) o% {. a: j6 \7 N( E1 y4 ]" [3 Gincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average# D2 m; l% l% @' H4 [7 a
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response" N9 s/ K! ~0 Q; Y& m$ K
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This" z- x) k, S$ q: e: _7 G5 _1 ~
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
! z: `  G; E4 \growth. The response appears to be greater in younger children, which is consistent with previ-
1 A) Y5 i+ M; aously published studies of age-related 5 reductase activity./ _  a/ D4 h* k3 `2 z1 R& E$ i! m
Children with microphallus regardless of its etiology will
5 \" _) N0 P8 n& Yrequire augmentation or consideration for alteration of exter-/ \9 p0 |& b. [: \5 W
nal genitalia. In many instances urethroplasty for hypo-. a+ S  E8 p$ }) X' r& Y, ?
spadias is easier with previous stimulation of phallic growth.4 J# p5 N: m. d! o; m5 Z) ]; N
The use of testosterone administered parenterally or topically
1 Z& L7 m% f( z1 Mhas produced effective phallic growth. 1- 3 The mechanism of
" L" S0 w( K% U0 b  K1 @response has been considered as local or systemic. With this5 e0 ^7 g* X3 G% O) t, M; v
in mind we studied 5 children with microphallus for response
+ I7 j. E9 ?# P& y2 u" [0 p+ wto gonadotropin and to topical testosterone independently.
0 m  n9 V/ {! ~% b( T! EMATERIALS AND METHODS" ^) E2 B: J8 s* m) T( E
Five 46 XY male subjects between 3 and 17 years old were
+ J$ w! n( N; _* H7 |/ y9 e) [& Kevaluated for serum testosterone levels and hypothalamic
) g5 w. G6 [: X2 K. [9 \9 J0 Ufunction. Of these 5 boys 2 were considered to have Kallmann's
3 K! p' i/ F( {1 O/ csyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-6 c0 E; N. _1 F( _: R# q/ q- }* `
lamic deficiency. After evaluation of response to luteinizing3 P5 }: {) k2 u5 s2 S
hormone-releasing hormone these patients were treated with
0 \* ]$ L6 q+ m4 V6 a$ q1,000 units of gonadotropin weekly for 3 weeks. Six weeks: C. x1 g+ z) i( f3 p: z* Y
after completion of gonadotropin therapy 10 per cent topical9 v$ u  O9 R1 V- y6 d; D
testosterone was applied to the phallus twice daily for 3 weeks.
: e$ W6 {5 Q+ q6 q" fSerum testosterone, luteinizing hormone and follicle-stimulat-
8 c" G7 t% t1 M$ t  uing hormone were monitored before, during and after comple-
# ?) ~- _8 B# ^$ x' H0 Ition of each phase of therapy. Penile stretch length was3 H) ^0 E( H! ?" n4 b1 P- Z' r- n6 I/ I
obtained by measuring from the symphysis pubis to the tip of( @" R' {' ?4 Q
the glans. Penile circumferential (girth) measurements were
1 N# m7 z: @. O3 Iobtained using an orthopedic digital measuring device (see
! U: R2 P3 \; Q3 }figure).3 O; H5 p! S6 L( e/ `
RESULTS
* \5 N9 j! m; P) A8 MSerum testosterone increased moderately to levels between
( l& b3 P% G& f8 l) P# J50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
5 E2 W! \( E. ^& N) n2 Tterone levels with topical testosterone remained near pre-
1 H. |8 U$ p( J9 k9 D) W6 Ztreatment levels (35 ng./dl.) or were elevated to similar levels
( W) m* |" H# ldeveloped after gonadotropin therapy (96 ng./dl.). Higher
3 `, H5 K. \8 k9 _. qserum levels were noted in older patients (12 and 17 years old),0 W% Y- V7 Y$ h+ N3 s
while lower levels persisted in younger patients (4, 8, and 10
. x! `3 t* a9 f2 t# k& c0 Z, H) [years old) (see table). Despite absence of profound alterations
+ I. y1 |+ t2 k( v3 `6 Aof serum testosterone the topical therapy provided a greater6 a9 i6 e9 L6 s9 w# y
Accepted for publication July 1, 1977. ·
6 y3 G* n. u" }9 [; YRead at annual meeting of American Urological Association,
: {( m8 r" m% L0 eChicago, Illinois, April 24-28, 1977./ g4 L9 \, c: h( e% s/ j. }& Y
* Requests for reprints: Division of Urology, Henry Ford Hospital,
# C; k6 j: c. M; w2799 W. Grand Blvd., Detroit, Michigan 48202.9 ~/ ?" I- E3 o" E% D' f& I
improvement in phallic growth compared to gonadotropin.
7 ?# |) q1 B* xAverage phallic growth with gonadotropin was 14.3 per cent
5 Z9 `, _# I' ]( s: h$ Hincrease in length and 5.0 per cent increase of girth. Topical, v) p: q2 d" T
testosterone produced a 60.0 per cent increase of phallic length
2 t4 U2 T& `2 m. L# K! Nand 52.9 per cent increase of girth (circumference). The
$ O2 X; C- D0 |5 ^5 P3 W: {response to topical testosterone was greatest in children be-
2 v. J: d/ w& ], i5 Etween 4 and 8 years old, with a gradual decrease to age 17
" O7 r* v  e: C: z" ryears (see table).
$ d% j9 I( j& |: z$ ^# K  YDISCUSSION7 e7 z$ v! b. B0 k& G
Topical testosterone has been used effectively by other
7 D% l- z- n6 T2 m& Cclinicians but its mode of action remains controversial. Im-
- P9 {" @7 O$ _/ mmergut and associates reported an excellent growth response
) z6 r" D1 x) n+ ], k7 [to topical testosterone with low levels of serum testosterone,: H* \, B, u; c- [1 i. g4 [
suggesting a local effect.1 Others have obtained growth re-
. V( v5 g9 `* t* }3 Z- Csponse with high. levels of serum testosterone after topical/ A; S) j6 |+ B8 [" A. u
administration, suggesting a systemic response. 3 The use of
. D, N5 L$ A' H& \gonadotropin to obtain levels of serum testosterone compara-: D4 N0 P5 D9 {. D- ?5 ?
ble to levels obtained with topical testosterone would seem to
1 h: C) l: J( ^provide a means to compare the relative effectiveness of) q7 i- U% d2 X8 ^# V" h" T
topical testosterone to systemic testosterone effect. It cer-  y! D( z- }6 A4 z+ F
tainly has been established that gonadotropin as well as par-& i' V' w5 M3 v+ k
enteral testosterone administration will produce genital: Q# f+ y, d/ w, P: ~
growth. Our report shows that the growth of the phallus was! }" g' f9 ~) x6 n" f7 c( ^
significantly greater with topical applications than with go-
. X- |6 I/ Q+ V/ N( o5 Znadotropin, particularly in children less than 10 years old.
1 d9 H& d: H9 g5 DThe levels of serum testosterone remained similar or lower
: P/ s( K- _- [/ Jthan with gonadotropin during therapy, suggesting that topi-
! \! e% N* h' \- n- j. ?cal application produces genital growth by its local effect as) b) z% m) D4 v+ m0 e! r# s$ o
well as its systemic effect.+ O3 g, _4 \2 [2 Q
Review of our patients and their growth response related to
8 x* A+ ?1 \6 p: X) R  h4 ^( {age shows a greater growth response at an earlier age. This is  |- R4 u4 N8 Q  [
consistent with the findings of Wilson and Walker, who
( W5 z3 ]7 }1 f5 kreported an increased conversion of testosterone to dihydrotes-, }: s6 s0 `9 r% _2 n# h: ?, J6 u
tosterone in the foreskin of neonates and infants.4 This activ-
5 |) N# J  o2 x, _ity gradually decreases with age until puberty when it ap-
' d% b- f' W( m  K; ^9 o" Pproaches the same level of activity as peripheral skin. It may) o% }6 C' J& ~/ p
well be that absorption of testosterone is less when applied at
* X% R5 i; J  b3 D2 ?7 x& O8 z4 q2 Uan earlier age as suggested by lower serum levels in children
# u: K# `: u# T  ]less than 10 years old. This fact may be explained by the
* s# T! w, E. l6 s% `, Agreater ability of phallic skin to convert testosterone to dihy-+ X+ p; `, M8 v. f0 W4 k
drotestosterone at this age. Conversely, serum levels in older
/ R/ a5 R: i/ C5 O) Q# t' z; rpatients were higher, possibly because of decreased local
4 F& v* c  N1 B" v+ i667
5 R; c1 W& d0 b668 KLUGO AND CERNY
6 b8 L) a! H8 W9 H  {8 C/ YPt. Age1 V7 V, }& \+ r4 j9 L
(yrs.)5 E# V) H7 N/ B- C8 r4 a1 F
Serum Testosterone Phallus (cm.) Change Length
% v1 o' E" s2 r(ng./dl.) Girth x Length (%)
) p% u" P% h) q" o) g4$ Y8 N% D- l. a, I) a3 N; m& R
8, Z; @; H$ y* g- O8 D5 C- {5 e
10
4 y4 J% E6 `1 w2 D12) O" q* n: K$ n8 @
17! ^4 `" i: ~; ]6 Z; \9 x, w( b% \
Gonadotropin
7 E& V3 B4 }4 h: p71.6 2.0 X 3 16.6$ w/ O1 {/ R  H% {: t' b
50.4 4.0 X 5.0 20.0" w& M4 s3 v# g! a; H
22.0 4.5 X 4.0 25.0
- O. s4 m5 i& V% G3 k& e3 V" O/ o84.6 4.0 X 4.5 11.1% n3 e/ N3 `, T0 l+ U$ A6 K$ _6 x4 T6 P
85.9 4.5 X 5.5 9.0' B% |' q! I+ ^9 q: c, {, M
Av. 14.3, T& a4 K, K; O% g- J7 q
4) P2 d) C7 x3 a0 ?
82 j( a1 i9 k( H  N* B$ |
10
7 ]/ O! L, k; R6 C' _& x3 t12
' ?/ Q% F4 T+ y# o7 t$ Y17
. w/ ~# }) g; h) Y. p( w$ [Topical testosterone
# ?' \3 ~$ I) _/ Q1 S34.6 4.5 X 6.5 85
9 u2 }& l: f0 @: D& X38.8 6.0 X 8.5 707 Q( N0 G# N9 r6 K; Y7 c6 ?7 M
40.0 6.0 X 6.5 62.5
5 h$ {9 b* I5 U4 z& C2 [) c93.6 6.0 X 7.0 55.5! C& _- U5 N% x. a$ O# W0 x
95.0 6.5 X 7.0 27.2! F/ j- G! t$ H( S1 G" O
Av. 60.0
9 t; @. g& B% g' E8 m' l. Aavailable testosterone. Again, emphasis should be placed on
  a. q! y- b% s! S  Aearly therapy when lower levels of testosterone appear to9 D2 O) S6 l6 F4 C2 d" Y% {
provide the best responses. The earlier therapy is instituted
" W" {. A0 f2 r; r- X' Nthe more likely there will be an excellent response with low+ q6 j, B" `2 V) O+ e
serum levels. Response occurs throughout adolescence as7 d# m! N! g. Y
noted in nomograms of phallic growth. 7 The actual response; n  S5 p( E" y7 Q: j
to a given serum level of testosterone is much greater at birth9 W# j: O- C: L! g! H; Z0 ]6 M
and gradually decreases as boys reach puberty. This is most
" p: y( ?! q# i' klikely related to the conversion of testosterone to dihydrotes-  l' p+ }" B4 z. V
tosterone and correlates well with the studies of testosterone" |7 l- a/ `9 C$ d' U; k+ w+ T  S
conversion in foreskin at various ages.: }" `# |4 c# W3 A/ s" @# t
The question arises regarding early treatment as to whether
3 z) P6 x- f8 y: V0 Y, P4 Z8 f# Rone might sacrifice ultimate potential growth as with acceler-
& E# ^% J7 O/ Q% sated bone growth. The situation appears quite the reverse
$ n3 _& E7 N3 s4 hwith phallic response. If the early growth period is not used
( g5 y' o4 {) Y- M9 V: k% ?when 5a reductase activity is greatest then potential growth+ v+ r5 S5 |- Y
may be lost. We have not observed any regression of growth
( g, O3 g& r9 q& q5 |+ x6 kattained with topical or gonadotropin therapy. It may well
# I! ~0 z- O: s( y$ `be that some patients will show little or no response to any$ K, O1 t" S/ @: s8 V0 C9 B* o* e
form of therapy. This would suggest a defect in the ability to: A7 k/ U! P/ ?" o/ h! K
convert testosterone to dihydrotestosterone and indicate that
) h6 t4 v. e9 h+ O9 b7 ~phallic and peripheral skin, and subcutaneous tissue should
8 \4 \  C4 k: n. q# Z' Y: v( E9 ^be compared for 5a reductase activity.7 G$ _8 G9 F- h! [( H* M- h  _
A, loop enlarges to measure penile girth in millimeters. B,% F0 f9 \' r1 u9 ^4 d- p
example of penile girth computed easily and accurately.
8 {  i9 S# s8 cconversion of testosterone to dihydrotestosterone. It is in this) T; y8 g2 c, t# Z4 S
older group that others have noted high levels of serum) p4 H  d4 W' L6 E0 g5 }
testosterone with topical application. It would also appear
/ W$ d" T; a) }! j6 u- othat phallic response during puberty is related directly to the
' p7 S+ V0 V4 u2 \+ m) I) jserum testosterone level. There also is other evidence of local3 p, @: S, _4 Z. S" f0 t+ P7 ?4 t
response to testosterone with hair growth and with spermato-) {# v; d$ `4 W8 ~  ?: S
genesis. 5• 6  ~  t9 d3 @; H
Administration of larger doses of gonadotropin or systemic
$ c* E) d: t7 a/ |4 V8 V: ptestosterone, as well as topical applications that produce8 }: ]6 v2 Z( Q( \$ B! G7 J
higher levels of serum testosterone (150 to 900 ng./dl.), will
. S5 C: Y7 j7 \$ [' @! S4 Ualso produce phallic growth but risks accelerated skeletal/ c- T2 Q3 i; `) K# s* ~2 w9 U
maturation even after stopping treatment. It would appear; H8 Y  R$ P! I3 i5 U/ m
that this may be avoided by topical applications of testosterone. o" b0 j, V$ w) Q6 K& d$ G1 f- M
and monitoring of serum testosterone. Even with this control
; l6 z  w, N5 J; Z( v- s- H& sthe duration of our therapy did not exceed 3 weeks at any
/ H; ?: f* @3 u3 {5 B9 R7 l$ n6 Xtime. It is apparent that the prepuberal male subject may
; `, b) k, i5 q/ Y+ ksuffer accelerated bone growth with testosterone levels near) f% ^  L, O0 H& u
200 ng./dl. When skeletal maturation is complete the level of
, A9 W+ I0 B* `$ L( I3 }5 @5 pserum testosterone can be maintained in the 700 to 1,300 ng./2 u; n' b! W; X6 {+ `; [
dl. range to stimulate phallic growth and secondary sexual
2 d. N, `! l5 R" Tchanges. Therefore, after skeletal maturation parenteral tes-
; f6 v* m6 }, f; y+ F6 H7 b0 P4 `tosterone may be used to advantage. Before skeletal matura-! h1 S& o( p; N/ n
tion care must be taken to avoid maintaining levels of serum( b3 w* v+ \+ c7 e$ d' v9 E
testosterone more than 100 ng./dl. Low-dose gonadotropin& \; I- W$ t7 u
depends upon intrinsic testicular activity and may require5 X8 }3 S# m* G% T) b( R0 T5 C
prolonged administration for any response.
: @4 k8 d4 m1 Z8 LAlternately, topical testosterone does not depend upon tes-
6 Y3 J9 D  I! _% ?/ |9 Pticular function and may provide a more constant level of' a; j% R2 ?/ `
REFERENCES
5 I4 I% M8 @, {" n1 \7 g1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
6 f) s; z2 Y0 `, U: DR.: The local application of testosterone cream to the prepub-& ]# n7 |$ s! c( |- K. t% k0 s& p
ertal phallus. J. Urol., 105: 905, 1971.
3 F$ I6 _8 m2 a4 i. b3 M2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone8 R/ W; ~2 c* P6 |8 E
treatment for micropenis during early childhood. J. Pediat.,& X+ A2 ]$ D. l+ I. P( F- M. l/ T
83: 247, 1973.; Q/ q5 m! p; X
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-/ J$ g! G4 ]( X1 Q
one therapy for penile growth. Urology, 6: 708, 1975.
4 ^3 `9 p( T# e; t4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
9 e# u' v( W8 }6 ]9 ^7 [to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by8 Q% x5 ]# f  A; q% ?0 e
skin slices of man. J. Clin. Invest., 48: 371, 1969.
( u& ^/ t8 }9 m0 C5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
% l  [$ Z5 r- @3 i$ j! Wby topical application of androgens. J.A.M.A., 191: 521, 1965.
, |8 c8 _3 {, \* B1 p7 m- p; ^" D* s6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local& y3 F% d# w" L6 \* O: t
androgenic effect of interstitial cell tumor of the testis. J.4 r  |( n5 F! y& [% w
Urol., 104: 774, 1970.! Z0 j) A5 @6 \/ z2 v3 I% n
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
0 P" Z. V# ~) ^, [7 t8 wtion in the male genitalia from birth to maturity. J. Urol., 48:
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