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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND5 Y9 {5 u6 X% I, S( s' f3 |/ y
GONADOTROPIN7 z# W8 |& |* g. {- s
RICHARD C. KLUGO* AND JOSEPH C. CERNY
3 g. O& \9 u. T9 @' ^6 jFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
# V: {3 ?: B. ^9 VABSTRACT0 S8 ]/ ]9 N. f& Q0 ~3 |8 n1 ?
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
& B/ g2 p3 V2 u! U) ^* E- ywith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-+ I, Q" E. G. T: v2 _9 x6 O, n2 z
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
% ]& p& A" \0 S) q( D) icream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
8 P. W9 @6 `4 Mfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
9 {+ R* p( d- \2 b/ K: m0 k' Oincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
% B# H( U& g! k0 B6 U0 Rincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
4 }& J( M! f3 c% ooccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
0 I3 O4 Y5 n6 ?$ g! n' Istudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile; P- P" q7 M( @4 C
growth. The response appears to be greater in younger children, which is consistent with previ-
* U2 b! ^3 ?4 O2 tously published studies of age-related 5 reductase activity.0 R  r! ~" }4 G1 ]/ ^
Children with microphallus regardless of its etiology will' }4 O) s$ Q. x# U- ]
require augmentation or consideration for alteration of exter-
$ M' s. m5 [' O5 Q- ?4 x2 P3 A  nnal genitalia. In many instances urethroplasty for hypo-7 A' m5 J$ h5 `+ I3 F) }* g% i
spadias is easier with previous stimulation of phallic growth.
% J1 Y# [% ~/ g5 H4 r/ [$ ZThe use of testosterone administered parenterally or topically
$ o% A8 Z2 x9 Z' T5 d1 v- d0 xhas produced effective phallic growth. 1- 3 The mechanism of
5 c. H7 n- ^: A; vresponse has been considered as local or systemic. With this
# z. E' V9 ~' f9 Z* o4 t  tin mind we studied 5 children with microphallus for response
3 w( }  V8 h! @4 a0 D! e+ Lto gonadotropin and to topical testosterone independently.
- i& y+ F- H. D# y: Y, gMATERIALS AND METHODS$ O' d/ S( V  D! S4 R$ I
Five 46 XY male subjects between 3 and 17 years old were* q9 C  ^9 B9 ~. l
evaluated for serum testosterone levels and hypothalamic
: w$ n, Q$ `! n8 I8 O( [function. Of these 5 boys 2 were considered to have Kallmann's
3 L  u! T& @. L( h, ?% k' Msyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
3 g/ B! N, h% {  flamic deficiency. After evaluation of response to luteinizing
2 Q+ c* F2 x  [4 bhormone-releasing hormone these patients were treated with
5 \: E2 m3 ]: m/ L3 l, n8 x( r1,000 units of gonadotropin weekly for 3 weeks. Six weeks3 ~9 h- ~' V4 c8 Q/ u
after completion of gonadotropin therapy 10 per cent topical
; ~6 ?2 `% D* s# Ltestosterone was applied to the phallus twice daily for 3 weeks.7 {( B3 |# f( \: Y
Serum testosterone, luteinizing hormone and follicle-stimulat-
/ m7 h, R# m) ~9 S, J/ Wing hormone were monitored before, during and after comple-: u1 p/ l0 q' j$ o3 D& Q) K
tion of each phase of therapy. Penile stretch length was
5 i9 y- V( _( Q/ c7 s" p9 `. p! Z: tobtained by measuring from the symphysis pubis to the tip of+ Z& j* ]" S, e0 r, L4 D1 V: S
the glans. Penile circumferential (girth) measurements were  B% C6 u8 a# m. |$ d% p9 s
obtained using an orthopedic digital measuring device (see" ~6 }  t9 ]. F& j
figure)., d9 Q1 @0 l$ m; y$ D& ~% E. }
RESULTS* L: E  f/ t8 M* N% l& U4 ?
Serum testosterone increased moderately to levels between
9 L( H4 ]' h# _50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
( J9 ~7 a" p. z. C: Pterone levels with topical testosterone remained near pre-. y5 \/ g0 J! y" c! R7 p
treatment levels (35 ng./dl.) or were elevated to similar levels
7 |/ H! i1 r4 n. \developed after gonadotropin therapy (96 ng./dl.). Higher
: q& s9 X0 f" `7 ?. I  V: yserum levels were noted in older patients (12 and 17 years old),, y: ^* p$ g# M( C* E, ]
while lower levels persisted in younger patients (4, 8, and 10
9 Y+ W" \! X' c" P% J* {years old) (see table). Despite absence of profound alterations, I  H1 r) ^0 F: _+ w: H
of serum testosterone the topical therapy provided a greater6 F6 ]0 m" o+ R
Accepted for publication July 1, 1977. ·: p5 g- [2 S) F- T2 v1 q4 N
Read at annual meeting of American Urological Association,
, W' T9 E1 Z. W9 I/ RChicago, Illinois, April 24-28, 1977.
5 V% z, O" x% }* Requests for reprints: Division of Urology, Henry Ford Hospital,6 W# G5 r1 ~; p, r  H
2799 W. Grand Blvd., Detroit, Michigan 48202.
2 \4 i: U' T3 c  c  p1 e& D% |improvement in phallic growth compared to gonadotropin.
: S: g9 a8 r8 @$ s" @0 M( O/ QAverage phallic growth with gonadotropin was 14.3 per cent
) E  l3 D: G2 v% L: e# ^increase in length and 5.0 per cent increase of girth. Topical7 K5 Z3 P5 H" F
testosterone produced a 60.0 per cent increase of phallic length
5 K: }; w+ N2 M4 O  M0 V" Dand 52.9 per cent increase of girth (circumference). The
2 `7 E* H! h( j! y; Wresponse to topical testosterone was greatest in children be-
0 }& l+ U% W2 h( S' X7 v6 C& dtween 4 and 8 years old, with a gradual decrease to age 17
# ?2 Z2 l' }, w" L& `) p, D5 _* yyears (see table).
  ~& L( M" i" CDISCUSSION* |4 B1 v6 {; x2 D" m! E
Topical testosterone has been used effectively by other
  ~5 |* ]' N1 d# [clinicians but its mode of action remains controversial. Im-9 }7 I5 o( y) E4 d$ X
mergut and associates reported an excellent growth response
3 C2 |; _% n4 X, a8 R1 l5 m2 Tto topical testosterone with low levels of serum testosterone,+ k! D4 N0 w! O5 s3 {  F: y
suggesting a local effect.1 Others have obtained growth re-
' f, z8 D) L" M$ X" Qsponse with high. levels of serum testosterone after topical
+ ~/ q" _& `! z) S# o2 X! iadministration, suggesting a systemic response. 3 The use of, h) N8 @: R( k2 u
gonadotropin to obtain levels of serum testosterone compara-, l/ x7 Z% }' B5 j  e( D) V' Y
ble to levels obtained with topical testosterone would seem to
+ _/ r& Q& X# m" ?" p! @4 gprovide a means to compare the relative effectiveness of
2 B* Q7 {9 q$ x# ytopical testosterone to systemic testosterone effect. It cer-
" u" x7 W/ \) q; _2 vtainly has been established that gonadotropin as well as par-
  Z/ [: L' Q' X  Venteral testosterone administration will produce genital1 E. W/ ~, @. Y
growth. Our report shows that the growth of the phallus was" q5 a0 `% t& V5 p" d  F
significantly greater with topical applications than with go-6 X! u  R1 ^- d6 N% F
nadotropin, particularly in children less than 10 years old.  x6 B. O* ]- X  m  N7 j
The levels of serum testosterone remained similar or lower
- _4 J$ p3 _$ S0 C. Lthan with gonadotropin during therapy, suggesting that topi-7 t$ b, T1 K0 x- l! c1 g3 A# [
cal application produces genital growth by its local effect as
; i0 Q: ]/ p! u/ r0 swell as its systemic effect.) M* h/ K+ U$ }
Review of our patients and their growth response related to9 Q& A) r! Y$ N. ^1 w
age shows a greater growth response at an earlier age. This is
! v5 P8 {% }! F* b% Iconsistent with the findings of Wilson and Walker, who1 ]. C3 a# ]9 _" C( o- ~" `: f
reported an increased conversion of testosterone to dihydrotes-2 s$ j, m3 K0 s6 Z
tosterone in the foreskin of neonates and infants.4 This activ-! s5 {+ V* ~" @. i# C0 y
ity gradually decreases with age until puberty when it ap-# j2 ~8 O9 [0 j) h8 K, B
proaches the same level of activity as peripheral skin. It may
# T( r7 P1 I0 Y+ ?well be that absorption of testosterone is less when applied at
0 c( C$ J" s/ i$ zan earlier age as suggested by lower serum levels in children3 v6 v6 A! n. }0 a0 X' e& d+ `0 P8 h
less than 10 years old. This fact may be explained by the
: N$ E2 b2 E0 R% M6 [greater ability of phallic skin to convert testosterone to dihy-
' H$ ^' |- _! x* v% A5 k( Pdrotestosterone at this age. Conversely, serum levels in older
7 @" Q$ i! Q) rpatients were higher, possibly because of decreased local
9 h* R1 L1 g$ t! ^7 J667
$ i  y% E4 F& D% L% m0 ?) `: v668 KLUGO AND CERNY/ X! J* A( Y& U2 v, V  r' ]% n
Pt. Age4 H) `2 {& e, @* Q2 ~
(yrs.)4 g# x; P4 T( W
Serum Testosterone Phallus (cm.) Change Length7 V! E+ J1 W- y6 r( S+ k
(ng./dl.) Girth x Length (%)2 x0 ]4 u. c, b
4. O2 E1 ?, S0 Q* c
8
4 B* i. \9 e- w8 F% Z7 N10/ J7 n6 w, J, k1 L3 G1 @
12
! y; a+ m4 Y: e; P, L1 @17
' l& ?" X' x' i. M( RGonadotropin( V7 f' D- G' L' t9 J
71.6 2.0 X 3 16.6% o3 i+ f, h$ b3 b$ z, Y+ Y
50.4 4.0 X 5.0 20.02 g( d+ G( b# p& f! L
22.0 4.5 X 4.0 25.0; p0 n6 l& z: n% j; z( `
84.6 4.0 X 4.5 11.1
  E  X7 G. l2 e8 W# M* T85.9 4.5 X 5.5 9.0* s# Y6 C( G- \' f+ g# _5 P
Av. 14.3
: E0 Y2 [) p0 `" [  k. |' U8 V* P: c4( w" k# y# p( ]) G) x6 e
8, x3 Q( N8 z9 R- ~3 S/ Q$ s
10; d9 X6 D6 d' T" l" {
12; j9 P  d0 S$ `" p) p) Y/ D
17
: C% N# C' o9 m; C- PTopical testosterone
" b2 [3 A0 R& L9 |- ^34.6 4.5 X 6.5 85
! V0 T- Q: z3 ?& G) [0 |2 S38.8 6.0 X 8.5 70
5 e* `) h4 c' G7 J) X40.0 6.0 X 6.5 62.5) F7 u+ M! _& N7 q5 l* d
93.6 6.0 X 7.0 55.59 q( i* ^. ^2 [) p) p) w4 ^$ T
95.0 6.5 X 7.0 27.2  n" q0 }9 h  E5 X* q: D: l
Av. 60.0
9 U" A' u. B- b- c# f5 b* Navailable testosterone. Again, emphasis should be placed on
8 m* y1 M  Z7 X" d7 l8 L$ zearly therapy when lower levels of testosterone appear to* p0 a" |# l: B9 m& c# o
provide the best responses. The earlier therapy is instituted- l. v. ?, W  h. r& t, l. A
the more likely there will be an excellent response with low
! U! l& ]7 i, d8 Yserum levels. Response occurs throughout adolescence as' l7 l1 v5 B9 q$ r! R
noted in nomograms of phallic growth. 7 The actual response
+ e8 c5 Q# G/ I! ^to a given serum level of testosterone is much greater at birth
0 V2 N& }. ]6 V1 `% hand gradually decreases as boys reach puberty. This is most' G$ k$ g5 d1 T0 n- l# O
likely related to the conversion of testosterone to dihydrotes-2 O1 }1 D- z$ l+ @, j, ]7 k  x
tosterone and correlates well with the studies of testosterone( F: `; O5 v8 e2 U$ W  x
conversion in foreskin at various ages.4 M$ D( Z# S: f
The question arises regarding early treatment as to whether
) \6 a3 S- T7 Yone might sacrifice ultimate potential growth as with acceler-
0 l7 n+ B% T! Q* K3 Mated bone growth. The situation appears quite the reverse
' J" V; v1 U) V1 R. pwith phallic response. If the early growth period is not used
& ~" s( U. v2 _when 5a reductase activity is greatest then potential growth
! {5 w1 ?2 j% rmay be lost. We have not observed any regression of growth/ @5 O% Q  Z6 V1 u; U  J; R2 i
attained with topical or gonadotropin therapy. It may well
2 F, h1 s+ Q' k8 s" D  Jbe that some patients will show little or no response to any
1 I" c) y' L' Q8 C" ~; P: lform of therapy. This would suggest a defect in the ability to  s" b" e+ G$ E, N0 F
convert testosterone to dihydrotestosterone and indicate that
0 s3 F9 s  \  s( Y& _phallic and peripheral skin, and subcutaneous tissue should
8 M0 \* m  G9 D! g; T4 x* a. xbe compared for 5a reductase activity.
( y, e  ^4 f. v% o, O' _: w% ?  tA, loop enlarges to measure penile girth in millimeters. B,( ~9 m6 a0 }' F3 H' v" v$ @" B! z
example of penile girth computed easily and accurately.
7 k" x0 Z, k9 M! j* @# B- Fconversion of testosterone to dihydrotestosterone. It is in this9 w1 D# d. O/ l( y8 [
older group that others have noted high levels of serum
# g  Y; L% J8 i: U0 F3 q+ Qtestosterone with topical application. It would also appear" H+ I" p# C# E2 Z3 _5 a
that phallic response during puberty is related directly to the
1 y- x. W& d. `3 [. N/ A3 @serum testosterone level. There also is other evidence of local( Q/ Q* z7 R/ |& [! {8 O1 M
response to testosterone with hair growth and with spermato-
$ }6 s" q; H2 h& a( ~genesis. 5• 6
& J# s  ]4 J8 B5 K$ c! r% v  D; l# eAdministration of larger doses of gonadotropin or systemic
/ ?" Q6 M' q& k. Dtestosterone, as well as topical applications that produce0 j; D" C$ M2 |4 G1 W. G; Y- ~
higher levels of serum testosterone (150 to 900 ng./dl.), will
5 C7 P8 _: `* [  }also produce phallic growth but risks accelerated skeletal# s* C' O  F3 G3 g
maturation even after stopping treatment. It would appear
& m$ D' \3 `. b% ^+ Q! cthat this may be avoided by topical applications of testosterone6 V1 z! H. I4 b9 ?
and monitoring of serum testosterone. Even with this control
' r8 H* V! K  C" Q+ t2 Ythe duration of our therapy did not exceed 3 weeks at any4 Q; L) i2 {; e$ X( ?0 g2 F/ ^1 q0 S
time. It is apparent that the prepuberal male subject may# c7 v! {' U/ X
suffer accelerated bone growth with testosterone levels near" q2 x8 W% l& K. I+ R5 R3 D
200 ng./dl. When skeletal maturation is complete the level of/ i0 }2 x& x$ ^% o" L( u
serum testosterone can be maintained in the 700 to 1,300 ng./
8 U" q+ `1 I) Qdl. range to stimulate phallic growth and secondary sexual* Z; Z; t+ k* T  m5 r* c/ B) f% L
changes. Therefore, after skeletal maturation parenteral tes-
: B, f. ?1 l# G3 R& ^8 ?* n: Utosterone may be used to advantage. Before skeletal matura-& y2 y! p: T1 k+ t8 U3 _
tion care must be taken to avoid maintaining levels of serum
# ~' `% u, {: C) N7 btestosterone more than 100 ng./dl. Low-dose gonadotropin
( D% V8 B9 V6 Tdepends upon intrinsic testicular activity and may require
& J3 J- v- }- @$ Pprolonged administration for any response.- ~) W3 n" Y7 r" h
Alternately, topical testosterone does not depend upon tes-
  n4 b6 m  u, y5 h3 o* r# W- a8 {ticular function and may provide a more constant level of" j, _2 {# y3 n
REFERENCES9 a% k/ k; s- h5 k! I/ q
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,8 k. \9 Z, ^' ]
R.: The local application of testosterone cream to the prepub-
+ \, b3 q( p  r, ~ertal phallus. J. Urol., 105: 905, 1971.4 _! s) j7 D4 M$ R: p6 p# L
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone$ G6 {5 }/ m/ a! q' O+ ^& Y
treatment for micropenis during early childhood. J. Pediat.,
' J* q. j5 T* P$ {! W/ w83: 247, 1973.
/ @9 P  N+ M- i8 Z3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
9 M" G3 C4 A' d; w3 S/ k6 @2 fone therapy for penile growth. Urology, 6: 708, 1975.; d! j  J) ]0 I8 o$ `
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone$ I- m7 c+ e% v& i* M0 Z; j3 S: Y
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
0 G7 M6 ]% t( F" K; }skin slices of man. J. Clin. Invest., 48: 371, 1969.
9 ?" v* y0 I, P9 }( R  y* {5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
( h- u6 b( _3 f# ~( E1 Q7 v- rby topical application of androgens. J.A.M.A., 191: 521, 1965.
: }. G) l2 l. X8 {! i6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local% b8 y, X; h0 ^+ v3 O
androgenic effect of interstitial cell tumor of the testis. J.
' L! l8 k# }/ EUrol., 104: 774, 1970.
' x! J& N# ~3 _: T* u* b# T% g7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-3 J0 d8 ~0 C: Q1 e" l5 _
tion in the male genitalia from birth to maturity. J. Urol., 48:
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