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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND( }7 @, u/ M6 S9 A( V1 [4 {  V
GONADOTROPIN9 S+ @; X3 }. W+ k: A' {* b7 {* K
RICHARD C. KLUGO* AND JOSEPH C. CERNY
6 j4 N! O* p/ Y  w# F" n! o1 w3 cFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
4 y6 }$ j, F0 D6 Q( i! D/ Y9 xABSTRACT( n- ]2 Y! V/ Z2 T
Five patients were treated with gonadotropin and topical testosterone for micropenis associated7 a, L% J1 [0 y5 p& k! I" h& y2 C
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
/ q5 e- w/ C) {. s2 ?tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone4 _2 M, H" W  f9 p
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent+ @* S6 ?2 a7 ?
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent! Y6 M0 z) r% F7 _" @1 D
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
* b4 {4 u8 Y: s# x7 Zincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response  ^' ^5 p( N  [% ]1 i. m4 I
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
% w* W# u$ d8 ]( @( W1 H' `study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile- K; R. u) ^4 h
growth. The response appears to be greater in younger children, which is consistent with previ-
* F; D( o3 j* rously published studies of age-related 5 reductase activity./ W) a/ x% ]; ^
Children with microphallus regardless of its etiology will
+ s; E; P( w8 q$ Urequire augmentation or consideration for alteration of exter-6 |9 N; B9 R# v
nal genitalia. In many instances urethroplasty for hypo-2 T& v$ ~2 l3 H5 b. d( b
spadias is easier with previous stimulation of phallic growth.
# h$ M' f! A) y' V' iThe use of testosterone administered parenterally or topically
; H- ^8 p& C9 Ahas produced effective phallic growth. 1- 3 The mechanism of
& K2 ^" a6 Z9 `3 \( Presponse has been considered as local or systemic. With this$ @4 {6 Y( K2 G8 `/ T: H
in mind we studied 5 children with microphallus for response
5 v' @1 H& ^. B; N5 f; fto gonadotropin and to topical testosterone independently.
( v0 _& y% A0 F* N6 @MATERIALS AND METHODS
# B6 p" K7 O8 b' _+ V, z& hFive 46 XY male subjects between 3 and 17 years old were7 V3 ]* C* }. {- y$ `$ H
evaluated for serum testosterone levels and hypothalamic
) I2 t# ^; s2 v: u# Zfunction. Of these 5 boys 2 were considered to have Kallmann's  ?4 q$ q- _9 ]; F
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-( @4 V/ c. |6 M0 z9 g0 P5 A2 G
lamic deficiency. After evaluation of response to luteinizing
0 F2 X, C- S9 ~/ H! x' x2 J: w, u5 ~hormone-releasing hormone these patients were treated with; j: x. f: i, H9 @
1,000 units of gonadotropin weekly for 3 weeks. Six weeks0 \: a- h  D8 t! v$ U6 E3 T8 ]
after completion of gonadotropin therapy 10 per cent topical. z5 d3 D6 _9 W! b9 {, ?
testosterone was applied to the phallus twice daily for 3 weeks.! V4 g2 u7 r2 P' U7 m) H; {
Serum testosterone, luteinizing hormone and follicle-stimulat-
' U2 _4 |7 v% U" ting hormone were monitored before, during and after comple-
7 {% ]9 x# f/ D: Y6 a. b% g; ^0 Dtion of each phase of therapy. Penile stretch length was
3 A3 w7 W% x1 I8 L# b; f: l0 D0 Dobtained by measuring from the symphysis pubis to the tip of& v, `; n0 v' {; h( T* N
the glans. Penile circumferential (girth) measurements were) l2 Z' ?1 t: Y4 |
obtained using an orthopedic digital measuring device (see
. E8 t6 R. e. L1 L) Y* Ffigure)./ D+ D, u1 J: I$ e3 q
RESULTS
4 y- h/ o) F) g) Q1 NSerum testosterone increased moderately to levels between
3 Q5 z* j$ z9 f: }50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-2 V# s+ ]: p' x4 L; b: Q, G
terone levels with topical testosterone remained near pre-: J( b" A% Z! p
treatment levels (35 ng./dl.) or were elevated to similar levels
, T4 J* l# ^. a3 u' _6 X5 zdeveloped after gonadotropin therapy (96 ng./dl.). Higher
& ]4 }8 ?& O  x0 sserum levels were noted in older patients (12 and 17 years old),. p/ n/ e+ l& e1 A
while lower levels persisted in younger patients (4, 8, and 10
& F5 C6 d  ]$ [8 i7 @7 {years old) (see table). Despite absence of profound alterations
# Y' `2 X* l& f3 M; pof serum testosterone the topical therapy provided a greater/ ?3 |8 L8 A4 w6 T  b
Accepted for publication July 1, 1977. ·/ V& [4 O: U- P
Read at annual meeting of American Urological Association,
3 ~! p, `1 E9 {( AChicago, Illinois, April 24-28, 1977.
& B1 }7 f0 U; O' q$ f# L* Requests for reprints: Division of Urology, Henry Ford Hospital,1 z+ g+ E' n! g
2799 W. Grand Blvd., Detroit, Michigan 48202.; b; u: N% `" K/ Z8 W$ u$ h
improvement in phallic growth compared to gonadotropin.0 O+ X  n5 O$ Q8 O, ^
Average phallic growth with gonadotropin was 14.3 per cent
' d; g/ z& u0 G  D1 @! }- a8 T4 c1 Xincrease in length and 5.0 per cent increase of girth. Topical6 X, a1 ^1 [: i- m2 J* L, |- I
testosterone produced a 60.0 per cent increase of phallic length
3 g9 j8 h/ ^& Xand 52.9 per cent increase of girth (circumference). The# G4 M8 D& R- y* R7 t
response to topical testosterone was greatest in children be-
8 h) T# t+ E: h+ G6 f& ~tween 4 and 8 years old, with a gradual decrease to age 17
( J" ?' J& }; i  J9 a. N, {years (see table).' ?$ f4 N! p; Y( k; x
DISCUSSION
  I0 r" h4 v& ATopical testosterone has been used effectively by other9 ?7 R  Z1 h  _/ {
clinicians but its mode of action remains controversial. Im-
+ J3 J, K1 G8 X6 l1 y" |3 Omergut and associates reported an excellent growth response; C$ q! `, Z- C
to topical testosterone with low levels of serum testosterone,3 a! S/ \" Q, l3 \; }- y$ p% z
suggesting a local effect.1 Others have obtained growth re-1 f2 X$ b( C$ M7 ^1 m
sponse with high. levels of serum testosterone after topical: F: y7 b3 q5 F: T" r6 F5 D( u( @, S' B
administration, suggesting a systemic response. 3 The use of& R9 Q: l- Y# [- B5 r
gonadotropin to obtain levels of serum testosterone compara-
; o6 a7 n5 u4 n8 r  \4 Gble to levels obtained with topical testosterone would seem to. ~8 Y0 N% c7 g8 v* D5 t
provide a means to compare the relative effectiveness of
$ j' f6 h- b, L! O5 S% k2 B, ^topical testosterone to systemic testosterone effect. It cer-
3 P" s; q; E% @& X* o. [' g5 Otainly has been established that gonadotropin as well as par-# T8 {$ Z3 P7 L5 X4 p& I, Q
enteral testosterone administration will produce genital; P+ o9 k2 m. I% O" k4 I- s
growth. Our report shows that the growth of the phallus was7 u  I* V8 A. c; z0 k3 d3 y
significantly greater with topical applications than with go-" o" Q7 q: V6 O" O3 r, J
nadotropin, particularly in children less than 10 years old.( r3 c' j5 D: P( Y! R: Z
The levels of serum testosterone remained similar or lower' b* n9 v7 J3 t/ Z- s1 n
than with gonadotropin during therapy, suggesting that topi-
; y& |$ l9 {9 z0 H  I& b& y! kcal application produces genital growth by its local effect as! ^/ R/ j8 @; i
well as its systemic effect.* f: ~0 O2 N6 L% L- r6 E
Review of our patients and their growth response related to
! w% Q  \( }" c5 T$ n# m- ^  ^age shows a greater growth response at an earlier age. This is
2 U: |0 e: ?; ?- |4 hconsistent with the findings of Wilson and Walker, who
! x5 C$ Z  y; F" a" F2 r  areported an increased conversion of testosterone to dihydrotes-
; W2 q* h' J+ C# u) U; [, Ktosterone in the foreskin of neonates and infants.4 This activ-
* n- a' j" l8 d9 B; K- K- hity gradually decreases with age until puberty when it ap-
) n* _% z/ R+ X. s% sproaches the same level of activity as peripheral skin. It may
( V/ q, |; l: E: Y! W! bwell be that absorption of testosterone is less when applied at
$ Y: e8 W3 ?5 O' u1 u1 l: Xan earlier age as suggested by lower serum levels in children9 y+ K* l3 C0 g7 w# I' N
less than 10 years old. This fact may be explained by the6 Z; T. i/ E9 ^8 J* A; l* J1 x: X
greater ability of phallic skin to convert testosterone to dihy-. Q5 C. N- T: m- T, Y
drotestosterone at this age. Conversely, serum levels in older. h' u3 \; E# g! x
patients were higher, possibly because of decreased local9 L: v9 ?* o2 y) v! O$ X: x
667, b" H( r6 h2 ?# o6 n
668 KLUGO AND CERNY8 f, b! Z& o) C0 o
Pt. Age
: ~( G5 a3 ?  p0 y(yrs.)
  C2 N- S4 a0 d; K. [- @Serum Testosterone Phallus (cm.) Change Length0 `6 P) f5 ~  ?' L8 H! @
(ng./dl.) Girth x Length (%)% d( o" c" w* d
46 ?% h9 A- A8 R# u& ]' u4 C3 h8 ]
8
, Z7 `6 v  h. k! v10, |! V  N6 Y, g- x$ C3 X
12
% x! p7 }9 r' N; s/ g' {2 K" @17
0 ~+ E$ `9 j/ Q# A- g+ ^- ]Gonadotropin6 K/ Y5 b6 R0 Q4 f) I2 i: [( h
71.6 2.0 X 3 16.6/ Z) \9 ^) V1 f  n# M6 D
50.4 4.0 X 5.0 20.0' H6 r: a& V. L( K$ R$ }' W
22.0 4.5 X 4.0 25.0  ^* K* X5 K9 Z) D7 i- Z
84.6 4.0 X 4.5 11.1
7 k) k) \. i) y/ u5 Z5 E: E85.9 4.5 X 5.5 9.0; D* i- l, a1 @% a: ]  D8 Z
Av. 14.3
. N. Q1 W5 T; h) W" I2 f, t4* h- N8 O* P+ t2 P& {1 ^
8
' u+ }( R* h0 ]. v# c4 K3 X! P10
, C+ Q  a( |! L0 Z1 m% X. W5 A. K' A12
+ i2 O; M# ?3 H  V8 ^6 G' }17
1 o: A) C  G: J6 Z  ^Topical testosterone
' l: N- x; v" ]5 N34.6 4.5 X 6.5 85* n' o: ?* C5 n1 m" P  C  B; o
38.8 6.0 X 8.5 70
  E( f" O/ U8 X40.0 6.0 X 6.5 62.5
: I4 _9 E2 _% y6 M93.6 6.0 X 7.0 55.5, t2 ^1 I1 o: S7 ]& ~% |
95.0 6.5 X 7.0 27.20 g' H3 d4 x4 z) _# w: Y
Av. 60.02 _: v* |5 V; M: q4 K/ W
available testosterone. Again, emphasis should be placed on
2 i* E9 X6 S' X1 `" a8 u5 Iearly therapy when lower levels of testosterone appear to
- \6 p) n5 d) K" z8 ]4 mprovide the best responses. The earlier therapy is instituted
+ C% f' W  t6 n) }+ C& y- d- Pthe more likely there will be an excellent response with low% _* R$ U8 }* Y0 |6 c  B& I% ?
serum levels. Response occurs throughout adolescence as
: W0 }- C. v" S! Y* v" b+ Lnoted in nomograms of phallic growth. 7 The actual response
6 @1 a' G: Q' D" pto a given serum level of testosterone is much greater at birth& @5 k3 |" B9 R, N- A  ]" A! {2 @, V
and gradually decreases as boys reach puberty. This is most
- E. A" a1 O# `* u( _) Wlikely related to the conversion of testosterone to dihydrotes-
. }) i3 B6 t- V6 s( x0 Vtosterone and correlates well with the studies of testosterone
" h* q& Q' g) L' P8 |/ o, Xconversion in foreskin at various ages.
, j1 p% o  F! L8 W3 A, x3 ]The question arises regarding early treatment as to whether* L! N1 n, q7 J
one might sacrifice ultimate potential growth as with acceler-
" S6 M: q! u; U' W9 hated bone growth. The situation appears quite the reverse, A% X) g3 G# D3 D" ~5 l2 ?
with phallic response. If the early growth period is not used
7 }( {( g$ u( f1 ^3 r8 [when 5a reductase activity is greatest then potential growth8 T' ?. y. l! m; e
may be lost. We have not observed any regression of growth
4 L6 D9 [1 a& [& rattained with topical or gonadotropin therapy. It may well! _" E+ Z( ]8 H" I- m- ]* I- d: w& K
be that some patients will show little or no response to any
% m% k  _6 P' zform of therapy. This would suggest a defect in the ability to
. V0 V- i2 Z7 m, C2 qconvert testosterone to dihydrotestosterone and indicate that
1 k5 f; K0 X0 c9 P( r( L* H! Y( V" tphallic and peripheral skin, and subcutaneous tissue should
4 _9 v6 h" e7 r3 ~1 U; Vbe compared for 5a reductase activity.
  W, S: q& n8 ?2 S0 iA, loop enlarges to measure penile girth in millimeters. B,
; Y' ], @) w: d6 C+ H7 H6 T% q- a$ jexample of penile girth computed easily and accurately.
; s% G) [/ _  qconversion of testosterone to dihydrotestosterone. It is in this& y9 c9 R  G4 }( ^
older group that others have noted high levels of serum
% p! h) q2 i5 Y# @. ?) ytestosterone with topical application. It would also appear) A7 H- o, v3 d, h% ~, n
that phallic response during puberty is related directly to the
3 D' K& Z' [! U% d; ?; Tserum testosterone level. There also is other evidence of local
! B8 R# u  G" K9 d: jresponse to testosterone with hair growth and with spermato-
: X! L5 Q! R- q* ]genesis. 5• 6
7 Y7 H9 V( }. m& OAdministration of larger doses of gonadotropin or systemic
; y  ]' l, w! Z. C& B' ]+ }. Y0 W+ Rtestosterone, as well as topical applications that produce
3 ?2 E1 }7 l4 {7 H! fhigher levels of serum testosterone (150 to 900 ng./dl.), will+ D2 }) e* @9 L, A" {# z
also produce phallic growth but risks accelerated skeletal
$ e9 \$ K7 q3 I, N: B; p7 _8 n8 lmaturation even after stopping treatment. It would appear# u8 ^# o3 c9 ~: t: `% C: t( \0 u
that this may be avoided by topical applications of testosterone
4 z+ Y( J2 i5 W* y$ a$ ^and monitoring of serum testosterone. Even with this control" j) |' o7 Q: @
the duration of our therapy did not exceed 3 weeks at any1 c9 c/ [0 u7 Y' d
time. It is apparent that the prepuberal male subject may
! A* Z5 f4 }# R; s* S3 \suffer accelerated bone growth with testosterone levels near
3 k+ H& l4 z+ N/ k( o  r. p, |2 B6 i200 ng./dl. When skeletal maturation is complete the level of: B! }9 g5 M. X6 w0 X
serum testosterone can be maintained in the 700 to 1,300 ng./
1 k, }- t/ U/ S. z3 [/ ydl. range to stimulate phallic growth and secondary sexual
" |3 I* w- F$ c  L+ _changes. Therefore, after skeletal maturation parenteral tes-! T) t! C! ~& Q2 }0 ?, q" f
tosterone may be used to advantage. Before skeletal matura-
3 A; H8 L4 a  ?% T& Stion care must be taken to avoid maintaining levels of serum
& Z7 `# X( A; k. a( o! {  c2 ftestosterone more than 100 ng./dl. Low-dose gonadotropin
+ R8 ]; O1 e+ I* O  r8 ddepends upon intrinsic testicular activity and may require
; u& g) Y+ [5 A. {, O) |prolonged administration for any response.1 g# T! \1 b) R
Alternately, topical testosterone does not depend upon tes-
( f9 D( A8 K2 g2 @; o9 x' Aticular function and may provide a more constant level of
5 c9 {$ c4 u  ]7 q/ @  N& xREFERENCES5 G  V; I9 W' Y! K
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
$ Q/ i$ \4 u8 I+ SR.: The local application of testosterone cream to the prepub-" ?9 K5 O* _- f) r. c$ t' Z& k
ertal phallus. J. Urol., 105: 905, 1971.
9 c5 o' o" w7 W# g- U2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
! K; M+ O3 |1 M1 ktreatment for micropenis during early childhood. J. Pediat.,+ X0 s0 E* o& E3 B
83: 247, 1973.
% [$ O) {& }& g4 u. _8 a3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
* r: O# a" e( B) {6 ?one therapy for penile growth. Urology, 6: 708, 1975.( U4 W0 p2 o$ L/ n6 j/ x' X
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
" Y' L2 T0 B6 U- a; `/ L6 _6 [6 rto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by7 }. D% n- H4 m5 n2 w4 B3 M
skin slices of man. J. Clin. Invest., 48: 371, 1969.- V  x' ?& U! F2 o
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
' s2 q) f# O3 i4 c$ Bby topical application of androgens. J.A.M.A., 191: 521, 1965.
) T* A; c  Z3 X" M( ]6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
2 B1 z+ j0 g5 E) f0 iandrogenic effect of interstitial cell tumor of the testis. J.9 X: W2 n4 H5 s0 Y! H
Urol., 104: 774, 1970.) o) L1 E5 ~2 o% i( R' \
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
( O8 `1 D- j0 m- }3 j" {& Ntion in the male genitalia from birth to maturity. J. Urol., 48:
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