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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
! @2 ~  U: s+ m6 C, p* pGONADOTROPIN* N! D0 n. U, }; d
RICHARD C. KLUGO* AND JOSEPH C. CERNY8 W9 M6 Z. C# P4 G
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
  o5 s5 f% T! tABSTRACT
$ s! \6 h; Q# b$ r" {Five patients were treated with gonadotropin and topical testosterone for micropenis associated9 G& X4 Q, u7 F; x
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
9 A. K! A8 Q, D+ v6 Jtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
) l+ ?2 d4 K% @cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent. x3 }2 G( v9 ^; r
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent( a5 W: q# ~  ^6 B8 H
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
& q4 p8 |- a& z7 H8 N( r+ C' zincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
! \- {' c9 k1 h  l) L! y: `9 roccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
+ @' F* P; z. y" Y9 e; qstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile: T; A) u; C  O
growth. The response appears to be greater in younger children, which is consistent with previ-. @  F" S* w. c6 V( u
ously published studies of age-related 5 reductase activity.* R: g# @+ y1 s5 j& U
Children with microphallus regardless of its etiology will
9 [- [7 g: \. V' v5 krequire augmentation or consideration for alteration of exter-
( w, N+ t+ X' n. Rnal genitalia. In many instances urethroplasty for hypo-! I0 o+ O  l0 A/ c1 U
spadias is easier with previous stimulation of phallic growth.
( {% o" B* q4 \/ r% n# M- VThe use of testosterone administered parenterally or topically
! @( S; W7 \2 C% }) Z* {has produced effective phallic growth. 1- 3 The mechanism of
& h! P) G5 L; H* q- k& {, Q7 x5 Rresponse has been considered as local or systemic. With this
* A. T; y- ?9 U+ B% ]in mind we studied 5 children with microphallus for response: d7 W. H# v( J9 v  {1 p1 U& \
to gonadotropin and to topical testosterone independently.
8 ]/ v0 T# ~8 s1 hMATERIALS AND METHODS. G# B" |3 I% d0 Y: b4 T) X# [% [6 F
Five 46 XY male subjects between 3 and 17 years old were
8 U3 G( u+ |1 s% i3 u( @4 I% }/ vevaluated for serum testosterone levels and hypothalamic2 Q7 K- v9 H: @) X
function. Of these 5 boys 2 were considered to have Kallmann's
- T' C9 r9 y4 U! l. _& ksyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-9 v0 Q5 F; P; D7 P% j3 v3 _& @5 U
lamic deficiency. After evaluation of response to luteinizing
8 t# M8 \- A4 x3 O8 G. ~! d' fhormone-releasing hormone these patients were treated with" i7 p0 ~+ J* V# `
1,000 units of gonadotropin weekly for 3 weeks. Six weeks9 w$ }- `; l9 O( S
after completion of gonadotropin therapy 10 per cent topical  l1 a+ H/ W: L2 n. r" |
testosterone was applied to the phallus twice daily for 3 weeks.
/ v: K5 E7 O6 F6 XSerum testosterone, luteinizing hormone and follicle-stimulat-
- o: ], e* y! E5 I0 L0 ]ing hormone were monitored before, during and after comple-
) n. z8 z2 K! S- h7 y3 {4 Ption of each phase of therapy. Penile stretch length was
1 l4 p3 ~) Y' X% d/ dobtained by measuring from the symphysis pubis to the tip of
8 \7 J9 T* J" T" Lthe glans. Penile circumferential (girth) measurements were8 h* @1 X; |# K& m
obtained using an orthopedic digital measuring device (see9 o# U! |$ t# k; d
figure).* @: J) I7 L4 w8 ~
RESULTS
1 M5 s& l( }- bSerum testosterone increased moderately to levels between0 Y, b: f1 W& F0 n
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
3 \% ~# p  g5 Q  Q2 i, Nterone levels with topical testosterone remained near pre-
& E9 H- i2 N( W- w# @5 Streatment levels (35 ng./dl.) or were elevated to similar levels
% @8 y. t* @% |2 W' |8 K# Rdeveloped after gonadotropin therapy (96 ng./dl.). Higher3 y7 j3 X4 i  l8 `) I% V
serum levels were noted in older patients (12 and 17 years old),
- A. E  `3 q: z- b3 m1 bwhile lower levels persisted in younger patients (4, 8, and 10
' V! m  e8 b2 p5 l- F9 Q4 Y/ Qyears old) (see table). Despite absence of profound alterations( t& ]$ n' k; j' j
of serum testosterone the topical therapy provided a greater2 F( D3 G: y* f0 D7 ?
Accepted for publication July 1, 1977. ·
# y, t4 w& ]" J% NRead at annual meeting of American Urological Association,6 P& b/ ~. M+ @
Chicago, Illinois, April 24-28, 1977.
5 g. a, t. U- _' S* Requests for reprints: Division of Urology, Henry Ford Hospital,9 E5 _0 m8 N  f% ^* I8 W8 [' `
2799 W. Grand Blvd., Detroit, Michigan 48202.4 o/ l. Y/ E0 }
improvement in phallic growth compared to gonadotropin.% j5 f4 g# l1 @3 W+ y& X
Average phallic growth with gonadotropin was 14.3 per cent
" o( ~3 q% i' z1 A) h) t! I* hincrease in length and 5.0 per cent increase of girth. Topical
! r5 ]) v7 @5 d7 L0 u# vtestosterone produced a 60.0 per cent increase of phallic length( J/ Z- f3 W) R2 g( F* [; s- @
and 52.9 per cent increase of girth (circumference). The
6 G; i1 W. F4 _3 r' G# qresponse to topical testosterone was greatest in children be-
. f( R+ a5 K: n" x: Jtween 4 and 8 years old, with a gradual decrease to age 17
; x8 B; S5 _- F0 Yyears (see table).
; M2 B& D4 N6 T6 x, T, ]0 CDISCUSSION% f8 _' U: T! i4 U; g
Topical testosterone has been used effectively by other/ z# J' F5 k! R0 R
clinicians but its mode of action remains controversial. Im-6 e" W7 ~0 P4 \
mergut and associates reported an excellent growth response
: H& S/ f! r1 `  U0 }7 v5 s2 oto topical testosterone with low levels of serum testosterone,
9 n" I; j4 i" p" g- a1 {suggesting a local effect.1 Others have obtained growth re-
3 u3 i6 D8 n& isponse with high. levels of serum testosterone after topical
* \, g# [! t- @administration, suggesting a systemic response. 3 The use of
2 D& |! ~" Q2 }5 A. M  Ogonadotropin to obtain levels of serum testosterone compara-1 A: n. R# w' t& _6 ]
ble to levels obtained with topical testosterone would seem to
% ~/ C7 X% x3 F7 n/ w7 Vprovide a means to compare the relative effectiveness of& E4 f5 u: w3 \7 n5 d" z' X% y) @7 c- P
topical testosterone to systemic testosterone effect. It cer-
1 g2 N# ~9 ]9 V6 Ztainly has been established that gonadotropin as well as par-
6 H( ~1 U' l" D: e# o$ \enteral testosterone administration will produce genital3 N( ~6 W/ \- `* t  ?8 Y" Q* `
growth. Our report shows that the growth of the phallus was1 G& o6 o7 `/ e
significantly greater with topical applications than with go-
, ^( w- L2 P5 w" b* c4 Onadotropin, particularly in children less than 10 years old.
' e( C3 [5 D" L0 q$ n7 V! yThe levels of serum testosterone remained similar or lower5 E+ F2 A8 D. q4 _& }
than with gonadotropin during therapy, suggesting that topi-" u% z  }8 R* x6 o, }
cal application produces genital growth by its local effect as% C) `) a, F, ]* `
well as its systemic effect.
* O9 y% ~" K) Q- i) a4 q* nReview of our patients and their growth response related to
/ L& |- U2 K# J' Gage shows a greater growth response at an earlier age. This is
! Y6 I  c6 Y$ iconsistent with the findings of Wilson and Walker, who6 g4 Z" A! g  @8 n/ X
reported an increased conversion of testosterone to dihydrotes-3 A* ?0 a1 _1 r# _( K0 N! [8 E6 }
tosterone in the foreskin of neonates and infants.4 This activ-
) G" F* G7 O" P6 qity gradually decreases with age until puberty when it ap-
$ q* M2 x' y# g7 eproaches the same level of activity as peripheral skin. It may2 J* v4 S5 |) @0 U. ~& w
well be that absorption of testosterone is less when applied at
( Y( p0 X  J  o4 Ban earlier age as suggested by lower serum levels in children) w# z' U! m. E$ N6 g& |( N
less than 10 years old. This fact may be explained by the
9 ]$ `5 p' V9 ?/ V  R; Wgreater ability of phallic skin to convert testosterone to dihy-- D9 s& q" H/ D% W) r  b
drotestosterone at this age. Conversely, serum levels in older
; U6 S! a5 t9 f& k5 n3 \' ppatients were higher, possibly because of decreased local
' A, s# z. B/ |9 W6 p. Y667
7 a5 V9 V$ [( v668 KLUGO AND CERNY
6 O6 v4 ^2 _- U$ i9 zPt. Age
9 z' y" `, |. v5 q. J9 `9 ](yrs.)
; z8 O2 B- h" [6 ?. n# P/ R8 M( YSerum Testosterone Phallus (cm.) Change Length
/ a1 M+ c7 k  Y(ng./dl.) Girth x Length (%)
  ?6 J8 B8 v  i( \0 ^$ V1 n" e4
. {; A# E9 R+ P0 h: F$ g! O8
+ Y  H0 \% [* B" U  |. ?$ O0 E9 x10
; P+ U. Y7 O; i, T5 c' Z" d12
+ v+ \$ L- _4 T9 E0 M2 ?17
% F7 `8 B6 M* K/ F# o( oGonadotropin
1 [3 @+ i2 k% ~7 T. M0 a9 k9 }71.6 2.0 X 3 16.63 H4 x' N* S& |1 D+ w0 X7 D2 M
50.4 4.0 X 5.0 20.0
0 g" Q4 P0 p$ q9 i( V22.0 4.5 X 4.0 25.0, O4 v1 [- H. B1 ?" H
84.6 4.0 X 4.5 11.1
% D) V$ o2 q1 ?1 g85.9 4.5 X 5.5 9.0) V1 A. V  X0 F* O7 Z
Av. 14.3" O5 O* q+ H( G% T4 x# B
46 R' s/ S9 N  M: t' P0 k! X4 H
8! F- l0 Z) G4 i6 D
10
2 S7 h) K5 ]9 d# y  M% T12
. a9 t  f& X# S3 x9 t- X17
+ G2 g- b, ]* @2 f2 Q$ a1 mTopical testosterone
6 o) Z- @- e- {! e& E( h34.6 4.5 X 6.5 85
/ C) t4 z( G5 r. a0 F0 `& F38.8 6.0 X 8.5 705 W: j4 {9 X- c$ F6 c6 C  M+ G
40.0 6.0 X 6.5 62.51 h& f5 v; {; Y8 r* c! c& ?
93.6 6.0 X 7.0 55.5
& G3 n; ]0 ^* D5 T6 ]. Z/ s8 s95.0 6.5 X 7.0 27.2
* }4 T4 ^! }# G* ~Av. 60.0
- O* C; p& I% i6 g7 T. gavailable testosterone. Again, emphasis should be placed on
* g% ~% J% r1 q2 W8 p$ e' ^6 eearly therapy when lower levels of testosterone appear to+ X1 y) x0 G$ x
provide the best responses. The earlier therapy is instituted
* r4 ]! t8 R9 |" w" k6 cthe more likely there will be an excellent response with low
  L, K' T: j8 B2 T5 ^! @serum levels. Response occurs throughout adolescence as
$ x0 A. N3 b4 ]9 R8 V5 Jnoted in nomograms of phallic growth. 7 The actual response
+ X* m* o% K$ x2 V! _+ Qto a given serum level of testosterone is much greater at birth9 g) Z( d* k3 m% N
and gradually decreases as boys reach puberty. This is most
, B9 `! n" {% l" Z2 C$ @likely related to the conversion of testosterone to dihydrotes-
! A- r, v. Q9 ^$ w9 x" a6 \, Ptosterone and correlates well with the studies of testosterone
7 B/ c: b+ [5 N( h% P# [) kconversion in foreskin at various ages.1 v+ U0 Q: \% e: g4 k
The question arises regarding early treatment as to whether& `; h, S8 g' o/ E. ]
one might sacrifice ultimate potential growth as with acceler-. u( w  C' a8 _& y7 F3 i
ated bone growth. The situation appears quite the reverse  Y  v' L. R- c
with phallic response. If the early growth period is not used: C: f8 _" a" _9 G
when 5a reductase activity is greatest then potential growth! H/ I3 F, m3 ?
may be lost. We have not observed any regression of growth
3 }, z+ Z0 V' ]" K8 l2 i2 h; Vattained with topical or gonadotropin therapy. It may well
! M. B1 ~+ K  a1 _# g! Q% pbe that some patients will show little or no response to any; ?' o9 F! H, ?: c1 D
form of therapy. This would suggest a defect in the ability to& `  C9 j/ {: c6 M0 Y
convert testosterone to dihydrotestosterone and indicate that
7 c8 C/ p; ^+ p7 `1 d7 n( l# H, g* |phallic and peripheral skin, and subcutaneous tissue should
& L# h3 X" Z$ A9 nbe compared for 5a reductase activity.
! g- L( y6 k, ?. p* I% _& B1 F- PA, loop enlarges to measure penile girth in millimeters. B,& h, C3 s1 W7 ]& q
example of penile girth computed easily and accurately.5 c2 ?9 a1 U( d9 ^8 A8 [7 W. d
conversion of testosterone to dihydrotestosterone. It is in this( ~1 z( ^) |: I$ {/ I# E. F
older group that others have noted high levels of serum
! Z! L8 U0 k2 ^4 atestosterone with topical application. It would also appear
1 Z. @0 l) ~" X6 N' Fthat phallic response during puberty is related directly to the- _; h" v6 Y$ V+ d
serum testosterone level. There also is other evidence of local) J1 H) Y2 A1 z- T0 m* s
response to testosterone with hair growth and with spermato-& G. z) D, D# O7 R: e2 q; _# P2 ~
genesis. 5• 66 [/ z7 V. y4 T1 {
Administration of larger doses of gonadotropin or systemic
9 `. A% q9 n# o) f! V4 Htestosterone, as well as topical applications that produce9 b6 D6 Q: n2 S6 z) c6 b1 \
higher levels of serum testosterone (150 to 900 ng./dl.), will
! o6 A% _  N7 ]$ ]also produce phallic growth but risks accelerated skeletal% E" Q% @. a; d" Z$ f' k
maturation even after stopping treatment. It would appear* P! {7 b' N5 u$ E9 I6 Y
that this may be avoided by topical applications of testosterone
( h* o; s! T8 z- tand monitoring of serum testosterone. Even with this control. m' t8 Y7 O6 I% o/ I3 \
the duration of our therapy did not exceed 3 weeks at any
+ Q# X, @/ |3 g/ r- [: Z  qtime. It is apparent that the prepuberal male subject may6 M, l. C; }7 s, O
suffer accelerated bone growth with testosterone levels near
" W' u+ B. R+ i4 X200 ng./dl. When skeletal maturation is complete the level of
* j/ ^8 c! e- R& Sserum testosterone can be maintained in the 700 to 1,300 ng./
3 G/ S$ n2 j& Y% s7 J$ v5 ^! W: n- tdl. range to stimulate phallic growth and secondary sexual# `9 y/ B% s* R+ Y; n
changes. Therefore, after skeletal maturation parenteral tes-
9 V: B3 Z2 e" H( d* `* ntosterone may be used to advantage. Before skeletal matura-7 k# u$ ?8 Y: Z& {! L. p' x
tion care must be taken to avoid maintaining levels of serum4 T+ Q1 ]" A2 q8 H& D7 j
testosterone more than 100 ng./dl. Low-dose gonadotropin
( z  T5 i- a5 v7 Udepends upon intrinsic testicular activity and may require
4 g& Z+ d, X# K: r" tprolonged administration for any response.
9 h* Q4 z, l5 jAlternately, topical testosterone does not depend upon tes-
9 E$ [2 a! H' }0 f, xticular function and may provide a more constant level of$ g' S" D6 t( F) Y
REFERENCES
: F8 J, r: N* b, O1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
; S! k8 L  M( M4 U! F6 n4 nR.: The local application of testosterone cream to the prepub-
0 G* M; H/ Q  T2 Xertal phallus. J. Urol., 105: 905, 1971.0 v1 Z0 V& Q6 l0 y7 _2 C, A% _. @
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
! R) S' W3 j5 p; R1 A% k9 D; rtreatment for micropenis during early childhood. J. Pediat.,
  k( O9 s& r% d% N83: 247, 1973.# n2 _4 l: M. e4 N
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
6 F6 |) r9 \; P; _one therapy for penile growth. Urology, 6: 708, 1975.
( e" g) a. X$ V& f4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
+ r( l0 K5 o4 v9 w+ ito 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by+ o' x2 k0 v+ R9 x3 \* z" ?
skin slices of man. J. Clin. Invest., 48: 371, 1969.  G' w. m0 T  `9 \: w, z+ s1 i
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth4 e5 ~8 t) Z8 b5 e2 t0 n5 ]' m: L
by topical application of androgens. J.A.M.A., 191: 521, 1965.4 k; r! V, k) V
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
" U- `- N3 I, e3 o/ m% Wandrogenic effect of interstitial cell tumor of the testis. J.
# D4 T( U) `4 n1 rUrol., 104: 774, 1970.+ X2 T7 n5 }9 l, b8 r
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
7 A4 S# G; k2 j6 h, k3 g+ ntion in the male genitalia from birth to maturity. J. Urol., 48:
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