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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND8 J# ]; Y  |% G4 G
GONADOTROPIN' c& K8 k/ }& Z  x5 Y# Y( _% k
RICHARD C. KLUGO* AND JOSEPH C. CERNY' i2 X3 r8 h% p" {, Q( z6 X
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
" b: ^4 T! x% r) f: jABSTRACT
( u9 s. V* F' {0 h* l. L( k: F; MFive patients were treated with gonadotropin and topical testosterone for micropenis associated$ o* G3 _8 ~* T& i
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
* K3 I2 y' M( G& h* c! ctropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone# J5 @5 F- ~# l: R- k
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
1 K4 R% T( I) f9 b, J$ k8 Dfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent9 D1 s' F" }/ \* I& o
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average! `; k( j/ k( ~7 a1 l
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
* M2 V& s5 q- A1 B" Q& }0 E" _occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
* D, k: p9 l$ v+ `/ G3 x4 Ostudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
) n% ?6 D/ S* K, A6 G/ m* cgrowth. The response appears to be greater in younger children, which is consistent with previ-
+ P# K$ e4 q0 L6 `ously published studies of age-related 5 reductase activity.
9 g3 ]  ^; V) z3 z* S3 b4 N' PChildren with microphallus regardless of its etiology will
# ?' i, U5 w$ i" G; Zrequire augmentation or consideration for alteration of exter-4 \0 n5 n  u3 N- x( K4 P
nal genitalia. In many instances urethroplasty for hypo-% d7 a! q- A0 d. {! K  N& f; c% B% b
spadias is easier with previous stimulation of phallic growth.0 ]; A! f+ P  a' q2 K% K
The use of testosterone administered parenterally or topically8 k7 E7 z4 n3 ?  R4 Z- a
has produced effective phallic growth. 1- 3 The mechanism of
, r% t2 g; a( _6 k& H( Dresponse has been considered as local or systemic. With this
$ \8 J( R! Z6 P* lin mind we studied 5 children with microphallus for response
: h5 w$ G. |' `) Y. o. R+ T7 Wto gonadotropin and to topical testosterone independently.
9 o' X0 A' `% M9 s6 KMATERIALS AND METHODS1 a3 W. K, B2 `) l. Y( ^; \
Five 46 XY male subjects between 3 and 17 years old were
& W7 R+ Y9 I' P9 tevaluated for serum testosterone levels and hypothalamic1 N) R& J2 O3 v, K! ~
function. Of these 5 boys 2 were considered to have Kallmann's
- a8 O6 h0 k/ u% l- xsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-4 `1 t+ U; }$ Z7 K. e6 x" q1 p7 x
lamic deficiency. After evaluation of response to luteinizing6 O3 `+ i" G7 M. }! J( d) @! L
hormone-releasing hormone these patients were treated with
9 @1 J+ n5 H" i1,000 units of gonadotropin weekly for 3 weeks. Six weeks  `% H: t4 o) e% b& T
after completion of gonadotropin therapy 10 per cent topical
& h/ s3 M: z/ Ntestosterone was applied to the phallus twice daily for 3 weeks.
: i) Z( m9 H# l# e7 v3 q. i  sSerum testosterone, luteinizing hormone and follicle-stimulat-) A% U8 }9 i: }
ing hormone were monitored before, during and after comple-# M" W: m: d- b* O5 G9 [
tion of each phase of therapy. Penile stretch length was
9 n) T. j" A' U8 _8 ^obtained by measuring from the symphysis pubis to the tip of
% h: V/ i* {5 ?/ d- S/ ]% g0 p0 Bthe glans. Penile circumferential (girth) measurements were1 \5 Q6 g/ Q  A5 \6 h" D* a/ i! E
obtained using an orthopedic digital measuring device (see( S' _- v% G& s$ r* e  F
figure).
9 `) j/ Y* o1 u9 r' X/ ]7 bRESULTS: d* l% ]. @$ r! }; M
Serum testosterone increased moderately to levels between
% r- {* a3 N1 X: y3 u. X50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-9 K& l' E5 _9 X/ F
terone levels with topical testosterone remained near pre-' \# v1 p( _. E; O& h% O; h
treatment levels (35 ng./dl.) or were elevated to similar levels, y/ N# _3 V5 U4 ]4 f
developed after gonadotropin therapy (96 ng./dl.). Higher
0 ?0 \7 P) ^* d" ]4 r1 rserum levels were noted in older patients (12 and 17 years old),1 K/ y2 l, T0 o( \9 H+ Y3 G6 K
while lower levels persisted in younger patients (4, 8, and 108 @+ q  A6 l  D+ m. Y! [8 {
years old) (see table). Despite absence of profound alterations: d" ~6 [" Z$ z. Y" k
of serum testosterone the topical therapy provided a greater
  R# e. u9 n) P8 N# f1 ]  h9 hAccepted for publication July 1, 1977. ·
; H, d& e$ v1 ?Read at annual meeting of American Urological Association,! L) H4 K4 u! z: Y7 O
Chicago, Illinois, April 24-28, 1977./ K: l: Q+ j* p, z; N$ B! o
* Requests for reprints: Division of Urology, Henry Ford Hospital,. u1 \, x1 ]6 |$ I4 O' D, X: A- j
2799 W. Grand Blvd., Detroit, Michigan 48202.
7 [9 T& g6 V9 Z+ F. R' k! eimprovement in phallic growth compared to gonadotropin.
5 H3 x# D' V0 a, UAverage phallic growth with gonadotropin was 14.3 per cent
8 q' f3 L$ q' L: Y+ ~. Xincrease in length and 5.0 per cent increase of girth. Topical
7 H, J6 L& J# L# Etestosterone produced a 60.0 per cent increase of phallic length, Z. ]8 g8 o( G" X2 I
and 52.9 per cent increase of girth (circumference). The
% t: }! x, [7 a; t. d# ]6 E6 Eresponse to topical testosterone was greatest in children be-; K5 {' K! z% U
tween 4 and 8 years old, with a gradual decrease to age 17
; O' |% \* t; u7 h* P! fyears (see table).0 c* j, C3 h# C' n- |, e0 U
DISCUSSION7 N- t$ b* S) [
Topical testosterone has been used effectively by other& x- u. F5 P" T$ s
clinicians but its mode of action remains controversial. Im-7 n( ^1 E2 m* A
mergut and associates reported an excellent growth response
1 K/ N# O' }2 n% i5 m0 K( D: }to topical testosterone with low levels of serum testosterone,: g- y/ ~7 a* w/ X) Y+ I
suggesting a local effect.1 Others have obtained growth re-2 s  s+ U1 Q6 f1 ]  O4 P4 R
sponse with high. levels of serum testosterone after topical
% _7 y# j( ?) E( |1 Sadministration, suggesting a systemic response. 3 The use of
- e, ?% {8 E; s1 b  W4 s2 dgonadotropin to obtain levels of serum testosterone compara-4 [! m* @/ f1 S0 T( O0 _
ble to levels obtained with topical testosterone would seem to1 |8 O8 {9 `, h) B% r6 d# u8 M4 }
provide a means to compare the relative effectiveness of2 V1 y9 t& n- d5 H+ ~* `
topical testosterone to systemic testosterone effect. It cer-
& j7 R0 n; a/ |: x/ s9 U- Jtainly has been established that gonadotropin as well as par-
7 [( I/ _% A6 q. fenteral testosterone administration will produce genital% o$ e6 T) p6 w2 h; {: O" P
growth. Our report shows that the growth of the phallus was
$ M4 D- H* V+ j% v5 nsignificantly greater with topical applications than with go-
. x8 Y! P1 Y& Wnadotropin, particularly in children less than 10 years old.
+ L0 H9 q2 Q; DThe levels of serum testosterone remained similar or lower: @2 x# R  P. S  {% D# J, m; C
than with gonadotropin during therapy, suggesting that topi-
9 e" C5 g, N0 G8 a* ?/ fcal application produces genital growth by its local effect as
1 m3 n/ O9 Z; ~6 a; Zwell as its systemic effect./ q% }3 P8 f8 H4 V, R" X
Review of our patients and their growth response related to7 L: |& O5 x6 }1 I2 t4 j
age shows a greater growth response at an earlier age. This is9 D" ]) ~) w% ^/ Y6 ]( N- W1 h
consistent with the findings of Wilson and Walker, who
3 Y$ F5 Q3 ~5 V$ A2 freported an increased conversion of testosterone to dihydrotes-
0 D2 q* a& u3 P9 |- wtosterone in the foreskin of neonates and infants.4 This activ-
) U& s; U) D+ uity gradually decreases with age until puberty when it ap-( S, y; g6 o2 _7 K, K3 f3 N
proaches the same level of activity as peripheral skin. It may
  Y4 g) o, @& Nwell be that absorption of testosterone is less when applied at
5 C1 E0 O3 |; v. e+ |0 pan earlier age as suggested by lower serum levels in children
; _& u+ @7 \5 x4 Lless than 10 years old. This fact may be explained by the' O' n1 X6 R2 |! F: s# \, ?
greater ability of phallic skin to convert testosterone to dihy-
% w% z% {+ `7 L0 @2 {& y5 Mdrotestosterone at this age. Conversely, serum levels in older
) v8 T2 P3 V4 `+ t( {" L( Wpatients were higher, possibly because of decreased local2 B6 O7 h. j* v) d: m! [
667% N7 b( ]! j) i- q0 w
668 KLUGO AND CERNY
0 x7 g6 x5 O/ w1 jPt. Age. C5 e% s3 X' t7 b- j
(yrs.). Y3 A* k, T2 [
Serum Testosterone Phallus (cm.) Change Length
4 E1 ~' a* v! z(ng./dl.) Girth x Length (%)
3 D* A2 ?+ ~, c4 }3 S1 e; M, S4
5 D5 V- U0 `- L% s) n% ]8/ h. _5 Y1 v& c0 d  d3 Q
10) x" W0 e( f2 l$ Q
12
$ c& J1 @+ `6 q4 A. w17% o- `: p' |5 u) v# l2 `9 q2 n
Gonadotropin
2 c1 t3 f* K2 ?71.6 2.0 X 3 16.6
4 H/ k7 d) Q$ L# A/ }50.4 4.0 X 5.0 20.0" _  _; A: s& V+ E. D1 p/ v  i5 V
22.0 4.5 X 4.0 25.0
" I- W$ N* p# }7 S1 P84.6 4.0 X 4.5 11.1. B# `: S1 o$ ^/ A
85.9 4.5 X 5.5 9.0; G$ I* {. E4 U) L8 w
Av. 14.3
( z$ K, V" _! c4
+ n$ R# m% b0 D: j! Z) O8/ V7 a- J1 N9 y! H) A9 J1 e5 U
10
* Q3 o( \* d% f& V- t12. A6 n9 z0 c# h; e0 r: n
179 z6 j4 `# O3 W6 [
Topical testosterone
  K- [) T/ k0 j4 T7 h6 z34.6 4.5 X 6.5 851 R4 G7 \# }. o9 b- F
38.8 6.0 X 8.5 70; F/ x+ V' _" Y- c. J, M' T& @  l7 L! l
40.0 6.0 X 6.5 62.56 Z. O1 y$ W! B$ a3 ^
93.6 6.0 X 7.0 55.51 s' m- B/ S0 J+ p5 M8 s5 V+ Z
95.0 6.5 X 7.0 27.21 `; P% O! Q* G" T# y( c" q
Av. 60.0
! V/ u& W$ U$ W9 pavailable testosterone. Again, emphasis should be placed on
* j, o4 r' X3 x, J- E2 Xearly therapy when lower levels of testosterone appear to. }9 I. L; U9 e8 w& f- S
provide the best responses. The earlier therapy is instituted
4 C3 t- k6 F; `# H; D! B. othe more likely there will be an excellent response with low3 Q2 G' j$ j/ M8 u
serum levels. Response occurs throughout adolescence as4 k  R! n( z! l& q/ E
noted in nomograms of phallic growth. 7 The actual response8 M7 [+ w$ m( a+ E0 s! S
to a given serum level of testosterone is much greater at birth
! T1 w9 u0 c+ R/ _/ Pand gradually decreases as boys reach puberty. This is most
7 ~9 F: k- o5 C  }* J5 Vlikely related to the conversion of testosterone to dihydrotes-
+ ^# ]! e4 F5 z) [7 f/ B* Ntosterone and correlates well with the studies of testosterone6 C, i! g0 n2 _. i$ @( L0 R
conversion in foreskin at various ages.. `* |" N/ P' i8 a
The question arises regarding early treatment as to whether
# L# Z2 A8 f% |5 h$ none might sacrifice ultimate potential growth as with acceler-
; H8 @! O7 A" U4 d  h/ J( r7 T1 I* s: nated bone growth. The situation appears quite the reverse
: i, h8 d6 Y' m; U, q  _with phallic response. If the early growth period is not used" g( u* e3 [# w( m  K
when 5a reductase activity is greatest then potential growth
% f& R  C( |' g9 d- [8 ~may be lost. We have not observed any regression of growth
! T$ D4 m( W% Zattained with topical or gonadotropin therapy. It may well3 O0 ~+ D8 K+ `9 \0 O8 _
be that some patients will show little or no response to any
5 u1 L; E/ ~* ^, U8 D+ lform of therapy. This would suggest a defect in the ability to
( D- v$ W7 m0 \! K1 P* S9 Rconvert testosterone to dihydrotestosterone and indicate that4 B2 ~! }4 o2 q' B/ b5 R/ H) F+ }
phallic and peripheral skin, and subcutaneous tissue should
% `+ H+ F7 b6 U8 wbe compared for 5a reductase activity.
- K4 }: B% D/ p; V: s9 Q% OA, loop enlarges to measure penile girth in millimeters. B,
: ]  o7 ~: _- d# L$ R- Q3 v4 Dexample of penile girth computed easily and accurately.
6 [8 b% l, A+ O; f0 S- @conversion of testosterone to dihydrotestosterone. It is in this
5 J: r8 K2 u, H, d4 bolder group that others have noted high levels of serum+ V, [) K4 B, y8 Z" `5 y
testosterone with topical application. It would also appear! i  i" i6 F/ ]+ d  \+ L, S2 M
that phallic response during puberty is related directly to the; b$ C! W' O  O
serum testosterone level. There also is other evidence of local
5 u, B& K, {4 Dresponse to testosterone with hair growth and with spermato-
$ [# w- t5 O# F0 L2 Ygenesis. 5• 69 s. j4 I& j0 x9 w' n2 J
Administration of larger doses of gonadotropin or systemic
1 K/ f  v/ w2 i: atestosterone, as well as topical applications that produce' E1 ?2 W: }0 ]5 v; m9 X
higher levels of serum testosterone (150 to 900 ng./dl.), will$ u1 z7 K8 N, H2 X. y6 U: t) O
also produce phallic growth but risks accelerated skeletal
  g. [8 a5 G, y$ Nmaturation even after stopping treatment. It would appear* J+ ^9 M6 L& s+ a0 k
that this may be avoided by topical applications of testosterone
% H+ z+ D  h6 Y+ T; L4 F& e. Qand monitoring of serum testosterone. Even with this control( J& {0 }( e4 {+ y- e
the duration of our therapy did not exceed 3 weeks at any3 J  h( f" B  {5 Z3 j8 A
time. It is apparent that the prepuberal male subject may& Z2 _# ^2 ^/ k+ L0 o
suffer accelerated bone growth with testosterone levels near' u( S& |/ L0 n0 x/ o5 r
200 ng./dl. When skeletal maturation is complete the level of) `  T0 B/ d/ r) ^: a+ p. u
serum testosterone can be maintained in the 700 to 1,300 ng./6 O: g+ ]- [' J! p( m
dl. range to stimulate phallic growth and secondary sexual) Z( ^5 ~- m* ~% `% q
changes. Therefore, after skeletal maturation parenteral tes-- ]8 J( @- j8 R: R
tosterone may be used to advantage. Before skeletal matura-
# |/ P- s& [6 mtion care must be taken to avoid maintaining levels of serum
6 w5 h4 c+ Q6 P2 o. Ltestosterone more than 100 ng./dl. Low-dose gonadotropin
- ^2 s0 u4 E; H+ ]depends upon intrinsic testicular activity and may require) g' K; t7 g6 L, V. ]% ]5 Y3 ?& T, J
prolonged administration for any response.2 [$ b; W$ r0 _/ m- N# U$ p( h
Alternately, topical testosterone does not depend upon tes-, a) _+ N% p# h: m' q
ticular function and may provide a more constant level of& m1 b. L$ I: F+ w' \3 F
REFERENCES" a9 g! _/ u% ]# X; H
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
5 C" u* G5 z5 s) QR.: The local application of testosterone cream to the prepub-
0 A/ H/ v8 W6 b7 H, qertal phallus. J. Urol., 105: 905, 1971.
6 C# R3 m; u1 A! V8 Z2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
0 _. |1 x  p8 e3 `treatment for micropenis during early childhood. J. Pediat.,
3 v  y$ o% c* |: y83: 247, 1973.% `, N' {' f7 s4 I: F1 ^
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
1 S) S# h/ a- k9 @) ~  }one therapy for penile growth. Urology, 6: 708, 1975.! D, E! S: `8 A: c. e" A
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone& e4 m/ n: t4 O4 m- v
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by" z; U5 `7 S8 Q
skin slices of man. J. Clin. Invest., 48: 371, 1969.& K( R3 z; a9 p' A
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
8 y& i/ a: c5 U- Jby topical application of androgens. J.A.M.A., 191: 521, 1965.+ I9 p; ?9 E! r
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local$ j$ {2 ~& u8 _0 t0 y
androgenic effect of interstitial cell tumor of the testis. J.; Z4 C3 @( y& ?# X5 t
Urol., 104: 774, 1970.
# c# x" d0 p' c" q6 M$ \0 m7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-  R5 L& C, W$ m/ X3 E, w/ k
tion in the male genitalia from birth to maturity. J. Urol., 48:
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