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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND3 d4 z+ |! ?. ^! D4 E
GONADOTROPIN
8 q3 E/ O) N- U& T* d7 M( H. WRICHARD C. KLUGO* AND JOSEPH C. CERNY" e) r2 _/ j2 _, [, Z
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
, A& _2 ]7 s" ]: s. q' I& V$ [ABSTRACT: P- ?1 t+ u# V3 S- R
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
9 d) t4 x# p- swith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
6 I# v$ o) w8 e% I4 t; W+ E$ Ztropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
5 M8 L/ |8 e0 b0 |6 @7 V0 hcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
' Y1 w$ y; H$ D6 ^for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent! h/ e; @$ V1 z9 J
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
3 k6 k. I) {# w1 M+ J0 kincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response1 C5 ^  m: h4 P* q
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This' A' K1 V% T# s- I
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile$ }2 ^7 Y1 H0 i2 _% z; Z
growth. The response appears to be greater in younger children, which is consistent with previ-( [; Q2 c/ s0 D/ @: C% V2 O
ously published studies of age-related 5 reductase activity.. g) f+ S" \2 v- y, Z( v
Children with microphallus regardless of its etiology will
  L) z) [2 T5 L( \$ u( {' b3 qrequire augmentation or consideration for alteration of exter-
3 i/ ~& {. W, p! f# \nal genitalia. In many instances urethroplasty for hypo-
! X/ t) c2 v; I1 Zspadias is easier with previous stimulation of phallic growth.( }% `) }% ~" S/ K4 p- x
The use of testosterone administered parenterally or topically* H$ E4 d& q2 ?, L; G" G$ d0 ~: c
has produced effective phallic growth. 1- 3 The mechanism of% |0 g  c* L! h: b/ c; e1 [
response has been considered as local or systemic. With this3 S: a6 d$ R" @3 I
in mind we studied 5 children with microphallus for response
3 @2 S: S0 C3 Uto gonadotropin and to topical testosterone independently.! `' l/ U( `  Z9 l! F3 l' b* |
MATERIALS AND METHODS
) S+ {1 ~% }  S8 b" tFive 46 XY male subjects between 3 and 17 years old were
4 O2 e) `  O  D$ uevaluated for serum testosterone levels and hypothalamic  t0 O$ m& D5 k% p
function. Of these 5 boys 2 were considered to have Kallmann's
5 D( x* e7 L: a; c/ n6 r8 Esyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-, E$ A  j8 ~0 f& z- v2 F
lamic deficiency. After evaluation of response to luteinizing
( P1 j2 n3 |5 }1 |2 P- z4 l% Shormone-releasing hormone these patients were treated with  Z* t4 Q! D1 y+ M
1,000 units of gonadotropin weekly for 3 weeks. Six weeks# i& }4 M1 j5 V4 n9 Z: ?8 h% _
after completion of gonadotropin therapy 10 per cent topical3 x7 P' u: S2 A
testosterone was applied to the phallus twice daily for 3 weeks., y% I9 M3 R" z9 v
Serum testosterone, luteinizing hormone and follicle-stimulat-+ o3 `1 ?$ \& b" E" k* j0 |, ]
ing hormone were monitored before, during and after comple-9 O& t- P1 y) t# U& Z
tion of each phase of therapy. Penile stretch length was6 f1 x# Y* c1 ~- C, Q3 }$ x
obtained by measuring from the symphysis pubis to the tip of1 ~* P1 s- O' w/ T
the glans. Penile circumferential (girth) measurements were* S, T8 F0 g' A0 P( ]% G. Q! W
obtained using an orthopedic digital measuring device (see/ w* _, L& @/ Y. V. l: h
figure).
6 J0 Z6 B6 s$ a. Z# J7 j; j1 }RESULTS
1 v" o0 h( |/ E: H1 Q4 _+ VSerum testosterone increased moderately to levels between3 ?5 m$ s: L. F' R
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-( i$ D: j+ C) ~4 C) [/ B, m7 b
terone levels with topical testosterone remained near pre-
8 \! J  {& W. L0 I% B, `treatment levels (35 ng./dl.) or were elevated to similar levels6 s  z3 Z0 [0 }* B' d
developed after gonadotropin therapy (96 ng./dl.). Higher  F9 n$ B' E) j7 c3 m4 N
serum levels were noted in older patients (12 and 17 years old),
3 ^8 ?# x* K4 K, o( t7 Fwhile lower levels persisted in younger patients (4, 8, and 109 B. v6 p- ?9 [5 \  z' z
years old) (see table). Despite absence of profound alterations3 s9 v2 D8 G3 \
of serum testosterone the topical therapy provided a greater' |2 i, b" K6 h6 b+ r8 r
Accepted for publication July 1, 1977. ·1 h0 A: U% D  J! g! l! ?8 L
Read at annual meeting of American Urological Association,
2 M/ W- U% ?/ N9 {Chicago, Illinois, April 24-28, 1977.6 ]% ^+ ], [7 r5 C- h# l
* Requests for reprints: Division of Urology, Henry Ford Hospital,
2 N1 f! o) D! ?% |  Y2799 W. Grand Blvd., Detroit, Michigan 48202.
2 V- l0 C4 W, p4 Q7 {improvement in phallic growth compared to gonadotropin.6 m3 A8 j4 V8 f+ u
Average phallic growth with gonadotropin was 14.3 per cent
7 g/ e# r* f4 H# Hincrease in length and 5.0 per cent increase of girth. Topical
$ y( J( e# l0 g: F2 s+ ?0 Ptestosterone produced a 60.0 per cent increase of phallic length
0 U6 T# B( U1 \: N- r' fand 52.9 per cent increase of girth (circumference). The
/ c; g2 s) v# lresponse to topical testosterone was greatest in children be-# t& j8 W' f9 N0 O0 z) t
tween 4 and 8 years old, with a gradual decrease to age 173 [+ v8 j; \) `" w: O
years (see table).0 C' t: X5 r3 T7 J' X$ @
DISCUSSION
. X" M/ J3 N6 U: X# ?/ VTopical testosterone has been used effectively by other
% a# m- V3 Z' m9 D7 \9 fclinicians but its mode of action remains controversial. Im-" |6 Z" @! L3 v0 @! }4 r6 y
mergut and associates reported an excellent growth response
" ^5 i8 m7 C6 l; s( Xto topical testosterone with low levels of serum testosterone,3 G; q7 d! \& d' J" V
suggesting a local effect.1 Others have obtained growth re-5 k5 D9 _8 }! u( @* S0 M  c' ?* z
sponse with high. levels of serum testosterone after topical
$ i. ^: D) ]) k1 B" r6 Kadministration, suggesting a systemic response. 3 The use of
4 P. \3 u8 n8 o3 K- r5 Cgonadotropin to obtain levels of serum testosterone compara-! _3 d1 R* c, p- D# _3 c8 T
ble to levels obtained with topical testosterone would seem to
, d; H6 L& [5 q7 M- i; nprovide a means to compare the relative effectiveness of* C+ p! n  n7 |: E
topical testosterone to systemic testosterone effect. It cer-
; W' ^4 _7 {; S0 X9 Ltainly has been established that gonadotropin as well as par-# G9 h4 E  Z4 W) p
enteral testosterone administration will produce genital
2 L4 P7 n2 @7 cgrowth. Our report shows that the growth of the phallus was
5 T6 z8 V4 K1 W1 H" e* x, N: {significantly greater with topical applications than with go-# P- s( ^$ F! E  }
nadotropin, particularly in children less than 10 years old.
9 E) E6 U3 {% g4 qThe levels of serum testosterone remained similar or lower! |: L/ R% S/ H: J& }! U3 f$ x, v
than with gonadotropin during therapy, suggesting that topi-" b1 f+ O7 y3 r; \. I$ ^1 [
cal application produces genital growth by its local effect as
! N" }- M( c* p  i- g! e# qwell as its systemic effect.
5 m* n( B" p+ ]1 xReview of our patients and their growth response related to& I- _8 k0 W9 ?6 _
age shows a greater growth response at an earlier age. This is
2 h9 L: T/ f; d: K8 L/ zconsistent with the findings of Wilson and Walker, who
- @2 T, ]- k8 P% W, x. rreported an increased conversion of testosterone to dihydrotes-
! j) u5 S* v0 Gtosterone in the foreskin of neonates and infants.4 This activ-
( b% I: J! f: `: X# q4 I3 eity gradually decreases with age until puberty when it ap-, @& r. T4 f: {# G! w' P3 ~
proaches the same level of activity as peripheral skin. It may2 K; M& ]( Q  P
well be that absorption of testosterone is less when applied at
( a/ d. B$ |, h! U5 Can earlier age as suggested by lower serum levels in children  o, X( V# c8 q6 f, K+ @
less than 10 years old. This fact may be explained by the
+ S5 w9 G" f5 c! k+ C/ `greater ability of phallic skin to convert testosterone to dihy-: [, i  x9 l% m: F7 U
drotestosterone at this age. Conversely, serum levels in older3 I; T- M2 x+ q* o0 _6 j
patients were higher, possibly because of decreased local* Z* g, `9 f# f; K
667
: q9 f# S+ v; c$ M8 _! J! Z668 KLUGO AND CERNY6 P6 h1 f" x  A0 i
Pt. Age
- n, c6 R1 z1 y, W) ?. A(yrs.)
8 s) V6 {* @/ ]% O7 ^Serum Testosterone Phallus (cm.) Change Length- p4 c. ?( [$ u" c$ @1 [0 w
(ng./dl.) Girth x Length (%)6 X6 X: P: W) @. h
4, I# O5 [* {' j* }" G
8
2 ]7 W2 f* s; k9 r) S# `101 ]( ^: N& h/ J6 U% ^
12
- J; N6 Z9 Y- l. m5 K  U17
7 t/ o( o# u2 ZGonadotropin
% i$ x5 D1 W; T1 C! ]* ^0 z71.6 2.0 X 3 16.6, [4 K# I4 A- ~3 }
50.4 4.0 X 5.0 20.0
' L( B/ f& o; j1 h! [! v  G" T22.0 4.5 X 4.0 25.0
9 [2 T' ^1 h$ c0 g6 ?, {" c5 B84.6 4.0 X 4.5 11.13 N4 |: t4 X" O  @. J' _4 F
85.9 4.5 X 5.5 9.0, \. T4 h8 g) s" n5 j
Av. 14.36 x$ P" S7 h. q$ p% ?
45 G2 z- s/ R. S: `# B0 T/ a8 w; U
8
+ x. o& Y- a+ M8 W6 a3 x10
" E1 l6 k5 D8 P+ H: A' ?% y12
2 u2 n' Y+ e/ j$ h+ B17
! f. j$ [# A& J1 ZTopical testosterone) ^3 `/ a: L2 a, n7 ?8 X
34.6 4.5 X 6.5 851 _5 x! L6 k6 T' X& j/ L- R3 u3 d( }
38.8 6.0 X 8.5 70! v% q, N7 E. ]
40.0 6.0 X 6.5 62.5
* a$ U1 |, C1 t93.6 6.0 X 7.0 55.5* m9 s( J/ m7 D# I& |1 N/ D
95.0 6.5 X 7.0 27.2
1 m- r- m  f2 w5 X, oAv. 60.0% ?# }$ u- P! z( a. Z1 P
available testosterone. Again, emphasis should be placed on. x1 u6 ]( `# D+ g0 _
early therapy when lower levels of testosterone appear to( j2 O3 ^: W6 G1 ?
provide the best responses. The earlier therapy is instituted" N! a/ |8 ]- ?  n4 N) S/ w
the more likely there will be an excellent response with low
1 L1 Z4 t+ l$ C4 x4 bserum levels. Response occurs throughout adolescence as
: k- i: y! v1 y8 }" O, Wnoted in nomograms of phallic growth. 7 The actual response
, N1 K8 a" k: T  C( K3 Z; T& [& pto a given serum level of testosterone is much greater at birth
4 A0 x8 p, D3 {/ j. g! Y) eand gradually decreases as boys reach puberty. This is most( y* R6 u5 P3 ?! ?% l
likely related to the conversion of testosterone to dihydrotes-- \' o3 E! E% e: h$ w
tosterone and correlates well with the studies of testosterone0 a$ U; c5 x% D5 b$ z4 a
conversion in foreskin at various ages.. V; |+ o/ o' V* ]9 [4 Z3 j
The question arises regarding early treatment as to whether( I5 w! S& a/ o; e' A6 W5 M
one might sacrifice ultimate potential growth as with acceler-
- t8 c8 A; X) ^ated bone growth. The situation appears quite the reverse2 d5 I& X& K; y3 _# h" ~) s; b5 O
with phallic response. If the early growth period is not used# Q, |6 Y8 e, K7 j2 e
when 5a reductase activity is greatest then potential growth) q- o& j5 k# u, y, W
may be lost. We have not observed any regression of growth* p2 I; B/ z) ^
attained with topical or gonadotropin therapy. It may well. q/ J+ W2 S1 i2 |' a' W) ~. S
be that some patients will show little or no response to any' t$ }  s8 S2 L/ C: s5 F5 k0 J3 _
form of therapy. This would suggest a defect in the ability to
3 l; k% g. K  ?! iconvert testosterone to dihydrotestosterone and indicate that8 \* f6 E# h8 q; ~4 P
phallic and peripheral skin, and subcutaneous tissue should3 u( h- X+ m) W+ C  x4 a3 P
be compared for 5a reductase activity.2 A. P: o; {3 e" h8 ?
A, loop enlarges to measure penile girth in millimeters. B,
. `4 {# J! b$ lexample of penile girth computed easily and accurately.
# `. Z9 Z0 e+ b+ D6 kconversion of testosterone to dihydrotestosterone. It is in this
. F1 E/ x) K# `  I( lolder group that others have noted high levels of serum2 {# G( Q: R1 T
testosterone with topical application. It would also appear+ D+ u; T& B; F* J
that phallic response during puberty is related directly to the7 a2 D. b4 M8 f- c, H" z/ d( _$ d' t
serum testosterone level. There also is other evidence of local6 k3 Z% d" y" j2 g
response to testosterone with hair growth and with spermato-
  z( X+ s* Z' Q: o" p. Mgenesis. 5• 6
! S* m' a. a& w! P. c# sAdministration of larger doses of gonadotropin or systemic
. n9 ~( S; A+ e$ ~- ^) v4 ntestosterone, as well as topical applications that produce
0 Y; _: r* U! g0 H" h" L1 T5 Ohigher levels of serum testosterone (150 to 900 ng./dl.), will' I2 t* J) R$ G. E5 @. d$ M9 X* z* _- J
also produce phallic growth but risks accelerated skeletal
7 S: \* W$ V% X' tmaturation even after stopping treatment. It would appear$ y3 N/ w; Q. d; o0 Z0 K1 ]/ P
that this may be avoided by topical applications of testosterone9 [9 [; g/ m' |; }9 @, q, P/ l, K
and monitoring of serum testosterone. Even with this control$ u3 w: k+ }" Q# g
the duration of our therapy did not exceed 3 weeks at any; I! K+ H7 L6 F6 r7 `
time. It is apparent that the prepuberal male subject may' @4 o' F$ x( ^0 N3 Q5 N
suffer accelerated bone growth with testosterone levels near
, A9 R) P5 X6 R& n' Z$ ~# |% p" t" ]200 ng./dl. When skeletal maturation is complete the level of
) K; o, D* \: p( ^serum testosterone can be maintained in the 700 to 1,300 ng./
* Q) [) G- l$ Y# d; S* n; ndl. range to stimulate phallic growth and secondary sexual! z1 Z6 e/ i% `0 e/ S
changes. Therefore, after skeletal maturation parenteral tes-4 y& y6 s4 ]7 N8 y( g- L' n
tosterone may be used to advantage. Before skeletal matura-
# Y  T: I# @5 p, K! M5 D% gtion care must be taken to avoid maintaining levels of serum3 {5 l8 r. l2 p7 X
testosterone more than 100 ng./dl. Low-dose gonadotropin0 x; k8 \( q! B. X
depends upon intrinsic testicular activity and may require
! y) _9 u" ~3 ?6 Mprolonged administration for any response.4 T+ Q" e5 P5 |3 ?) a
Alternately, topical testosterone does not depend upon tes-
, `  Q# L2 R7 d- b: r* F" Dticular function and may provide a more constant level of
  i( X  E. S0 }REFERENCES$ _) s! c; M" l- u* S+ c
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,* V. [; o7 |  @5 V! d; C
R.: The local application of testosterone cream to the prepub-
# h- R' s& K5 N; aertal phallus. J. Urol., 105: 905, 1971.) h8 f6 `. m" F  [/ ~9 Q
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
; M# H) x' _/ K8 {6 t+ n6 Dtreatment for micropenis during early childhood. J. Pediat.,
5 k' H+ D4 R! k& Q' {( `83: 247, 1973.
' _3 x' c: j5 Z( Q" V+ N3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
; [& F4 R6 |; s. Cone therapy for penile growth. Urology, 6: 708, 1975.
- g! L8 a, A+ Z) D4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone9 Q2 O( `3 \. r
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
* W8 a" i) \6 ^! e2 n' _skin slices of man. J. Clin. Invest., 48: 371, 1969." o6 z( C! `0 {0 t, G
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
" ?: z% @; N! P0 r2 W/ h( x2 H" Hby topical application of androgens. J.A.M.A., 191: 521, 1965.4 D7 C0 b  ~2 `: c( p1 ^0 y0 ^
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local& |! {6 @: |% x
androgenic effect of interstitial cell tumor of the testis. J.* z2 u5 ^! Z0 a& T( ]3 o0 N7 F
Urol., 104: 774, 1970.
* z0 |7 \, }& e+ }# |! ?7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-/ f9 Q6 s! u3 o% g& v' d% ^
tion in the male genitalia from birth to maturity. J. Urol., 48:
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