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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND9 W. E" G' b9 B
GONADOTROPIN2 K. P8 V( i% v
RICHARD C. KLUGO* AND JOSEPH C. CERNY& d7 e, f  ^$ _& T, e4 ?; z* ~
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan# M$ ?5 r# m3 g9 i3 e  _% E; j3 k1 h
ABSTRACT
0 G# j3 c2 h' B/ a3 ~) K+ V. AFive patients were treated with gonadotropin and topical testosterone for micropenis associated. V% g/ N5 D4 T8 u8 j7 W; Y
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
) j1 _) C& U6 {tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone2 s/ ^; E: r* }. p9 `2 q
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent7 [* e' L3 Q! ^; F+ s1 e- B
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
4 f9 @' ^4 n1 U. o, S. Jincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
9 ~1 \- g! h2 U  f4 y; C" m+ vincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response$ |+ o* n, p8 G
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This" g, z* ?3 M2 [6 r, J% K# Q. V
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
, Y  u; z* o' M/ E- n0 Fgrowth. The response appears to be greater in younger children, which is consistent with previ-
# @5 \& R& O* \0 B' Q# A( {  Eously published studies of age-related 5 reductase activity.
  U0 k* s; G: z' m* nChildren with microphallus regardless of its etiology will8 ~& C2 Q6 {4 n3 J4 m9 H+ H
require augmentation or consideration for alteration of exter-
7 F0 M# V: o# @1 }nal genitalia. In many instances urethroplasty for hypo-3 ^, c3 D  c. B7 M  e2 ]
spadias is easier with previous stimulation of phallic growth.
0 {% h2 v, W' oThe use of testosterone administered parenterally or topically
+ {' f% D- f0 y+ e: o- t2 k' Ihas produced effective phallic growth. 1- 3 The mechanism of
" @# M( {6 b1 {9 dresponse has been considered as local or systemic. With this
% _6 D: b2 c& C9 W% a  W6 {9 q7 jin mind we studied 5 children with microphallus for response
9 ~8 L! K6 T! d0 R: b' Lto gonadotropin and to topical testosterone independently.5 n9 x% n+ J; P1 R& y
MATERIALS AND METHODS
/ k3 }6 I# {3 r) }$ _: Y+ `Five 46 XY male subjects between 3 and 17 years old were. @: \) J  P( ~6 \! D
evaluated for serum testosterone levels and hypothalamic
/ I/ n; s& z5 K( F( Pfunction. Of these 5 boys 2 were considered to have Kallmann's1 U; ~0 O$ v( Q. N" S( \
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
! X3 _0 |0 M- E3 D. t& t) vlamic deficiency. After evaluation of response to luteinizing" Q3 ]/ U: y. j6 N- G6 f
hormone-releasing hormone these patients were treated with& L  T8 e5 T) F! q
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
# i- ^3 S# r( R( x6 \0 h2 N- Eafter completion of gonadotropin therapy 10 per cent topical0 u8 U; I  F: S  K& y
testosterone was applied to the phallus twice daily for 3 weeks.3 R; d5 G& L" L0 l
Serum testosterone, luteinizing hormone and follicle-stimulat-9 @* y% s/ v! M# S4 }0 u- H
ing hormone were monitored before, during and after comple-
9 C" b6 S8 b. _1 A1 btion of each phase of therapy. Penile stretch length was
5 s( F. V. o7 K4 Z! u% e4 i% _obtained by measuring from the symphysis pubis to the tip of  F7 M- b  P% g" {! M" |) N5 {
the glans. Penile circumferential (girth) measurements were- [- @7 K2 y, H) X, e' Y8 m
obtained using an orthopedic digital measuring device (see* J  I) f) p+ ]* a) [* H
figure).3 L! T& O& ]$ q0 e: E4 T
RESULTS
' M1 C5 T- P. |& p) x. u5 GSerum testosterone increased moderately to levels between$ }. b( B! P# R1 Y( w' ^7 i
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-* `5 Q" x: E$ E( t  N. E) ~
terone levels with topical testosterone remained near pre-
; R0 i$ ~* @  u0 g) ]/ X: L& gtreatment levels (35 ng./dl.) or were elevated to similar levels
! t) |0 d0 ~* W, u! I0 g  Ideveloped after gonadotropin therapy (96 ng./dl.). Higher. w+ E, O# Q: m# @5 p$ A
serum levels were noted in older patients (12 and 17 years old)," W; _  o& T9 A
while lower levels persisted in younger patients (4, 8, and 107 u3 d6 [6 ?; w
years old) (see table). Despite absence of profound alterations8 K' M0 H+ `+ h/ N6 C
of serum testosterone the topical therapy provided a greater
- r! V. c0 K" v' hAccepted for publication July 1, 1977. ·
' B$ L/ Y+ Q( t. L4 E$ ]Read at annual meeting of American Urological Association,
3 `" k& u* B& h/ h$ ~5 r- ~Chicago, Illinois, April 24-28, 1977.& X. I* Q* h8 e2 A" m
* Requests for reprints: Division of Urology, Henry Ford Hospital,; ^. }0 J. i+ ^
2799 W. Grand Blvd., Detroit, Michigan 48202.
1 b* J- S( p- `' F- v( @improvement in phallic growth compared to gonadotropin.  y, R- [8 M5 Q$ ^: [2 D
Average phallic growth with gonadotropin was 14.3 per cent2 A8 I9 u5 |' Q$ P* z" u/ y
increase in length and 5.0 per cent increase of girth. Topical7 v5 k3 L# A/ ]
testosterone produced a 60.0 per cent increase of phallic length* ^: _- k+ m& ~, J' K9 R0 W& ?
and 52.9 per cent increase of girth (circumference). The: d8 \, x+ s( n: W
response to topical testosterone was greatest in children be-
0 d$ u- I5 o5 ~; `8 A& Ttween 4 and 8 years old, with a gradual decrease to age 17! L6 y: A6 Z8 p5 c7 z6 G
years (see table).
" D( x2 v: J7 ?+ p) C+ M) r3 KDISCUSSION; P. M. B' j: m0 @2 G
Topical testosterone has been used effectively by other8 @) ?8 l+ e1 X% B9 ?$ L
clinicians but its mode of action remains controversial. Im-
: Q4 G/ Y# V% H8 B+ }7 _mergut and associates reported an excellent growth response
; B) W9 M9 V( Q8 Y6 x9 Ito topical testosterone with low levels of serum testosterone,' l3 M) ?3 O2 H$ Q2 Y
suggesting a local effect.1 Others have obtained growth re-& R' o2 S- P4 M6 A
sponse with high. levels of serum testosterone after topical
) X4 q+ G# `! n, ^- Jadministration, suggesting a systemic response. 3 The use of
( M0 d, O, Z/ x8 W: z- o0 ggonadotropin to obtain levels of serum testosterone compara-8 j; v2 |$ x) ~& n
ble to levels obtained with topical testosterone would seem to% w# S+ m0 G( K
provide a means to compare the relative effectiveness of
; D4 }/ r/ k/ A! X; utopical testosterone to systemic testosterone effect. It cer-
+ [. H+ H. J3 x: Q& Mtainly has been established that gonadotropin as well as par-
5 o/ [- |1 M) J% menteral testosterone administration will produce genital
0 p4 U2 |# W; ugrowth. Our report shows that the growth of the phallus was2 i3 u  e+ N+ d0 k8 u
significantly greater with topical applications than with go-/ |( ?6 `, j$ Y
nadotropin, particularly in children less than 10 years old.% ?5 D& D( ^! x7 j
The levels of serum testosterone remained similar or lower
8 l5 s' o) e$ o9 l: b+ Ythan with gonadotropin during therapy, suggesting that topi-! _7 o# ^3 r, U9 s* B7 A1 X
cal application produces genital growth by its local effect as- ~) P( `1 T+ t) d  k* z7 k
well as its systemic effect.
. ~6 f/ J7 I7 UReview of our patients and their growth response related to& j3 ?& ]  ^3 S3 |* q
age shows a greater growth response at an earlier age. This is6 g1 }2 M* {' h4 J1 z$ w
consistent with the findings of Wilson and Walker, who
8 p" p9 W, h& t, Q6 Q2 ~( G" Yreported an increased conversion of testosterone to dihydrotes-
( t, a/ w" k, ~5 \# G: v1 w1 Y. C8 Stosterone in the foreskin of neonates and infants.4 This activ-( p9 z2 s, p( [. R0 Y
ity gradually decreases with age until puberty when it ap-
  u2 W( v2 v/ L+ Bproaches the same level of activity as peripheral skin. It may
  ?0 }% H3 R( Q# [9 mwell be that absorption of testosterone is less when applied at
  j4 m) |+ q! H1 Ran earlier age as suggested by lower serum levels in children
* x$ [# N1 U2 S) Y" iless than 10 years old. This fact may be explained by the& M: Y3 T6 Y* e6 D. B1 P+ @0 `
greater ability of phallic skin to convert testosterone to dihy-
% L8 Q8 t+ ]$ k- O" p8 {$ Bdrotestosterone at this age. Conversely, serum levels in older, w, i+ v* b" @0 ?$ D2 U! Y
patients were higher, possibly because of decreased local$ }8 d3 F) a. U: g7 b4 t
667: V1 v; t) h- J+ ^
668 KLUGO AND CERNY1 E  f" q3 |1 Z
Pt. Age
2 @4 {" @5 y3 E  m(yrs.)
4 p" w& u/ \; K1 s' X, R6 r  G+ L/ eSerum Testosterone Phallus (cm.) Change Length6 h  G6 e# W5 ^" @0 A6 h2 `
(ng./dl.) Girth x Length (%)( d! a7 i  s8 W8 H0 j& k  B
4' _5 h9 x/ N7 T: @- ^$ ~
8  {0 x- ^, |/ O( W  b+ _
10
) s4 A/ x* q+ G4 k7 @! O127 ?' O2 X; p5 y8 m+ |. z
177 O- I3 I2 w$ S  |. Y6 q
Gonadotropin
5 I) c( a' k  b1 L71.6 2.0 X 3 16.6+ l4 [( E/ ?$ A# {9 x( t- @% L
50.4 4.0 X 5.0 20.0# O  z2 {% \5 ^4 Q- n9 \+ U3 l
22.0 4.5 X 4.0 25.0& v7 ~! L1 e6 n% _- X4 K
84.6 4.0 X 4.5 11.1) L: }9 X. m3 ~8 e) j
85.9 4.5 X 5.5 9.0
+ J2 B+ o( ?& ZAv. 14.34 x5 ?0 K( n2 C- L
44 y7 {' a  B) [
86 I9 t! ]$ I. ~8 t  C- g3 k
10
! d5 r( A2 g/ I$ W5 [* o12
9 ]5 o8 T. ]: H+ ^! {" y8 B179 I/ v3 v! d6 p& G9 W! J
Topical testosterone
1 Z3 {1 p& o% s# C8 X2 k. A, K34.6 4.5 X 6.5 85
$ N. \1 _/ j# Y38.8 6.0 X 8.5 70
) H) u  N6 q9 n. a* k* Z& u40.0 6.0 X 6.5 62.5
+ O$ Z2 M2 D" M6 D+ M  Q, k$ q93.6 6.0 X 7.0 55.52 t/ M1 U& [7 s5 H. q6 |& |! V
95.0 6.5 X 7.0 27.2
2 F% n8 k, P0 w0 ^Av. 60.0% B; W- S. u, K1 t% I
available testosterone. Again, emphasis should be placed on
( A* @& b% y7 P1 k: Xearly therapy when lower levels of testosterone appear to
9 K' s' ^% z5 k( Kprovide the best responses. The earlier therapy is instituted2 u: v. r% h, m4 u
the more likely there will be an excellent response with low6 @0 T7 X0 l/ M
serum levels. Response occurs throughout adolescence as+ W7 p( W; ?7 d, F( \5 q" e
noted in nomograms of phallic growth. 7 The actual response
+ z+ g7 [/ E0 G' p6 j! @to a given serum level of testosterone is much greater at birth
" B3 r$ \  k+ d  r+ X0 r( B( pand gradually decreases as boys reach puberty. This is most
7 P- K7 B+ H3 xlikely related to the conversion of testosterone to dihydrotes-
4 _# X% b/ W0 {+ u' v/ Q6 X% [tosterone and correlates well with the studies of testosterone
4 n; g/ `$ A# i& oconversion in foreskin at various ages.+ J. s; g4 n6 ~7 H0 O( J: V2 ^
The question arises regarding early treatment as to whether5 K6 x6 W& W5 e  H) A
one might sacrifice ultimate potential growth as with acceler-
" d" R8 }$ H' T+ e' Qated bone growth. The situation appears quite the reverse! \# U6 F1 u( s0 K# r) D
with phallic response. If the early growth period is not used
+ \( E8 w' h+ g! d6 ^) @when 5a reductase activity is greatest then potential growth: }& i7 h' C9 i5 y4 {) Z8 N
may be lost. We have not observed any regression of growth. t% w  l$ Z2 m# O
attained with topical or gonadotropin therapy. It may well4 G3 |8 [) b- Q5 P6 O: w
be that some patients will show little or no response to any( e6 V& _- B3 {; |( }, D
form of therapy. This would suggest a defect in the ability to. R' k! L! O) _: \' i) p9 |4 n
convert testosterone to dihydrotestosterone and indicate that
. x7 B1 y* U( q% {# w3 aphallic and peripheral skin, and subcutaneous tissue should- o* ~- X0 K1 d( z  M
be compared for 5a reductase activity.
  i  t* b8 G; \* W4 ^4 O0 U$ }A, loop enlarges to measure penile girth in millimeters. B,
9 }& F* r# M4 `, W4 A2 t' hexample of penile girth computed easily and accurately.
& P& j9 v3 ?; l) B: a& g5 N) Cconversion of testosterone to dihydrotestosterone. It is in this8 j% L  J& L7 a
older group that others have noted high levels of serum7 |  j" I; x2 w1 m) w& x
testosterone with topical application. It would also appear
* I4 ]6 y. @0 [2 `! B4 P5 w5 W) ~that phallic response during puberty is related directly to the
" m- t4 H4 @! U9 L* T5 }+ L1 hserum testosterone level. There also is other evidence of local8 a+ l7 M2 g4 Q  m, W9 n1 \
response to testosterone with hair growth and with spermato-& c, S; ?2 ?9 f; i4 b) ]8 n" a
genesis. 5• 6! z6 S' |5 \  ^4 L
Administration of larger doses of gonadotropin or systemic
) ?" w9 M) ~9 @testosterone, as well as topical applications that produce  ^) M. B0 p: Q7 J9 I
higher levels of serum testosterone (150 to 900 ng./dl.), will
; N. _0 m$ r% P/ d; P: l; Talso produce phallic growth but risks accelerated skeletal  E* a5 v) Y7 X. o
maturation even after stopping treatment. It would appear
" {$ _8 f  |! j6 jthat this may be avoided by topical applications of testosterone
) @4 e' K8 H' {- ^and monitoring of serum testosterone. Even with this control
8 M. }7 h# d- ?the duration of our therapy did not exceed 3 weeks at any  `& G" {2 C- f' [/ r
time. It is apparent that the prepuberal male subject may; s, C' }) U* m, S! Y9 k
suffer accelerated bone growth with testosterone levels near
6 \" Y) s6 D& M3 \2 H) Y200 ng./dl. When skeletal maturation is complete the level of
  u" n4 S/ O) h5 v  Rserum testosterone can be maintained in the 700 to 1,300 ng./0 K; v5 t1 h4 A5 N7 y
dl. range to stimulate phallic growth and secondary sexual
1 o) s, ?$ r6 d+ M5 w8 T# n& y+ {changes. Therefore, after skeletal maturation parenteral tes-
, |& h* {7 s/ I3 E2 ?6 F+ ~tosterone may be used to advantage. Before skeletal matura-
8 B6 p3 x3 l. `9 s7 ?tion care must be taken to avoid maintaining levels of serum) P2 O& @" E; V; B- Q* ~
testosterone more than 100 ng./dl. Low-dose gonadotropin' u4 v8 y8 k* ]" C, g  u% Y1 t8 I! {
depends upon intrinsic testicular activity and may require( k- p/ z- k# }$ N
prolonged administration for any response.
- g# ^, v1 q7 ?3 w; FAlternately, topical testosterone does not depend upon tes-5 T$ g0 s0 U1 r5 v# \, s
ticular function and may provide a more constant level of
/ m/ b* w4 D4 ]  A, V4 C) qREFERENCES
! Z9 L& o+ c5 R. `! n1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
$ L  p7 }2 y5 t' WR.: The local application of testosterone cream to the prepub-; o9 w; U, \7 {1 m# E
ertal phallus. J. Urol., 105: 905, 1971.
) k$ ^* O" P7 l# G2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
9 K( w6 q' n/ W5 O- u2 rtreatment for micropenis during early childhood. J. Pediat.,
1 `# \3 s0 f  H2 x& W+ ^" {83: 247, 1973.
, \( p0 n3 g, ^) D7 C8 w3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-& Y0 N% i5 h! F5 b9 _1 o
one therapy for penile growth. Urology, 6: 708, 1975.
' u0 q! n9 E. @) B4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
4 A) i( s# u/ }& H' ?7 `8 j7 \to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by, m5 v/ }, M! f5 z. F1 U, o
skin slices of man. J. Clin. Invest., 48: 371, 1969.1 e9 Q1 ?8 H; U8 \0 F
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth, L# v. W3 A2 z7 i
by topical application of androgens. J.A.M.A., 191: 521, 1965.
- W$ F$ k& j1 T) W5 R2 v8 M3 d2 v) i6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
- K# {5 G- h9 I' T  F+ O* y1 g* uandrogenic effect of interstitial cell tumor of the testis. J.
: v4 K' p! ^& H; i2 PUrol., 104: 774, 1970.
- E( z2 S: _% j, f% e* E4 \7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-+ B5 z: P. S9 @5 o+ }6 f
tion in the male genitalia from birth to maturity. J. Urol., 48:
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