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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND. y1 V) w) a" s4 L
GONADOTROPIN' H% a% d* j" }  T) y: g- S
RICHARD C. KLUGO* AND JOSEPH C. CERNY5 L/ w* u- L" B  S0 {% n
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan, H2 \% c1 a; i7 `' M
ABSTRACT
7 O. z2 t0 V9 j9 N' kFive patients were treated with gonadotropin and topical testosterone for micropenis associated) q! B' F) Q* G( p+ i/ A
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-+ W: n, ?( i  p* o- l1 _
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
0 P/ a9 |3 x% k3 O9 p2 ccream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
% Y( B2 Z# U# i  `1 P- W+ ufor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent; k, ]$ w! C" u, ?' C. F
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average3 n& e, i5 D% e. }- @
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response, m) n/ q% r$ G, }& t4 h+ O
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
8 d3 O5 m& [8 X" x  J5 M+ O) Jstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile  e' Z* p3 |# S) \$ d/ h  t" K
growth. The response appears to be greater in younger children, which is consistent with previ-, B! G$ r3 q) C: `+ B7 t
ously published studies of age-related 5 reductase activity., ^  k9 V, K& K/ N( w$ P- R& O
Children with microphallus regardless of its etiology will/ Z1 s! t$ q0 ?! v3 H" @
require augmentation or consideration for alteration of exter-% d( r% m# i8 K9 i# M# Q- S
nal genitalia. In many instances urethroplasty for hypo-( O  u1 M% e6 _7 S5 }; B. g+ z8 Y
spadias is easier with previous stimulation of phallic growth.5 I# e9 p" K% |' q
The use of testosterone administered parenterally or topically8 C* x% O- A! k7 E
has produced effective phallic growth. 1- 3 The mechanism of) H/ n6 Y% Z( u- p7 G  R
response has been considered as local or systemic. With this; s5 v4 G& \( _  v
in mind we studied 5 children with microphallus for response
; o; ^3 E5 B! G7 W  A6 k  Ato gonadotropin and to topical testosterone independently.+ Q, S. q2 z4 `% I4 K
MATERIALS AND METHODS& V0 j' n2 z! s" Q1 \/ a0 C! N
Five 46 XY male subjects between 3 and 17 years old were0 G8 \3 t& q0 S. p" d
evaluated for serum testosterone levels and hypothalamic
' o) @/ ]. ]. S7 Z- _. ]- d: Zfunction. Of these 5 boys 2 were considered to have Kallmann's
+ v! l) K" z, Dsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
! s/ N& N- l8 f& |9 O6 O4 clamic deficiency. After evaluation of response to luteinizing" x3 B0 e. L6 j6 T$ D" U. t4 X6 U" _
hormone-releasing hormone these patients were treated with
3 G# D9 q) P! c  f1 u$ \1,000 units of gonadotropin weekly for 3 weeks. Six weeks# [+ M; u8 e8 W3 }- k: I: ^' o
after completion of gonadotropin therapy 10 per cent topical
$ t" k1 n+ \: i8 o: y! A0 V" ^testosterone was applied to the phallus twice daily for 3 weeks.
) o  u6 h& s; E7 B, sSerum testosterone, luteinizing hormone and follicle-stimulat-. R7 ]( G/ W6 M3 z; [1 w
ing hormone were monitored before, during and after comple-6 `* ?6 v& d9 v1 n
tion of each phase of therapy. Penile stretch length was0 M7 M7 L" o2 N) J* m
obtained by measuring from the symphysis pubis to the tip of6 ?" p2 s, y- u; V
the glans. Penile circumferential (girth) measurements were: t5 N1 O* a1 N
obtained using an orthopedic digital measuring device (see
% B* c8 Q+ N7 a+ tfigure).* Q; {$ |. |' o% V
RESULTS$ U" h0 R7 \( ^; ?* S1 B/ K  ]
Serum testosterone increased moderately to levels between9 J& ]+ q& l1 T& q4 M, t$ d9 O* [
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-) d  _/ N) l. g! l& N: F$ }2 d
terone levels with topical testosterone remained near pre-
- |5 J/ G# `' x! U+ Ntreatment levels (35 ng./dl.) or were elevated to similar levels
, |( S; {& f4 u6 C, T3 ~developed after gonadotropin therapy (96 ng./dl.). Higher
1 Z" m$ }% X# |* n, x1 Hserum levels were noted in older patients (12 and 17 years old),
9 n6 q' Y* J$ I7 Ewhile lower levels persisted in younger patients (4, 8, and 100 V* S9 H( L# a* R7 T
years old) (see table). Despite absence of profound alterations" Q' ^( s- |6 O& P- U
of serum testosterone the topical therapy provided a greater
: p8 Q. Z' y5 }$ `Accepted for publication July 1, 1977. ·
0 k2 c$ C1 g. y- j+ kRead at annual meeting of American Urological Association,9 j* V) B! a; ^( O8 P* L
Chicago, Illinois, April 24-28, 1977.
  d3 W, t7 H  ]/ `8 b* Requests for reprints: Division of Urology, Henry Ford Hospital,6 A# }" f+ ~- z6 |% o; J6 y+ ]# r
2799 W. Grand Blvd., Detroit, Michigan 48202.
; f) R  e5 B' W$ g( n8 k' limprovement in phallic growth compared to gonadotropin.2 V" W( V; s; Q& o2 ^. |
Average phallic growth with gonadotropin was 14.3 per cent0 ~4 w# l: D9 `! W4 {. D
increase in length and 5.0 per cent increase of girth. Topical
3 h3 v3 b$ j9 v( N' I$ N! Ptestosterone produced a 60.0 per cent increase of phallic length
% j5 @. U+ o$ N$ k6 L# Y1 [and 52.9 per cent increase of girth (circumference). The
, W' q- d7 E2 Eresponse to topical testosterone was greatest in children be-$ j  w& b8 g% Z* ?! R* G# @! m0 D
tween 4 and 8 years old, with a gradual decrease to age 17
/ c. K7 K$ D3 ?; x: D# {years (see table).
5 T& @0 V$ y" WDISCUSSION" i) S6 ~2 {: z# O" g# K( N. I
Topical testosterone has been used effectively by other( \: j- \: k9 \6 K+ l
clinicians but its mode of action remains controversial. Im-
% Y8 q: }! c- S% qmergut and associates reported an excellent growth response, z! x& ?6 S3 H8 w/ h2 \$ L) G; e/ }9 k
to topical testosterone with low levels of serum testosterone,
3 d, `+ F% m; I& b0 K( V( C# V% Zsuggesting a local effect.1 Others have obtained growth re-9 r5 h& M0 \5 s+ ~7 N) ~
sponse with high. levels of serum testosterone after topical4 `) g5 M  V) Q! {' y% n9 x
administration, suggesting a systemic response. 3 The use of
8 s+ [$ n( v% h, L9 a" R$ n$ ~8 pgonadotropin to obtain levels of serum testosterone compara-
  ^( O" |, s4 Y$ X& l2 `ble to levels obtained with topical testosterone would seem to
( F1 F4 R) J! Gprovide a means to compare the relative effectiveness of4 m" W- \( V% h, o1 J8 d9 T8 s
topical testosterone to systemic testosterone effect. It cer-% b  v5 {9 M' q2 }
tainly has been established that gonadotropin as well as par-
  n) [, O2 J' |% {  A# x# {enteral testosterone administration will produce genital4 Q. I. C$ Q) F/ l# G9 T$ B5 B) `
growth. Our report shows that the growth of the phallus was
, M& Z& ]/ G* e* }% x$ @significantly greater with topical applications than with go-
. r5 b+ P2 u8 P4 c- |  e& enadotropin, particularly in children less than 10 years old.
3 _9 Z3 Y/ A/ ~6 ]5 lThe levels of serum testosterone remained similar or lower
+ a7 E0 Q# s: B* {& Cthan with gonadotropin during therapy, suggesting that topi-
+ ]) b7 Y  G0 v4 tcal application produces genital growth by its local effect as
% [/ k7 e% y1 Jwell as its systemic effect.
2 a2 z  m8 ]7 O. J7 g; a2 b+ i- kReview of our patients and their growth response related to
$ A  W4 Z, H0 g$ E" tage shows a greater growth response at an earlier age. This is: T( P" Q+ x3 H5 o# h+ s7 y
consistent with the findings of Wilson and Walker, who
( j5 o6 }: K8 k& r& yreported an increased conversion of testosterone to dihydrotes-; `: F4 i/ ~) d3 g# o: |* Q# Y" s
tosterone in the foreskin of neonates and infants.4 This activ-0 r- w# b! B1 r  B3 @6 A% f
ity gradually decreases with age until puberty when it ap-
! t6 p& J; A5 h5 _$ zproaches the same level of activity as peripheral skin. It may9 A/ ?  ~; E! t1 W
well be that absorption of testosterone is less when applied at
3 r  U( l0 r9 r0 O, ?3 _an earlier age as suggested by lower serum levels in children6 B5 P3 d) H/ B9 m! Y
less than 10 years old. This fact may be explained by the6 {! @3 v, s! S, ^" T
greater ability of phallic skin to convert testosterone to dihy-
1 F/ G+ m  S! Q  @drotestosterone at this age. Conversely, serum levels in older
: W, y6 H4 P$ W. ?4 ^patients were higher, possibly because of decreased local
1 A- v, M% @# ~% x+ Z! |8 v667% g, T9 c0 J6 N" b8 o; m# W
668 KLUGO AND CERNY3 q0 Z" l% Q2 Y: o6 t8 O
Pt. Age' Z% m0 w0 d* L. ?# u8 c" W
(yrs.)# U: a6 t* B( [$ F$ k& t. K: v
Serum Testosterone Phallus (cm.) Change Length& p( Y1 X. E/ x' y5 M
(ng./dl.) Girth x Length (%)! {- g* C) f0 W) y: J
4
8 X0 m. j( o* [2 \) V8" |, o; A' u, @' `% x
10
$ i6 }( U- g5 G3 q) y1 M; Q9 P- f12
9 ]0 O4 q2 r4 l$ i171 q8 Q; u, L$ l8 {. J
Gonadotropin
& \! n  x. c; e  @" Y8 r71.6 2.0 X 3 16.6
8 B: e4 a9 n( U3 }! c50.4 4.0 X 5.0 20.0
7 m7 Z# x2 Y/ E9 g& b22.0 4.5 X 4.0 25.0" I, l0 [" `8 ~
84.6 4.0 X 4.5 11.1
8 i2 u' _$ l1 e$ w9 `# D85.9 4.5 X 5.5 9.09 Q8 q: y/ x7 I1 k0 e
Av. 14.3
9 e+ ~" k- T" j4$ B$ P% Z+ |+ ]9 ]& ^
8* I5 \8 p! x9 N6 J! f" z# F8 P
10) i, g" C6 G1 P' [, i
12! M2 Y& V, x0 e" P1 E5 L
17
; n" g: L" D1 `  @4 Y. `4 wTopical testosterone& h! M) D! V- T
34.6 4.5 X 6.5 85
5 d: C7 e: K( T- j/ q38.8 6.0 X 8.5 707 \0 x! O% n# |  S& @, V# r
40.0 6.0 X 6.5 62.5. U8 S2 N9 ?4 D
93.6 6.0 X 7.0 55.5: I4 U- C+ x" U) j1 g2 I+ p
95.0 6.5 X 7.0 27.2
5 v2 _$ e2 |3 b: V4 ^" IAv. 60.0
! D+ Z7 i( C4 ^8 L4 @; q# Favailable testosterone. Again, emphasis should be placed on2 S/ Z& ~$ L3 b
early therapy when lower levels of testosterone appear to
7 L0 B) x8 i. L8 O$ x+ g# aprovide the best responses. The earlier therapy is instituted
, L6 m* ~1 K( s7 `) c9 M' [3 _the more likely there will be an excellent response with low
1 g! ]& P0 n9 l; r" H( r) fserum levels. Response occurs throughout adolescence as' ^/ r' M0 I/ c6 t" S1 L5 `
noted in nomograms of phallic growth. 7 The actual response
! {' p: `: k2 f) g& C# jto a given serum level of testosterone is much greater at birth
, W8 h2 h$ C1 t( x0 Z  Eand gradually decreases as boys reach puberty. This is most
3 R( l3 x: k$ N7 Y  elikely related to the conversion of testosterone to dihydrotes-# l# |9 [7 x$ A4 l; r4 \0 d
tosterone and correlates well with the studies of testosterone
; a: O: F) W0 l. _! Z/ ?conversion in foreskin at various ages.8 l5 l) u1 ^, Q( d
The question arises regarding early treatment as to whether
- y3 t7 M" ~: Z+ H1 T) M6 a& C3 uone might sacrifice ultimate potential growth as with acceler-8 [% h1 P: B: @. q
ated bone growth. The situation appears quite the reverse; O: D- x1 _' V8 \! g% M& o
with phallic response. If the early growth period is not used
# @% z6 s9 [! }; R3 X+ w) pwhen 5a reductase activity is greatest then potential growth* f6 o- _4 U  D) C  h
may be lost. We have not observed any regression of growth
2 v) M/ U# y( M( S+ b$ E/ mattained with topical or gonadotropin therapy. It may well
3 f  h6 Z+ r% \7 E9 t1 Wbe that some patients will show little or no response to any
- D( C5 J1 v  n! r, Aform of therapy. This would suggest a defect in the ability to
- @( w- \/ j& v5 W+ o# p& iconvert testosterone to dihydrotestosterone and indicate that* @' V( B# U/ w* Y0 o2 a# j1 x# y0 c
phallic and peripheral skin, and subcutaneous tissue should
1 \! t6 j/ b  q  B* b, Xbe compared for 5a reductase activity.9 X) t6 C7 D% h/ R5 x  B
A, loop enlarges to measure penile girth in millimeters. B,! W3 ^0 b* N5 f, n
example of penile girth computed easily and accurately./ I4 b) @9 ~: [' ?
conversion of testosterone to dihydrotestosterone. It is in this
8 j$ V- P7 N/ q2 G/ bolder group that others have noted high levels of serum8 f6 I. K3 g9 Q& n/ v/ |7 e
testosterone with topical application. It would also appear7 l4 n- v* h1 q/ O
that phallic response during puberty is related directly to the! r& T7 v5 P% U
serum testosterone level. There also is other evidence of local  y1 K9 b. ]6 |2 {
response to testosterone with hair growth and with spermato-5 G6 q# \4 f4 u: g
genesis. 5• 6
0 z' O" x  s' s- {0 A) _6 B; w( GAdministration of larger doses of gonadotropin or systemic
' B+ @+ B1 W) T' wtestosterone, as well as topical applications that produce: W1 [: i& j0 x$ G& c, P
higher levels of serum testosterone (150 to 900 ng./dl.), will
7 ]" T' P+ @6 l& x; ralso produce phallic growth but risks accelerated skeletal
+ A* S0 q6 o5 ?6 w% Q8 [maturation even after stopping treatment. It would appear8 A5 [4 b: a% l8 n; W$ n+ p- C
that this may be avoided by topical applications of testosterone" K/ g1 v" l1 L" P- v) n5 w
and monitoring of serum testosterone. Even with this control
$ |& u0 h. c/ k& @# r+ t& I& \& Hthe duration of our therapy did not exceed 3 weeks at any( f/ Z0 L3 x# C5 L! E. D
time. It is apparent that the prepuberal male subject may. p$ ^# F3 m- L" E2 [3 T+ Q* r
suffer accelerated bone growth with testosterone levels near
5 ?) O/ @. j  b! ], L0 A) N200 ng./dl. When skeletal maturation is complete the level of: ~3 H; k: ~% k# N" N. B+ p- i
serum testosterone can be maintained in the 700 to 1,300 ng./, x* U: K  H. d+ [
dl. range to stimulate phallic growth and secondary sexual3 j* x/ @+ b1 p  b4 s
changes. Therefore, after skeletal maturation parenteral tes-- q, G* p4 O* W6 ?# u3 w
tosterone may be used to advantage. Before skeletal matura-
9 m1 T0 ^! T/ m/ N$ u7 [1 }: ltion care must be taken to avoid maintaining levels of serum
! C3 I" w, d+ t! n$ k$ Rtestosterone more than 100 ng./dl. Low-dose gonadotropin; c6 \% J. t, Z
depends upon intrinsic testicular activity and may require
, l9 h, m2 Z! `% Tprolonged administration for any response.
8 H7 r8 a  N. @& u% k4 R, @* s, UAlternately, topical testosterone does not depend upon tes-) g8 M# l/ e$ f
ticular function and may provide a more constant level of
# C7 ?1 c. ^) v" b4 `6 F& O+ T8 C6 yREFERENCES* O- K9 Y1 w, U" F' R0 r% U- _/ G
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
3 z! H+ i6 g( e% X3 bR.: The local application of testosterone cream to the prepub-
( u" _$ c4 _0 P! Nertal phallus. J. Urol., 105: 905, 1971.
' h& M/ p- n  N% r2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
6 _1 i/ u% Y3 T. j0 M7 L. ftreatment for micropenis during early childhood. J. Pediat.,* j; V6 N: {5 ~9 B5 W7 R( ?; t- i
83: 247, 1973.. f% m- A& o. [9 v. t8 b$ [
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
; R  W  x, Q8 X4 u6 Done therapy for penile growth. Urology, 6: 708, 1975.
; x, k9 M: f0 l' \. k4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
) h! y# {4 y, F4 z  A* J* Pto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
: ~  H) x6 v9 ^: W; @$ e: Y1 sskin slices of man. J. Clin. Invest., 48: 371, 1969.% i$ x4 p, i1 K
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth' _6 G1 s1 v2 A6 k3 f8 p! y1 s# c
by topical application of androgens. J.A.M.A., 191: 521, 1965.
! m* g: P/ r" j6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local( a! ?; K/ }/ G  I* ~. l& U* X+ Q
androgenic effect of interstitial cell tumor of the testis. J." A' q) a7 i& N; D' L; H  P
Urol., 104: 774, 1970.
! e6 X+ G% i, ^( [( s' T7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-+ ?5 ?9 K- j7 i) V& g5 q
tion in the male genitalia from birth to maturity. J. Urol., 48:
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