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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
% R/ h, @! _- A8 Q7 s( wGONADOTROPIN& L/ p/ U6 z# [5 y& S3 H3 n( k
RICHARD C. KLUGO* AND JOSEPH C. CERNY4 G5 Z7 p H/ ?! O) u! O
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
9 U" \9 f# v9 f. {: S. Y" V7 DABSTRACT9 h0 L9 S) S+ S, Y `' E
Five patients were treated with gonadotropin and topical testosterone for micropenis associated. I1 N( `; y6 H& p0 a# R4 J
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
, l1 Y0 ?$ K5 b# D9 R0 H. Etropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone$ E9 Y' ] M- N3 ^7 S! w
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent2 x; U; _8 O" }+ [; ]8 w# E6 u
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
% U% A( S0 }3 F) B6 Bincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
7 {5 D& B: H6 ]) P) b5 m _increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response7 p6 P7 f" |9 a( x
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
L& x7 l" I4 q' }, H/ Kstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
7 y! U, s! ]4 Dgrowth. The response appears to be greater in younger children, which is consistent with previ-- F6 l9 X9 c" a
ously published studies of age-related 5 reductase activity.
1 L' Z/ C- r( }: a- w7 NChildren with microphallus regardless of its etiology will
2 m+ W2 L" R1 B( w( U1 A# @6 o: }5 jrequire augmentation or consideration for alteration of exter-
: |3 |, E3 r4 Z- P& J* A' mnal genitalia. In many instances urethroplasty for hypo-
6 o( r8 V8 L" M6 J6 x+ H) U, uspadias is easier with previous stimulation of phallic growth.
. L$ N" X: d3 |! n, r6 WThe use of testosterone administered parenterally or topically
9 K# k: y- w- y" n& ^has produced effective phallic growth. 1- 3 The mechanism of
% U2 S/ n5 Z$ K- ?4 U, Q: Gresponse has been considered as local or systemic. With this
3 U2 {7 n A; y: W, s7 jin mind we studied 5 children with microphallus for response7 d5 P3 a$ {. c9 H2 m _
to gonadotropin and to topical testosterone independently.! h. m6 ~ q: y, x" _- l! `3 l
MATERIALS AND METHODS
$ g; r; f/ \4 ]Five 46 XY male subjects between 3 and 17 years old were1 e1 h F: }& G: D. J7 B2 M7 o
evaluated for serum testosterone levels and hypothalamic
( b( b% e6 I2 Z `2 Ifunction. Of these 5 boys 2 were considered to have Kallmann's8 A" p6 D$ v: Y
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
- E6 w1 A3 x: n8 F" @lamic deficiency. After evaluation of response to luteinizing; Z; g. C- A# n) N6 r: w% m
hormone-releasing hormone these patients were treated with
' Y5 T1 Y- p0 ^$ h) G1,000 units of gonadotropin weekly for 3 weeks. Six weeks; j- h2 c' N2 F+ B2 L
after completion of gonadotropin therapy 10 per cent topical; `2 d$ d& @* r" Q
testosterone was applied to the phallus twice daily for 3 weeks.
; i$ O; |! L9 ^: `# ~Serum testosterone, luteinizing hormone and follicle-stimulat-4 G: a% J9 I6 Q" H2 g, O' s) I1 K
ing hormone were monitored before, during and after comple-
7 G0 S0 m# z( k4 Rtion of each phase of therapy. Penile stretch length was8 r* x* P; a( ~ c
obtained by measuring from the symphysis pubis to the tip of* R) i* k) N6 a4 J
the glans. Penile circumferential (girth) measurements were
% t" p5 L) a1 v6 T1 T: \1 s- C6 {obtained using an orthopedic digital measuring device (see
3 @! L! |: u* o0 M! J( Tfigure).
+ @2 h- U$ H# M* D3 ^5 SRESULTS
2 C! x+ p7 A& M! D+ _# }4 KSerum testosterone increased moderately to levels between
2 X/ @9 m5 o* k- w- X! z# e' ?5 ~0 O; A50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-7 \& [. M5 r) b5 F
terone levels with topical testosterone remained near pre-0 N" r. ?: @- h/ n- N
treatment levels (35 ng./dl.) or were elevated to similar levels W- \) x" J, w/ H
developed after gonadotropin therapy (96 ng./dl.). Higher
5 k6 Y7 ~, p' q$ ]- sserum levels were noted in older patients (12 and 17 years old),
4 `- p7 H3 e- K1 d- Rwhile lower levels persisted in younger patients (4, 8, and 109 V0 A. w& v% I% F
years old) (see table). Despite absence of profound alterations8 h% Q% [# c% D) D- c
of serum testosterone the topical therapy provided a greater
" \$ ^% y' R l. aAccepted for publication July 1, 1977. ·
" `$ O0 {/ t5 X; bRead at annual meeting of American Urological Association,
/ M& Q& d1 N. ]3 z% [Chicago, Illinois, April 24-28, 1977.
9 u+ A0 ]3 O8 m V! c& ?* Requests for reprints: Division of Urology, Henry Ford Hospital,6 a$ l$ L3 \3 C+ i9 o# q% M9 C
2799 W. Grand Blvd., Detroit, Michigan 48202.
2 V5 U' n* c9 A: }1 _% Q1 Jimprovement in phallic growth compared to gonadotropin.
3 U5 a. i$ Y9 @& Q/ N u( sAverage phallic growth with gonadotropin was 14.3 per cent! V& y* j* ?9 r' X( C7 B" A
increase in length and 5.0 per cent increase of girth. Topical
" D4 d1 {) r% H8 Wtestosterone produced a 60.0 per cent increase of phallic length
; L) V9 Q, u- v$ }0 ]' H+ Land 52.9 per cent increase of girth (circumference). The9 g) [3 {: J( `& I
response to topical testosterone was greatest in children be-2 V8 K; |5 l1 [: V' S
tween 4 and 8 years old, with a gradual decrease to age 17
1 h5 ^: ]0 C- Fyears (see table).8 x5 w* w7 K4 B" |$ u" Z
DISCUSSION
6 s* X) D( M9 y2 q1 R5 m2 uTopical testosterone has been used effectively by other; R/ R$ w( w8 p
clinicians but its mode of action remains controversial. Im-
) G# u. l4 K& r, }% ?mergut and associates reported an excellent growth response+ [6 a; I" [! i+ J( X" @# \8 P
to topical testosterone with low levels of serum testosterone," U4 U# Q8 ?& W- _6 e
suggesting a local effect.1 Others have obtained growth re-
& i) @+ K( [6 u& @sponse with high. levels of serum testosterone after topical9 Y) ~1 T7 R( ^' `
administration, suggesting a systemic response. 3 The use of, m1 J- Q: Y) q/ W
gonadotropin to obtain levels of serum testosterone compara-/ u" ]+ |5 H' s% M' b
ble to levels obtained with topical testosterone would seem to
) q4 ?, w( H* q2 ~/ W5 i: B; S6 a, Kprovide a means to compare the relative effectiveness of
7 i+ Z! y K# Stopical testosterone to systemic testosterone effect. It cer-, Z. x- ?+ j- L. T% @0 T1 t% R+ d
tainly has been established that gonadotropin as well as par-
" O; ^) V9 H- j: b3 }* B+ p4 kenteral testosterone administration will produce genital* h. @5 t0 L# Q
growth. Our report shows that the growth of the phallus was
: o( @# i7 z7 e, Ysignificantly greater with topical applications than with go-% T( s( T: r0 z7 a9 a
nadotropin, particularly in children less than 10 years old.3 ^$ b6 n' @9 M9 u
The levels of serum testosterone remained similar or lower
' g: m5 n; L; g" U6 q3 |9 o7 a- Ythan with gonadotropin during therapy, suggesting that topi-
6 ]7 `3 k% e& K( {" }0 Ucal application produces genital growth by its local effect as
8 S- r2 e4 B2 [: Iwell as its systemic effect.% K# Q& L7 j! n6 L* L
Review of our patients and their growth response related to
: X8 V% e1 u. | A0 r6 wage shows a greater growth response at an earlier age. This is
* M8 x8 U( W# bconsistent with the findings of Wilson and Walker, who) ?2 k" r3 ~ e% m- u& A6 v
reported an increased conversion of testosterone to dihydrotes-
( \7 k/ h) e* H3 D. t1 Stosterone in the foreskin of neonates and infants.4 This activ-
: V; w4 f7 Z1 q! [6 U% J; I. |ity gradually decreases with age until puberty when it ap-3 ~6 H$ P+ C6 j4 ~
proaches the same level of activity as peripheral skin. It may
/ m/ A' J7 y* |7 iwell be that absorption of testosterone is less when applied at
" v/ a( {3 _- y) @; _- aan earlier age as suggested by lower serum levels in children
}* j$ K0 ^6 |less than 10 years old. This fact may be explained by the2 u3 r" [/ d6 G/ d; L+ k1 L1 g
greater ability of phallic skin to convert testosterone to dihy-
9 |4 t) | l1 \) Wdrotestosterone at this age. Conversely, serum levels in older
" n. a2 g: k: N. M$ tpatients were higher, possibly because of decreased local
$ l2 o9 i6 Z6 u$ [. y2 [+ ]( q2 f- {6676 |. P+ `% w: P4 C
668 KLUGO AND CERNY
* ~3 `# r1 M1 M/ j+ q5 cPt. Age9 S& c$ q+ j( W$ k: K3 q U5 d
(yrs.)- K: w5 `6 k |6 m; [( K* o
Serum Testosterone Phallus (cm.) Change Length
$ X- O/ J9 R, a( ~6 a(ng./dl.) Girth x Length (%)
& E) U# q; A: ~7 U {48 x I1 u' _4 i& `$ C# @/ {
85 _: c9 ]5 \" d0 [, r' ]; a. m( n
10
- c" \# f- g0 i, g8 d, J# Q$ Y4 X( K12/ }( @8 t5 d2 s5 O
17
- r$ s/ P* r0 J4 bGonadotropin
# H7 j2 @$ [3 M71.6 2.0 X 3 16.67 E& Z$ x5 I2 u, u
50.4 4.0 X 5.0 20.0
7 i2 K' [% n! j$ H6 ^" v( Y22.0 4.5 X 4.0 25.08 h3 u4 q' d4 O: E6 Q6 P0 s. w
84.6 4.0 X 4.5 11.1
- n1 @/ |# [6 i+ J$ B4 y6 S85.9 4.5 X 5.5 9.0
" V+ q: E# J$ j; ~( ^* t$ ^Av. 14.3( V% m8 e% P" h+ d( }0 F
4; _1 M2 Q' P$ B+ u* }2 H0 N
8! i. i+ v* Z6 y ~, f4 A
10; b" W# ^7 P1 N# b$ x! \3 D, V
12& z* v1 Q! L7 Z l3 |# n+ @
17, o/ O# `6 A7 `
Topical testosterone) }. q* u- O. g0 ]" ^: W/ |6 X
34.6 4.5 X 6.5 85
4 q3 [5 q2 z1 K) f: L* ^38.8 6.0 X 8.5 70
" a) S1 w3 k3 B* K/ y. j6 v6 R; p/ D40.0 6.0 X 6.5 62.5
/ k2 K5 ^% @" F8 U- M9 \93.6 6.0 X 7.0 55.5& n9 {6 n, R$ W; I% [0 _0 i( M/ ^
95.0 6.5 X 7.0 27.2
% z2 D* P& v. R. d4 T; t3 t9 IAv. 60.0
+ n6 }1 k g$ G' d5 Y8 c t; [available testosterone. Again, emphasis should be placed on
9 B/ N) n, A: l- xearly therapy when lower levels of testosterone appear to
4 q2 w) n+ s$ ^provide the best responses. The earlier therapy is instituted5 W2 _0 K4 U* z9 L9 ~! G
the more likely there will be an excellent response with low
0 D7 ^& n3 `$ _4 \# A/ C& K# Fserum levels. Response occurs throughout adolescence as
8 H- L7 S+ D- M! D" J% V7 L( @" Ynoted in nomograms of phallic growth. 7 The actual response
, N C; i) n @9 Tto a given serum level of testosterone is much greater at birth+ f s$ o, F( W! C( o6 a/ P
and gradually decreases as boys reach puberty. This is most
" r! c$ u! h6 @- ~likely related to the conversion of testosterone to dihydrotes-
2 l5 B/ e4 l$ C( O$ ^# Htosterone and correlates well with the studies of testosterone0 V4 E* a9 G( `2 |$ C
conversion in foreskin at various ages./ Z* I3 x; |. [: f
The question arises regarding early treatment as to whether
7 N4 J+ V% C( t' h. l; c/ g' ]; c& Jone might sacrifice ultimate potential growth as with acceler-
+ a9 i' y, c: j/ f0 v* N! `) G4 qated bone growth. The situation appears quite the reverse* T" J9 L) M3 @# V
with phallic response. If the early growth period is not used
1 J: a) P; w2 z0 U: u" ]when 5a reductase activity is greatest then potential growth, t/ p* m9 s' U! n% G
may be lost. We have not observed any regression of growth. r0 \9 L; l1 P: v0 C8 g! \9 X
attained with topical or gonadotropin therapy. It may well
2 {5 n: @! C r F5 U! |3 {be that some patients will show little or no response to any" \: u. S' x3 _# d5 T
form of therapy. This would suggest a defect in the ability to g7 p4 X2 J+ G8 U
convert testosterone to dihydrotestosterone and indicate that
w) n( u" f$ ^) Q' c1 g+ ]phallic and peripheral skin, and subcutaneous tissue should# M8 H0 w3 a' L2 d
be compared for 5a reductase activity./ d/ |" G1 X; a N8 V
A, loop enlarges to measure penile girth in millimeters. B,% _$ ?, d" f: m( ]8 Q9 p
example of penile girth computed easily and accurately.: w+ L6 z1 t! s4 H9 i1 A& `9 @7 B
conversion of testosterone to dihydrotestosterone. It is in this
, g; ^: v3 e2 N: i/ \ k" oolder group that others have noted high levels of serum
E7 B4 K& x8 ?( i& }testosterone with topical application. It would also appear" m8 i7 w2 |( B8 M* U) |4 \
that phallic response during puberty is related directly to the
5 R! `# D! x5 z/ dserum testosterone level. There also is other evidence of local) w g s8 c7 {, {
response to testosterone with hair growth and with spermato- K0 \4 Y+ w0 A8 o
genesis. 5• 6: n, T- N# T& a% i0 u
Administration of larger doses of gonadotropin or systemic- D! Y C! ?5 L) v1 R
testosterone, as well as topical applications that produce
) ]7 E, P6 [# M9 rhigher levels of serum testosterone (150 to 900 ng./dl.), will1 C7 Y/ n+ ]9 n* u
also produce phallic growth but risks accelerated skeletal0 Q, i2 ^4 c) ]/ D/ n4 n
maturation even after stopping treatment. It would appear& ^4 I! G! K! X3 h; n' n
that this may be avoided by topical applications of testosterone* C" s5 R1 j1 h. \( w
and monitoring of serum testosterone. Even with this control; r3 N& R5 r( X( H% W3 D
the duration of our therapy did not exceed 3 weeks at any
6 o' C; n" Z$ z% _time. It is apparent that the prepuberal male subject may1 G) G' q" P& K9 U* S0 F
suffer accelerated bone growth with testosterone levels near
4 D, r5 ]" T; g" V/ J2 t+ ]& C200 ng./dl. When skeletal maturation is complete the level of
: {( z; m. j' ^4 M1 {serum testosterone can be maintained in the 700 to 1,300 ng./# J# j$ ^" e- }5 U6 ]
dl. range to stimulate phallic growth and secondary sexual* N. Z! o/ n. p1 I9 C. y1 z3 w) O, Z
changes. Therefore, after skeletal maturation parenteral tes-
; [4 d! J0 _: K' Stosterone may be used to advantage. Before skeletal matura-
% a+ k! Q; q! a% h! r: n2 ^tion care must be taken to avoid maintaining levels of serum
: D5 b3 f$ y8 h- Dtestosterone more than 100 ng./dl. Low-dose gonadotropin
% b* H% V7 m0 A/ x. k" t/ rdepends upon intrinsic testicular activity and may require$ n( B8 L: [6 ?2 Y' ?3 s
prolonged administration for any response.
; p* h5 @. {% r1 JAlternately, topical testosterone does not depend upon tes-
: G* w( d3 a6 j' Vticular function and may provide a more constant level of0 K( Q3 T3 c. y/ z7 p( V+ n
REFERENCES) j% b) l- B! j) H9 K- a5 V! j" K
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,3 c$ M8 C0 p0 F G' c! Y: M2 Q& O
R.: The local application of testosterone cream to the prepub-& S y& ~3 i; t7 V7 W
ertal phallus. J. Urol., 105: 905, 1971./ H8 a" K( g _0 z3 c
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
7 ~- x8 |; s# i5 |treatment for micropenis during early childhood. J. Pediat.,' V9 E9 \' ^( R" {, y/ g
83: 247, 1973.
6 h" k5 o' L! h, P6 W3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-$ w) E Q, S2 p7 U
one therapy for penile growth. Urology, 6: 708, 1975.
2 F" k* ~ ~% R' z3 M, i4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone" ]$ U" C' A; J0 ]: p2 P0 w8 }
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by3 m% F1 F2 B/ Q _, Q8 j
skin slices of man. J. Clin. Invest., 48: 371, 1969.$ `' k5 J$ a5 u0 G& @' ]3 E- d
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth. I+ n/ {# S7 c; i4 ~
by topical application of androgens. J.A.M.A., 191: 521, 1965.
% J3 w. d) j! M3 K6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
8 F$ }% s: [0 e; @1 x$ l- ]1 mandrogenic effect of interstitial cell tumor of the testis. J.
. ]' f a% n: G( ~% V W, nUrol., 104: 774, 1970.
- e/ f) p6 L4 Q! K7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
8 X8 j# W1 X+ U! x1 U2 Ntion in the male genitalia from birth to maturity. J. Urol., 48: |
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