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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
' a0 a2 S2 S! Z" v0 ?3 W" ]GONADOTROPIN
. f% ?( r O+ X' URICHARD C. KLUGO* AND JOSEPH C. CERNY
* q# c/ ]6 s! u$ b3 E3 ~From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
$ I6 D5 i3 S: E8 Q) z3 l' RABSTRACT, T* H7 z+ l1 I" F8 z# p$ O) H# j
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
$ M! L+ [+ C5 R- ]9 b& |with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
6 H n! l' s% |/ ^( \( rtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone3 p! N4 U( l) l3 U1 T8 {+ }: f
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent" W% [; O5 E& ?" j/ A: N( e4 K1 x
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
7 H& O8 k$ ]* qincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
G0 j) j r6 Y7 s6 [# q) jincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response* L8 U6 d% |0 l1 Y+ v& V
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
) H& ]: W4 m4 \$ M6 g3 Jstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile( P# b5 w8 Q: v" n+ q
growth. The response appears to be greater in younger children, which is consistent with previ-* @4 Z) ]- N# k# g
ously published studies of age-related 5 reductase activity.
- q8 E2 A6 ^! J1 N5 E& C$ N6 u6 P" vChildren with microphallus regardless of its etiology will. ?3 ^, V8 `& H [$ g z' }
require augmentation or consideration for alteration of exter-$ o0 z/ z4 `+ B$ j
nal genitalia. In many instances urethroplasty for hypo-
3 K8 g2 J$ Y) D# K z" Pspadias is easier with previous stimulation of phallic growth.. m9 U! e" ^; k B) |4 ^
The use of testosterone administered parenterally or topically& k, R6 a5 X* g
has produced effective phallic growth. 1- 3 The mechanism of
6 T+ C7 g a( Presponse has been considered as local or systemic. With this8 s, Q- N9 q9 P
in mind we studied 5 children with microphallus for response
; l, V# t) P* J3 \ Eto gonadotropin and to topical testosterone independently.$ _1 @4 @; x7 N' V
MATERIALS AND METHODS
& [- a8 C4 U" f1 ~/ s! `- jFive 46 XY male subjects between 3 and 17 years old were
6 ~! a9 z2 ?+ d9 d J- \4 v; a7 nevaluated for serum testosterone levels and hypothalamic; ^4 @/ u9 Z/ y3 `
function. Of these 5 boys 2 were considered to have Kallmann's2 K9 H, E, Y/ Y: N! A0 Y1 b
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-9 b8 U O. e( W) r ^
lamic deficiency. After evaluation of response to luteinizing' @+ L3 o4 r/ o! I
hormone-releasing hormone these patients were treated with9 k u8 I$ I2 o- j- A* [ |) z
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
; Q5 }8 F( S, |9 n0 U+ Y9 Q6 bafter completion of gonadotropin therapy 10 per cent topical A5 X- A" H! H2 o$ b+ ]
testosterone was applied to the phallus twice daily for 3 weeks.
g/ C, Z) x( M- ZSerum testosterone, luteinizing hormone and follicle-stimulat-" |1 N. w9 D) q! @+ b
ing hormone were monitored before, during and after comple-
5 i: y6 [# d7 [! J! x3 E9 ]tion of each phase of therapy. Penile stretch length was
' D9 @' r/ Y1 F6 _obtained by measuring from the symphysis pubis to the tip of- h+ n, A" O+ e; h) E/ C
the glans. Penile circumferential (girth) measurements were4 n' }, g5 S! D( ~( ~- ~( m( ^& }
obtained using an orthopedic digital measuring device (see
9 g z5 O* z2 ^7 [! L: ?3 mfigure).
- A$ w1 L5 A7 k# q% ~9 I. FRESULTS3 b$ I J* x( p6 g
Serum testosterone increased moderately to levels between. `4 \* s( ?& {; \" c
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-) A& n* `' Y% I9 V( h
terone levels with topical testosterone remained near pre-
( Z: C& @0 U; M* x) [( V& ?. v& ltreatment levels (35 ng./dl.) or were elevated to similar levels2 V4 s) y0 i* x! d. P
developed after gonadotropin therapy (96 ng./dl.). Higher
o; j1 Q, b% Iserum levels were noted in older patients (12 and 17 years old),
4 L7 `/ f, }; n, V; r8 ywhile lower levels persisted in younger patients (4, 8, and 10
- ]2 r2 T9 v/ \/ A' ~* tyears old) (see table). Despite absence of profound alterations
- p, Y* E$ j) M: e( T, X1 aof serum testosterone the topical therapy provided a greater) F1 J% l( D5 g& j9 n/ ~$ Z+ U! m
Accepted for publication July 1, 1977. ·# J' t; R2 f, y' i
Read at annual meeting of American Urological Association,$ R) A! g" p8 V/ l; h
Chicago, Illinois, April 24-28, 1977.
9 l2 {4 B' l6 n* Requests for reprints: Division of Urology, Henry Ford Hospital, Z3 v; M7 e* z$ \3 U. f2 v) U
2799 W. Grand Blvd., Detroit, Michigan 48202.! _ R1 _9 A0 T4 o2 e
improvement in phallic growth compared to gonadotropin.
# Y6 J, @& f& d$ hAverage phallic growth with gonadotropin was 14.3 per cent) z( n. p# p. n, V; g- @& E" w
increase in length and 5.0 per cent increase of girth. Topical7 m& L4 Y) S3 m
testosterone produced a 60.0 per cent increase of phallic length
% O& E$ i/ _$ w( b6 x5 l6 W1 kand 52.9 per cent increase of girth (circumference). The5 N5 y3 C6 j U+ `3 E5 W
response to topical testosterone was greatest in children be-
0 L- A. F' G$ I. r" {% t3 ptween 4 and 8 years old, with a gradual decrease to age 17
% R2 j# T( P. p t7 tyears (see table).
* [! y+ ?' g6 M d- G3 L `9 Y+ _DISCUSSION
4 m( S' K- u/ ~, W& F, ^Topical testosterone has been used effectively by other' x9 ]. I% G5 j# w
clinicians but its mode of action remains controversial. Im-( T6 X1 x. ]% e- w' }
mergut and associates reported an excellent growth response
" f' W2 V, L5 @to topical testosterone with low levels of serum testosterone,2 k: u+ w+ F' W2 E- A$ N3 m! w
suggesting a local effect.1 Others have obtained growth re-
6 a: H% k7 z- Z/ K: R" ]9 U$ }! Csponse with high. levels of serum testosterone after topical
& S8 {8 g _0 h6 E: Oadministration, suggesting a systemic response. 3 The use of# L* j- g# j) ?* F9 q/ a
gonadotropin to obtain levels of serum testosterone compara-
* Y! }; @1 d! l& j( Q( H1 ^) d4 ible to levels obtained with topical testosterone would seem to4 D9 }5 u* b. |- L. k
provide a means to compare the relative effectiveness of! X: P6 c5 I5 z+ F. S1 X
topical testosterone to systemic testosterone effect. It cer-
) _: \9 w! E6 @( N5 jtainly has been established that gonadotropin as well as par-. p. D4 M V- h% {% Y+ e" m
enteral testosterone administration will produce genital
0 O9 A( l2 h- rgrowth. Our report shows that the growth of the phallus was
+ H0 u2 D4 g4 u/ u" r. h Fsignificantly greater with topical applications than with go-
J; n5 v& e @9 q$ A1 @5 E% gnadotropin, particularly in children less than 10 years old.
g. _" r7 {) d" W U% A! G9 DThe levels of serum testosterone remained similar or lower
/ y3 r% [6 F/ _; j+ J) v* h5 Athan with gonadotropin during therapy, suggesting that topi-/ M. j- \2 `9 V6 g0 _' B. Z8 B
cal application produces genital growth by its local effect as: Z" l6 s- i) i' Q, [! _6 y
well as its systemic effect.
& r9 d( V/ \: J0 E9 mReview of our patients and their growth response related to4 G, E; U I2 ?0 q; _% a
age shows a greater growth response at an earlier age. This is
: Y+ M1 I6 T1 K/ h( _consistent with the findings of Wilson and Walker, who2 \1 ]5 O' e& _, F8 i
reported an increased conversion of testosterone to dihydrotes-6 G, ]- e1 ^% m' A+ C* P& k# z. [
tosterone in the foreskin of neonates and infants.4 This activ-
; j( e( i& m6 |( Mity gradually decreases with age until puberty when it ap-. r! R9 A$ M: g6 z- \. K9 O, @- F) U
proaches the same level of activity as peripheral skin. It may, o2 v6 {2 {% I* t; B2 }
well be that absorption of testosterone is less when applied at- W9 w% ~% ^/ O8 A' y# L
an earlier age as suggested by lower serum levels in children* p& l9 N- J) C. n! k
less than 10 years old. This fact may be explained by the
9 v- U1 X' c8 Y6 V8 P6 zgreater ability of phallic skin to convert testosterone to dihy-
' k _- X+ `- u# Jdrotestosterone at this age. Conversely, serum levels in older
, h: L% ?& `9 `7 n* c& N$ Cpatients were higher, possibly because of decreased local3 m* {' G4 r$ }3 f5 B. ^1 j0 }
667
. M& i2 k! e: P5 j6 B668 KLUGO AND CERNY7 G& D; o" f8 b# Q$ g
Pt. Age
4 A/ i2 @5 q7 r3 j2 m/ j(yrs.)' _5 B4 }' y. @3 Y
Serum Testosterone Phallus (cm.) Change Length. ]1 ^$ x4 G. f0 o7 W
(ng./dl.) Girth x Length (%)
/ O' A. f0 Z4 D9 e5 c4
; ^9 X; Q2 H1 l1 N: \% `8
" P7 G/ f2 ]- C! c: {! ]1 s10
% G5 {/ |9 z( K3 j12 `& f6 b' Y+ e+ `7 ^% E/ e
17% Q5 o& p" i* ?$ z! b
Gonadotropin+ A$ p0 R, g4 I. M& p) l2 H1 ~
71.6 2.0 X 3 16.62 C3 w/ {5 Z7 B
50.4 4.0 X 5.0 20.04 I1 R% K1 n3 ?5 ], g$ {' b: E
22.0 4.5 X 4.0 25.09 x! ?. S. s0 M
84.6 4.0 X 4.5 11.17 C; e* n( B/ x+ X R0 s5 Z
85.9 4.5 X 5.5 9.0) l& E8 w( l3 U& ]
Av. 14.3
& `* c9 M" a# W8 Y, p) r6 K1 ~! C9 {4- W0 ~% C$ r6 d+ a
8- o% n# ]2 O( C
10+ v9 w& W0 }! F. ~# V* u# m
12
' @* U8 s( w5 t$ b- d2 }173 h1 R9 H8 Z6 g1 g. l
Topical testosterone, \4 u5 G ~* L5 x; O) T% b
34.6 4.5 X 6.5 85: ~6 z7 g. ?, ^) C
38.8 6.0 X 8.5 70
8 e _2 `* R+ I$ o2 O2 c40.0 6.0 X 6.5 62.5& m- K3 G5 M- D$ ]7 I; U
93.6 6.0 X 7.0 55.5( n6 P. f7 J! p7 Q3 h" U- }
95.0 6.5 X 7.0 27.2
6 l% B7 s& {+ |) g8 u# Q" @Av. 60.0% M3 q- b8 B* e) U. [
available testosterone. Again, emphasis should be placed on
* T* I; [1 P7 }* |! @# E/ L; Vearly therapy when lower levels of testosterone appear to
3 N5 {. s/ `- T, j1 }( j% H$ S' `provide the best responses. The earlier therapy is instituted2 d3 n: c/ t1 Z/ J+ c
the more likely there will be an excellent response with low
2 K y6 d9 E, x( R% _: I; v4 mserum levels. Response occurs throughout adolescence as2 e4 C- \5 R: @; T$ \! C+ f
noted in nomograms of phallic growth. 7 The actual response
* y& f; \% l! M/ Q4 Wto a given serum level of testosterone is much greater at birth4 [/ Z B9 a3 p# @7 x
and gradually decreases as boys reach puberty. This is most
/ |, p- h1 E1 f. ]" i# blikely related to the conversion of testosterone to dihydrotes-
$ Z8 V0 }" ^8 Stosterone and correlates well with the studies of testosterone& d; Z8 h+ o. {+ r- A" R( L
conversion in foreskin at various ages.2 R, m0 E$ X/ X4 Q. K: }- L
The question arises regarding early treatment as to whether6 ~4 N7 K8 A( |
one might sacrifice ultimate potential growth as with acceler-
; Q& y/ J& Q" M- Mated bone growth. The situation appears quite the reverse
4 u5 b$ j0 e8 j9 |4 b4 `with phallic response. If the early growth period is not used
' B L( d) X% [0 Y9 i4 q+ iwhen 5a reductase activity is greatest then potential growth" d4 [* a! R& {/ B
may be lost. We have not observed any regression of growth
! |, K1 ]% y; y) a" p d4 sattained with topical or gonadotropin therapy. It may well
S3 j) ^' B% x) s& G9 k2 Jbe that some patients will show little or no response to any
' t+ M* [4 x1 a# o3 d2 lform of therapy. This would suggest a defect in the ability to
6 f9 q" }/ b, s' ?convert testosterone to dihydrotestosterone and indicate that
U& S. |2 O( O# E5 Aphallic and peripheral skin, and subcutaneous tissue should
) c+ g3 @8 t% A4 N, Wbe compared for 5a reductase activity.' U% J+ w4 l+ P+ G4 w( E
A, loop enlarges to measure penile girth in millimeters. B,8 {6 g1 X4 q* s( R& F
example of penile girth computed easily and accurately.
8 j# j% S e2 h7 Lconversion of testosterone to dihydrotestosterone. It is in this
6 d9 u& o, q3 R' A2 xolder group that others have noted high levels of serum* X. C C0 B$ t: `0 o
testosterone with topical application. It would also appear8 g# l$ f. s1 F
that phallic response during puberty is related directly to the
5 S1 {" d2 U/ u/ cserum testosterone level. There also is other evidence of local
$ @& g% o, @( n! Lresponse to testosterone with hair growth and with spermato-! w6 Z/ m1 w: \4 M' s4 a
genesis. 5• 6; q9 i2 G% m% e8 a/ V
Administration of larger doses of gonadotropin or systemic
' H' N, k+ {/ q# V+ Otestosterone, as well as topical applications that produce
" j$ D. K$ j" d! J t4 yhigher levels of serum testosterone (150 to 900 ng./dl.), will
% x4 s6 R4 x3 }7 c" r3 Jalso produce phallic growth but risks accelerated skeletal8 h6 [/ y) Z. I b! u
maturation even after stopping treatment. It would appear
" J$ m; v1 s+ |4 {that this may be avoided by topical applications of testosterone/ s9 I5 z5 A- C' q3 @
and monitoring of serum testosterone. Even with this control
r. `9 C( X' o1 c$ K, Cthe duration of our therapy did not exceed 3 weeks at any5 V7 B; h! S9 d* o
time. It is apparent that the prepuberal male subject may1 B$ r4 M% P8 ^$ [" ?- S* I
suffer accelerated bone growth with testosterone levels near. V& A7 x/ i- ~) Q
200 ng./dl. When skeletal maturation is complete the level of
+ B1 P9 p% T8 q( v: \: m$ g4 R/ Vserum testosterone can be maintained in the 700 to 1,300 ng./
) Y! h3 F4 H% [ J7 I+ w+ |dl. range to stimulate phallic growth and secondary sexual0 W* O& n# H3 i4 r' ] H3 @2 a7 \
changes. Therefore, after skeletal maturation parenteral tes-
8 u1 O0 g; O# B0 N3 t+ xtosterone may be used to advantage. Before skeletal matura-
! j; ~' C& U: t# D. P* Ution care must be taken to avoid maintaining levels of serum7 Q& U2 R& p: _8 R
testosterone more than 100 ng./dl. Low-dose gonadotropin: H2 s4 Z5 l5 x: X' l
depends upon intrinsic testicular activity and may require( i$ L& y( V5 P2 p8 k) t
prolonged administration for any response.
; e* ]( S0 u8 v9 N$ j, i; O bAlternately, topical testosterone does not depend upon tes-
8 G/ j) I B2 Dticular function and may provide a more constant level of* _5 R- l. C8 T
REFERENCES
' M3 s, Z9 o: ]0 y1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,2 P* a, K% C9 N4 L$ \' R5 g/ W
R.: The local application of testosterone cream to the prepub-: K% `) h# L1 p) P' M6 K
ertal phallus. J. Urol., 105: 905, 1971.
7 ?( p1 z( }* H6 L* n% F! [, K2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone' w) c: \0 p" ?( S- X
treatment for micropenis during early childhood. J. Pediat.,
; M8 V; z P/ _+ X! v- D5 A83: 247, 1973.
7 }8 c' E# y. v* D3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
5 S& g+ i2 A, C4 j9 z0 zone therapy for penile growth. Urology, 6: 708, 1975.1 {, q9 D4 o7 g: N' x J9 p
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone4 h5 s) p/ B! h N" \" q8 m! e
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
" E" k" ]( y3 z$ A4 \4 s: X4 Fskin slices of man. J. Clin. Invest., 48: 371, 1969.2 {3 D- J) j" y2 z
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth. Q$ q9 D% o2 U4 a
by topical application of androgens. J.A.M.A., 191: 521, 1965.6 N4 l9 c7 d- k* ^
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
2 g$ T( D! U! Oandrogenic effect of interstitial cell tumor of the testis. J.
' f1 j: z& \3 \3 |! CUrol., 104: 774, 1970.
3 [$ N4 f2 g* E9 x. {7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
; v0 l5 G2 D9 K9 Q. Wtion in the male genitalia from birth to maturity. J. Urol., 48: |
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