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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
6 q- \9 {) z+ l$ l/ vGONADOTROPIN8 u: }) D7 p4 O
RICHARD C. KLUGO* AND JOSEPH C. CERNY
; y) B" M& u$ m: n* aFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
1 K8 a: |+ f) nABSTRACT
) n8 O3 c$ z- x& N# b/ lFive patients were treated with gonadotropin and topical testosterone for micropenis associated6 h% c; U! u. e0 V; s' C! A
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-3 f5 Z# P% n4 D3 {
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone3 l/ S+ j \# w# x1 T
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent& W9 B; v) S9 x) _! U1 u
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent. Q& Z: w/ m- B+ U8 F
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average( B( i; h# z5 ?: W9 M; P
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
3 t1 D' `3 a) x: s' @4 Moccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This7 ^8 x& u/ i7 P! M1 Y
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile, n" G: y' h, ?" u4 C" F
growth. The response appears to be greater in younger children, which is consistent with previ-3 ]" n& {/ W- b$ r, d
ously published studies of age-related 5 reductase activity.
! v u/ I8 H: T; a, GChildren with microphallus regardless of its etiology will
/ C3 K$ g8 C' m; wrequire augmentation or consideration for alteration of exter-
* \* a4 J( [8 {nal genitalia. In many instances urethroplasty for hypo-
7 y# x3 \: T" A: A3 ]8 ^8 \spadias is easier with previous stimulation of phallic growth.
% [; w$ ?; B8 gThe use of testosterone administered parenterally or topically6 D2 F. j/ z N9 p* h6 B2 l
has produced effective phallic growth. 1- 3 The mechanism of
5 C6 S A/ L) o, z8 G( [( wresponse has been considered as local or systemic. With this) Z6 K) l) }& m7 Z F9 T
in mind we studied 5 children with microphallus for response! [( w2 V. v, P3 i0 B D
to gonadotropin and to topical testosterone independently. E% J- o3 }$ [- d5 a. e
MATERIALS AND METHODS
( v' _4 _3 S+ [( o! gFive 46 XY male subjects between 3 and 17 years old were
$ A$ [' {# q8 w& o3 |. aevaluated for serum testosterone levels and hypothalamic2 }( I Y) y1 J: C
function. Of these 5 boys 2 were considered to have Kallmann's. X' k2 B! e r) e5 k5 e# }, M
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
- `1 l4 J2 F, {# }0 R* \: h6 Mlamic deficiency. After evaluation of response to luteinizing7 ]% G) P/ z% M$ |, |
hormone-releasing hormone these patients were treated with
7 I$ h' C, e1 x' r9 e1,000 units of gonadotropin weekly for 3 weeks. Six weeks
( x' A) C2 \! x R$ s$ f* ?after completion of gonadotropin therapy 10 per cent topical
0 M6 V9 }$ B: s) D% o) Btestosterone was applied to the phallus twice daily for 3 weeks.* m F/ c' v5 a: {; S" d/ f0 Y
Serum testosterone, luteinizing hormone and follicle-stimulat-" J8 u4 e i9 |: Q, y
ing hormone were monitored before, during and after comple-/ q# g5 u5 T2 O
tion of each phase of therapy. Penile stretch length was
9 K5 s) z$ `: wobtained by measuring from the symphysis pubis to the tip of
6 ?9 _3 r: H. T( {the glans. Penile circumferential (girth) measurements were4 \* \' j: `0 x$ W) e
obtained using an orthopedic digital measuring device (see
. U" v4 C. P3 d+ i: j; Vfigure)." e& [3 U" }# O% X; l* W
RESULTS& U; b% ^9 T* S, w4 W1 J
Serum testosterone increased moderately to levels between( w# r, N8 w7 z4 Z- A
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-6 a; r/ |6 o0 }
terone levels with topical testosterone remained near pre-% o/ R8 U) M) x) F
treatment levels (35 ng./dl.) or were elevated to similar levels
! s% D+ E6 x* {+ mdeveloped after gonadotropin therapy (96 ng./dl.). Higher. u+ _: F" I8 ?
serum levels were noted in older patients (12 and 17 years old),
; T6 i3 {3 p: n5 J9 s' ]9 w$ iwhile lower levels persisted in younger patients (4, 8, and 10$ w \/ S& d- u
years old) (see table). Despite absence of profound alterations( y; P) f7 T u/ n$ r) I
of serum testosterone the topical therapy provided a greater' K- S/ e+ b, l# j5 `
Accepted for publication July 1, 1977. ·9 _* u9 e: p3 r& j8 |; @2 G
Read at annual meeting of American Urological Association,8 o+ z7 ~8 e X) ]; A
Chicago, Illinois, April 24-28, 1977.
7 r4 r) |: }9 g7 ]- Y1 z* Requests for reprints: Division of Urology, Henry Ford Hospital,
" X, U" w& m$ j8 i' R7 _2799 W. Grand Blvd., Detroit, Michigan 48202.
p' Q* T% k4 y; n4 @5 Yimprovement in phallic growth compared to gonadotropin.+ D9 N% ]- v& G: a& w& H8 P, \: A- \$ u
Average phallic growth with gonadotropin was 14.3 per cent$ C& Y7 H5 x" O" m# o8 F5 Q* d# S
increase in length and 5.0 per cent increase of girth. Topical( w+ X5 m0 S7 y- C( a( k
testosterone produced a 60.0 per cent increase of phallic length
. J9 m+ ~6 c+ m- L; f: [and 52.9 per cent increase of girth (circumference). The; ^: P5 H+ W6 F' e% O. B6 a2 m5 w
response to topical testosterone was greatest in children be-- X# O# d1 T$ m& ^: C
tween 4 and 8 years old, with a gradual decrease to age 17* X8 K+ R, c3 p2 I
years (see table).
+ L y8 B3 v2 E. C X& jDISCUSSION2 |! P' A0 J9 X6 g; F
Topical testosterone has been used effectively by other2 X$ T1 V$ h/ K I1 M
clinicians but its mode of action remains controversial. Im-
9 V# l: U3 k& @4 c$ r+ Emergut and associates reported an excellent growth response6 _+ X% W) D3 D) p, ~* Q% G% {# t1 d6 b
to topical testosterone with low levels of serum testosterone,
; Q! C5 O2 K; b6 |& W( Rsuggesting a local effect.1 Others have obtained growth re-
" Y' a! h$ z' c f" X2 N8 gsponse with high. levels of serum testosterone after topical
2 ?3 c! `" }) P, W; xadministration, suggesting a systemic response. 3 The use of
/ G- Q8 s& f3 S7 Tgonadotropin to obtain levels of serum testosterone compara-
2 Q* Q" U" ?& A/ Q! Fble to levels obtained with topical testosterone would seem to
, E! d: x0 t# n* u4 c3 ]( @0 {provide a means to compare the relative effectiveness of0 l+ f4 ^; c/ ~" n0 y9 Z
topical testosterone to systemic testosterone effect. It cer-
$ E8 u! t" ]& }5 I9 u- q* m! Ctainly has been established that gonadotropin as well as par-* Y/ }) e$ Y( h3 ^8 ^7 i- v$ m4 z
enteral testosterone administration will produce genital4 M. ~4 Z) n7 ?9 }' N5 S, J0 D F
growth. Our report shows that the growth of the phallus was
4 v3 J- F& Q7 f3 tsignificantly greater with topical applications than with go-
- A6 j0 }8 ], O6 [nadotropin, particularly in children less than 10 years old.
5 t5 z" @5 Z) zThe levels of serum testosterone remained similar or lower+ \) ]0 C* S, @5 f$ q, K* X
than with gonadotropin during therapy, suggesting that topi-2 [5 Z+ N4 _3 ?% p* H8 e9 x
cal application produces genital growth by its local effect as
" D, A. u, z6 \/ pwell as its systemic effect.
! T9 a3 o# ]5 o8 _Review of our patients and their growth response related to
1 a! f0 R9 }$ K4 [+ mage shows a greater growth response at an earlier age. This is2 g3 N0 l" L [6 r. N; J7 p6 Q) U
consistent with the findings of Wilson and Walker, who
5 N2 T' [7 w M4 g( r4 wreported an increased conversion of testosterone to dihydrotes-" A# k$ e- _5 _- `9 [
tosterone in the foreskin of neonates and infants.4 This activ- d8 o) Q% N/ t- Y
ity gradually decreases with age until puberty when it ap-
3 d U- f4 J* M. j. n# S' s$ u/ Eproaches the same level of activity as peripheral skin. It may
& W7 v) y7 D" k" n; F: p+ X6 {9 x3 Uwell be that absorption of testosterone is less when applied at
1 T, ^# I2 N8 van earlier age as suggested by lower serum levels in children
7 j0 ~4 c. @* b6 j9 Vless than 10 years old. This fact may be explained by the
2 R% o) O5 c6 v$ j/ c7 Qgreater ability of phallic skin to convert testosterone to dihy-8 ]0 V! w6 w u* Q4 ]9 [
drotestosterone at this age. Conversely, serum levels in older" w; c! Z5 G3 a" U4 D
patients were higher, possibly because of decreased local
2 }8 q# \, M5 w9 e667' G' O! h) W, T- C) E9 N; Q1 L& K
668 KLUGO AND CERNY
; g. d4 ?% G: ?0 C6 O* wPt. Age, y5 v2 N0 Z# O7 U# I
(yrs.)
* a$ v3 w- k( _9 @* H \% B" eSerum Testosterone Phallus (cm.) Change Length/ i9 u. [# P7 W% C0 d4 E
(ng./dl.) Girth x Length (%)
0 a& G7 ]( k# t8 c0 E$ B4
4 Y7 s9 W" |. x. X- Q8: X0 s, T) A- K+ B. E4 C
10
# R3 I( O- L, a: b# \* j125 }) A' d0 `$ s8 ~$ t9 O
17
, T$ \+ {- ]4 X1 X# x5 \& ~Gonadotropin
9 d5 b1 i* Y$ x1 A2 A/ \71.6 2.0 X 3 16.6( Z4 c2 v9 R+ o: l8 J+ Y
50.4 4.0 X 5.0 20.09 K; L; n$ d0 M6 M0 m( K' a
22.0 4.5 X 4.0 25.0& q2 u6 K4 a. _8 V9 w r
84.6 4.0 X 4.5 11.1
1 L% n0 B) Y& }# y1 f85.9 4.5 X 5.5 9.01 _7 o, N$ Q; Y
Av. 14.3
3 Y, Y- v! x9 R; u2 A' ?& Q1 Q/ ~40 V+ T2 B0 A8 B4 r' j5 k
8 ?- u$ f) _. `! o3 q% Q
10- a7 \1 m' e8 b: n! M$ W
12" E/ \& v3 G( g9 R
171 ^6 k8 G0 u) p* O3 v8 C* h( A
Topical testosterone
8 S8 p. }+ }8 x# t' `34.6 4.5 X 6.5 858 C B/ s8 {; V, X
38.8 6.0 X 8.5 70
$ p& [3 c @) Y' \3 @( c, Q40.0 6.0 X 6.5 62.5
+ L" i! S! `5 |4 U/ \$ L1 k93.6 6.0 X 7.0 55.5
5 y% j9 w$ k( M) U95.0 6.5 X 7.0 27.27 f' u8 ^ E5 |5 W/ f+ e C! c
Av. 60.0& ]5 w' K6 i4 B% Z4 L# N9 c
available testosterone. Again, emphasis should be placed on
+ `: ^$ a; F7 g+ y/ l2 Jearly therapy when lower levels of testosterone appear to* u: T" P. }. V% K
provide the best responses. The earlier therapy is instituted& Q; O" a* G, z5 I) b! ~% g
the more likely there will be an excellent response with low
* U7 |0 [6 k* |serum levels. Response occurs throughout adolescence as+ Q# |8 `8 W" v
noted in nomograms of phallic growth. 7 The actual response7 @* w6 s4 ?: ^5 L7 q' \, g4 R
to a given serum level of testosterone is much greater at birth& _: g' \7 S* l- e& e1 C
and gradually decreases as boys reach puberty. This is most
3 O9 c- ?0 r4 R6 Ulikely related to the conversion of testosterone to dihydrotes-
7 I4 ]. h5 E( S. V( {tosterone and correlates well with the studies of testosterone; f/ x U% N7 U5 c$ o$ G+ t t& Q
conversion in foreskin at various ages.1 _/ m G! p: v& H# K
The question arises regarding early treatment as to whether9 p9 W/ s/ E5 G- m4 w G
one might sacrifice ultimate potential growth as with acceler-
7 p* u8 h6 V2 m+ h7 R( nated bone growth. The situation appears quite the reverse' j) q! j) _) w$ N. V( @+ k9 U
with phallic response. If the early growth period is not used
# O7 `$ W4 }1 `! K! [& q1 [: qwhen 5a reductase activity is greatest then potential growth
/ s) O" I7 x6 q/ w0 k+ }/ r2 Amay be lost. We have not observed any regression of growth
8 ]& l% n3 O' l. oattained with topical or gonadotropin therapy. It may well
. O( q9 U; g! w$ Ube that some patients will show little or no response to any$ H( [3 S& J7 [* T2 I) v3 g
form of therapy. This would suggest a defect in the ability to
9 p r1 D. _0 \8 J/ |convert testosterone to dihydrotestosterone and indicate that7 m4 b7 X$ X1 q* x: ^) k4 Q( C: A: y" M
phallic and peripheral skin, and subcutaneous tissue should& v6 X7 `. N7 G3 C
be compared for 5a reductase activity.
: N2 r3 Q( { g6 yA, loop enlarges to measure penile girth in millimeters. B,
0 W8 h' j* ]0 V% |$ c9 c/ Vexample of penile girth computed easily and accurately.0 w0 Y v' j' ~5 ^4 ?7 W
conversion of testosterone to dihydrotestosterone. It is in this% k& L. X7 z' I0 S; E, h* x$ ?: J
older group that others have noted high levels of serum
! w) o" a4 X+ A8 J$ W/ Gtestosterone with topical application. It would also appear
" Z6 Y) z \; lthat phallic response during puberty is related directly to the
% x$ f! [! l& r8 o; Yserum testosterone level. There also is other evidence of local
( q( M3 A% M+ _# R# E2 Oresponse to testosterone with hair growth and with spermato-
# k$ \! D6 z3 y* h- {genesis. 5• 6$ s6 X& V( K) R* Q8 d3 p
Administration of larger doses of gonadotropin or systemic6 F$ ]5 z* B9 m, K
testosterone, as well as topical applications that produce- b/ Q3 K5 ?! A
higher levels of serum testosterone (150 to 900 ng./dl.), will
/ j8 c3 C- y, j7 i9 D6 Dalso produce phallic growth but risks accelerated skeletal7 e5 r N# w3 r) {* S# c
maturation even after stopping treatment. It would appear
1 N8 l. f9 f: o9 tthat this may be avoided by topical applications of testosterone
1 N. \* F/ l, {0 b( Aand monitoring of serum testosterone. Even with this control' N6 k( R9 u+ P
the duration of our therapy did not exceed 3 weeks at any
: ^& E) d6 @# A+ `- S( P* O+ J# qtime. It is apparent that the prepuberal male subject may
2 P) a" K/ ^+ f( N; g D' k4 rsuffer accelerated bone growth with testosterone levels near1 v( c J W8 _. \
200 ng./dl. When skeletal maturation is complete the level of& U. t3 L1 {9 Y p
serum testosterone can be maintained in the 700 to 1,300 ng./8 K9 e7 E8 s N- F/ ]& A1 K
dl. range to stimulate phallic growth and secondary sexual
( y" a8 L! G% {) K9 ~1 z z' Ychanges. Therefore, after skeletal maturation parenteral tes-
e, ~' x! F0 H8 i$ ^tosterone may be used to advantage. Before skeletal matura-
6 k2 U8 H/ N Y8 x( C8 ttion care must be taken to avoid maintaining levels of serum1 ~% |# C9 ~# ~ F5 j
testosterone more than 100 ng./dl. Low-dose gonadotropin
& X) `: E0 U- h& h$ r2 _8 W1 e. Cdepends upon intrinsic testicular activity and may require3 A3 p1 p/ O- h& o% r3 _
prolonged administration for any response.) e! ~8 d& `4 F% a
Alternately, topical testosterone does not depend upon tes-
4 y/ g \) p, zticular function and may provide a more constant level of
+ W/ G; n9 b* R! F! C% ]REFERENCES+ ~% k# Y$ T! v9 ^/ n
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
9 S4 `6 x+ G7 K0 C* UR.: The local application of testosterone cream to the prepub-- q) t0 [) W* ~( f
ertal phallus. J. Urol., 105: 905, 1971.4 z$ b4 @3 M. s6 z5 u! q
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
3 u9 \! R: S5 ^treatment for micropenis during early childhood. J. Pediat.,5 F' `/ h3 w9 l1 x& \. s+ I
83: 247, 1973.
B: e/ s, j/ J8 {3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
& F9 P- g+ t- o0 {one therapy for penile growth. Urology, 6: 708, 1975.
4 X( F. B; Y& ?' v8 R# T4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone9 u' {, i. v) n/ K
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by% H7 s+ @+ n4 y! e" c# ?
skin slices of man. J. Clin. Invest., 48: 371, 1969.$ r# [+ p1 ?8 k
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth1 z5 J; H0 R9 }
by topical application of androgens. J.A.M.A., 191: 521, 1965.
) u! g8 p( U+ S9 @1 a9 `$ o6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local1 m3 v1 O4 r* {; d/ ?+ n+ p
androgenic effect of interstitial cell tumor of the testis. J.! b& j k7 A: o8 x# a; n$ U* U' x- ]
Urol., 104: 774, 1970.
7 i! S: t- A1 b2 M2 A# y: t/ O$ P7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-2 }% {* G8 R! ?
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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