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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
: S1 b6 c; `& V% C$ G7 O* e% xGONADOTROPIN
( O- |# B0 l7 ~6 S/ q& {, c$ _RICHARD C. KLUGO* AND JOSEPH C. CERNY
/ t! e; j+ i1 Z5 J: ]From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
4 f) I! s4 Q4 S5 O% _ABSTRACT8 j% w# i' z& J: S
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
( w" V A. a$ d9 xwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
) C/ O5 _& ]( @tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
: b4 m; ~8 F3 a: n3 M9 Y) ycream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
r( J: Q8 H( Y! ffor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
1 d: a* _! O7 e4 k" y; h* ]& Oincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average4 {8 ~; ?8 h* f) i$ G, ^( U% m6 ?
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response+ b2 G+ U' E; J" E: f
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
. [. Z q4 O6 [$ vstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile8 X# }6 `) z% X$ ] l7 Y
growth. The response appears to be greater in younger children, which is consistent with previ-
. |6 q7 M6 O/ q4 a2 G) `- eously published studies of age-related 5 reductase activity.8 V- s }9 E, M
Children with microphallus regardless of its etiology will) u, ~" J5 D6 D
require augmentation or consideration for alteration of exter-; H8 U7 O3 e% Q, C0 F
nal genitalia. In many instances urethroplasty for hypo-5 U, {0 \* e/ |9 E3 l s
spadias is easier with previous stimulation of phallic growth.+ a, u" u0 N( n" ~: c k& s
The use of testosterone administered parenterally or topically' V/ z, U2 y/ p, E/ R* `
has produced effective phallic growth. 1- 3 The mechanism of
" m: l9 B8 [) [! W4 k0 Oresponse has been considered as local or systemic. With this4 d$ a7 f$ {) R0 }) O
in mind we studied 5 children with microphallus for response3 @/ @% X2 F( s9 Q7 o# h
to gonadotropin and to topical testosterone independently.
) t- H W8 |3 N7 D0 }6 E2 b( {4 tMATERIALS AND METHODS
) k5 s. h: K" S9 l' }) s% WFive 46 XY male subjects between 3 and 17 years old were
0 \* e( P$ @/ I. n; u; q5 f5 D5 pevaluated for serum testosterone levels and hypothalamic
0 K4 |. k' w3 J) q- R B4 u4 sfunction. Of these 5 boys 2 were considered to have Kallmann's# |9 v9 j' Q9 N' R) I4 @
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-, B) v4 m- J; v" A7 I% @8 ]
lamic deficiency. After evaluation of response to luteinizing
8 Z$ D: b7 b3 hhormone-releasing hormone these patients were treated with
" U/ A6 p& [1 L$ N1,000 units of gonadotropin weekly for 3 weeks. Six weeks- q! c! A% n+ y! S; N1 }, f
after completion of gonadotropin therapy 10 per cent topical+ W9 O% L7 i# p: b$ _3 Z$ I
testosterone was applied to the phallus twice daily for 3 weeks.; x) j( d+ t- Z. Y6 S0 m& x
Serum testosterone, luteinizing hormone and follicle-stimulat-, U3 i4 P4 _% q. k5 K: U- Q% b
ing hormone were monitored before, during and after comple-
. L8 n$ \" Y: J! @$ qtion of each phase of therapy. Penile stretch length was
7 r8 w7 v; z9 g7 [' Xobtained by measuring from the symphysis pubis to the tip of* w2 j( K' d2 y( K
the glans. Penile circumferential (girth) measurements were, w1 j9 @. o. K5 r, I; Y- R, T1 J
obtained using an orthopedic digital measuring device (see7 p# ]# b+ t! C7 t1 r2 a/ l0 {
figure).0 @& {% J3 k9 U. l" Q' ^! F
RESULTS* n0 {; W8 I( @3 r3 Z! }: s
Serum testosterone increased moderately to levels between1 s0 `9 n* O* L( g) S
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
7 ]: Q% c- b9 s$ Y0 W' l2 [: Vterone levels with topical testosterone remained near pre-+ x+ Q3 ?; j9 e& X8 G* ~" o6 Z
treatment levels (35 ng./dl.) or were elevated to similar levels
# c/ n G* d/ F% Vdeveloped after gonadotropin therapy (96 ng./dl.). Higher b) V7 ?+ u3 o! G) Z; v5 _
serum levels were noted in older patients (12 and 17 years old),
3 r+ f9 i: t* @- K ^while lower levels persisted in younger patients (4, 8, and 10
- g+ \# }' F- \1 ^ dyears old) (see table). Despite absence of profound alterations5 C- @* t0 o) g- ?0 D
of serum testosterone the topical therapy provided a greater
) e: t4 p: p/ m: ]& wAccepted for publication July 1, 1977. ·
: _) O+ r. d$ q9 `3 @Read at annual meeting of American Urological Association,
: M) \) n3 l# A) v$ L# RChicago, Illinois, April 24-28, 1977.
2 m5 e) T- f @& ^6 e. W/ R" X# i* Requests for reprints: Division of Urology, Henry Ford Hospital,7 b5 F: ~5 y$ G* _: `" d9 } n% E
2799 W. Grand Blvd., Detroit, Michigan 48202.% i: z9 \' [4 ]2 ?
improvement in phallic growth compared to gonadotropin.
5 J% I& \" F6 ?5 PAverage phallic growth with gonadotropin was 14.3 per cent
2 V% P! X2 n7 i* L8 x! {increase in length and 5.0 per cent increase of girth. Topical+ v% \; J4 P L: c9 S3 q ?7 o
testosterone produced a 60.0 per cent increase of phallic length3 l( [ ~& K/ n) I0 q2 @
and 52.9 per cent increase of girth (circumference). The
: p8 n: s* W9 y( b+ b( @ xresponse to topical testosterone was greatest in children be-- p9 m! B5 p3 x) k5 @1 E5 d) |1 v
tween 4 and 8 years old, with a gradual decrease to age 17' c2 R- M) x0 \( X/ }3 b9 m+ F
years (see table).& N6 H! y7 B% X! x" _4 A
DISCUSSION
$ `& Y7 |& L6 E% Q' qTopical testosterone has been used effectively by other+ h7 I9 Q. M; E) s! [" Z& g2 I8 @# y
clinicians but its mode of action remains controversial. Im-
" t2 K7 s# ?. {4 p! {2 Ymergut and associates reported an excellent growth response
1 V5 T# g- q3 ~- r. t& z4 F0 eto topical testosterone with low levels of serum testosterone,
' E& o( G8 x! L* B' V: ^+ ?2 y# _suggesting a local effect.1 Others have obtained growth re-
: }9 F9 U6 ?% [sponse with high. levels of serum testosterone after topical/ c( S/ Y# d: H9 K" E/ g& M
administration, suggesting a systemic response. 3 The use of
8 F4 `+ \$ n( o' U8 ^, x/ sgonadotropin to obtain levels of serum testosterone compara-5 A( o5 Z& b! G
ble to levels obtained with topical testosterone would seem to
; @0 i, ^4 Z7 l% {7 }0 C! nprovide a means to compare the relative effectiveness of
: E' Q3 j& K' e! ytopical testosterone to systemic testosterone effect. It cer-- P* }( S, N5 `) j% M/ k
tainly has been established that gonadotropin as well as par-
' Y& s6 k9 h* t& _5 T: Kenteral testosterone administration will produce genital
, d( ^9 N! f3 j9 O% Q: E1 |growth. Our report shows that the growth of the phallus was7 H2 T, M' a# L5 b) B; F. h
significantly greater with topical applications than with go-
" n4 [2 O: S* [/ z% E# f8 xnadotropin, particularly in children less than 10 years old.. E( X0 m5 G9 \, V4 o1 O
The levels of serum testosterone remained similar or lower. F& u$ |) N( e) ?; [& ]8 y B- E
than with gonadotropin during therapy, suggesting that topi-' [% o' E" F5 s+ g
cal application produces genital growth by its local effect as
9 l- W$ A5 y/ B; }( {- Kwell as its systemic effect.
" M( R0 g/ P: c1 w4 F5 {; `& S# X4 sReview of our patients and their growth response related to
# T3 r8 t( y7 _( n1 ?3 Iage shows a greater growth response at an earlier age. This is
9 E' }4 d: n) B R" X) k) nconsistent with the findings of Wilson and Walker, who' C) U* L+ s- w6 b) [
reported an increased conversion of testosterone to dihydrotes-
( {! E' D0 Q& D) ]tosterone in the foreskin of neonates and infants.4 This activ-
2 q' ]: S8 N6 B8 M/ N( V* O, z* A. Uity gradually decreases with age until puberty when it ap-
& ]6 m/ Y5 M: n, u( vproaches the same level of activity as peripheral skin. It may
8 C: P, L, F! A% ~# O/ r# wwell be that absorption of testosterone is less when applied at; _& p8 ]* f. j. I1 I+ d
an earlier age as suggested by lower serum levels in children* l' U3 T) ^4 f }; c
less than 10 years old. This fact may be explained by the
% j& @7 F& x* Q5 ]6 @/ T5 bgreater ability of phallic skin to convert testosterone to dihy-' Q. W; S1 p$ M0 d* o1 K( |
drotestosterone at this age. Conversely, serum levels in older* [* i1 u7 H- \
patients were higher, possibly because of decreased local- c7 r( ?& Q& @$ g) ~
667
z) V5 r B/ P5 H7 B# l668 KLUGO AND CERNY3 u! x0 M* E/ V! t$ M/ Z" W% |
Pt. Age
6 \7 l/ o. w, y# T( _) J P. P' I(yrs.)) ?7 {: Y/ S: m2 |+ h1 i7 t( v
Serum Testosterone Phallus (cm.) Change Length8 y5 o" o* k3 k3 r. a$ b @5 x; ~7 S
(ng./dl.) Girth x Length (%)
7 S; J! y! ^: q4
* p6 l+ n) {% `, v8
+ \6 I2 G# C4 G* [& ?. k( l* G. G9 T10
7 Z8 W% H8 f' Q, D. R126 _# ?! o) j: g I. r9 r& n. v
178 A D4 u/ S, Q
Gonadotropin
0 k7 x, m% G, v1 W71.6 2.0 X 3 16.6! S: g3 }* E. H1 w
50.4 4.0 X 5.0 20.0
. Y9 P+ i# C& a" Z+ f22.0 4.5 X 4.0 25.0+ f+ b5 k# _# l( n% \
84.6 4.0 X 4.5 11.1. V$ U6 L( E- T' S
85.9 4.5 X 5.5 9.05 A8 y" u5 e8 w! {: p* V5 ]$ r
Av. 14.3
; A, {! \% X: i) m49 z! ^* F" A$ z! h% K$ |" ?1 s) [
8
* {9 e6 U3 f6 j: o& ^105 P1 S# a* q' ?3 s
12
- }' s" F7 w* M17; Z i2 A5 K w- J) L
Topical testosterone; d0 a8 _1 L* M W$ J0 [
34.6 4.5 X 6.5 85
. ^2 q( a# z' o3 L' v L38.8 6.0 X 8.5 705 z3 y; r) J% ~$ {7 p! c y$ D
40.0 6.0 X 6.5 62.52 @- ?+ s A' O. M) [7 ?5 L
93.6 6.0 X 7.0 55.56 M% L" _ j3 |. j# \8 P! K( Z
95.0 6.5 X 7.0 27.2( u9 y: ^- ]/ c5 q R8 g+ L3 j
Av. 60.03 E/ r" L2 J8 t# \; {% G9 g3 {: Q
available testosterone. Again, emphasis should be placed on
% f6 ~3 t9 E, W) a: Tearly therapy when lower levels of testosterone appear to4 V5 l6 E& @" `1 C5 g6 j
provide the best responses. The earlier therapy is instituted$ C$ i2 B, u" b$ `* T2 c( G
the more likely there will be an excellent response with low
" U4 b! i3 ~7 ^ F6 d9 _serum levels. Response occurs throughout adolescence as: b- {9 l3 g3 c
noted in nomograms of phallic growth. 7 The actual response
/ l& a; N C* ]- bto a given serum level of testosterone is much greater at birth, X4 ?$ W* J) K* [: }) b% I; C& u1 }! h
and gradually decreases as boys reach puberty. This is most0 a0 X8 U* S0 }" o' S% {
likely related to the conversion of testosterone to dihydrotes-
/ T8 ^& s& x! T* |tosterone and correlates well with the studies of testosterone% u' o$ S$ d) u8 P* U
conversion in foreskin at various ages.7 D4 H, r' N9 A7 ?) p/ @4 r- A2 Y" s( ]
The question arises regarding early treatment as to whether' V: @# O: d2 f* b+ n/ N: C, U( a
one might sacrifice ultimate potential growth as with acceler-
* v X6 K6 L+ dated bone growth. The situation appears quite the reverse
- a9 \% m# P' ~: w5 f) H, [7 Fwith phallic response. If the early growth period is not used
8 \% i0 ]" Z0 F) J. x; lwhen 5a reductase activity is greatest then potential growth$ ?( x8 D0 k4 r0 ]& v4 x
may be lost. We have not observed any regression of growth
3 c4 Z+ L `% N A# P7 mattained with topical or gonadotropin therapy. It may well
$ k1 G9 M a& \5 ?2 rbe that some patients will show little or no response to any
) ^9 R9 J7 c+ O- ^3 Xform of therapy. This would suggest a defect in the ability to
! a4 G& D* s" Y% r9 `convert testosterone to dihydrotestosterone and indicate that
5 V9 J; n3 n# uphallic and peripheral skin, and subcutaneous tissue should7 }2 d# m- Z& r# @; d
be compared for 5a reductase activity.
/ m6 U8 ~1 t i, ~: g8 M8 d2 h' b" hA, loop enlarges to measure penile girth in millimeters. B,
6 r9 H! y2 s+ B0 F* f1 L2 ?" j4 X# q. i5 `example of penile girth computed easily and accurately.* v) {$ w! B3 r. D5 G6 Z
conversion of testosterone to dihydrotestosterone. It is in this% p* W0 P+ e4 |1 `" {. y
older group that others have noted high levels of serum
8 M [: _( ?$ B9 u* M" T3 e* y% Ttestosterone with topical application. It would also appear
6 l; i1 C# O1 x2 bthat phallic response during puberty is related directly to the+ ?! \, T$ `9 d/ C
serum testosterone level. There also is other evidence of local( ^& L8 S& y0 M: J$ n, i9 x
response to testosterone with hair growth and with spermato-
6 R q9 x, c E4 \5 V2 Ugenesis. 5• 6
2 z$ {; h& z; [3 t2 TAdministration of larger doses of gonadotropin or systemic
% K6 w6 @) Y- m9 m6 t: F6 gtestosterone, as well as topical applications that produce v, p1 y: ]; N7 `
higher levels of serum testosterone (150 to 900 ng./dl.), will0 z# A* L, ^$ f! K
also produce phallic growth but risks accelerated skeletal; K& j+ ~, ~% f' p) p. a# m
maturation even after stopping treatment. It would appear
) M" ~/ S% t& o7 m) ^2 B" ^8 Mthat this may be avoided by topical applications of testosterone0 q3 B4 B. n0 t0 r$ G1 q
and monitoring of serum testosterone. Even with this control
% `, }/ D/ L' s: C& e7 d; ?the duration of our therapy did not exceed 3 weeks at any
* @( q: [' C6 C% ^, b" A# ?time. It is apparent that the prepuberal male subject may% N3 s' ]$ Y7 V1 \: C
suffer accelerated bone growth with testosterone levels near4 B F' _2 }* }& r" I* v
200 ng./dl. When skeletal maturation is complete the level of# `" z0 f; m8 X p/ m' V
serum testosterone can be maintained in the 700 to 1,300 ng./! f6 U% M; D6 Y9 O2 g, E$ o
dl. range to stimulate phallic growth and secondary sexual1 g6 e! m; f. t" N& p/ }
changes. Therefore, after skeletal maturation parenteral tes-$ D( Z1 A+ w* B/ Y
tosterone may be used to advantage. Before skeletal matura-% s( \9 [ _ b7 R
tion care must be taken to avoid maintaining levels of serum
8 A _, ~+ X' [, X9 q3 ptestosterone more than 100 ng./dl. Low-dose gonadotropin
, L% G1 T* x/ m4 n8 F( Udepends upon intrinsic testicular activity and may require
; K' N* ?3 _5 P4 v! x, Qprolonged administration for any response.
; f& @3 }* v/ i, \: X }3 ?& l8 sAlternately, topical testosterone does not depend upon tes-$ y6 Z6 _: a4 P& C% q$ E
ticular function and may provide a more constant level of
0 Q3 ~& o; ?6 | ?REFERENCES
o% @; | {2 E1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,6 P7 w/ h2 \( J
R.: The local application of testosterone cream to the prepub-
' t& r- E9 V# fertal phallus. J. Urol., 105: 905, 1971.
$ M9 ?9 a2 ]) ]8 \2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone Z3 s+ Q: J, f0 x5 Y$ U8 ]
treatment for micropenis during early childhood. J. Pediat.,2 q8 `3 n5 N& y4 B7 r
83: 247, 1973.
( r* o& [1 ~' P/ X e6 V3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
, h$ g6 F1 u/ {0 l9 Y- T T! r- Z3 P4 cone therapy for penile growth. Urology, 6: 708, 1975.) L! [4 z' [3 d: ~+ ^- y' d
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
! @5 V, z7 f$ g6 t/ tto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by) C) j; A- e) Z& f4 O g
skin slices of man. J. Clin. Invest., 48: 371, 1969.
4 q6 x5 \! `2 C& c) W5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth2 \2 y" j6 f4 V* h
by topical application of androgens. J.A.M.A., 191: 521, 1965.' b# O, i- R: v s1 ~/ g" Q' M4 f
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local2 |: ]8 g! p7 {
androgenic effect of interstitial cell tumor of the testis. J.& l+ [6 x9 q& `/ g, v8 m
Urol., 104: 774, 1970.. B/ G5 n; {. D! D! [" N2 Z4 s
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-9 m9 X- _1 }. T1 o3 c
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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