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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
. Q! x- v1 m1 ~GONADOTROPIN8 x) H% J) r" r" C* @
RICHARD C. KLUGO* AND JOSEPH C. CERNY J z& E3 o1 l7 o
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan# I% D; ~5 V9 x0 i
ABSTRACT
. Z& ^0 B9 y4 j! vFive patients were treated with gonadotropin and topical testosterone for micropenis associated6 @6 w7 r# ?4 ~* {6 y
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
8 e ^) P% N/ R4 B9 N: ~tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone& l: x" w) L; D6 c4 O3 v! k. Y
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent% m) @- c8 j9 Y
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent* Y; e$ U2 D8 i' c3 L% s
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
. C, ^ }- v7 Gincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
- q. o3 w# G& ]8 Poccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
" a( n4 Z" H/ l- f$ }0 s, i1 X7 zstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
4 i7 @# z M. n0 ?growth. The response appears to be greater in younger children, which is consistent with previ-" A1 r9 {& V. x/ r& C
ously published studies of age-related 5 reductase activity.
8 b( }2 {& c; D; i3 kChildren with microphallus regardless of its etiology will4 }3 @( l. m4 d) e5 l# l; k
require augmentation or consideration for alteration of exter-) r( u, m' n# s8 o) {$ i# [
nal genitalia. In many instances urethroplasty for hypo-
) J) c3 r+ q' p% fspadias is easier with previous stimulation of phallic growth.
" h' |: b( F# Z' pThe use of testosterone administered parenterally or topically s, C" B; G* ^* U2 g6 j" T
has produced effective phallic growth. 1- 3 The mechanism of
. O u5 s* d3 `9 O" Bresponse has been considered as local or systemic. With this
& C1 `; I E! c% v0 f. ~- `* rin mind we studied 5 children with microphallus for response
( E: F! I4 X; S" gto gonadotropin and to topical testosterone independently.
; f5 c; {& M( H7 A J/ GMATERIALS AND METHODS6 U# ^7 a7 e3 }. n% j
Five 46 XY male subjects between 3 and 17 years old were5 w9 H6 x$ Y. M1 P, T' z1 c
evaluated for serum testosterone levels and hypothalamic
% M0 U5 y4 W+ v# {3 U9 hfunction. Of these 5 boys 2 were considered to have Kallmann's
) p5 s% h; }0 W: _syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-: K7 A" G9 I% w7 V
lamic deficiency. After evaluation of response to luteinizing2 S/ f/ u$ L/ U- F g: l4 B2 C
hormone-releasing hormone these patients were treated with
& x; ?' B9 E& j1 n8 G" Z' \$ Q. b1,000 units of gonadotropin weekly for 3 weeks. Six weeks
2 C: p" p4 Z# F/ A* Pafter completion of gonadotropin therapy 10 per cent topical
, T$ H8 R5 S) ]5 X, p# J0 ltestosterone was applied to the phallus twice daily for 3 weeks." C& ?( x$ g! k ~7 `3 B P: i
Serum testosterone, luteinizing hormone and follicle-stimulat-1 S. R- C0 k: E
ing hormone were monitored before, during and after comple-
- L' |3 O' q0 W; d3 mtion of each phase of therapy. Penile stretch length was
9 s# ~1 |' s1 U. ?5 C. Yobtained by measuring from the symphysis pubis to the tip of
2 ^; y. h: `6 \* K/ N! Sthe glans. Penile circumferential (girth) measurements were
7 W6 U$ y4 j2 K' m3 N' W" a' j' Kobtained using an orthopedic digital measuring device (see
! I- e! y2 D- g& Lfigure).
( a. C4 ?1 E8 @; D" y! d5 R6 g+ ERESULTS: W# ?: e0 ]8 e/ `# g- P. c
Serum testosterone increased moderately to levels between5 F7 h$ |9 ]0 Z1 L }* X: {
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
" A1 q- M7 K$ s j' B8 C8 J2 p4 n. Oterone levels with topical testosterone remained near pre-8 K- ^' l& ~4 S0 H
treatment levels (35 ng./dl.) or were elevated to similar levels$ Y! f" D4 i4 e7 h7 W0 E
developed after gonadotropin therapy (96 ng./dl.). Higher6 r+ Z' [ B7 Y$ s
serum levels were noted in older patients (12 and 17 years old),
" K+ c% O# A& K4 t" p3 ]6 wwhile lower levels persisted in younger patients (4, 8, and 107 X' R; Y# Q5 ~0 }
years old) (see table). Despite absence of profound alterations- C. u2 e6 l7 S8 V. Y" D9 O. @
of serum testosterone the topical therapy provided a greater, ]* N( }& R; p; L. P+ K
Accepted for publication July 1, 1977. ·0 I6 E* b4 i1 f
Read at annual meeting of American Urological Association,
: N( W. e5 \5 U8 NChicago, Illinois, April 24-28, 1977.4 x2 c# G9 P" a& P/ J( F
* Requests for reprints: Division of Urology, Henry Ford Hospital,8 d5 f% l0 h) H
2799 W. Grand Blvd., Detroit, Michigan 48202.
# v) n% \# U2 G: N7 a1 N1 N' iimprovement in phallic growth compared to gonadotropin.& P# \4 ~5 a% T9 |( l" i6 ^- T
Average phallic growth with gonadotropin was 14.3 per cent3 S: I% m# I- ^5 N8 M; v) {
increase in length and 5.0 per cent increase of girth. Topical
( [: v& q- N: }, B1 gtestosterone produced a 60.0 per cent increase of phallic length
) Z+ s' D* y: V: t% z3 A+ qand 52.9 per cent increase of girth (circumference). The6 a4 D9 A# ^( ~
response to topical testosterone was greatest in children be-' _7 b8 P7 `4 d9 V6 p
tween 4 and 8 years old, with a gradual decrease to age 176 R" l" X, L0 }2 O6 ?' E
years (see table).
) x( P p4 Q# ?DISCUSSION
" }$ g) x" `( dTopical testosterone has been used effectively by other
3 p# B" v! e/ [9 I; s3 vclinicians but its mode of action remains controversial. Im-4 I1 n7 \6 o" n1 a5 o' n
mergut and associates reported an excellent growth response# W( N; z) b# p% j& d1 P
to topical testosterone with low levels of serum testosterone,% Y W& D! e0 x
suggesting a local effect.1 Others have obtained growth re-/ Y- u$ |# A$ A) D
sponse with high. levels of serum testosterone after topical
6 L {2 |7 | `* e8 X! Fadministration, suggesting a systemic response. 3 The use of7 L4 ]5 y3 ~# C2 @" t# J
gonadotropin to obtain levels of serum testosterone compara-7 \# y, L6 r) n5 ]5 N
ble to levels obtained with topical testosterone would seem to
( R `/ A8 Q$ q) X( B0 ^provide a means to compare the relative effectiveness of8 r9 M. X4 S( S2 Q2 d6 q7 b
topical testosterone to systemic testosterone effect. It cer-; W" H4 T5 P, m$ C0 _, u
tainly has been established that gonadotropin as well as par-2 N' r1 e# |* K$ g4 I
enteral testosterone administration will produce genital
3 F+ Q& P4 i8 r9 e5 L0 q4 R6 Mgrowth. Our report shows that the growth of the phallus was. }0 W# S1 N! |' I/ N( p" E0 I
significantly greater with topical applications than with go-
8 H- J. `% ~7 m+ Z- U( ?- w- P: ^nadotropin, particularly in children less than 10 years old.. T/ ^* F, q1 q1 E" m7 ]
The levels of serum testosterone remained similar or lower
3 ?7 m6 Y2 n+ rthan with gonadotropin during therapy, suggesting that topi-; N5 G* x# w9 m" U
cal application produces genital growth by its local effect as A7 f& Y; e. ?" T
well as its systemic effect.3 v- Z# ^9 [. i
Review of our patients and their growth response related to
% D. l% _5 ~; g4 x& \7 {9 G J& o; [age shows a greater growth response at an earlier age. This is
! s; Q! |: a V" _5 xconsistent with the findings of Wilson and Walker, who
# ?) e9 |9 o) d% h% ereported an increased conversion of testosterone to dihydrotes-
% y% s" Y6 u1 c% s5 R+ Ztosterone in the foreskin of neonates and infants.4 This activ-
' F- c7 ]- F, Wity gradually decreases with age until puberty when it ap-" ~/ o8 B, ]1 H: j" |
proaches the same level of activity as peripheral skin. It may- L" p% |" }2 b1 J. \
well be that absorption of testosterone is less when applied at
. ~; {# ]* ]1 \$ g8 g! I* ban earlier age as suggested by lower serum levels in children
, R0 P+ O7 c3 jless than 10 years old. This fact may be explained by the; C; V5 |) l0 F$ W J" x
greater ability of phallic skin to convert testosterone to dihy-
0 S* o$ V" c" |5 bdrotestosterone at this age. Conversely, serum levels in older) U0 g- x% v k6 T( R3 j: x9 N+ t/ P7 v
patients were higher, possibly because of decreased local
1 |$ D* b/ s! ?$ R# |$ I; @0 a667
; ]& [6 f5 _% Q668 KLUGO AND CERNY9 {0 ?/ O, R+ A0 j/ `" Q
Pt. Age
4 K; Y9 b3 O8 U, ^3 A(yrs.)
3 T# \/ R7 s- n1 t: R7 k. x/ ZSerum Testosterone Phallus (cm.) Change Length8 D7 {. U) q+ \$ A8 W& O8 M0 Y
(ng./dl.) Girth x Length (%)* |" Q9 Y8 F3 z3 O/ Q' Y: p, b6 i
4( Z* y4 H4 |. f ~
86 T7 c( d/ |# a6 ]
10- f3 V# E7 s! |$ X/ S7 L
12
! z/ @5 w7 e$ X2 Z+ w: E/ x17
5 G; B8 ^5 v- m7 m aGonadotropin" |" }& r# T. h
71.6 2.0 X 3 16.6
9 \+ v, J% ]% [50.4 4.0 X 5.0 20.0( x. P3 e; \+ w: w& {' ]
22.0 4.5 X 4.0 25.0
% B) ]; v! E6 {; p' n84.6 4.0 X 4.5 11.17 ?6 L7 O: @! x7 x0 w( W: g/ q
85.9 4.5 X 5.5 9.0
5 l! P c% U2 y0 jAv. 14.3
' N8 g4 b, L' R4
& S& o6 c w8 y7 y+ P8
. y" \. o" q7 `& l10% f# S( K( f/ W& X+ L/ j: t) w9 m
12
, B# H9 J% k" m9 n17
/ B R8 ^# Z$ I' ZTopical testosterone
, I5 S) F; t) O34.6 4.5 X 6.5 85
7 O/ @# n0 v8 o- T. }% F5 b38.8 6.0 X 8.5 707 D( W& k' ~8 ]/ H4 s* L& v
40.0 6.0 X 6.5 62.5& P# T7 p, A- i
93.6 6.0 X 7.0 55.5 q" ^7 w/ C& k% G& p& h
95.0 6.5 X 7.0 27.25 q* R5 r1 j% `7 o! x2 l7 \
Av. 60.04 w) J+ Y) F7 D W) M. O6 O' {* r
available testosterone. Again, emphasis should be placed on
* N4 H! R+ r8 }2 u# E* `- @2 f# y: ]early therapy when lower levels of testosterone appear to/ |% w5 E5 L( f; q
provide the best responses. The earlier therapy is instituted
, s3 G% v( @7 F% m( a$ e9 @the more likely there will be an excellent response with low
# I' V; Y6 }: Bserum levels. Response occurs throughout adolescence as4 E1 s4 J( d& Z8 @' ~9 F
noted in nomograms of phallic growth. 7 The actual response! b+ L0 W5 W0 u: H
to a given serum level of testosterone is much greater at birth0 g$ @! g4 U, o9 X& ^# p& t
and gradually decreases as boys reach puberty. This is most' G/ Z+ @: K5 M4 L
likely related to the conversion of testosterone to dihydrotes-
* @$ U1 z4 A( B) S+ ntosterone and correlates well with the studies of testosterone) |4 H# j! ^4 k
conversion in foreskin at various ages.( T1 \; T# [- l' i
The question arises regarding early treatment as to whether
8 o; |% N) t/ c' oone might sacrifice ultimate potential growth as with acceler-: E4 s8 f0 V( F# y
ated bone growth. The situation appears quite the reverse
2 F2 y) o* }4 _with phallic response. If the early growth period is not used. a) Q' v( I: l) w2 H' V' r
when 5a reductase activity is greatest then potential growth) x5 N9 ?4 O& U% s+ k8 e9 F
may be lost. We have not observed any regression of growth
, [/ X# @# j$ Qattained with topical or gonadotropin therapy. It may well I# Q3 J: {9 g
be that some patients will show little or no response to any
# K( E: z9 _) E( V1 gform of therapy. This would suggest a defect in the ability to& t) V9 J3 I2 t# z5 Q
convert testosterone to dihydrotestosterone and indicate that, l+ j/ x$ ~. E/ y: K) Q6 z2 z
phallic and peripheral skin, and subcutaneous tissue should
, S; A( |5 W7 s2 S/ ube compared for 5a reductase activity.
' D8 ~( d% e! W! b/ M% OA, loop enlarges to measure penile girth in millimeters. B,
# e- @ P! d, h: h0 O8 Eexample of penile girth computed easily and accurately." @) @* j) [: V
conversion of testosterone to dihydrotestosterone. It is in this+ R/ \' z; ]: \% F- Y
older group that others have noted high levels of serum: u5 c1 y4 H+ F( J g' T! L& }
testosterone with topical application. It would also appear" ?( H" f! |2 z0 s* k
that phallic response during puberty is related directly to the" }6 p `. M/ q' u, b( r7 p
serum testosterone level. There also is other evidence of local" t& e; N1 F0 o% H2 Q! o$ |% R
response to testosterone with hair growth and with spermato-# l( |" a; ]7 K* d ]; L! g$ O
genesis. 5• 6, V; B, ?4 C Z1 {8 t W
Administration of larger doses of gonadotropin or systemic; ?7 ^# W6 `) f- a
testosterone, as well as topical applications that produce" Q; ^0 j- ]2 t/ C
higher levels of serum testosterone (150 to 900 ng./dl.), will
8 ?% {# q/ U- Q; v6 {6 j0 zalso produce phallic growth but risks accelerated skeletal# j5 K* i& U* U Q# \4 q
maturation even after stopping treatment. It would appear
- N# @) t' S7 L7 Lthat this may be avoided by topical applications of testosterone* H5 x2 b% s' o8 y
and monitoring of serum testosterone. Even with this control7 c* ^' `" Q/ @
the duration of our therapy did not exceed 3 weeks at any
% s$ x0 [5 h$ u: l) w5 n6 Htime. It is apparent that the prepuberal male subject may
% ]5 H' T7 W' Z: c! u! c1 Ysuffer accelerated bone growth with testosterone levels near$ y4 ^; j1 p. b8 B$ Y
200 ng./dl. When skeletal maturation is complete the level of* u% Q/ l, p; c. k; D
serum testosterone can be maintained in the 700 to 1,300 ng./
0 ~$ e$ W! t x0 ]' f5 @dl. range to stimulate phallic growth and secondary sexual, [; z7 s; ], ~
changes. Therefore, after skeletal maturation parenteral tes-
& }) }# U% s9 A& q1 K' ]3 Atosterone may be used to advantage. Before skeletal matura-
, `& S- u3 @/ p, h! Ktion care must be taken to avoid maintaining levels of serum
1 K! B$ A: ?% B6 X& _3 ntestosterone more than 100 ng./dl. Low-dose gonadotropin5 U/ O/ `7 N' ?6 j! I: t- l$ I
depends upon intrinsic testicular activity and may require
+ Y: k+ K3 h+ c' B% ?4 m, _. `& cprolonged administration for any response.
) Q& X. u/ r. G6 p6 rAlternately, topical testosterone does not depend upon tes-3 o5 N, m! N) \
ticular function and may provide a more constant level of
/ d; T1 ], }0 D+ G! s% _* @REFERENCES( f2 H1 g' q/ c
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,' S( ^5 M4 h& J K
R.: The local application of testosterone cream to the prepub-
9 t) [# W' M! A5 M+ o8 Rertal phallus. J. Urol., 105: 905, 1971.
+ Z3 q9 I, |0 C9 I2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone7 {% `# c* B7 T: q+ e8 m
treatment for micropenis during early childhood. J. Pediat.,
+ t3 j$ ^. Q9 u( m! p83: 247, 1973.
! ]4 n# | _0 t3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-/ k( _, H; z; Q$ l* T2 W' p- }
one therapy for penile growth. Urology, 6: 708, 1975.
% `$ A7 }# ]: f4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone- v3 e; q* p% [6 Z) r
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
?, m$ D1 t( m# O; \skin slices of man. J. Clin. Invest., 48: 371, 1969.3 s8 ]( {, A" e
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
1 i* J! i4 b, ~/ A2 ]$ Cby topical application of androgens. J.A.M.A., 191: 521, 1965.) {+ W O7 G5 n$ d
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local. p+ z- ? B- l5 _( R0 l
androgenic effect of interstitial cell tumor of the testis. J.7 P$ e) w' s$ D$ E# ^
Urol., 104: 774, 1970., U8 D% d \% m2 @. |1 w
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-/ `! O8 k$ S% Q1 J: Z% O
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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