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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
2 h% t2 Z% V! g8 qGONADOTROPIN0 A/ w" b$ c" J, V+ s" D9 I- [
RICHARD C. KLUGO* AND JOSEPH C. CERNY4 v6 F3 M+ ~1 V, b9 L
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
* ]+ d2 C( z& s: m6 RABSTRACT
7 S0 P& g8 \7 S) yFive patients were treated with gonadotropin and topical testosterone for micropenis associated2 A# j, o& a u% Q
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
2 G6 o! k4 f O0 @) p: e% htropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone9 Y6 m8 N9 G4 F5 Z" C0 d) [4 h7 C
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent/ ~: @( i) O! H* h; [
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent: I% k8 M3 J/ z4 c6 o+ D
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
3 @- V1 a9 P3 x$ L& dincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response+ v" A! V! A7 E U. B: b2 L( e% x
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
, F+ ]6 X; A+ t& K$ Zstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
) \* \3 b& F$ E" b$ J" vgrowth. The response appears to be greater in younger children, which is consistent with previ-
' I e; m5 o# T8 wously published studies of age-related 5 reductase activity.
) A9 ^/ N' @. h% `% MChildren with microphallus regardless of its etiology will" J- u( b$ e) d+ ^0 ~9 ^" X
require augmentation or consideration for alteration of exter-
5 G" U3 B! Z7 }nal genitalia. In many instances urethroplasty for hypo-3 w5 |% ?+ Z7 j. [
spadias is easier with previous stimulation of phallic growth.8 P. B8 S4 T8 W* l
The use of testosterone administered parenterally or topically) F. r4 N1 l( R( n1 U' O
has produced effective phallic growth. 1- 3 The mechanism of) P0 g* s+ m3 C9 Y* w2 k5 d
response has been considered as local or systemic. With this
8 K" f# Y5 P/ P6 M2 Nin mind we studied 5 children with microphallus for response
) W+ D" b0 S3 D$ cto gonadotropin and to topical testosterone independently." N+ z9 N, Q9 H
MATERIALS AND METHODS8 c; @8 @) F: k7 P
Five 46 XY male subjects between 3 and 17 years old were" ^5 @9 {: O1 D9 p. j
evaluated for serum testosterone levels and hypothalamic
1 L$ s& @4 T& Ofunction. Of these 5 boys 2 were considered to have Kallmann's
q2 w! v. y1 ]* rsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
& M( M4 Q8 j: hlamic deficiency. After evaluation of response to luteinizing
+ D% }- z6 S1 N( ]2 H2 v8 M7 thormone-releasing hormone these patients were treated with
; D; @/ `- y% A- [- i" ]- d3 q0 p* D* t1,000 units of gonadotropin weekly for 3 weeks. Six weeks
* a7 e# W4 x' b h, z. Pafter completion of gonadotropin therapy 10 per cent topical3 i$ M' ~! l0 r; I: J% ^
testosterone was applied to the phallus twice daily for 3 weeks.0 C: s$ r2 I4 [: M2 D3 o. Z
Serum testosterone, luteinizing hormone and follicle-stimulat-
2 Y2 G* d: p$ X$ Ving hormone were monitored before, during and after comple-
* m; e+ r( s9 y) D, W# Etion of each phase of therapy. Penile stretch length was; g1 F. [; B& D' S) J9 V; s1 N
obtained by measuring from the symphysis pubis to the tip of
# g% {+ |" Y: k1 W) m: _the glans. Penile circumferential (girth) measurements were
( C) i( J. m, H e) r4 D- yobtained using an orthopedic digital measuring device (see
/ d* G( X3 G: bfigure).
' G' L" ^( X, \+ j$ I! tRESULTS
8 Q* I& C9 o1 m$ r' c! e% h4 zSerum testosterone increased moderately to levels between$ r# g7 O7 L- Y. y
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-5 V l, G( m, U! y
terone levels with topical testosterone remained near pre-% N4 u# ? k; g1 ^! H/ w: {
treatment levels (35 ng./dl.) or were elevated to similar levels
1 c$ \0 C: x- q& B8 mdeveloped after gonadotropin therapy (96 ng./dl.). Higher; ]2 Z' N2 L: H& J
serum levels were noted in older patients (12 and 17 years old),
3 U7 P, u3 P, B- {while lower levels persisted in younger patients (4, 8, and 10
2 v1 Z8 }3 ?6 p/ x: R* }years old) (see table). Despite absence of profound alterations
, F1 ]( }+ z! X1 H: s$ f0 Gof serum testosterone the topical therapy provided a greater. A* W$ q+ H7 X, B! N* j
Accepted for publication July 1, 1977. ·
" X3 Q* O- H. G! e" r" N+ |Read at annual meeting of American Urological Association,; l7 Q0 D% w1 G# T) L! A* o
Chicago, Illinois, April 24-28, 1977.
! H) v0 M* J9 G* Requests for reprints: Division of Urology, Henry Ford Hospital,
- B- C& I8 K0 E! O g2799 W. Grand Blvd., Detroit, Michigan 48202.$ { I D; E: B; @
improvement in phallic growth compared to gonadotropin.: J- T# B3 i3 x1 K h
Average phallic growth with gonadotropin was 14.3 per cent
& N( Y; w1 S4 O, Fincrease in length and 5.0 per cent increase of girth. Topical; R+ w. m- T8 z& J! z* ^
testosterone produced a 60.0 per cent increase of phallic length s1 X; O) O7 s+ r( }2 L# u& |
and 52.9 per cent increase of girth (circumference). The
6 |* U+ _2 x0 E1 T2 c0 Yresponse to topical testosterone was greatest in children be-. l% i+ |& N8 C6 p" l. M
tween 4 and 8 years old, with a gradual decrease to age 17
) e# l/ R5 a$ byears (see table).6 O- l, m; x) y# ]3 m9 n
DISCUSSION2 [) }; C ]) B/ p, g1 ~* `+ [# M
Topical testosterone has been used effectively by other" _+ P% s& Q$ ^$ @' J0 @* Y
clinicians but its mode of action remains controversial. Im-
$ U: X5 V: \7 B$ W. x2 @5 tmergut and associates reported an excellent growth response
8 j* b4 \0 |2 i4 c+ C" ato topical testosterone with low levels of serum testosterone,
0 N5 T& s* b$ G5 Dsuggesting a local effect.1 Others have obtained growth re-2 F: C) O j# s, A, j2 }
sponse with high. levels of serum testosterone after topical4 S2 S! z# ^- m# |
administration, suggesting a systemic response. 3 The use of
- v M) A) o7 |; Q) W2 Egonadotropin to obtain levels of serum testosterone compara-
7 q" B9 Z$ l& }+ u* Zble to levels obtained with topical testosterone would seem to
8 C% |% q7 b' o) M# e0 K Rprovide a means to compare the relative effectiveness of
: @; R+ D8 O8 r6 X7 Q1 A: v, { |" ctopical testosterone to systemic testosterone effect. It cer-
8 y7 F+ u9 R) t( D1 Xtainly has been established that gonadotropin as well as par-
* _# s$ r1 M3 x5 ^enteral testosterone administration will produce genital: G0 w* ~$ O" T& S
growth. Our report shows that the growth of the phallus was
! P0 E3 f' @# }# R2 _1 Ksignificantly greater with topical applications than with go-
9 D: L7 k% `7 i6 u* E; i5 X6 Dnadotropin, particularly in children less than 10 years old.
# n# @% I6 w: w( X0 k9 }The levels of serum testosterone remained similar or lower
, Y U( ] S2 N3 `than with gonadotropin during therapy, suggesting that topi-3 h' O5 u, r2 x, o
cal application produces genital growth by its local effect as) v2 k# g1 _ P/ r
well as its systemic effect.
; p4 N1 z) M; i$ t7 f4 FReview of our patients and their growth response related to+ a5 A3 H9 D2 k9 `# R# s) B9 X
age shows a greater growth response at an earlier age. This is% d) O% y- s( P( ]! H2 m
consistent with the findings of Wilson and Walker, who4 V4 F9 b# e0 R. ?# m
reported an increased conversion of testosterone to dihydrotes-
/ V1 G+ A- r& L4 K/ ttosterone in the foreskin of neonates and infants.4 This activ-2 C; S6 n2 ]# _. E+ k
ity gradually decreases with age until puberty when it ap-2 U, c1 V8 I8 i
proaches the same level of activity as peripheral skin. It may; [2 X2 f) x1 M* B9 P0 M/ a7 E
well be that absorption of testosterone is less when applied at0 L/ ` ^3 {) R3 s: Y ]
an earlier age as suggested by lower serum levels in children) @3 P2 M. a9 P$ h/ c
less than 10 years old. This fact may be explained by the* L7 U4 x. z6 U% n5 Y# q
greater ability of phallic skin to convert testosterone to dihy-! F+ s* {5 R7 w4 F0 L
drotestosterone at this age. Conversely, serum levels in older8 P, F- L4 A* |* I* f
patients were higher, possibly because of decreased local0 ?8 |+ k+ a$ c) F! F2 K! d
667
s/ e. e/ m5 x3 J H5 R668 KLUGO AND CERNY; k/ c* z5 _1 T0 D
Pt. Age u. q6 I' b6 H, Y
(yrs.)% ?* u& R; M1 a: N' H. I& l/ Q" n; O
Serum Testosterone Phallus (cm.) Change Length3 p. E! G. z& ]) r( h [9 O7 F
(ng./dl.) Girth x Length (%)& ^- a% ]% a- {" B
4
2 P3 F3 C) z/ @8$ n- B3 E& T& @6 R
10& d# X' ~- h' O
12- C9 K& ]5 S2 a" l$ c
178 y$ I* C# D: U* z
Gonadotropin4 e4 I; j1 _% e. h4 ~. @' Y
71.6 2.0 X 3 16.6
0 n7 H! B( C2 i5 Z50.4 4.0 X 5.0 20.08 L8 Q: @6 A: T) ~
22.0 4.5 X 4.0 25.0
" ^8 v, ~# S W! p' M& I84.6 4.0 X 4.5 11.1
$ z- T" A5 E+ y( |) L85.9 4.5 X 5.5 9.0, x9 M7 Z3 z6 I9 u v
Av. 14.3
* n+ _' N. ]* Y# I46 c0 P& S( o: O$ C& {: ~% a
8' B9 [3 ~; y' y# D, n6 V) v
10
! V! f0 ^( V( Y" O12
t5 ] [5 b" e% O2 b+ K% |1 L17. O0 R0 g' J$ Z
Topical testosterone
' |2 Z; o# L' [34.6 4.5 X 6.5 85
$ }+ r4 L8 I) b/ ?2 B3 ~38.8 6.0 X 8.5 70, v% _% c7 d& y1 D
40.0 6.0 X 6.5 62.5/ K3 y' O& N1 d8 y, i$ }$ a" B
93.6 6.0 X 7.0 55.5+ b7 e, w/ Q, t0 B0 J
95.0 6.5 X 7.0 27.2
9 d1 y( @: g" D7 _; _& GAv. 60.0
1 s. h ^8 H, Iavailable testosterone. Again, emphasis should be placed on
2 `% m* I/ {* t* iearly therapy when lower levels of testosterone appear to, [& }3 ^' v" y) D# f7 L* d* S
provide the best responses. The earlier therapy is instituted
$ A, n" _8 ~& U3 u' @, m9 ethe more likely there will be an excellent response with low
4 T. _& k+ [' Q$ tserum levels. Response occurs throughout adolescence as: T5 x; `) _- M7 F& b7 S
noted in nomograms of phallic growth. 7 The actual response1 M5 S0 L0 J7 @
to a given serum level of testosterone is much greater at birth% B+ c$ t8 s j. g" e0 b
and gradually decreases as boys reach puberty. This is most
$ _* J' C9 i5 H2 T, A5 g' f9 Ilikely related to the conversion of testosterone to dihydrotes-
; q" }' n" V$ z. Htosterone and correlates well with the studies of testosterone
/ Z: d' t* Y- s, Uconversion in foreskin at various ages.6 d/ G! g. z+ K8 e/ s
The question arises regarding early treatment as to whether( d* T- k! }) L, v" q
one might sacrifice ultimate potential growth as with acceler-
; Q( b8 y7 R! J5 E4 g' Nated bone growth. The situation appears quite the reverse
4 C1 \" l) b8 Y1 V: R. H- gwith phallic response. If the early growth period is not used% t7 f+ i; @, ]- q
when 5a reductase activity is greatest then potential growth- n/ {2 [) v' X( k- Z+ i
may be lost. We have not observed any regression of growth
( B, a2 M7 o% t: f4 m6 wattained with topical or gonadotropin therapy. It may well8 ^) k; Q" l6 T3 h$ |2 h
be that some patients will show little or no response to any7 ~9 U4 Q. K: Z) _9 ]
form of therapy. This would suggest a defect in the ability to
% {! p$ j& I7 I: P, t* Z4 O/ @convert testosterone to dihydrotestosterone and indicate that
2 p% O0 L. M* F1 a9 c# q& N/ sphallic and peripheral skin, and subcutaneous tissue should$ x$ X7 N1 s) D: x# h. D, a$ A7 ?* j
be compared for 5a reductase activity.
) W8 X: R& ], GA, loop enlarges to measure penile girth in millimeters. B,
, b& \5 j( H8 [% H+ [6 @8 ^: hexample of penile girth computed easily and accurately.
- k( Z8 L. x- f& n& S2 o+ tconversion of testosterone to dihydrotestosterone. It is in this
0 e, L- Q3 p, t3 r- I6 P5 d6 \1 \older group that others have noted high levels of serum# j# @1 S: |" m; \ F( x
testosterone with topical application. It would also appear
% m, {5 Y6 J, n- f- kthat phallic response during puberty is related directly to the6 i1 H9 U4 Q6 R
serum testosterone level. There also is other evidence of local7 T' o* ~: l; `8 A- K, h7 e
response to testosterone with hair growth and with spermato-( l5 H/ T/ F8 _
genesis. 5• 6
( I, p) ?; n5 G lAdministration of larger doses of gonadotropin or systemic. }5 H6 w0 j) i% p3 K7 e' G
testosterone, as well as topical applications that produce
3 n }2 _; {2 n7 d R5 W9 Bhigher levels of serum testosterone (150 to 900 ng./dl.), will N" b( G) [0 x( P) c- X' N
also produce phallic growth but risks accelerated skeletal
, t) ~- v! y% M0 E" X( hmaturation even after stopping treatment. It would appear
! K) c: J+ b- ]; ~) R" {that this may be avoided by topical applications of testosterone' x. R8 ^) E; L' ~* }
and monitoring of serum testosterone. Even with this control
# m# B" M# m! T p+ Nthe duration of our therapy did not exceed 3 weeks at any6 k2 ?6 N* J* ?: {1 T$ h
time. It is apparent that the prepuberal male subject may' t/ O# X; O7 A1 G2 Q! H
suffer accelerated bone growth with testosterone levels near
7 V: \: w, m" Q& D) M4 Y200 ng./dl. When skeletal maturation is complete the level of
- ~1 F/ h1 g! p! M S) j% z7 V6 vserum testosterone can be maintained in the 700 to 1,300 ng./
4 ], [1 U$ v: L" R8 c! vdl. range to stimulate phallic growth and secondary sexual
- N9 |9 `; q6 q1 G" R) U5 h* Tchanges. Therefore, after skeletal maturation parenteral tes-
+ m2 j! S! q+ u: I7 ttosterone may be used to advantage. Before skeletal matura-+ E) c# I V/ b7 R9 T; ~
tion care must be taken to avoid maintaining levels of serum
3 E* {0 A. {1 Z3 Ytestosterone more than 100 ng./dl. Low-dose gonadotropin3 w* j* \) T5 B2 c, S" |
depends upon intrinsic testicular activity and may require- Q" _2 h9 V' R' ^2 E
prolonged administration for any response.
2 |1 h4 t# q& S8 B7 }; D4 f. WAlternately, topical testosterone does not depend upon tes-
6 J, ~. f$ \/ p7 s: ~5 Xticular function and may provide a more constant level of
, s( E6 B9 F+ ?$ zREFERENCES
9 v1 e0 L3 V9 l+ j1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,- c) N* h. s/ t1 G9 f
R.: The local application of testosterone cream to the prepub-
2 [% s3 W% D- \# p, Vertal phallus. J. Urol., 105: 905, 1971.: _6 ~! {% q( [" p+ ^
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone$ z' E) p! o$ m
treatment for micropenis during early childhood. J. Pediat.,
0 o( s/ y. j. `- I83: 247, 1973.
: m4 U$ z3 C! g' e3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
* {8 `$ w v2 }7 `; mone therapy for penile growth. Urology, 6: 708, 1975.' t: r! g; J! |& x; [7 a; I
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone0 q0 u% I- A( K: `6 c
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by& t" B4 D0 D: T2 J" ^
skin slices of man. J. Clin. Invest., 48: 371, 1969.4 N, O) {- }6 Y% A+ p
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
; R6 O- y9 P1 J& T p" e/ Y5 [by topical application of androgens. J.A.M.A., 191: 521, 1965.
/ U+ I3 u+ d5 f d: s1 M3 X6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local/ P B. `# v5 P, A S& E: ?, V
androgenic effect of interstitial cell tumor of the testis. J.
1 Y8 A( h5 }. C$ `5 GUrol., 104: 774, 1970.+ H5 i4 B* j; w2 y5 V. r* r
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
$ B8 b1 L2 ]( b6 p, `tion in the male genitalia from birth to maturity. J. Urol., 48: |
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