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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
7 v$ H5 R! h) e A9 {1 {GONADOTROPIN
$ B/ _8 w: F) v/ f, s& I: J+ vRICHARD C. KLUGO* AND JOSEPH C. CERNY
3 R" J* P% s+ |) k4 z; TFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan" L- G/ F2 {+ o9 V/ @
ABSTRACT5 x2 Z3 \4 x A! W
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
) s' Q# n5 E8 e0 A4 g: w1 u: m9 zwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado- M! g* @# m+ C; B) d0 g z: B
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
/ J9 p9 P; N9 X# Q) t3 O/ l' Icream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent* i' j: K t% ^* Z- _
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent- t0 Z" z/ n2 i3 Q* V' D5 r/ [
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
1 P2 L; b8 o- Z5 l! gincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response; a! A% j& {) b, i
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
3 L( s; n+ a$ v$ r D2 }study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile/ f- n9 M" z* b
growth. The response appears to be greater in younger children, which is consistent with previ-
6 v( G' O) X( F5 x- N! }% j: Rously published studies of age-related 5 reductase activity.
& _# r& S* p/ IChildren with microphallus regardless of its etiology will
! @1 X) F e3 G) {require augmentation or consideration for alteration of exter-
+ s& ^8 H$ z/ T- P" X: Vnal genitalia. In many instances urethroplasty for hypo-4 ^" s# ~4 M" J# N3 \ Q
spadias is easier with previous stimulation of phallic growth.
# `' B9 Q4 @. q; M# s: fThe use of testosterone administered parenterally or topically: w( @% g* {# r5 O$ ^
has produced effective phallic growth. 1- 3 The mechanism of; }( U0 `& s) f: E: a0 V" ^
response has been considered as local or systemic. With this1 _2 L5 N2 s+ j/ t
in mind we studied 5 children with microphallus for response
. S. q# X6 r/ x* A7 a5 Nto gonadotropin and to topical testosterone independently.0 T2 G9 N( z+ G! l6 q
MATERIALS AND METHODS
' g2 ?3 _. \, ]+ }7 A KFive 46 XY male subjects between 3 and 17 years old were
3 C9 K4 [+ Z: o: X8 W1 \evaluated for serum testosterone levels and hypothalamic
* z3 F% O" l5 V/ A& ^" Qfunction. Of these 5 boys 2 were considered to have Kallmann's9 u' Y3 Q5 B1 [- y2 w' f! f$ c+ I
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
% T# ^3 v$ e) h9 e: m) Jlamic deficiency. After evaluation of response to luteinizing
" p1 M! d2 X8 `) h' Ghormone-releasing hormone these patients were treated with
( E; k! ]' B& _& s; @1,000 units of gonadotropin weekly for 3 weeks. Six weeks3 u' e9 s. | H9 }) ]! O3 @
after completion of gonadotropin therapy 10 per cent topical: W e4 {% J# b: L
testosterone was applied to the phallus twice daily for 3 weeks.
* Z+ v6 n; a: m4 VSerum testosterone, luteinizing hormone and follicle-stimulat-
0 a0 m p8 X3 d2 E, bing hormone were monitored before, during and after comple-! m0 s& W5 X* W6 ~( H' d
tion of each phase of therapy. Penile stretch length was
4 V& M: c1 g; fobtained by measuring from the symphysis pubis to the tip of
9 g1 l- U7 B) n0 I) W5 p2 E& othe glans. Penile circumferential (girth) measurements were r1 J0 a8 H' P9 Y- v
obtained using an orthopedic digital measuring device (see; C( P2 ?! `. ~5 q+ ?
figure).5 q! o6 O: f/ g! @+ p
RESULTS
% y0 [2 J% U k- G" oSerum testosterone increased moderately to levels between
. B, ^* m4 J4 X4 ~8 n50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
% }7 i- V& K8 t; ~. Yterone levels with topical testosterone remained near pre-2 K9 h x1 s6 \( n4 l- E
treatment levels (35 ng./dl.) or were elevated to similar levels
) S% A9 U) {6 ^developed after gonadotropin therapy (96 ng./dl.). Higher) |' ~ i! L$ y* z
serum levels were noted in older patients (12 and 17 years old),
# W7 S" K5 _* ?while lower levels persisted in younger patients (4, 8, and 104 @: ]4 l5 l" N0 p4 X
years old) (see table). Despite absence of profound alterations: Z: z- ~- H8 L' B$ G0 K1 b& L8 Z9 |
of serum testosterone the topical therapy provided a greater
5 P* t/ ^0 A. ]: H1 zAccepted for publication July 1, 1977. ·, b( V9 o/ j$ _+ }: m0 A
Read at annual meeting of American Urological Association,
9 Z" r$ g8 M- }# U3 _Chicago, Illinois, April 24-28, 1977.
. F7 U$ o2 c, ]1 c" j* `* Requests for reprints: Division of Urology, Henry Ford Hospital,
1 F; l& h- j# T9 R/ I# ~# i; ], J2799 W. Grand Blvd., Detroit, Michigan 48202.
) Y, L' y' X& y+ x6 Simprovement in phallic growth compared to gonadotropin.
& d- v |0 g3 r$ PAverage phallic growth with gonadotropin was 14.3 per cent
2 p% _3 I6 G1 `* d5 B j6 G' ^increase in length and 5.0 per cent increase of girth. Topical
+ s4 w, x m6 i+ |. B, j( atestosterone produced a 60.0 per cent increase of phallic length
0 y1 a; o/ [# H+ t$ j. Tand 52.9 per cent increase of girth (circumference). The# h. n2 B3 u: h9 W D
response to topical testosterone was greatest in children be-/ @, B- _8 Y7 \/ ?* D8 s
tween 4 and 8 years old, with a gradual decrease to age 17' a8 U+ P2 {" F: O3 f
years (see table)., ^8 Q* u4 r, }' g
DISCUSSION3 I w" f9 |% `$ R X7 Y
Topical testosterone has been used effectively by other
0 `3 K9 t+ ~& G0 o+ Qclinicians but its mode of action remains controversial. Im-
7 L# i2 `$ |5 T9 A' E m/ |. jmergut and associates reported an excellent growth response7 j: K/ t! D' z6 X: k' {2 D
to topical testosterone with low levels of serum testosterone,% [8 i" S' k7 Z6 ^4 [7 Y7 a
suggesting a local effect.1 Others have obtained growth re-; o5 B; v" V$ Y. A
sponse with high. levels of serum testosterone after topical; c) C: t) t( z2 p( \
administration, suggesting a systemic response. 3 The use of
6 I' t0 g( L, b3 R7 j. M) f9 z' jgonadotropin to obtain levels of serum testosterone compara-/ A" R4 @8 I! l- Q2 s4 v
ble to levels obtained with topical testosterone would seem to1 g) H7 W: T6 v/ @
provide a means to compare the relative effectiveness of
9 l% f% I; e" u# X9 x9 o! }topical testosterone to systemic testosterone effect. It cer-+ Q$ C: e6 G4 b2 r3 I' q
tainly has been established that gonadotropin as well as par-
. v( v% d) L6 v2 J" k% genteral testosterone administration will produce genital
7 N9 T/ u5 c* n# l/ Ggrowth. Our report shows that the growth of the phallus was5 S* `+ |2 q( u2 _4 `
significantly greater with topical applications than with go-
5 n3 l' Z8 W' n' F, B" onadotropin, particularly in children less than 10 years old.8 k& e. ]( C1 C1 W+ Z) N$ N
The levels of serum testosterone remained similar or lower
7 Z+ w$ H- c% H( v, \than with gonadotropin during therapy, suggesting that topi-3 C* V+ K. Z$ N. @1 a& H
cal application produces genital growth by its local effect as" S! L; ?" e' e8 w
well as its systemic effect.( r% \. W) f% A I$ @3 [+ c G
Review of our patients and their growth response related to
. j( S) g) Z: {age shows a greater growth response at an earlier age. This is
2 t+ C! l* k/ T( s: _3 g- E9 xconsistent with the findings of Wilson and Walker, who
, h5 J& {; x' U" I' [' [: U- areported an increased conversion of testosterone to dihydrotes-
) A9 ^ p& y- B8 Wtosterone in the foreskin of neonates and infants.4 This activ-1 A1 D; w% E3 O$ I! e
ity gradually decreases with age until puberty when it ap-6 I) \, s; Z! G i$ e; H+ [, b
proaches the same level of activity as peripheral skin. It may# W3 T# j/ R1 B: }
well be that absorption of testosterone is less when applied at9 h) \; F+ t& T$ M$ m0 T7 Q( P
an earlier age as suggested by lower serum levels in children! ~9 ^3 \5 `: ?
less than 10 years old. This fact may be explained by the& x) D2 O, B9 M0 i
greater ability of phallic skin to convert testosterone to dihy-
: k" x# O3 J8 ^' C* _4 qdrotestosterone at this age. Conversely, serum levels in older! o5 C. t0 h1 Y& E. P1 U* X) V* g
patients were higher, possibly because of decreased local
2 O' U6 Q2 Q7 \( c# h8 m6671 @3 h0 u: X4 K1 z5 W- s
668 KLUGO AND CERNY
8 J3 \9 I( ?) z1 C5 @/ CPt. Age
5 f+ n: }% }; \ U, s(yrs.)+ ]1 b4 X. o( a; _3 W
Serum Testosterone Phallus (cm.) Change Length4 C! }) h( n& `2 q6 X' V- G$ B
(ng./dl.) Girth x Length (%)
/ n# y2 b3 ?; s3 z4' b# T D3 E! u2 A
8
) k* N& [1 x% ~, `6 A" c10
: r- O3 a! g/ Y7 r% K) D7 ^12
3 O: w8 u5 h; h* k5 u17$ i3 H+ `; J0 I& H) S
Gonadotropin
1 ~- T' R5 h9 k71.6 2.0 X 3 16.6
0 b! h9 q/ d3 p- L1 D6 j( X50.4 4.0 X 5.0 20.04 K; Z' m' R. b' z( ^
22.0 4.5 X 4.0 25.0
7 C' c% }5 L1 A. T, x3 e84.6 4.0 X 4.5 11.1+ N) i2 Q, T8 h7 u
85.9 4.5 X 5.5 9.0+ W1 D( p a; Q- i: }% Q
Av. 14.3
: n* v5 a) G+ D" x7 b9 U4
3 X) [# Q+ _& R% S# Y' W y8
* E% ^1 x: ?6 _, V: p% h10* b0 i! M' j* O
12
8 m- h& O0 P1 V. R( L* B2 H- G17* i; A9 ~, k& ~; @" Q
Topical testosterone
" X9 I+ i8 @: S/ m' Z34.6 4.5 X 6.5 85) T8 ^; d/ U% [5 Y3 V6 r z- O
38.8 6.0 X 8.5 70/ A: g, F# r! u1 y! o% w
40.0 6.0 X 6.5 62.5( D, U, q/ W9 p+ ^4 J$ }$ U6 Z
93.6 6.0 X 7.0 55.5" `4 Q& E! X( I+ Z% a3 V' z) R& |
95.0 6.5 X 7.0 27.2
& k8 ]# L7 A# _4 r- @. ?$ KAv. 60.0
7 K$ V3 h: j* |, H8 P) p( D8 ^: Iavailable testosterone. Again, emphasis should be placed on
. T$ F; Z! Q0 y f8 T9 q7 `, @early therapy when lower levels of testosterone appear to) s' B4 G0 c# m1 M0 b. ~
provide the best responses. The earlier therapy is instituted
: `: Z$ S% Z, zthe more likely there will be an excellent response with low
% I; k- Y/ o5 _, D) Z8 Z [serum levels. Response occurs throughout adolescence as6 |) l; x7 q, H$ z1 d: U# I
noted in nomograms of phallic growth. 7 The actual response
$ z$ @+ }/ D+ e) ~0 M; _$ oto a given serum level of testosterone is much greater at birth
4 v9 ?6 Z0 W7 tand gradually decreases as boys reach puberty. This is most d- z2 [7 j* f# b" [; H& i& z
likely related to the conversion of testosterone to dihydrotes-
. R- R1 g' u [, D; `tosterone and correlates well with the studies of testosterone% Y v& z6 h: V% ^% T# \/ H
conversion in foreskin at various ages.' z8 Y& W7 N4 R
The question arises regarding early treatment as to whether( \% _0 `8 O4 }1 K
one might sacrifice ultimate potential growth as with acceler-
4 h# l2 X9 \8 N, ?' }/ \1 Mated bone growth. The situation appears quite the reverse
& _6 l: W8 @8 B0 U g x7 Mwith phallic response. If the early growth period is not used$ [6 O8 x3 C. L0 s) X, x6 v2 t. B/ y
when 5a reductase activity is greatest then potential growth
$ n- S6 a1 t8 ?' Gmay be lost. We have not observed any regression of growth" N. y5 x+ \$ x: \1 V
attained with topical or gonadotropin therapy. It may well( m2 R: M( \% ^3 j
be that some patients will show little or no response to any
. H7 X1 O# E) H1 Qform of therapy. This would suggest a defect in the ability to/ v1 ?8 k% u: c L2 g
convert testosterone to dihydrotestosterone and indicate that
* n* b; Z v% I' @5 }" Iphallic and peripheral skin, and subcutaneous tissue should; }+ g0 [, |+ N7 ^# P6 {- X( b) \" n
be compared for 5a reductase activity.. I" {4 a- k( F6 v0 J0 j
A, loop enlarges to measure penile girth in millimeters. B,7 h% W1 _. Y% g& S& F; v9 o/ h- E& i
example of penile girth computed easily and accurately.
/ I" T- d+ D4 T. K( f5 F" b, w ]conversion of testosterone to dihydrotestosterone. It is in this/ z8 {, }) Z9 ]5 u
older group that others have noted high levels of serum
. m! p4 g: a% N+ p; r8 ztestosterone with topical application. It would also appear
4 v# Y5 ?2 Q/ l$ ?: Rthat phallic response during puberty is related directly to the
+ Z! S C3 {' o0 y b7 `serum testosterone level. There also is other evidence of local
1 l; T% Y u9 \/ }5 \0 sresponse to testosterone with hair growth and with spermato-
& b: x1 F/ W" c; v2 bgenesis. 5• 65 q3 E9 Z) B' W2 |1 a
Administration of larger doses of gonadotropin or systemic0 u6 U8 \1 D, |7 X& d
testosterone, as well as topical applications that produce. P( Z: Y- x0 |6 p1 g& {
higher levels of serum testosterone (150 to 900 ng./dl.), will- p3 m2 ~' R2 `( s2 u
also produce phallic growth but risks accelerated skeletal& J- M9 |& ?9 Z F3 a, d
maturation even after stopping treatment. It would appear# p) }6 A7 x' A8 r5 J
that this may be avoided by topical applications of testosterone( H$ Q2 I. j# Q
and monitoring of serum testosterone. Even with this control
, _1 \8 j6 Y/ i2 Q. e; m/ Xthe duration of our therapy did not exceed 3 weeks at any* c2 M2 w8 l) k' z5 y
time. It is apparent that the prepuberal male subject may
# T- m; h+ W4 X5 wsuffer accelerated bone growth with testosterone levels near9 d1 ]' f8 P9 K5 g/ n4 ^( M: E; b
200 ng./dl. When skeletal maturation is complete the level of
8 k8 [/ {0 j& r5 z9 c1 Gserum testosterone can be maintained in the 700 to 1,300 ng./
; C! n% r$ D5 Kdl. range to stimulate phallic growth and secondary sexual
! u2 |/ }* r8 e* schanges. Therefore, after skeletal maturation parenteral tes-# u3 Y* P' i( s% ?. w6 i
tosterone may be used to advantage. Before skeletal matura-; t5 }- C2 J/ S
tion care must be taken to avoid maintaining levels of serum! }7 R" u" X, S( a) @5 {
testosterone more than 100 ng./dl. Low-dose gonadotropin
: k; e# n1 o ]: {" udepends upon intrinsic testicular activity and may require2 A. X- C* d+ S" J$ J
prolonged administration for any response.( [: z4 M- x R- }" j/ m
Alternately, topical testosterone does not depend upon tes-
( s8 s: d3 I( P* Wticular function and may provide a more constant level of$ ]7 D2 t$ n& n2 J6 n( W- }4 c( b
REFERENCES
, ]. f1 C7 M0 o6 ]& \7 r! m' d1 x- _1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
, P7 h/ q$ y9 D7 J& |6 tR.: The local application of testosterone cream to the prepub-9 ?" ^: t2 _* c, F4 Z* l
ertal phallus. J. Urol., 105: 905, 1971.
( t6 g( I$ V- k" A$ n2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone1 [- k, l4 F' G, e: @
treatment for micropenis during early childhood. J. Pediat.,
+ j3 ~8 f3 e2 N2 p; _; i83: 247, 1973.& R& ?% @' p' J, b7 f
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-# _3 K3 d# g% }3 ~/ e1 k! V j
one therapy for penile growth. Urology, 6: 708, 1975.( @& c& |# {2 |9 F
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
* M) o6 `- D2 K" oto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
9 k. ~# p5 G, d( p" \skin slices of man. J. Clin. Invest., 48: 371, 1969.
1 p- O# @7 Y# ?. L5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
" V1 A5 l" Y$ w. T0 I( Cby topical application of androgens. J.A.M.A., 191: 521, 1965.
& q% M& @# ~. q' T7 f% @6 A6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local5 R$ V0 o% j; }2 d6 i G+ p* H
androgenic effect of interstitial cell tumor of the testis. J.4 e; L1 F% K4 B( D7 O
Urol., 104: 774, 1970.
F) Q0 N& h# B3 L7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-& C2 T3 S: M" g! \, E; \
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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