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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND+ b, h* b1 P- p8 [' p6 n- i
GONADOTROPIN
, H' H# l0 l9 M, M8 ^; v% _, ^RICHARD C. KLUGO* AND JOSEPH C. CERNY4 Y) u0 ~( S: |+ H
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan5 f1 W* h) C. G4 \( x5 m6 x( k
ABSTRACT
5 `1 S5 I* `3 _6 l; I$ ?Five patients were treated with gonadotropin and topical testosterone for micropenis associated: C$ P! P4 _/ }& l+ t l9 N5 W7 e
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
- I5 B7 o }0 h9 }, [ Ltropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone: P$ @+ u! P# x
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent( [9 |: Y+ m; ` L4 `
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent3 l& L; m8 {! |! L3 a* Z
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
" A C3 c% q+ {- ~% Dincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
3 v) y. M5 h+ L: }0 noccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This; G$ r; {# z8 |
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile \ J+ O% e0 a* \
growth. The response appears to be greater in younger children, which is consistent with previ-
* R4 l- c9 G9 h9 X+ d! Yously published studies of age-related 5 reductase activity.
! G3 R% d' a/ O# b# H- [% fChildren with microphallus regardless of its etiology will
6 e! t" F! R5 `3 m' t$ frequire augmentation or consideration for alteration of exter-
* V o* d2 n3 H5 F2 b" v8 cnal genitalia. In many instances urethroplasty for hypo-! C. }# L @/ H: e
spadias is easier with previous stimulation of phallic growth./ O& q3 K: [/ U
The use of testosterone administered parenterally or topically
6 E9 C4 O2 U3 U! X! A8 E$ Xhas produced effective phallic growth. 1- 3 The mechanism of ]$ {- Q5 P5 Z( _$ h6 E) {
response has been considered as local or systemic. With this
$ P6 Y' H8 m) B' Y) n2 [7 oin mind we studied 5 children with microphallus for response' T. Z0 t. r$ ~8 n: T9 _( k
to gonadotropin and to topical testosterone independently.
7 q& F" G7 X( h' i7 q9 K# X4 ?, ~MATERIALS AND METHODS" J: S9 |- y L8 S" y: \5 O& G0 ^9 ^
Five 46 XY male subjects between 3 and 17 years old were
9 O" `4 {( p4 D, pevaluated for serum testosterone levels and hypothalamic
+ q- ]/ y& ]' T4 }function. Of these 5 boys 2 were considered to have Kallmann's
, ]" W3 N+ c% a' O* P; Y, Ssyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-1 L$ q+ N$ W0 O
lamic deficiency. After evaluation of response to luteinizing
S W4 W! F3 x- R( p5 W' T' l0 {hormone-releasing hormone these patients were treated with; g- J/ G m R3 ]. r0 s; E6 f
1,000 units of gonadotropin weekly for 3 weeks. Six weeks* x7 S' |7 X. K( [3 ?5 A) w
after completion of gonadotropin therapy 10 per cent topical
/ _ [( A9 b" p/ mtestosterone was applied to the phallus twice daily for 3 weeks.( ]" v/ S4 V, o5 p" H
Serum testosterone, luteinizing hormone and follicle-stimulat-
: @) j: y9 n) h) T5 {1 b9 \3 Wing hormone were monitored before, during and after comple-
2 i: G% R. b/ c/ Dtion of each phase of therapy. Penile stretch length was# k% J* Q# @7 r1 g: S
obtained by measuring from the symphysis pubis to the tip of
) \; E/ L: K- ]1 ^8 c7 r* o( a+ }the glans. Penile circumferential (girth) measurements were
' y) E; B1 E1 l Hobtained using an orthopedic digital measuring device (see8 H4 l: O4 G v7 [# J3 N) A
figure).8 y( l/ v- V1 f7 l" J
RESULTS$ F9 O w0 x4 `- G1 U# a9 t+ ?; f: M
Serum testosterone increased moderately to levels between) i4 d+ D `5 S6 G- @% L" Q
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
7 W4 N- O& U2 }8 V5 gterone levels with topical testosterone remained near pre-
6 t8 R0 I5 [ b, x3 ~- Jtreatment levels (35 ng./dl.) or were elevated to similar levels; U& {4 Y8 z+ ~ ~3 U, a, b6 ^' l
developed after gonadotropin therapy (96 ng./dl.). Higher0 H: Q6 s' w, n9 e( z* X+ P4 M' @
serum levels were noted in older patients (12 and 17 years old),# Q2 a D7 a7 v
while lower levels persisted in younger patients (4, 8, and 10) u& \# J. O# Q' J
years old) (see table). Despite absence of profound alterations5 k) P. t s2 `* G' Z' v
of serum testosterone the topical therapy provided a greater
: {: B. w" U+ f& b/ ~: m- z0 z' N7 y( AAccepted for publication July 1, 1977. · W* t1 H; l- T" u$ v
Read at annual meeting of American Urological Association,
1 W1 \ q- W3 c% \+ v9 ?8 C/ IChicago, Illinois, April 24-28, 1977.& M3 d( R" {: A2 J% g
* Requests for reprints: Division of Urology, Henry Ford Hospital,
% _7 l$ K8 I' D+ w1 B" _+ M2799 W. Grand Blvd., Detroit, Michigan 48202.2 K9 @, C6 }; g. s4 G
improvement in phallic growth compared to gonadotropin.+ N/ |4 V7 _+ B) {! @5 H
Average phallic growth with gonadotropin was 14.3 per cent$ X& U6 `, O- [, s3 [, {7 w
increase in length and 5.0 per cent increase of girth. Topical/ @( T1 _% E: q) {4 j
testosterone produced a 60.0 per cent increase of phallic length4 P* a0 F$ z3 e: {- b3 M7 n
and 52.9 per cent increase of girth (circumference). The/ K% R# @2 H' S f/ y* G6 Q
response to topical testosterone was greatest in children be-
# d) |0 S4 w' _: ]8 Ktween 4 and 8 years old, with a gradual decrease to age 176 J& K3 o, _9 h
years (see table).6 G: ~9 H# g& o1 V0 f3 @8 b
DISCUSSION
+ C) d) b( y/ }3 a) xTopical testosterone has been used effectively by other
: J8 k& b0 [1 b/ d; nclinicians but its mode of action remains controversial. Im-
/ @/ \& j$ {8 {% Smergut and associates reported an excellent growth response
( e5 K9 o' \( c! G# Cto topical testosterone with low levels of serum testosterone,& z/ X* x6 \0 _: j6 \4 }5 D
suggesting a local effect.1 Others have obtained growth re-% S0 W- w- S, l* ]( |' r3 W
sponse with high. levels of serum testosterone after topical
; K7 r1 L0 {! |6 G( U: t+ `% Sadministration, suggesting a systemic response. 3 The use of1 `0 ~8 b$ J* y: i% R
gonadotropin to obtain levels of serum testosterone compara-
* Z1 N8 E X5 B& Y6 |% O, `ble to levels obtained with topical testosterone would seem to1 z8 H+ r i$ r0 K
provide a means to compare the relative effectiveness of" m0 w( S; j1 P" p1 T' I M
topical testosterone to systemic testosterone effect. It cer-8 _$ o6 \0 q" C6 f
tainly has been established that gonadotropin as well as par-
- r% V9 |% ]! Y# {enteral testosterone administration will produce genital
2 m) _: ^5 A& Hgrowth. Our report shows that the growth of the phallus was
8 n$ `* p* o5 i, U2 A6 Y, ssignificantly greater with topical applications than with go-
8 O7 c! P- n# `2 k0 Nnadotropin, particularly in children less than 10 years old.) `' r! r3 i. J- x6 c
The levels of serum testosterone remained similar or lower/ c) f! E7 P$ n k1 h0 S
than with gonadotropin during therapy, suggesting that topi-8 O! ^8 y( A* i" h; O8 k- `
cal application produces genital growth by its local effect as
M( C( x: F' r: mwell as its systemic effect.1 l7 `7 C' w) E, \& h& S
Review of our patients and their growth response related to# l0 c; o! l6 |; i' [% S. Y
age shows a greater growth response at an earlier age. This is4 Z, w" P0 |: t X0 G
consistent with the findings of Wilson and Walker, who, A2 n" @$ V" ~; t3 T {6 s' _- Y
reported an increased conversion of testosterone to dihydrotes-- N4 \5 @$ v+ m) l: s; E1 U
tosterone in the foreskin of neonates and infants.4 This activ-, f# t3 H! t3 ~2 g- r$ \& y
ity gradually decreases with age until puberty when it ap-; V. o( M9 q* Z3 j7 Q: `3 b7 S7 Q
proaches the same level of activity as peripheral skin. It may
. D" j4 R6 F" F% y+ {well be that absorption of testosterone is less when applied at; j& ` A: H3 J
an earlier age as suggested by lower serum levels in children+ ~ k( k6 @& Z' Q8 k
less than 10 years old. This fact may be explained by the
) |1 R) j. l( n% `; E2 `; P% _greater ability of phallic skin to convert testosterone to dihy-6 ~6 V3 s2 b" c
drotestosterone at this age. Conversely, serum levels in older
3 D2 l& F) ^* N; Y3 Rpatients were higher, possibly because of decreased local
( W% l/ C; A/ r+ U# H9 f: U6674 O. Y: K9 }7 T: c6 b
668 KLUGO AND CERNY
! }/ c! [, p; {( bPt. Age
8 C$ g! n4 O* L' l* L(yrs.)0 R- \/ |) B8 m- o( z: \
Serum Testosterone Phallus (cm.) Change Length$ |3 E) g& f" t) G: x/ S
(ng./dl.) Girth x Length (%)
- S( s' f( T+ G! P) w4! a0 e1 B/ e9 o
8
5 X5 G) t+ S5 ~! g& T* w z5 e10 U1 f. Z7 s6 ^' m4 h! U4 g S0 A
12
/ n8 v6 H* w1 C3 y3 Y2 ~+ L4 |3 N17/ y0 I4 i- y4 e2 ^1 l: p+ l
Gonadotropin
0 s9 k ?& N4 a M/ |& `. S71.6 2.0 X 3 16.6* {3 I* k: }/ N# s0 m& h
50.4 4.0 X 5.0 20.0
; B8 l, W+ H1 U4 O n7 E22.0 4.5 X 4.0 25.0: T' j: n' V0 u- D2 c5 p! q6 M
84.6 4.0 X 4.5 11.19 A# t; _1 y4 r+ O
85.9 4.5 X 5.5 9.0
& S9 H8 \, _( \7 E, K0 s) ~0 I0 A1 m2 lAv. 14.3
* n% |# }1 B% C4
- K; F" ~& u* T% b4 f, I8
+ j) K: B7 C% N102 E8 \ O" `9 w+ y
125 |5 }/ A& t% P9 T2 F
17
8 k) ~, _3 R0 U; D' m' MTopical testosterone
; i: N" E' r" O5 a, [34.6 4.5 X 6.5 85# J4 ]: B9 Y+ J! l2 {
38.8 6.0 X 8.5 70* ]0 d1 {6 g, W0 W# K$ u' T* l
40.0 6.0 X 6.5 62.5+ b1 {2 e" p& V
93.6 6.0 X 7.0 55.5
4 ?+ a: g1 h1 ]. {7 w95.0 6.5 X 7.0 27.23 d# K# Z6 h: b, Z0 Q" t2 O
Av. 60.0 L& P7 _0 u+ s6 U" x8 L8 E
available testosterone. Again, emphasis should be placed on/ b: F) X) J0 @. E: B
early therapy when lower levels of testosterone appear to7 I" ~9 _" ~7 b8 n( B# F
provide the best responses. The earlier therapy is instituted' y; ^) M1 _% K1 P
the more likely there will be an excellent response with low
2 L3 i x" ^3 |" ?serum levels. Response occurs throughout adolescence as5 s. k+ n- h- K S
noted in nomograms of phallic growth. 7 The actual response3 ~7 c8 E' Y6 i& R1 u
to a given serum level of testosterone is much greater at birth7 g: |+ @. p$ t
and gradually decreases as boys reach puberty. This is most
! G2 p" K! Y4 g: H/ H5 rlikely related to the conversion of testosterone to dihydrotes-0 [8 t" v" Z/ V: X5 r) g
tosterone and correlates well with the studies of testosterone! p. S& p& {1 A; @
conversion in foreskin at various ages.. r* h( Z& E7 D, n# f' C! s
The question arises regarding early treatment as to whether; V) w/ D( h2 ?: M& _7 q
one might sacrifice ultimate potential growth as with acceler-
/ k* e: R' P2 |$ ]ated bone growth. The situation appears quite the reverse
* U9 w" Q- O) l5 s* ^ j1 dwith phallic response. If the early growth period is not used; `9 R3 k% J8 |8 X0 S5 j# d# B# c: C
when 5a reductase activity is greatest then potential growth1 ]" B) s2 Y/ t7 q; n9 l" R
may be lost. We have not observed any regression of growth
3 z/ |' v& i$ \0 pattained with topical or gonadotropin therapy. It may well
% e0 |9 r* {3 d/ o7 ~/ zbe that some patients will show little or no response to any
5 T9 [! O+ j! E' w- E% Aform of therapy. This would suggest a defect in the ability to' M) f1 p2 T# G+ f
convert testosterone to dihydrotestosterone and indicate that
" z- t1 a* J* Z& N/ }phallic and peripheral skin, and subcutaneous tissue should
) G. X. c) M+ K9 vbe compared for 5a reductase activity.1 m1 x2 l' s1 G2 {) x5 f, b
A, loop enlarges to measure penile girth in millimeters. B,
+ y U+ o) E7 S3 ]( Gexample of penile girth computed easily and accurately.6 i, }$ z) j9 c% p3 ^2 r( ^5 c5 A
conversion of testosterone to dihydrotestosterone. It is in this/ h: n Q" [; j D& B& S1 @
older group that others have noted high levels of serum2 n# y6 k# F3 W) t% B, p( K
testosterone with topical application. It would also appear
/ V: m* X$ U/ ^0 tthat phallic response during puberty is related directly to the
8 n. S2 j* `* G$ o. o( j( Rserum testosterone level. There also is other evidence of local
' Q! `- u2 ?7 e. n* x- xresponse to testosterone with hair growth and with spermato-: u7 A+ x- s+ l
genesis. 5• 6 D7 Z" v3 J( w5 X
Administration of larger doses of gonadotropin or systemic x8 I% \' R% u4 o7 b
testosterone, as well as topical applications that produce& P+ Q# \: Z9 H, w+ X$ \
higher levels of serum testosterone (150 to 900 ng./dl.), will* n# N9 y. C( `9 w
also produce phallic growth but risks accelerated skeletal
' m6 F$ V; P. `! Umaturation even after stopping treatment. It would appear) i0 r' R. Q4 |. Z3 v& K, d7 T
that this may be avoided by topical applications of testosterone
' S- w+ C6 ]7 e9 y7 n4 nand monitoring of serum testosterone. Even with this control, h5 N2 z1 ~5 z: l' [
the duration of our therapy did not exceed 3 weeks at any
! [& v/ m& }2 N Atime. It is apparent that the prepuberal male subject may3 p* T- P4 q- W' S) N
suffer accelerated bone growth with testosterone levels near3 F! Q; w6 w8 G$ G0 N' g
200 ng./dl. When skeletal maturation is complete the level of% Z3 a0 D4 Y0 E# P6 y7 X7 C7 P
serum testosterone can be maintained in the 700 to 1,300 ng./+ z# o8 ^! [; V+ Y
dl. range to stimulate phallic growth and secondary sexual
/ g1 X. D* H! t) C, U- I( v o% Dchanges. Therefore, after skeletal maturation parenteral tes-1 o3 j( m9 y& M0 Y5 h
tosterone may be used to advantage. Before skeletal matura-+ |1 ]) o5 [; w6 X4 d& b
tion care must be taken to avoid maintaining levels of serum- U/ D% L' T! N+ |- @) v8 l
testosterone more than 100 ng./dl. Low-dose gonadotropin F/ C$ K5 w8 X- K* x% h
depends upon intrinsic testicular activity and may require
1 v3 x" v2 [; F, sprolonged administration for any response.
9 J5 o7 v3 R$ aAlternately, topical testosterone does not depend upon tes-6 N7 F1 C/ |& U% X% U5 {
ticular function and may provide a more constant level of/ e8 ?: B4 g( G" v$ G# j
REFERENCES
5 h; w9 n/ C' L8 j, q1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,9 Q) f/ m- l* w* ?8 F. N3 q5 z5 J
R.: The local application of testosterone cream to the prepub-
4 @" o7 \- W' R+ W4 F O% J5 `' z6 @ertal phallus. J. Urol., 105: 905, 1971./ y/ f# p8 a% ]/ D0 w; x
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone3 C; G m2 s4 p# H: w/ [* J9 U, F
treatment for micropenis during early childhood. J. Pediat.,
) B1 O6 n. K/ T$ _83: 247, 1973.8 r; j) `* e' J2 u# q n7 k
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-9 E9 g3 v7 f" ^
one therapy for penile growth. Urology, 6: 708, 1975.
+ K% W6 h: d0 r1 [3 D- Y1 o4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
* v: U Z. D5 X: d& |: kto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by4 }, K' C; r6 y* W! |" s& U7 @
skin slices of man. J. Clin. Invest., 48: 371, 1969.) z8 u7 m$ E$ _% I, a
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
! p6 f$ z# X0 y E" c! Vby topical application of androgens. J.A.M.A., 191: 521, 1965." l# M/ W% i8 W, C; X7 j8 q" S
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
& C7 o4 Y0 S4 w( h9 U Qandrogenic effect of interstitial cell tumor of the testis. J.
. r$ B, x! o8 RUrol., 104: 774, 1970.. w& O2 T3 Q4 Z! g
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
; f! t, W. I+ f$ K5 a' Z4 ntion in the male genitalia from birth to maturity. J. Urol., 48: |
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