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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND! f, k# V' r) B6 v$ U; a
GONADOTROPIN6 @. c) o& K' t0 T# k
RICHARD C. KLUGO* AND JOSEPH C. CERNY* G* |5 w2 Z% K3 `$ g2 O$ `. o9 Z: m
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan% [8 S8 i9 B- C, y4 D1 U/ x
ABSTRACT
& t! A' |2 M, M; X6 LFive patients were treated with gonadotropin and topical testosterone for micropenis associated
0 }1 j6 c4 x7 hwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
; P% ~- o6 `3 z: a5 C& j/ @0 htropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
) j; L- e: r l$ r) ~- Tcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent! O$ M3 o9 P. k+ H0 |2 K2 u
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
3 ?: s( M3 I: X9 }; V* ?increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average" A0 b: g3 F; w
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response: `$ r3 A, j% n( ^. H
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
' h y m$ B' qstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
% }8 x; k+ T! z! `8 w% z& Ogrowth. The response appears to be greater in younger children, which is consistent with previ-, w8 ~2 o% V, V! m/ a
ously published studies of age-related 5 reductase activity.' D, q% v, i+ F- p1 V
Children with microphallus regardless of its etiology will
- H+ E( E0 M- Rrequire augmentation or consideration for alteration of exter-: I- I* n& E+ ?2 q1 f+ F" w; y
nal genitalia. In many instances urethroplasty for hypo-
5 O# J; F! l3 espadias is easier with previous stimulation of phallic growth.- l9 z" b2 x6 {& M& m( G
The use of testosterone administered parenterally or topically
0 _1 j# G. c& m" |: d6 M4 B5 mhas produced effective phallic growth. 1- 3 The mechanism of1 a0 a9 J2 D: b4 M$ Y7 @9 u j
response has been considered as local or systemic. With this
; S" Q4 A2 ?5 ]' y7 m7 ain mind we studied 5 children with microphallus for response
3 A) V1 g- e. ?: [to gonadotropin and to topical testosterone independently.
$ {4 i- d$ V- @) i( KMATERIALS AND METHODS' ^3 {$ f( ~& u2 Z: F
Five 46 XY male subjects between 3 and 17 years old were
: L" L- L# h1 V! [% N; g/ O8 X% {evaluated for serum testosterone levels and hypothalamic( L* G2 N0 j, p% [9 i3 D& y( i4 K
function. Of these 5 boys 2 were considered to have Kallmann's; j; c$ k) X5 |- S0 p
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-# K6 T, P4 O2 V7 o. Q
lamic deficiency. After evaluation of response to luteinizing
6 I2 r+ Q6 `" Uhormone-releasing hormone these patients were treated with/ z9 r2 i6 P/ C$ K7 Y
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
* M9 i& [- A5 N1 wafter completion of gonadotropin therapy 10 per cent topical
{$ \5 l* T; R2 o: h4 ltestosterone was applied to the phallus twice daily for 3 weeks.2 \* u. Q) G# K& h2 g* W- Y
Serum testosterone, luteinizing hormone and follicle-stimulat-
) L( |* p* n& Wing hormone were monitored before, during and after comple-
. s2 J9 ?, D4 k+ Htion of each phase of therapy. Penile stretch length was
* f S8 N2 a- x+ Y& Y3 Kobtained by measuring from the symphysis pubis to the tip of$ a, ^4 h j! B3 a$ |$ r8 q/ q5 Z
the glans. Penile circumferential (girth) measurements were
% \2 L3 F8 ^) g; Fobtained using an orthopedic digital measuring device (see
9 g O6 w% g7 hfigure).
' s+ d- O! p, Q4 {6 r% D9 iRESULTS9 ]7 ]& ]) X* H9 Y1 [
Serum testosterone increased moderately to levels between
+ |/ H9 t* }3 }; S50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
5 P. b* v" w, a+ bterone levels with topical testosterone remained near pre-
N3 d0 ?9 y8 |* v- Gtreatment levels (35 ng./dl.) or were elevated to similar levels
b, c6 ]2 b' jdeveloped after gonadotropin therapy (96 ng./dl.). Higher$ ]$ D( H9 {7 _8 ^3 Z; _5 u# q5 w7 L
serum levels were noted in older patients (12 and 17 years old),
7 I" P( F. C6 Z1 {" ^8 }while lower levels persisted in younger patients (4, 8, and 10
+ s3 T0 r. @( _# V; a( fyears old) (see table). Despite absence of profound alterations0 ]* d! o$ v1 ?) |' n( @
of serum testosterone the topical therapy provided a greater
2 }8 D( w" N/ x) `Accepted for publication July 1, 1977. ·
# |4 b T3 t3 a- F* C6 \- ` RRead at annual meeting of American Urological Association,* a, }5 @; f1 L( a0 s
Chicago, Illinois, April 24-28, 1977.# z& D }6 b# _, y7 U5 o1 q
* Requests for reprints: Division of Urology, Henry Ford Hospital,
' S8 T( P8 @$ w" W* W( a" z8 D2799 W. Grand Blvd., Detroit, Michigan 48202.3 _- [# V: W1 c; ]& D! h& \3 m
improvement in phallic growth compared to gonadotropin.: \* Q* I0 p" b' p: b0 D
Average phallic growth with gonadotropin was 14.3 per cent; Z+ }% b. k7 ?/ l2 o+ T
increase in length and 5.0 per cent increase of girth. Topical
2 G$ V0 f/ s/ [: z/ xtestosterone produced a 60.0 per cent increase of phallic length- ~6 ?) O1 q3 b
and 52.9 per cent increase of girth (circumference). The# U5 ?3 R6 T$ o7 \8 Q: R6 \
response to topical testosterone was greatest in children be-
: W6 n) F6 `. y% A$ u7 Etween 4 and 8 years old, with a gradual decrease to age 174 \7 b; H2 |" e* A/ Y6 J
years (see table)./ \1 y0 \$ X+ ?! E& i, ?) k$ E
DISCUSSION* d# h. m( T. Q% r1 @
Topical testosterone has been used effectively by other
+ O" S. z- m* F8 Kclinicians but its mode of action remains controversial. Im-
: M0 N! d$ a# f3 ~) Y; ?, E2 Hmergut and associates reported an excellent growth response: W9 U) |7 ^3 j' ^8 Z+ V; o: d
to topical testosterone with low levels of serum testosterone,; z+ v, E* n' X* h1 t, _
suggesting a local effect.1 Others have obtained growth re-( \, f7 ^' d, A k2 R1 z
sponse with high. levels of serum testosterone after topical
, v, c0 Y& T( e& c' jadministration, suggesting a systemic response. 3 The use of+ ]* P! J5 c7 `! T
gonadotropin to obtain levels of serum testosterone compara-
) ?# A# T1 y" Hble to levels obtained with topical testosterone would seem to0 R' p. ?7 ~, U# I) ]
provide a means to compare the relative effectiveness of& R* E# A6 y4 C1 r7 I a" t/ |
topical testosterone to systemic testosterone effect. It cer-7 J) k* K! R# g B
tainly has been established that gonadotropin as well as par-
# m ?# ~2 N* b5 L( q- qenteral testosterone administration will produce genital
2 s7 s; E0 I9 X( ?- p5 \ J4 Agrowth. Our report shows that the growth of the phallus was2 y/ A0 T' ?& f* k& r# X) ~
significantly greater with topical applications than with go-7 n. D5 N) J. f& A0 `6 x
nadotropin, particularly in children less than 10 years old.
& j+ J; t! R3 j) }) W* D% EThe levels of serum testosterone remained similar or lower. f( W( D% e; z3 m3 p
than with gonadotropin during therapy, suggesting that topi-3 T0 L3 Z1 `6 ~7 l/ |- X
cal application produces genital growth by its local effect as! B. Z! @) p/ z
well as its systemic effect., t `% U. j7 r& P9 R6 u
Review of our patients and their growth response related to# g, X+ h0 ~/ j6 L
age shows a greater growth response at an earlier age. This is
' _/ q# _' @! k9 o" [consistent with the findings of Wilson and Walker, who$ C7 t8 N$ T3 s: V/ f
reported an increased conversion of testosterone to dihydrotes-
% O: @9 c# V7 |9 y9 [- H5 Stosterone in the foreskin of neonates and infants.4 This activ-4 k/ q2 _5 m* c1 s4 J6 J( c4 H
ity gradually decreases with age until puberty when it ap-2 p9 j$ Y+ s/ y
proaches the same level of activity as peripheral skin. It may4 u3 A- ?" w7 _! n4 m/ j1 k
well be that absorption of testosterone is less when applied at& A7 }# H3 y1 S9 S/ T5 v
an earlier age as suggested by lower serum levels in children
) x$ F* ^2 k8 h# D1 a0 ?less than 10 years old. This fact may be explained by the( ]% @% O9 H9 T
greater ability of phallic skin to convert testosterone to dihy-+ y/ {2 r6 x/ J' C3 Q( a8 N, J/ t
drotestosterone at this age. Conversely, serum levels in older( t7 }' h# ~: D, ?6 |4 U
patients were higher, possibly because of decreased local0 b- L( @/ m3 }# f% }: s. z: B1 q* b
667# o1 `4 ^8 K! i* {& t
668 KLUGO AND CERNY
6 @2 m, |. W% t! P5 }$ @. b6 c0 z/ HPt. Age' v m. E& o1 l- i4 D
(yrs.)
$ y4 w5 j7 _0 TSerum Testosterone Phallus (cm.) Change Length( n0 S2 C- P' G1 w
(ng./dl.) Girth x Length (%)" z) G7 f0 |) `: Z+ }
4
0 j9 Z; U9 C- C; M8! ?2 I C6 G2 z+ f; d4 V5 L
10
: k7 O4 U* i$ g12
% H! V2 [. T0 t! C7 A178 p( J4 Q) o7 T' z
Gonadotropin
7 A/ K! l- {( c, f, _71.6 2.0 X 3 16.6
1 S& R' e r* ]# z% W. z; t" |50.4 4.0 X 5.0 20.0
1 A8 d {) F$ Y; C- G7 _8 j0 i22.0 4.5 X 4.0 25.0
8 P- @ R: e5 s* E84.6 4.0 X 4.5 11.19 Q( a7 @% V0 a! Y! J8 V
85.9 4.5 X 5.5 9.0
V8 s7 o# P% ]& [; k7 t$ x" |Av. 14.3
; u0 K7 f; V5 Q4% a" e5 z+ \2 B; A& q; e* ]6 K$ _+ f
8
/ b$ f" N* S5 [0 r" P10/ X% M U l7 a. l( @& N# W
12. p2 N! z3 a& e
17
! c0 s; C. S1 I" r2 @6 ]8 ]. lTopical testosterone/ ^- @5 o7 ?; k' t' u7 H" v, p
34.6 4.5 X 6.5 85
: H; u/ V& j# X: Q: l9 _ d; P38.8 6.0 X 8.5 701 d; G+ i. U5 i4 u& j+ R
40.0 6.0 X 6.5 62.5
. r) C6 w- c, x. [! d93.6 6.0 X 7.0 55.5
& I: C! V8 o: }* B* H2 \$ g/ v4 f95.0 6.5 X 7.0 27.2
3 @$ s' I6 i# `0 q" M- M% ^; yAv. 60.0
* G7 K* X1 ]3 Z# `2 `6 }available testosterone. Again, emphasis should be placed on3 l. d9 j! v9 C" K' z7 ~
early therapy when lower levels of testosterone appear to+ k5 M+ I$ i+ x W" \4 U
provide the best responses. The earlier therapy is instituted" g2 D6 j7 d6 r* d5 k
the more likely there will be an excellent response with low
8 u( G6 P, `# i- `5 Oserum levels. Response occurs throughout adolescence as- c0 `5 x/ m: Y( h4 m8 S
noted in nomograms of phallic growth. 7 The actual response
/ H# ~* x. ]# K+ x9 r! P' tto a given serum level of testosterone is much greater at birth5 D* r- [6 a4 {
and gradually decreases as boys reach puberty. This is most
* X' D: w9 ?% t- F& Qlikely related to the conversion of testosterone to dihydrotes-
! J& |3 h y) {/ _) G# atosterone and correlates well with the studies of testosterone
% R e& B3 o& u7 b vconversion in foreskin at various ages.$ ~& I# N b: l) `3 d7 w: _
The question arises regarding early treatment as to whether% h; S2 j6 F; t0 Q' |/ u# u3 |
one might sacrifice ultimate potential growth as with acceler-
' ^' [& T9 A/ w) ]5 ?ated bone growth. The situation appears quite the reverse& m, Y9 V5 k: ~, T5 K
with phallic response. If the early growth period is not used. M+ {3 A5 _6 K" V! h, G+ e3 H
when 5a reductase activity is greatest then potential growth
; s8 F# [" Y/ K% M$ vmay be lost. We have not observed any regression of growth
8 g/ B% k( j; `) q1 _ ^/ Xattained with topical or gonadotropin therapy. It may well
+ l) q2 j! n8 u4 [7 }be that some patients will show little or no response to any& D) e) |% r ^; z1 e
form of therapy. This would suggest a defect in the ability to
. m( }& `1 _5 K- Y) L/ k1 M7 n# \8 kconvert testosterone to dihydrotestosterone and indicate that0 A( e4 l+ ~* ^& M j
phallic and peripheral skin, and subcutaneous tissue should& P- n$ i. X2 c; O* i9 s9 ~$ d
be compared for 5a reductase activity.4 v' C5 T; J* a; J* v
A, loop enlarges to measure penile girth in millimeters. B,- _2 t5 ~2 j9 [' Z7 F9 X
example of penile girth computed easily and accurately.% w, i* T f/ T9 O8 y
conversion of testosterone to dihydrotestosterone. It is in this
! k0 P- B6 t& @. f2 k' a- Polder group that others have noted high levels of serum
4 X4 s7 V& O. u& `testosterone with topical application. It would also appear. L" E& Z9 S/ @1 ?
that phallic response during puberty is related directly to the
0 ^. G& h# z. D" B$ Mserum testosterone level. There also is other evidence of local
" ~ F6 j( V% Z$ ]& @response to testosterone with hair growth and with spermato-
' M" `$ N& h: J3 J* cgenesis. 5• 6/ b+ W! ]; l) q7 M6 Y1 M
Administration of larger doses of gonadotropin or systemic3 w0 M( E% Z& J# p6 s* z- h9 `# G0 ?
testosterone, as well as topical applications that produce- O- K5 A/ a8 K: K
higher levels of serum testosterone (150 to 900 ng./dl.), will
6 o; V6 p2 `7 L" k7 g& K/ Walso produce phallic growth but risks accelerated skeletal
5 |: h0 M6 E( f7 smaturation even after stopping treatment. It would appear
# v& r' U1 n; B+ K% R( U2 \8 Dthat this may be avoided by topical applications of testosterone
* @: W7 d- `: f4 I; Uand monitoring of serum testosterone. Even with this control
2 Y1 f" h' J: K- _the duration of our therapy did not exceed 3 weeks at any
% z0 K& A; D, _ wtime. It is apparent that the prepuberal male subject may b1 }% U8 P9 t! W6 i& F) m
suffer accelerated bone growth with testosterone levels near
0 I) a8 l; b& w200 ng./dl. When skeletal maturation is complete the level of
) u( d1 f3 p/ w, f, ]serum testosterone can be maintained in the 700 to 1,300 ng./
% b e" e7 ]# m7 U! J8 J# \dl. range to stimulate phallic growth and secondary sexual
$ d( ]' c$ i1 U: ]9 H0 }changes. Therefore, after skeletal maturation parenteral tes-. U, i# X* O. U: a9 p" v. R; o
tosterone may be used to advantage. Before skeletal matura-
- w5 b8 |$ T) G8 f( Ltion care must be taken to avoid maintaining levels of serum
& v* k* ^; d' K2 _3 |4 Atestosterone more than 100 ng./dl. Low-dose gonadotropin
! x0 W4 q) O# \depends upon intrinsic testicular activity and may require
. x2 i6 O9 F4 jprolonged administration for any response.
- w5 T+ H# C: {' f }Alternately, topical testosterone does not depend upon tes-* [ f" n- a( J
ticular function and may provide a more constant level of
8 _8 G) E0 U+ T# GREFERENCES$ W5 Z; S' c( v# M x1 v0 [
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
. i+ t! a% C" Z! XR.: The local application of testosterone cream to the prepub-5 v: l1 j6 z$ G. ?! B8 V$ S
ertal phallus. J. Urol., 105: 905, 1971.
, \; a" p0 E- w8 L f$ N' U3 K2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone4 U2 Z7 y9 i1 Z3 o
treatment for micropenis during early childhood. J. Pediat.,
" a5 Z% O- h$ Z0 {83: 247, 1973.' `& U3 [2 H" B* H
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-1 g) j" x' M- {: u. {$ [
one therapy for penile growth. Urology, 6: 708, 1975.0 L' d. m) V9 z$ o/ e% P. Z! @) A
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone+ ^; r' }5 C: j; Q8 @
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by3 z5 C) |, G7 o/ {
skin slices of man. J. Clin. Invest., 48: 371, 1969.
& C; ?( k5 o. {- I5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth5 q! E9 I- b* S; P" A j
by topical application of androgens. J.A.M.A., 191: 521, 1965.
+ [& W% _$ z; |: \6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local6 c5 ~: k# {% x2 V. A4 {: A
androgenic effect of interstitial cell tumor of the testis. J. A! k) r5 ~3 A' L
Urol., 104: 774, 1970.
0 E k6 ^: [8 |7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-- w J A- p" H7 u8 N; x% x
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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